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111 Cards in this Set
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Pharm-08B1 Outline the potential beneficial and adverse effects of isoflurane on the cardiovascular system (include mechanisms of effect) in patients with ischaemic heart disease. 41% |
41% of candidates passed this question. |
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Pharm-08A1 An 80 year old woman is undergoing major emergency surgery. Describe the maintenance inhaled concentration of sevoflurane you would choose and the factors that might influence this.
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Clinical Question
Aim : induce hypnosis to provide adequate surgical conditions while balancing against unwanted side effects (mainly hypotension) Aim for an end tidal sevo of 1.5% Sevo is isopropyl methyl ethyl ether MAC 1.8% BP 58 MW 200 BG 0.6 OG 53 MAC is mean alveolar concentration where 50% of subjects will not move following a standard surgical incision. Useful to compare potencies of inhalation agents. Factors decreasing MAC in this patient -age : decrease 6% per decade -drugs : morphine, benzo's -pathology : hypothermia, acidosis Side effects of SEVO CVS : dose dependent vaso/venodilation, depression of baroreceptor reflex, HR and CO. Exacerbated by hypovolaemia, antihypertensive drugs. CNS RESP GI/GU Use of intra arterial BP monitoring and BIS. |
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Pharm-07B1 Describe the adverse effects that may occur with the administration of desflurane.
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Desfluane is a flurinated methyl ethyl ether.
Adverse effects (PD) Resp -irritant/pungant : bronchospasm, breath holding, cough -dose dependent resp depressant : central + chemoreceptor response -reduced RR, TV, minute vent CVS -dose dependant central depression + baroreceptors -reduced BP, HR, CO -but increased if given too quickly : automonic stimulation : tachy -no steel -dose dependant vasodilation : drop in afterload + venodilation : reduced preload CNS -uncoupling at MAC>1 -hypnosis at MAC .4 -no seizures GI -heptotoxicity : oxidised by cyto P450, can produce acteylated liver protein which are immunogenic, but more stable than halothane and little is metabolised Urol -no fluoride toxicity as very stable agent Uterine -relaxation : unwanted post delivery, atony will increase bleeding Metabolic -malignant hyperthermia Absorbant -CO produced with diccessated absorbant |
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Pharm-06B2 Compare and contrast the clinically significant respiratory, cardiovascular and central nervous system effects of desflurane and isoflurane. 70%
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Examiner's Comments
70 % of candidates passed this question. Cardiovascular effects were well answered with most correctly describing the effects on heart rate, systemic vascular resistance, contractility and cardiac output; though there were some incorrect statements such as, hypotension at one MAC is primarily due to impaired contractility. Better answers discussed the theoretical risk of coronary steal with isoflurane and the practical risk of increases in catecholamine levels with sudden increased desflurane concentration, however there was no mention of the secondary effect on the renin angiotensin system. Common errors in respiratory effects included unqualified comments that both agents could be used for gaseous induction. Some candidates confused the respiratory effects of these agents with opioids where tidal volume is maintained or increased and respiratory rate is reduced. CNS effects were well answered, though only a minority mentioned the faster return to consciousness with a comparable depth of anaesthesia with desflurane. Some said that these agents usually decrease cerebral blood flow. Presentation was of a good standard with most information for the least effort being conveyed with tables. There were some good answers, though in plain text. Significantly there were no blank answer papers. |
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Pharm-06A3 List the non-ideal features of nitrous oxide.
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Comments
Anaemia: B12 & Methionine synthetase activity decreased. After >6-8 hours, or after repeated exposure, methionine synthetase is deactivated. Homocysteine---------(meth. synth. enzyme)------>Methionine This inhibits DNA and protein synthesis, including myelin. Bone marrow is significantly suppressed, leading to anaemia and leucopenia. Folate metabolism is also affected. Low concentrations for long durations may have marked effects on RBC synthesis, as well as a possible link to abortion or foetal abnormality, as well as myeloneuropathy (ie. risk to theatre staff). N2O compounds any pre-existing B12 deficiency, by irreversibly oxidising cobalt in B12. Expansion of air cavities (worsens pneumothorax/pneumocranium, bowel obstruction). May also worsen penetrating eye injuries. Risk of worsening air emboli, eg. cardiac surgery. At 75% inspired gas, N2O may increase gas cavity by 3-4 times initial volume within 30 minutes. Diffusion hypoxia: opposite of second gas effect. Diffuses out into alveoli, diluting O2, which decreases O2 concentration in alveoli. Decreases PaO2, PAO2, (and PACO2, so it decreases breath stimulus). Recovery depends on Ventilation, so opioid increase recovery time. Bonus points: * PONV (? Secondary to raised middle ear pressure) * Pulmonary hypertension * Increased cerebral blood flow * Myocardial depression (mild). Direct myocardial depressant, but minimal effects in healthy patient, due sympathetic stimulation. If high levels of pre-existing stimulation pre-op (eg. trauma), and low myocardial contractility, N2O may cause decreased BP and cardiac output. * Sympathetic stimulation (indirect). Possible bonus points: * Supports combustion (oxidising agent, used in cars, so may pose fire risk). * Increases p50 on Hb-O2 dissociation curve (by about 1.6 mmHg) * Low potency (MAC = 105% at sea level) * Impurities in manufacture may cause adverse effects. * Difficulty in monitoring bottled supply (must weigh cylinder, not use pressure gauge). * 0.004% reduced (metabolised) in G.I.T. Products include free radicals. |
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Pharm-05B1 Describe how isoflurane is metabolised. In your answer give reasons why the overall extent of metabolism of isoflurane is so low. 44%
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Examiners Comments
Expected in the answer to this question was some description of what isoflurane was. A majority of candidates provided a formula (a few incorrectly) and a minority just a written description. That metabolism occurred in the liver was mentioned by the majority of candidates but fewer went on to describe cytochrome P-450 as the predominant mechanism. Better answers mentioned the CYP450 2E1 as being the relevant isoform and the relevant significance of kidney CYP450 (vs. methoxyflurane). A surprisingly wide range of percentage liver metabolism was provided, the most frequent error being 2% when in fact it is only 0.2%. The breakdown products TFA and fluoride ions were discussed by most but only about half of the candidates mentioned both. Potential end organ toxicity (liver and kidney respectively) and the relevance of this compared to older agents was discussed by a minority of candidates. Very few candidates could describe the breakdown sequence of isoflurane, though this was not required to pass. Finally, most candidates discussed the position, number and inherent stability of the C-F bond as well as the relatively low solubility of isoflurane as being important in its low rate of metabolism. Only a minority mentioned both factors however. Degradation of isoflurane in soda lime was not considered to be metabolism. |
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Pharm-04A1 Describe the effects of isoflurane on intracranial metabolism, intracranial haemodynamics, intracranial pressure and the EEG. 71%
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1. Induction and maintenance of Anaesthesia
• Mechanism is not completely understood. • It was previously thought a lipid site (ie membrane lipid bilayer) is likely since OGPC correlate well with potency = Myer Overton rule. • Cell membrane expansion hypothesis leading to compression of ion channels, hence reduced ion flux was the other old theory • Now, recent evidence suggests that GABAa receptor is a possible target for VIA GABA mediated effect is to cause increase Cl- influx cell hyperpolarisation and inhibition 2. Amnesia – at 0.4 MAC 3. CMRO2 • Dose dependent decrease in CMRO2 (greatest with isoflurane than equivalent MAC of halothane) down to isoelectric line at 2 MAC (except enflurane), which indicates CMRO2 decreased down to 55% • When EEG is isoelectric, additional concentration of volatiles does not produce further reduction in CMRO2 • Reduced CMRO2 -> reduced CO2 produced -> reduced vasodilatation, esp with isoflurane, thus minimize the rise in CBV and ICP 4. CBF • >0.6 MAC - cerebral vasodilatation (direct effect) -> reduced cerebrovasc resistance -> increase CBF -> increase ICP (worst with halothane, least with isoflurane) • Isoflurane/Des – preservation of reactivity to CO2 • Autoregulation of CBF in response to changes in MAP is retained with 1 MAC of isoflurane/Des/sevoflurane, but not halothane • Isoflurane posses greater capability to maintain global CBF relative to CMRO2 cf halothane and sevoflurane 5. Uncoupling of CMRO2 and CBF (worse with halothane, better with isoflurane) 6. Cerebral protection Isoflurane offers better global O2 supply demand balance than halothane, hence offers cerebral protection during induced controlled hypotension (eg clipping of cerebral aneurysm) 7. CSF • Enflurane increase rate of production, increase resistance to absorption -> increase ICP • Isoflurane does not alter production, reduce resistance to reabsorption, minimal changes in ICP 8. ICP • Increase ICP that parallels increase CBF • Hyperventilation to pCO2 < 30mmHg opposes the tendency of volatiles to increase ICP • (NB – enflurane has increase risk of seizure with low pCO2, seizure causes increase CMRO2, increase pCO2 -> vasodilation -> increase CBF -> increase ICP 9. EEG • MAC 0.4 – shift of high voltage activity from anterior to posterior portions of the brain • MAC 1 – EEG frequency drops, maximum voltage occurs • Isoflurane – burst suppression at 1.5 MAC, electrical silence at 2 MAC • Electrical silence does not occur with enflurane, and only at unacceptably high levels of halothane 10. Seizure activity • Enflurane produce seizure like EEG activity, which may be accompanied by tonic clonic twitching of skeletal muscle in the face and extremities, esp with >2MAC or with hyperventilation (pCO2<30mmHg), or with repetitive auditory stimuli • Isoflurane/Des/Sevoflurane – do not evoke seizure activity on EEG (can even suppress seizure activity) 11. Evoked potentials • Dose related decreased amplitude, and increase latency of cortical component of median somatosensory, visual, and auditory evoked potentials 12. Nausea and vomiting 13. Central respiratory centre depression leading to • decreased tidal volume leading to decreased minute ventilation and increase pCO2 (despite increase RR) • decrease ventilatory response to increase pCO2 • decrease response to hypoxia (via carotid body) 14. Halothane decrease central sympathetic outflow -> decrease HR, contractility and CO -> reduced BP (N2O increase central SNS outflow -> increase HR, SVR, BP) |
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Pharm-03B8 Outline the pharmacological differences between neonates and adults with reference to sevoflurane, vecuronium and morphine. 42%
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Examiner’s Comments
42% of candidates passed this question. In order to pass the candidate needed to make a number of correct statements pertaining to the question. These statements may have included, but are not limited to the following: • definition of neonate • brief description of sevoflurane, vecuronium and morphine • definition of pharmacology-pharmacokinetics/dynamics • kinetics: key differences between neonate and adult i.e. relativities of TBW, ECFV, comparison of protein binding, renal and hepatic clearance, different ratios of ventilation and FRC • dynamics: different sensitivities to drugs, permeability of BBB, sensitivity of respiratory centre • morphine: in neonate increased t½ increased respiratory depression and apnoea • sevoflurane: more rapid induction in neonate, reduced blood gas solubility, MAC higher in neonate than adult • vecuronium: increased Vd reduced clearance increased t½ in neonate with increased sensitivity of neuromuscular junction. Net effect dose per kg similar to adult. Common omissions include widespread lack of definitions e.g. of neonate, drugs. No candidate referred to the effect of prematurity on neonatal drug effects. Common errors: Many candidates were unclear as to the relative sensitivities of neonates to non-depolarising muscle relaxants NDPMRs. Many stated MAC for sevoflurane is lower in neonates than adults. There was much confusion over the effect of an increase in Vd for a polar drug. Many candidates stated that morphine was a highly polar drug. Many stated that neonates have increased TBW and increased fat content compared to adults. |
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Pharm-03B2 Describe the potential interactions of sevoflurane, desflurane and isoflurane with carbon dioxide absorbents. 60%
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Given the use of rebreathing circuits on anaesthetic machines, there must be a means of absorbing CO2 from exhaled alveolar gas.
There are a number of agents used. 1. Soda Lime Composed of: * 94% Ca(OH)2, 5% NaOH, pH indicator, water, KOH, Silica Absorption occurs by: CO2 + 2NaOH = Na2CO3 + H2O + heat Na2CO3 + Ca(OH)2 = 2NaOH + CaCO3 Water is required for efficient absorption and heat is generated. 2. Baralyme Composed of: * 80% Ca(OH)2, 20% Ba(OH)2, water, KOH, pH indicator Absorption occurs by: Ba(OH)2 + CO2 + 8H2O = BaCO3 + 9 H2O = heat 9CO2 + 9 H2O = 9 H2CO3 9H2CO3 + 9Ca(OH)2 = 9CaCO3 + 18 H2O + heat Volatile anaesthetics have the potential to interact with these. Sevoflurane * Reacts with both baralyme and soda lime to form the breakdown products - compound A - E. * Compound A is produced in greatest amounts. * Compound A has been shown to be nephrotoxic in rats at higher doses than those seen clinically. No human toxicity has been reported and hence the clinical relevance of compound A can be debated. * Fresh gas flow rates of at least 2L/min are recommended to prevent accumulation of compound A in the circuit. * A greater amount of compound A has been noted to be produced with Baralyme compared with Soda Lime. This may be due to higher temperatures. * Dehydration of Baralyme results in increased production of compound A. * Dehydration of Sodalime resuluts in decreased production of compound A. Desflurane/Isoflurane/Enflurane * Interact with CO2 absorbents to form CO. * Concentrations up to 30% can occur * Production of CO is increased with dessication of the absorbents and with increased temperatures. Prolonged high gas flows will tend to dessicate the absorbers, for example if O2 left on over a weekend. * More CO production is seen with Baralyme compared with soda lime. * Production of CO is greatest with Desflurane, then enflurane and least with isoflurane. Halothane * Is degraded to difluorovinyl which has been shown to be nephrotoxic to rats * No clinical significance. Trichloroethylene At high temperatures, degrades to toxic substances including dichloroacetylene (a neurotoxin) and phosgene (a respiratory toxin). It should NEVER be used with sodalime or baralyme. CO2 absorbers can absorb some volatile agent itself which could then be released to subsequents patients. This is a potential risk for triggering malignant hyperthermia for an at risk patient if not changed. |
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Pharm-03B1 Draw and label, on the same X - Y axis, FA/FI curves for the following halothane concentrations in oxygen, showing a 30 minute period from starting administration. a. Halothane 1%, subject breathing spontaneously. b. Halothane 6%, subject breathing spontaneously. c. Halothane 6%, subject paralysed and ventilated. With reference to the major factors determining the shape of FA/FI curves explain the differences between (a) and (b), and (a) and (c). 29%
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Pharm-03B1 Draw and label, on the same X - Y axis, FA/FI curves for the following halothane concentrations in oxygen, showing a 30 minute period from starting administration. a. Halothane 1%, subject breathing spontaneously. b. Halothane 6%, subject breathing spontaneously. c. Halothane 6%, subject paralysed and ventilated. With reference to the major factors determining the shape of FA/FI curves explain the differences between (a) and (b), and (a) and (c). 29%
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Pharm-03A1 Briefly outline the effects of isoflurane on skeletal, smooth and cardiac muscle tissues. Indicate how these effects are mediated and their clinical significance. 74%
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• Skeletal Muscle
1. Blood flow Reduced MAP reduced skeletal muscle BF (except isoflurane) minimal clinical significance because muscles are inactive during GA, hence no ischaemia ensues Isoflurane increases skeletal muscle BF 4x due to vasodilatation increased drug delivery to the NMJ faster onset and enhanced effect of NDMB 2. Skeletal muscle relaxation and potentiation of NDMB due to: - Central depression leading to reduced muscle tone, and muscle relaxation - reduced muscle nerve stimulation - presynaptic inhibition of Acetylcholine release - reduced sensitivity of post-junctional membrane to depolarisation / stabilisation of post-junctional membrane These lead to - impaired ability to sustain contraction in response to continuous stimulation (with ether but not halothane), and - dose dependent enhancement of NDMB (> with halothane) Skeletal muscle relaxation from ether derivatives are 2x greater than comparable doses of halothane Clinical significance – facilitate surgery - reduce the amount of NDMB needed to maintain paralysis N2O - produces no muscle relaxation - can cause muscle rigidity in doses >1MAC. - Does not significantly potentiate NDMB - Mechanism is uncertain but may be due to impairment of calcium influx 3. Malignant Hyperthermia - Halothane is the most potent trigger - Occur in genetically susceptible patients – autosomal dominant abnormality in muscle metabolism - Mechanism – increase Ca+ influx through L-type Ca+ channels, causing muscle rigidity, rapidly increasing temperature within a few minutes of administration, CK> 50 000IU/L, hyperK+, SNS overactivity (increase HR, BP, sweating) - Previously 60-70% mortality, now reduced to 5% since dantrolene - Management – Prophylactic – reduce anxiety with midazolam, remove vapourisers, flush circuit with 100% O2 at 10L/min, ETCO2 monitor, nasal temp probe - If it occurs cease triggering agent, ABC, Cardiorespiratory and renal support, active cooling (cold Nsaline, stomach lavage), bicarb to correct metabolic acidosis, Dantrolene 2-10mg/kg • Smooth Muscles VIA cause smooth muscle relaxation 1. Vascular smooth muscle relaxation from endothelial release of NO, and calcium channel blockade • Cerebral vasodilation reduced CVR increase CBF increase ICP • Coronary artery dilatation increase coronary BF, but potential for steal esp isoflurane, but not clinically significant • Pulmonary vasculature inhibit HPV leading to V/Q mismatch • Reduced sphlancnic, liver, renal BF from reduced BP and redistribution of blood volume 2. Bronchodilatation from • Direct effect on bronchial smooth muscle – inhibition of Ca+ mobilisation • Reduced vagal nerve traffic from the CNS • Inhibit histamine induced bronchoconstriction • Good for asthma 3. Uterine relaxation • Dose dependent reduction in uterine contractility and BF • Adv – facilitate removal of retained placenta • Disadv – increase blood loss post LUSCS or STOP from uterine atony 4. Gut • Reduced BF esp with halothane • Usually no clinical significance, but may cause ischaemic gut in susceptible individuals in long operations • Cardiac Muscle 1. Reduced cardiac contractility from reduced Ca+ influx • Halothane reduces contractility reduced SV reduced CO (can be dangerous in patients with cardiac failure) reduced MAP • Isoflurane has mild beta adrenergic activity, hence maintains CO (but still get low BP from reduced SVR) 2. Rhythm disturbance – halothane depresses SA node conduction and prolongs AV refractory period and depress ventricular conduction – arrhythmogenic potential 3. Halothane sensitizes myocardium to cathecolamine increase risk of arrhythmia |
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Pharm-02B3 Draw a graph comparing the ratio of inspired to alveolar concentrations during the first half hour of administration for nitrous oxide, isoflurane, and halothane. Outline reasons for observed differences between the agents and indicate the effects of increases in alveolar ventilation and cardiac output. 73%
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Pharm-02B3 Draw a graph comparing the ratio of inspired to alveolar concentrations during the first half hour of administration for nitrous oxide, isoflurane, and halothane. Outline reasons for observed differences between the agents and indicate the effects of increases in alveolar ventilation and cardiac output. 73%
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Pharm-01A12 Briefly describe the respiratory effects of the volatile agents 58%
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Volatile Agents
- General anaesthetic agents administered via an anaesthetic breathing circuit as a vapour - Include halothane, enflurane, isoflurane, sevoflurane and desflurane - Xenon and nitrous oxide are anaesthetic gases and not volatile agents (included here for sake of completeness) Pattern of Breathing Respiratory Rate - Produce dose dependent increase in frequency of breathing except for isoflurane - Isoflurane does increase frequency up to 1 MAC then no further change with increasing doses - Effect is presumably due to CNS stimulation - Nitrous oxide increases the RR more than the other agents at >1 MAC, may be due to stimulation of pulmonary stretch receptors - Xenon decreases the respiratory rate via central depression Tidal Volume - TV is depressed by the volatile agents resulting in the rapid and shallow pattern of breathing during anaesthesia - Xenon leads to an increase in TV that partially compensates for the decreased RR Respiratory Depression - Net result with dose dependent reduction in MV - Mechanisms o Direct depressant effect on medullary ventilatory centre o Interference with intercostal muscle function o Reduced lung volumes esp. FRC - Xenon > Enflurane > Isoflurane > Sevoflurane > Desflurane > Halothane >> N2O Ventilatory Response to Carbon Dioxide Increased PaCO2 (Fig 2-30 Stoelting) - Increases proportionally with degree of respiratory depression - N2O therefore produces only a minimal rise in PaCO2 or not at all - The use of N2O in combination with the other agents reduces the depressant effect compared with the same MAC of the volatile agent alone - The presence of COPD may accentuate the increase in PaCO2 Response to PaCO2 (Fig 2-31 Stoelting) - All inhaled anaesthetics produce similar dose-dependent decreases in the ventilatory response to carbon dioxide (including N2O) Extended Duration - The level of PaCO2 decreases back toward normal after 5 hours duration - The response to PaCO2 also returns toward normal after 5 hours of administration - The reason for this apparent recovery from the ventilatory depressant effect of volatile anaesthetic agents with time is not known Hypoxic Pulmonary Vasoconstriciton - Reduced HPV Ventilatory Response to Hypoxaemia - All inhaled anaesthetics (including N2O) profoundly decrease the ventilatory response to hypoxemia that is normally mediated by the carotid bodies - 0.1 MAC produces 50 – 70% depression - 1.1 MAC produces 100% depression of this response - Inhaled agents also attenuate the synergistic effect of arterial hypoxemia and hypercapnia on stimulation of ventilation Airway Resistance - Volatile agents produce dose dependent decreases in airway resistance in the presence of bronchoconstriction - The effect is difficult to demonstrate in normal airways because bronchomotor tone is usually low - Agents act principally by producing a central reduction in vagal stimulus - Their effect is additive with β2 agonists - Halothane prevents and reverses airway constriction in asthmatics and attenuates histamine mediated bronchoconstriction - Xenon is four times more dense than air and twice as viscous and theoretically could lead to increased airway resistance but this is not seen clinically Airway Reflexes - Airway irritation is caused by desflurane and isoflurane which may lead to coughing, upper airway irritability and breath holding - With increasing depth of anaesthesia upper airway reflexes are reduced - Reduced ciliary function |
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Pharm-00A9 Compare and contrast the effects of halothane and isoflurane on the heart 65%
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Halothane
Inotropic : myocardial depressant, potent, dose related Chronotropic : minimal change, depresses baroreceptor reflexes Arrthymic : Junction rhythms, depresses SA/AV/ prolonged QT. sensitivity to cateloamines Cornonary : variable effects, no steel Myocardial O2 : decreased SV : decreased SVR : no change BP : drop due to decreased CO CVP : raised Isoflurane Inotropic : less potent, still does related Chronotropic : reflex tachycardia, intact baroreceptor reflex Arrthymic : low incidence, little sensitization Cornonary : potent coronary dialator, steal Myocardial O2 : decreased SV : decreased SVR : big decreased, direct vasodilation action, BP : drop due to decreased SVR CVP : raised |
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Pharm-99A14 Briefly outline the pharmacological effects of the volatile anaesthetic agents on the kidneys. 64%
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General/Indirect effects:
Dose related response * decreased renal blood flow * decreased GFR * decreased urine output Direct effects: 1. Nephrotoxicity related to INORGANIC FLUORIDE production - tubular damage, high output renal failure Results in: * polyuria/inability to concentrate urine * hypernatraemia * hyperosmolarity * increased plasma creatinine - threshold for tubular damage - fluoride levels of 50μmol/L Depends on: a) amount and duration of exposure - quantified by MAC hours, increased amount increased fluoride ion production b) proportion of volatile metabolised - greater metabolism, greater risk of toxicity. Methoxyflurane metabolised 80%. Risk sevoflurane(3%)/enflurane(2-8%)>isoflurane(0.2%)>desflurane(0.02%) c) extent of intra-renal metabolism - increased risk if fluroide ions produced in the kidney - ie. methoxyflurane and enflurane d) solubility - increased solubility -> increased availability for metabolism 2. Compound A Sevoflurane interacts with CO2 absorbents (soda lime and baralyme) to form Compound A. This is increased at low fresh gas flows and at higher temperatures. Found to be nephrotoxic in rats but no experimental evidence of significance in humans. Greatest risk at > 8 hours at MAC 1.25. |
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Pharm-08A7 Describe the terms train-of-four stimulation and double burst stimulation with respect to the peripheral nerve stimulator. Describe their advantages and disadvantages when used to evaluate non-depolarising neuromuscular blockade.
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Peripheral nerve stimulation
-used to assess depth of neuromuscular blockaid. Supra maximal electrical stimulus applied to a peripheral nerve, muscle twitch is assessed distant to this stimulus. eg. ulnar nerve and abductor pollicus facial nerve and obiqularis oris Train of Four * Four supramaximal stimuli @ 2 Hz i.e. 1 every 0.5 sec * each set repeated every 10-20 secs * Ratio of amplitude of 4th twitch to 1st twitch is TOF ratio Control- TOF ratio is 1 Depolarizing agents- twitch height reduced but TOF ratio is 1 NDMR and phase II block- Fade and TOF ratio <0.4 Advantages 1. More sensitive than single twitch 2. Can be used in absence of control value 3. Less painful than tetanus 4. Does not affect degree of NM block 5. Can be repeated more frequently Evaluation of response * Intense Block- after giving intubating dose, no response * Surgical block- TOF appears, maintain TOF at 1-2 responses First response-90-95% recpetor blocked fourth response- 60-75% receptor blocked * Recovery- Reversal of NM block attempted when atleast 3 TOF response seen( around 75% recpetors blocked) Double Burst stimulation * Two short bursts of 50 Hz tetanic stimulation at 750msec interval * DBS3,3 DBS3,2 Control- response equal Partial paralysis- 2nd response weaker than 1st(DBS ratio) Advantages 1. reliable mode of recovery 2. Shorter duration than tetanus(50Hz for 5 sec), so less painful 3. More sensitive than TOF stimulation for clinical evaluation of fade |
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Pharm-07B6 Describe how suxamethonium produces neuromuscular blockade. WHat is the mechanism of recovery of neuromuscular function and what mechanisms may be involved in Phase II block?
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Answer 3 parts :
-mode of action -mechanism of termination o feffect -mechanism of Phase II block Mode of action -features of the ion channel comprising the ACh R at the NMJ and the role of the alpha subunits -sux induced inactivation - |
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Pharm-07A1 Describe the potential adverse effects of administering neostigmine post operatively. 68%
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Neostigmine is a reversible cholinesterase inhibitor administered to 'reverse' neuromusclar blockage with non depolarisors.
Mechanism -formation of a carbamyl ester complex at the esteractic site of the cholinesterase -decreased metabolism of acetylcholine at both nAChR and mAChR. Stimulates both muscaric and nicotinic receptors. Most the unwanted effects after muscarinic effects, therefore given with muscarinic antagonist : atropine, glycoperylate. Muscaric Effects (major effects) -brachycardia -hypotension -asystole -bronchoconstriction -enhanced peristalsis : breakdown of bowel anastomosis, perforated bowel. minor effects -lacrimation -salivation -bronchial hypersecretion -nausea + vomiting Other -phase II block post repeated doses -prolong NMB with sux and miv |
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Pharm-06B4 Describe the advantages and disadvantages of rocuronium for rapid sequence induction. 28%
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Rocuronium is a aminosteriod non depolarizing neuromuscular blocking agent.
True rapid sequence induction : -advanced medical procedure, designed for the expeditious intubation of the trachea of a patient. -minimise increased risk of aspirating stomach contents into the lungs due to a current disease process. -Use of sux and thio using predetermined doses. -Use of rocuronium is modified rapid sequence Advantages ED95 0.3mg/kg, intubating dose 0.6-1.0 mg/kg -intubating conditions in 60seconds (comparable to sux) -priming : 70% receptor antagonism required for NMB, large margin of safety, can give small roc dose prior to induction, priming reduces intubation time -used when sux is contraindicated -burns, spinal transection, anaphylasis -cardiovascular stablitity : no histamine release -avoids side effects of suxamethonoim : histamine release, raised intraocular pressure, intracranial pressure, intragastric pressure + MH trigger Disadvantages -intubating conditions not as good as sux -anaphylasis -long duration of action 50-60 minutes for 0.6mg/kg (can’t ventilate can’t intubate => hypoxia=death) + unprotected airway |
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Pharm-06A6 Explain the possible mechanism for prolonged neuromuscular blockade after a four hour procedure using a non-depolarising muscle relaxant.
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Pharm-06A6 Explain the possible mechanism for prolonged neuromuscular blockade after a four hour procedure using a non-depolarising muscle relaxant.
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Pharm-05A4 Outline the mechanism of action of drugs that inhibit cholinergic transmission at the neuromuscular junction giving examples. 59%
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Mechanisms of NMB
Depolarising Neuromuscular Blockers * 2 suxamathonium molecules bind the 2 α subunits on the nicotinic AChR. * Opening of the central cation channel. * Influx of Sodium and Calcium. * Depolarisation of the membrane around receptor. * Open of ψ-gated Sodium Channels. * Further depolarisation and threshold reached and spread of depolarisation. * But persistence of Sux at NicAChR causes small zone of depolarisation to persist around receptor. * This prevents adjacent Sodium Channels from cycling from inactivated state back to resting state. * 'End-plate' block. Non-depolarising Neuromuscular Blockers * Competitive block of Postsynaptic nicAChR (α subunit) to cause dose dependent decreased response to Single Twitch or TOF. * Block of presynaptic receptors causes fade to Tetani Stimulation. * Require 70% receptor occupation before effect. * Features of block the same as a Phase 2 block. Central Motor Inhibition * Volatile anaesthetics inhibit α motor neurons. (In contrast, IV anaesthetic agents have minimal effect). Pre-synaptic Calcium Channels * Magnesium * Aminoglycosides (also post-synaptic effect) * Calcium channel blockers * Frusemide inhibits cAMP in presynaptic neurons Pre-synaptic ACh Receptors * Non-depolarising NMB Post-synaptic ACh Receptors * Non-depolarising NMB * Depolarising NMB * Aminoglycosides * Tetracyclines * Clindamycin Post-synaptic Sodium Channels * Lithium * Local Anaesthetics * Phenytoin Membrane stabalisation * β blockers * Local Anaesthetics (pre- and post-synapse) Direct action on Muscle * Dantrolene * Theophylline (increase intracellular Calcium) |
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Pharm-04A2 Outline the factors determining speed of onset of neuromuscular blocking agents. 71%
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Pharmacokinetics (Patient factors)
Drug delivery - rate and site of injection Rate of injection The faster the rate of injection, the faster the onset of neuromuscular block owing to the larger concentration gradient between the plasma (central compartment) and the biophase (the neuromuscular junction Site of injection Injecting to a vein more proximal to the heart (e.g. internal jugular vein) will reduce the time the drug takes to reach the heart and hence be pumped to the muscles, hence a faster onset Cardiac output The greater the cardiac output, the faster it takes the drug to move from the site of injection to reach the biophase i.e. the neuromuscular junction Onset may be slower with decreased cardiac output due to Age e.g. elderly patients have a reduced cardiac output Drugs eg concomitant drug administration eg beta-blockers may reduce cardiac output Muscle blood flow Differences in onset of varying skeletal muscle groups probably due to more rapid equilibration of the drug in skeletal muscles with greater blood flow Distribution The delay between IV administration of the drug and onset of paralysis reflects time necessary for the circulation to deliver the drug to the biophase (neuromuscular junction) Effect-site equilibration time The half-time of equilibration between the plasma concentration and the drug effect Receptor kinetics Pharmacodynamics (Drug factors) Type of neuromuscular blocking agent used Shortest onset time Suxamethonium > Rapacuronium (ORG 9487) > rocuronium Interaction at the effector site Dose The dose of drug necessary to produce a given degree of neuromuscular blockade at the diaphragm is about twice the dose required to produce a similar block of the adductor pollicis muscle Potency concepts Steroidal relaxants e.g. Rocuronium and Rapacuronium (ORG 9487) have a faster onset of blockade than the more potent drugs pancuronium and vecuronium Other factors The differences in responses different muscle groups that are monitored Neuromuscular-blocking drugs affect small, rapidly moving skeletal muscles (eyes, digits) before the intercostals muscles and finally the diaphragm The onset of neuromuscular blockade is more rapid (but less intense) at the laryngeal muscles (vocal cords) than the peripheral muscles (adductor pollicis) May reflect skeletal muscle fibre types Thyroarytenoid muscles have fast contraction times whereas adductor pollicis is composed of slow fibres Density of Ach receptors is greater in fast than in slow contraction fibres Likely that more receptors need to be occupied to block fast muscle than slow muscle The rapid more rapid onset of action at vocal cords than at the adductor pollicis suggest a more rapid equilibration between plasma concentrations and vocal cords compared with adductor pollicis Effect of the priming principle (Stoelting p 205) The speed of onset of intermediate-acting (except Rocuronium) may be accelerated by administering an initial small sub paralyzing dose (approximately 10% of the drug’s ED95) followed in approximately 4 minutes by the larger dose (2-3x ED95) of the drug. - this divided dose technique is known as the priming principle Based on the concept that the onset of neuromuscular blockade consists of 2 steps: 1) initial binding of spare receptors during which no clinical effect is observed 2) subsequent deepening of blockade The initial sub-paralyzing dose is presumed to decrease the safety margin of neuromuscular transmission, allowing a more rapid onset of effect after the second larger dose Priming principle may serve as a useful alternative when Suxamethonium is contraindicated but a rapid onset of neuromuscular blockade is needed. The need for priming principle is questionable when a single large IV dose of rocuronium produces a rapid onset of neuromuscular block without the risk of drug-induced weakness in an awake patient |
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Pharm-04B6 Compare and contrast neostigmine and the organophosphorus compounds. 52%
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compounds
Classification - Anticholinesterase drugs are classified by the mechanism by which they inhibit acetylcholinesterase (AChE) - Pyridostigmine , neostigmine and organophosphorus compounds (but not edrophonium) also inhibit plasma cholinesterase (PChE) Reversible Inhibition - Edrophonium - A quaternary ammonium anticholinesterase producing reversible inhibition through electrostatic attachment to the anionic site of the enzyme - Stabilised by H+ bonding at the esteratic site - Predominant site of action thought to be presynaptic Formation of Carbamyl Ester - Neostigmine, physostigmine and pyridostigmine act as competitive substrates for AChE - Form a carbamyl ester complex at the esteratic site - Longer lasting bond (15 – 30 minutes). AChE is not capable of metabolising Ach until bond dissociates Irreversible Inhibition - Organophosphates echothiophate, nerve gases (sarin) and insecticides - Form a stable covalent bond at the esteratic site - Inactive phosphorylate complex does not undergo hydrolysis - Restoration of AChE activity depends on synthesis of new enzyme Pharmacological Effects - The drugs exhibit similar clinical effects that are a reflection of accumulation of Ach at muscarinic and nicotinic cholinergic receptor sites - The duration of effects is similar for edrophonium and neostigmine but greatly increased with the irreversible block of the organophosphorus compounds - Toxic effects are an extension of clinical pharmacology - SLACK BLUDGERS - SLACK for muscle weakness progressing to paralysis - Bradycardia, Lacrimation, Urination, Diarrhoea, GIT disturbance, Emesis, Respiratory distress, Salivation - Progress to tremor and convulsions followed by depression, coma and respiratory paralysis - Treatment of organophosphate poisoning is with pralidoxime: able to reactivate phosphorylated AChE by promoting hydrolysis. Atropine may also be required Cardiovascular - Bradycardia leading to reduced cardiac output. Potential cardiac arrest - Decreases the effective refractory period of cardiac muscle - Increases conduction time Respiratory - Increases bronchial secretion - May cause bronchoconstriction CNS - Effects most marked with those drugs that cross BBB and act centrally - Agitation and dreaming may occur progressing to delirium and seizures - Muscular effects from weakness, fasciculations to paralysis can occur - Eye predictably develops meiosis (constriction of sphincter of iris and ciliary muscle) also inability to accommodate and reduction in IOP due to increased outflow of aqueous humour GIT - Increase gastric fluid secretion including salivation - Increase gastric motility esp. large intestine producing diarrhoea, abdominal cramps - Nausea and vomiting may occur GUT - Increase in ureteric peristalsis may lead to involuntary micturition |
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Pharm-03A8 Describe the onset and offset of neuromuscular block at the diaphragm, larynx and adductor pollicis after administration of 2.5 x ED95 dose of vecuronium. Comment on the differences observed. What are the clinical implications of these differences? 50%
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Examiner's Report
The pass rate for this question was 50%. In this question the candidate was expected to address the issues of the kinetics of onset and offset of neuromuscular block (NMB) and the known different levels of sensitivity of the muscles mentioned. It was important to mention that although the diaphragm (D) and larynx (Lx) are relatively resistant to competitive NMB with respect to the adductor pollicis (AP), the major determinant of onset under these circumstances is blood flow. Thus onset is more rapid in the Lx and D and slowest in the AP. Candidates needed to define ED95 and that the ED95 referred to is that for the AP. At the time of AP twitch disappearance both the D and Lx may have been maximally blocked and may be beginning to recover. Thus it is also critical to mention that the order of recovery is D, Lx and then AP. Clinical implications that should have been discussed included onset of block and intubating conditions, offset of block and adequacy of recovery and monitoring of block at AP, orbicularis oculi and prediction of block at AP, Lx and D. Useful diagrams (as are found in both Miller and Stoelting) to explain these phenomena were used by some candidates to their advantage. [edit] Comments ED95 = dose of NMBD required to produce 95% suppression of the single-twitch response measured at adductor pollicus. In general, 2.5xED95 is the dose required for optimal intubating conditions. Muscle relaxation occurs only after >75% receptor occupancy spare receptor theory Vecuronium - Amino-steroid non-depolarising NMBD Onset of Neuromuscular Blockade NMBD achieve their action by diffusing from circulation into NMJ - have to move down their concentration gradient. Speed of onset primarily dependent on muscle blood flow – high blood flow areas receive high concentrations of NMBD faster than areas of low blood flow → more rapid equilibration b/n plasma and muscle - More rapid at the larynx/diaphragm - Slower at the adductor pollicus (AP) Minor factors affecting speed of onset: Muscle size – small, rapidly moving muscles are blocked before larger muscles - Larynx before diaphragm Muscle type – muscles with ‘slow oxidative’ twitch fibres have less density of nAChR than ‘fast glycolytic’ twitch fibres → slow twitch reach required receptor occupancy faster, fast glycolytic fibres more resistant to blockade - Larynx / diaphragm more resistant to blockade than AP Therefore, onset of blockade by muscle group: larynx > diaphragm > AP Offset of Blockade Offset primarily determined by blood flow Also, more resistant fast glycolytic fibres will recover more quickly. Therefore, offset of blockade by muscle group: diaphragm > larynx > AP Clinical Implications Time to ‘ideal’ intubating conditions (onset) not easily measured as measurable muscles by nerve stimulator (AP, obicularis oculi) are last to experience neuromuscular blockade - peak effect may have come and gone for laryngeal relaxation AP is also the last to recover - diaphragm & larynx will already be recovered. Note: obicularis oculi may more closely reflect recovery of diaphragm |
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Pharm-02B5 Outline the possible reasons for prolongation of paralysis induced by an intravenous dose of 1 mg.kg-1 of suxamethonium. Briefly indicate the consequences of such a prolonged block. 60%
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Acquired/genetic/pharmacokinetic effects.
This is a normal dose, so it is unlikely that it would cause an overdose leading to phase 2 blockade. Suxamethonium: metabolised by pseudocholinesterase. A change in PCE concentration will change the duration of the block. Acquired changes in PCE concentration/activity: severe liver disease. Pregnancy (down by 25% at 10/40 until 6/52 post partum), drug interactions. Concentration changes: Investigations: may need to check patient and family for psedocholinesterase activity. Atypical PCE can’t hydrolyse the ester bonds. -dobucaine number: Dobucaine = an amide L.A. which decreases normal plasma cholinesterase activity by 80%, and Abnormal PCE activity by only 20%. Thus, a high dobucaine number of say 77-83 means normal PCE activity (quality, not quantity. Liver disease can still show a normal PCE activity). A low dobucaine number of <30 means abnormal PCE. -homozygous atypical = 1:3200 people. With Dobucaine number <30. Blockade time about 60-180 minutes. -heterozygous = 1:480, with dobucaine number between 45-68, blockade time about 20 minutes. Gene: E1u = normal gene amino acid sequence. Mutation = : E1a = 4% of Caucasian population, = most common mutation. Others include : E1f fluoride & E1s silent genes. Other agents added after sux. may prolong the block, including adding more sux. The sux is largely broken down in plasma by PCE prior to reaching NMJ, and has to be washed out of the NMJ to reach the PCE, to break it down more. Drugs: Anticholinesterases used to treat myasthenia gravis, or chemo drugs (cyclophosphamide, nitrogen mustards) may drop PCE levels. Neostigmine will prolong, rather than reverse, the depolarising block. Other drugs are broken down by PCE, reducing its availability to deal with sux: MAOIs, etomidate, ester L.A.s, methotrexate, mivacurium. Plasmapheresis, cardiopulmonary bypass, and renal disease can also lower PCE levels. Consequences: need prolonged ventilation and sedation, until block wears off, in suitable environment. ??Consider a source of cholinesterase, such as FFP |
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Pharm-00B16 Compare and contrast the pharmacology of atracurium and cis-atracurium 26%
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Pharm-00B16 Compare and contrast the pharmacology of atracurium and cis-atracurium 26%
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Pharm-98A15 Compare the metabolism of suxamethonium to that of atracurium. 83%
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Suxamethonium
• Intubating dose = 2mg/kg • Duration of action = 5min • T ½ elimination 0.5 - 1 min - difficult to measure • Metabolised in plasma by pseudocholinesterase (which is produced in the liver) • Metabolism impaired in v. severe liver disease (due to reduced production of pseudocholinesterase) • Metabolised to succinyl monocholine and choline. The mono ester is metabolised much more slowly than sux itself • Subject to genetic variation (dibucaine, fluoride, impaired synthesis, silent and increased activity) • No chiral centre Atracurium • Intubating dose = 0.6mg/kg • Duration of action = 35min • T ½ elimination 13 - 20 mins • Metabolised by plasma and tissue esterases (2/3rds) • Hoffman elimination (1/3) • Some renal elimination (it’s highly polar) • Unaffected by severe liver disease • Metabolised to laudanosine, acrylates, alcohols, and acids. • Although laudanosine has CNS-stimulating properties, the clinical relevance of this effect is negligible. • • 10 Stereoisomers- it’s all over the shop |
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Pharm-08B7 List the agents used therapeutically to reduce platelet function. Outline their mechanisms of action, adverse effects, mode of elimination and duration of action.
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82% of candidates passed this question.
Relevant agents for this question include aspirin, pro-drugs at ADP receptor, atagonists at the IIb/IIIa receptor and phosphodiesterase inhibitors. This question had the option of being answered in the form of a 'table' format using dot points outlining the componets asked for about platelet function reduction. Marks were enhanced by including explanation of how the drug action interferes e.g. blocking the IIb/IIIa receptor interrupts the binding of fibringen hence the failure of adhesion and aggregation of platelets. The 'thrombus/platelet' diagram in Katzun page 544 illustrates in summary form the information and it was included in some candidate answers. There is always a risk of elaborating on adverse effects probably more than the mark allocated at the expense of time spent on other agents. Medications who unwanted side effects include platelet inhibition are not used therapeutically for that ideal purpose thus not gaining marks. Comments on dextran and thrombin inhibitors gained credit. |
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Pharm-07B2 Outline the important pharmacological considerations when stopping warfarin and commencing prophylactic (low dose) low molecular weight heparin (LMWH) in the peri-operative period.
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22% of candidates passed this question.
Candidates generally performed poorly on this question. Often mainly warfarin or LMWH were discussed with little discussion of the other drug. Unfractionated heparin was frequently discussed. Better answers included an introduction outlining the issues of balancing the risks of thrombo-embolism Vs bleeding and a summary of the relevant pharmacology of warfarin and LMW heparins. An outline of the relevant pharmacology is summarised below. This degree of detail was not required for a pass. The summary is provided to assist candidates with future exam preparation. Warfarin Long acting agent, inhibits Vit K reductase production of Factors 2,7,9,10,Protein C,S Metabolised in liver, low clearance, T 1/2 40 hrs Thus clearance of warfarin and resynthesis of new factors 2,7,9,10 required for offset Approximately 3-5 days required for offset Warfarin action potentially prolonged in; Decreased warfarin metabolism- liver impairment, cytochrome inhibition e.g. amiodarone, fluconazole, metronidazole Decreased synthesis of clotting factors- liver impairment, Vit K deficiency, cephalosporins Check INR day before surgery Small dose Vit K, e.g. 1mg can revers but potential problems with warfarin effect post op FFP will reverse but risk with blood products Recommence after surgery when minimal risk of surgical bleeding May be initially hyper coagulable due to inhibition of protein C,S (endogenous anticoagulants), thus continue LMWH until INR therapeutic LMWH Activates anti-thrombin 3, inhibits factors 10 and 2 but much greater inhibition of Factor 10 Commence 2-3 days after warfarin ceased Predictable and reliable, doesn't require monitoring, once daily administration due to longer T1/2 compared to heparin S.C admin, high bio-availability, at home administration feasible Prophylactic dose enoxaparin 40 mg daily, dalteparin 5,000 units daily Decrease dose in renal impairment, renally excreted Last prophylactic dose minimum of 12 hours before surgery, neuraxial blockade |
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Pharm-05A5 List the antiplatelet agents and outline their mechanism of action, adverse effects, mode of elimination and duration of action. 68%
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Anti-platelet drugs:
* cyclo-oxygenase inhibitors eg, Aspirin ,NSAIDs * Platelet PGE inhibitors eg: Dipyridamole * ADP inhitor eg: Clopidogrel * Glycoprotein IIb/IIIa receptor anatagoinst eg: Abcixamab(Reopro) * Dextrans 40&70 * Prostacyclin-PGI2 * Hirudin |
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Pharm-04A8 Describe briefly the side effects and complications of heparin therapy. 71%
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Heparin is a mucopolysaccharide produced naturally within the body and named for its discovery in liver tissue in 1916 in the USA. Heparin’s action is primarily of anticoagulation and indications for clinical use include DVT, PE, AMI, other arterial thrombus or anticoagulation for haemofiltration or for cardiopulmonary bypass.
Pharmaceutics: • Heparin is presented as a heterogenous group of compounds with molecular weight varying between 3000 to 30,000 daltons. • Commercially, heparin is derived from bovine lung, bovine gastrointestinal tract mucosa or from porcine git mucosa. • Heparin is found endogenously within basophils, mast cells and the liver and endogenous heparin has the same effects as externally derived heparin. • Heparin is presented in units of Heparin sodium or Heparin Calcium (rather than in mass units)Different commercial preparations of heparin have different potency and thus heparin is tested and presented in standardised units . • Heparin exists in both its unfractionated form or as low molecular weight heparin which is used as an anticoagulant but has significantly different pharmacokinetic properties Pharmacokinetics: • Heparin has high molecular weight • Heparin has poor lipid solubility • Because of its high molecular weight and poor lipid solubility heparin is poorly absorbed from the gastrointestinal tract and is normally administered intravenously or subcutaneously • Heparin does not cross the placenta and is the anticoagulant of choice in pregnant women • Heparin is largely protein bound once injected. Around 1/3 of heparin is bound to antithrombin III with the rest bound to albumin and fibrinogen, LMWH is less avidly bound to proteins and thus has a better available portion which is more predictable. • T1/2 of UFH is approximately 90 minutes (hence infusion) • Elimination T1/2 of LMWH is 0.5 – 2.5 hours and can be given once daily as prophylaxis • Vd 40 - 100 mls/kg (small Vd) • Clearance 0.5 – 2 ml/kg/min • The elimination half time is greatly prolonged with hypothermia, presumably as heparinase acts more slowly with decreased temperature. Hepatic and renal dysfunction may also increase elimination half time. • The action of heparin is unpredictable for any given patient and if heparin is infused, the activated partial thromboplastin time (APTT) is measured with a target range of ~ 1.5 to 2.5 times the predrug value (typically 30 seconds). The variable response to heparin may be in part due to variation in proteins to which heparin is bound. • Anti Factor Xa levels can also be performed to quantify heparin levels or LMWH levels Pharmacodynamics Heparin binds to antithrombin III and increases its activity by up to 1000 times. Antithrombin III exerts its anticoagulant effect by inhibition of thrombin and other serine proteases. The heparin – antithrombin III complex acts on thrombin and to a lesser extent Factors IX, X, XI and XII. LMWH increases the action of antithrombin III on Factor Xa but not on thrombin because the molecules of LMWH are not large enough to bind to antithrombin III and thrombin simultaneously (see diagram). Heparin prevents the production of clot once active and thus allows the physiological process of Fibrinolysis to occur and the balance swings from clot production to clot resorption. Side Effects • Bleeding – An extension of the anticoagulant effect, most seriously GIT bleeds or intracranial bleeds • Thrombocytopenia o 1) A common, less serious abnormality in which platelets may fall transiently to less than 100 ×109 but which does not relate to an increased risk of coagulation or organ failure o 2) Heparin inducted thrombocytopenia (HITS) – IgG/IgM antbodies are formed in response to the heparin/platelet factor 4 complex. Platelets aggregate and occlude small vessels, consumption of platelets leads to thrombocytopenia . Heparin should be ceased and if anticoagulation is required the patient should be treated with danaparoid (a low molecular weight heparinoid). HIT occurs less with LMWH but they should be avoided in the context of HIT caused by heparin administration. • Osteoporosis – usually occurs with prolonged use of heparin for months • Alopecia • Hypoaldosteronism • Hypersensitivity reactions (less commonly than with protamine sulphate) |
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Pharm-02A15 Describe the mechanism of the anticoagulant effect of coumarin derivatives and what determines the onset and offset of action. 45%
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Oral Anticoagulants are derivatives of 4-hydroxycoumarin. Warfarin is the most frequently used because of its predictable onset and duration of action, as well has a high oral bioavailability
Pharmaceutics Structure A synthetic coumarin derivative A racemic mixture of the R- and S-enantiomers. The S-enantiomer has 2-5x more anticoagulant activity than the R-enantiomer Presentation Tablets containing 1/3/5 mg of a racemic mixture of warfarin sodium. Half life of Vitamin K dependent clotting factors: (*Protein C – half life 5 hours) Factor VII – half life 6 hours Factor IX – half life 24 hours Factor X – half life 40 hours Factor II – half life 60 hours Pharmacokinetics Absorption Rapidly and completely absorbed from the GIT i.e. 100% bioavailability Peak concentration within 1 hour Time to onset of action dependent on depletion of existing factors: Factor Half-Life (hrs) Protein C 8 Protein S 30 II 60 VII 6 IX 24 X 48 Distribution 97% bound to albumin Does not diffuse into CSF, Breast Milk or erythrocytes Does cross the placenta and has exaggerated effects in the foetus VD 0.1 l/kg Metabolism CYP 450 metabolism to inactive metabolites which are conjugated to glucuronide Clearance of R-warfarin is generally half that of S-warfarin Time to offset of action delayed by time needed to synthesis new facotrs Elimination Excreted in Bile and urine Elimination half-time of 24-35hrs Clearance 3-4ml/kg/min Pharmacodynamics Mechanism of Action − Coumarin derivatives competitively antagonise the reduction of vitamin K to its active form. − Synthesis of factors II, VII, IX & X involves the γ-carboxylation of glutamic acid residues − This process requires the active (reduced) form of Vit K and converts it to the inactive (oxidised) form of Vit K − Coumarin derivatives inhibit Vitamin K reductase, preventing the cycling of Vit K to its active form Factors potentiating action Disease − Liver Disease − Thyrotoxicosis – increased breakdown of clotting factors Drugs − Inhibitors of CYP450: Citimidine, imipramine, co-trimoxazole, chloramphenical, ciprofloxacin, metronidazole, amdiodarone, and antifungals − Anti-platelets: No effect on INR, but may potentiate bleeding − Cephalosporin’s: Inhibit the reduction of Vit K to its active form Factors inhibiting action Disease − Pregnancy – pro-coagulant state − Hypothyroidism – decreased breakdown of clotting factors − Hereditary warfarin resistance Drugs − Vitamin K − Inducers of CYP450: carbamazapine, barbiturates, Rifampicin − Reduced absorption from GIT – cholestyramine Dosing and Monitoring Adult oral dose is usually 3-9mg/day Treatment monitored by PT, which is sensitive to 3 of the 4 vitamin-K dependent clotting factors Adverse Effects Excessive bleeding Teratogenic in pregnancy Skin necrosis |
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Pharm-95A10 Outline the importance of vitamin K and the factors determining its uptake 68%
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Vitamin K1 (phylloquinone)
Vitamin K (K for Koagulation , german) is a group of fat soluble vitamins occurring naturally in plants (and particularly in leafy green vegetables). In addition to dietary Vitamin K, Vitamin K2 is also produced by bacteria in the gut (eg E Coli). Vitamin K is required for the production of clotting factors II, VII, IX and X (tv stations), Protein C and Protein S. Without γ – carboxylaxtion of glutamate residues, there is no binding between Factors II, Factor X and platelets. Therefore, thrombin is not produced from Prothrombin without Vitamin K. Also, the Vitamin K must be in the reduced form (hydroquinone form) to allow it to perform γ – carboxylation of the glutamate residues of the clotting factors. Warfarin relies on the competitive inhibition of the reductase enzyme which normally reduces Vitamin K to its active form. Aside from its important role in clotting, Vitamin K is also involved in bone metabolism. Physiologically, Vitamin K is a fat soluble vitamin absorbed from the small intestine in a saturable energy requiring process which requires the presence of bile salts. In the absence of fat in the diet, Vitamin K is poorly absorbed although this extreme is unusual and dietary vitamin K is normally sufficient. Other conditions affecting the adequacy of Vitamin K uptake include inflammatory conditions of the gut eg Coeliac disease or IBD in which the intestine is simply not able to absorb Vitamin K adequately. In newborns, clotting factors are at a lower level than in adults and the gut is sterile which prevents the production of Vitamin K by EColi in the gut, thus reduced uptake of Vitamin K occurs in this group. There is minimal storage of Vitamin K in the body. Metabolism is to more polar substances which can be excreted in the urine and in the bile. Clinically, Vitamin K can be administered orally, subcutaneously or intravenously and is indicated: 1) for treatment or prevention of bleeding from excessive oral anticoagulation (ie warfarin induced coagulopathy). In bleeding patients with high INR, FFP may also be indicated. 2) to prevent haemorrhagic disease of the newborn 3) For Vitamin K deficiencies in adults, eg Malabsorption diseases or bile deficiency (eg Obstructive Jaundice) |
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List the effects of histamine. Write a brief outline on the pharmacology of the H1 blocking drugs.
(26% pass rate) |
Definition
Histamine is a basic amine produced from L-histidine with roles in inflammation, gastric acid secretion and possibly as a neurotransmitter [edit] Effects H1 receptor - bronchoconstriction - vasodilation - incr vasc permeability - stimulation of cutaneous nerve endings - pruritis - input from vestibular apparatus to vomit centre H2 receptor - increases gastric acid production by incr adenyl cyclase - bronchodilates - vasodilates -CNS stimulation -Increase Cardiac inotropy,chronotropy & antidromic effect H1 &H2:Vasodilation and increase capillary permeability H3 receptor - central & peripheral presynaptic inhibition [edit] H1 receptor antagonists All are reversible competitive antagonists Centrally acting 1st Generation (cross BBB) * diphenhydramine (benedryl) * chlorpheniramine * Promethazine (Phenergan) These have antiemetic and CNS sedative effects 2nd Generation (do not cross BBB) * loratidine (claratyne) No central effects Kinetics - Good oral absorption - High 1st pass metabolism - BA promethazine 25% Distribution - High PPB (~70-90%) Metabolism - hepatic mixed function oxidase system Elimination - Variable between drugs Mechanism of Action - Competitive antagonists at the H1 receptors - also anticholinergic effects Side effects 1st generation - Anticholinergic effects Dry mouth, blurred vision, urinary retention, impotence - Anti-emetic effects (ie. cross BBB) - Sedation, somnolence - Overdose: seizures, hallucinations, coma CVS • Tachycardia • prolonged QT • arrhythmias 2nd generation - lacks anticholinergic and CNS effects - similar CVS effects |
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Pharm-01B14 Outline the direct effects of endogenously released histamine. 49%
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Histamine:Basic amine produced by decarboxylation of histidine.
Found in most tissues, with high concentrations in lungs/skin/GIT. (Areas exposed to environmental allergens). Contained in cells such as: * Mast cells. * Basophils. * Histaminocytes in stomach. * Histaminergic cells in CNS. Acts on specific receptors: H1, H2 & H3. (Recently identified H4 in intestine, spleen thymus and immune/inflammatory cells). Effects of Histamine: * Gastric secretion: Stimulates gastric acid secretion by activation of H2 receptors. Blocked by H2 antagonists (cimetidine, ranitidine). * Smooth muscle contraction (except vascular): H1 receptor activation in lungs (bronchi & bronchioles), GIT (weak effect) and uterus. This is seen in COAD and asthma. H2 receptor stimulation causes bronchial smooth muscle relaxation. * CVS: o vascular dilatation by H1 receptors at low concentrations of Histamine. Produces rapid, short-duration vasodilation. Also mediated by H2 receptors at higher histamine concentrations (slower, more sustained). Causes: + flushing, especially face & upper torso. + decreased peripheral vascular resisitance + drop in BP + increased capillary permeability - leads to leakage and oedema. o Positive inotropic and chronotropic effect by H2 receptors in heart, plus catecholamine release from adrenal medulla. o Antidromic effect by slowing AV conduction due H1 activation o H1: coronary vasoconstriction o H2: coronary vasodilation * Skin: triple response via H1 receptors. o reddening due vasodilation o wheal due increased capillary (?and post-capillary venules) permeability -> oedema o flare due dilatation of arteries surrounding the oedema - an axon reflex mediated via sensory nerve fibre stimulation (causes itching) * CNS: Histainergic neurons in hypothalamus, with axons to all parts of brain. H1 receptor located postsynaptically (excitatory). H2 also postsynaptic (inhibitory). H3 PREsynaptic inhibitory (negative feedback loop). Histamine is an important component of inflammation and alergy, but is only one of several mediators released in these conditions. Histamine receptor antagonists are an important part of Rx of oedema & itching from allergy/inflammation, but not for Rx of hypotension or bronchoconstriction. Some drugs (eg. atracurium) cause histamine release, resulting in hypotension & tachycardia. This can be reduced by using H1 & H2 blockers (but H2 blockers may cause some H3 blockade). The BP drops is less if using an H1 blocker than if using both H1 & H2 blockers. |
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Briefly outline pharmacological methods of reducing gastric acidity. Indicate the mechanisms of action and the advantages and disadvantages of each method.
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Methods to reduce gastric acidity
Anti-muscarinic agents eg Pirenzepine - selective gastric M1 muscarinic receptor antagonist antacid used prior to the newer agents Disadvantage: Anticholinergic side effects Anti-histamines (H2 receptor antagonists) Eg Ranitidine Advantage: Powerful antacids capable of suppressing 90% of food stimulated and nocturnal secretion of gastric acid Disadvantage Does not influence acid already in stomach (this is dependent on gastric emptying) Older drugs in this group eg Cimetidine increase the rate of drug interactions owing to its actions on cytochrome P450 Anti-Gastrin Eg Somatostatin, Octreotide (synthetic somatostatin analogue) Has been shown to reduce gastric acid secretion Disadvantage Require parenteral administration because they are peptides Expensive Proton-pump inhibitors Eg. Omeprazole Advantage Very powerful antacid because it blocks the final common pathway to gastric acid secretion Well tolerated Minimal side effects Disadvantage Expensive Concerns re the effects of prolonged acid suppression on bacterial colonisation Chemical neutralisation (Alkalisation) - Stoelting p 444 Eg Magnesium Hydroxide, Aluminium Hydroxide, 0.3 M Sodium citrate Advantages Good immediate neutralisation - single dose of sodium citrate raises gastric pH > 2.5 (critical pH in aspiration) Disadvantages Unpleasant taste Does not suppress acid secretion therefore rapid gastric emptying will decrease pH again When given prior to anaesthesia, will increase gastric volume MgOH or Al OH3 are particulate and dangerous in aspiration MgOH: Can cause osmotic diarrhoea AlOH3: Hypophosphatemia can occur because it binds phosphate and prevents its absorption Hypercalcuria and nephrolithiasis from increased calcium absorption Slowing of gastric emptying and constipation+ Sodium bicarbonate: systemic alkalosis and alkalinization of urine, predisposing to UTIs and leading to changes in renal elimination of drugs increased sodium load with chronic use Acid rebound Caused only by calcium-containing antacids Marked increase in gastric acid secretion several hours post neutralization Milk-alkali syndrome Characterized by hypercalcaemia, increased urea and creatinine and systemic alkalosis Occurs with ingestion of large amounts of calcium carbonate plus >1000 ml of milk daily Prostaglandins (Stoelting p 382) PGE1 Eg Misoprostol Both gastrin and Histamine stimulate the production of cAMP which is inhibited by PGE1 analogues thus preventing Histamine-stimulated gastric acid secretion Maintains or increases mucosal blood flow in response to gastric irritants and may increase secretion of mucus and bicarbonate by gastric and duodenal mucosa Disadvantage Increased uterine contractions which can provoke abortion |
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Pharm-06A7 Briefly outline the pharmacology of naloxone.
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Naloxone is a competitive opioid receptor antagonist, used to reverse unwanted effects of opioid receptor agonists, including respiratory depression, hypotension, sedation and pruritis. Has also been used in animal studies to reverse hypotension 2 to hypovolaemic/septic shock.
[edit] Pharmaceutics * substituted oxymorphone derivative: the tertiary amine methyl group of oxymorphone is substituted with an alkyl group, giving antagonist activity * OH group at the 3-carbon atom is retained. * pure mu, kappa and delta opioid receptor antagonist (competitive antagonism). * presented as clear solution for IV/IM injection, containing 20mcg/ml or 400mcg/ml naloxone hydrochloride. [edit] Pharmacokinetics absorption: oral: high absorption from the GIT (90%) but subject to high first pass metabolism- therefore not used orally (as opposed to naltrexone). IV: administered incrementally. 100 to 200mcg generally required for reversal of respiratory depression. Acts within 2 minutes when given IV. offset of effect may be within 45 minutes, and may necessitate continuous infusion (eg 5mcg/kg/hr) of naloxone if the opioid being reversed has a longer duration of action. IM/SC: onset of effect slower than IV but sometimes used in doses from 400mcg to 2mg. distribution: 46% protein-bound. Vd 2 litres/kg. highly lipid soluble. metabolism: hepatic, conjugated to glucuronide form, naloxone-3-glucuronide. excretion: clearance is 25ml/min/kg. elimination half time 60-90 min. [edit] Pharmacodynamics CNS: rapid reversal of opioid effects incl respiratory depression and sedation. also antagonises analgesic effects of opioid agonists. drowsiness at high doses. decreases pain threshold and antagonises placebo effect. CVS: increased SNS activity (?2 to sudden increase in pain) -> increased HR, BP, pulmonary oedema at high doses. Has reportedly been associated w cardiac dysrhythmias. has been used in animal studies to reverse hypotension of septic/hypovolaemic shock. GIT: reverses spasm of the sphincter of Oddi. associated w nausea and vomiting, esp with rapid IV administration. Obstetric/Paediatric: crosses the placenta. may cause acute withdrawal in the foetus or neonate after administered to an opioid dependent parturient. |
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Pharm-09A5 Outline the effects of an opioid injected into the spinal intrathecal space.
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Intrathecal opioids are often given to enhance analgesia in the intraoperative and post-operative period in some cases they have been used as the sole agent.
Pharmaceutics • Many preservatives and anti-microbials in opioids have been implicated in causing neurotoxicity and it is recommended that preservative free solutions be used. Pharmacokinetics • Intrathecal injection causes high concentrations of opioids to appear in the CSF. • There is rapid diffusion into the tissues of the spinal cord due to the high concentration gradient. • It has been suggested that highly fat soluble drugs are less likely to be carried away from the site of injection by the CSF to other areas of the spinal cord although some studies have shown no difference between intrathecal morphine and fentanyl in terms of respiratory depression. • Metabolism requires that the opioid diffuse away from the spinal cord into the plasma where it is carried away to be metabolised. • Opioids need to diffuse through pia-glial membrane, deeper access is via perivascular Virchow Robin spaces • Hyperbaric/hypobaric solutions modify spread. Pharmacodynamics CNS • Presynaptic effects are a decrease in the release of Substance P and possibly glutamate from excitatory fibres (esp. C fibres which mediate dull pain). • Postsynaptic effects are a decrease in Ca entry and increased K entry as well as modulating cAMP levels. • Effects are achieved via G protein coupled receptors and μ,δ,κ are all present in the spinal cord with high numbers of opioid receptors in the sub gelatinosa. • There may also be direct ion channel effects- unclear. • Effect is to promote analgesia especially ↓dull pain mediated by C fibres but also sharp pain mediated by Aδ (although less effectively). • Vomiting has a incidence of 20% • Urinary retention has an incidence of 20%. • Opioids may potentiate the effects of sedative drugs and therefore may lead to excessive sedation although the expected incidence is less than that with systemic administration.. • Viral reactivation of herpes simplex virus - ? interaction with trigeminal nucleus after cephalad migration • Water retention via stimulation of ADH Respiratory • Incidence of respiratory severe depression is 0.6% -worse in the first 12 hours unusual after 24 hours. • Respiratory depression may be worse with morphine due to an increased ability to distribute through the CSF • Early respiratory depression may be due to absorption of lipid soluble opioids being absorbed • Caused by activating μ receptors on the floor of the fourth ventricle. • Respiratory depression is worse if concurrent systemic opioids (IV/ Oral etc) are given Cardiac • Foetal bradycardia has been reported- may be due to decreased maternal catecholamine levels with the sudden onset of analgesia • Neonatal effects can be exaggerated due to ion trapping Dermatological • Pruritus is a common side effect and the incidence may be as high as 40%-80% Miscellaneous • Vertigo, nystagmus, and miosis may occur • Sustained erection and inability to ejaculate • Inhibition of shivering leading to delayed • Delayed gastric emptying |
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Pharm-07B3 Outline the important pharmacological considerations concerning choice of opioid and dosage when converting from intravenous morphine to oral opioid analgesia in the post operative period.
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The question asked about the science behind our choice and dosage of oral opioids. The other information in the question was that the patient had been on intravenous morphine in the post-operative setting.
Good answers covered the rationale of what drugs we use, how and when we use them and why. Patient factors included the fact that acute pain is usually diminishing, the importance of the oral route and gut function returning, patient illness, type of surgery, age and previous opioid use. Dosage of the drugs can be calculated from intravenous morphine requirements in the previous period, usually using a prn (as required) dosing schedule and erring on a lower conversion dose and longer dosing interval for safety. Use of adjuvant drugs such as paracetamol and NSAIDs reduces the dose of opioid and use of sedative drugs increases the risk of side effects such as respiratory depression. Many candidates answered the question using a template; Pharmaceutics / Pharmacokinetics / Pharmacodynamics. In many cases it was possible to change the word "opioid" to any other drug and still have a correct statement. However, if this did not answer the question, no marks were awarded. |
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Pharm-05A2 Outline the acute adverse effects of opioid receptor agonists. Describe the mechanism of the acute adverse effects of opioid receptor agonists.
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Opioid Agonists
- Drugs that act via the opioid receptors (mu, kappa, delta) - Morphine is prototype Acute Unwanted Effects - Undesirable, potentially deleterious effects of drug administration that may be o An extension of therapeutic action o Side effect o Related to toxicity or idiosyncratic reactions - “Acute” will, for the sake of this answer, be considered to be any effect occurring within approximately 24 hours following administration (does not include tolerance, dependence issues) Modifying Factors - Specific opioid receptor involved o Mu2 producing respiratory depression, bradycardia, inhibition of gut motility o Kappa producing sedation, meiosis and resp. depression - Specific opioid agonist and its unique spectrum of effects o Morphine producing histamine release o Pethidine toxicity via nor pethidine accumulation - Dose and rate of administration o Higher doses and more rapid administration typically lead to more acute complications as they are assoc. with higher peak concentrations of drug. - Route of administration o Intravenous administration is associated with rapid rises in plasma concentration o Complications related to the process of administration per se e.g. muscle haematoma from IM injection o Neuraxial opioids have unique and sometimes delayed side effects - Age of recipient and any pathophysiology o Elderly patients are typically susceptible to opioid effects and the therapeutic index is narrower o Pre-existing disease e.g. COPD may exacerbate consequences of respiratory depression Cardiovascular - Hypotension due to o Direct myocardial depression and venodilation o Secondary to histamine release (marked individual variability) o Baroreceptor response attenuated - Bradycardia through (effects more marked with fentanyl) o Vagal stimulation in the medulla and o Direct depressant effect on the sino-atrial node and o Slowing of AV conduction - CVS effects are typically exaggerated in presence of other depressant agents e.g. volatiles - Pethidine can cause o Tachycardia due to mild anticholinergic effects o Hypotension due to histamine and alpha 1 receptor blockade Respiratory Effects - All opioid agonists produce dose dependent depression of ventilation, primarily through agonist effect at mu2 receptors - Direct depressant effect on brainstem ventilation centres may lead to apnoea - Reduced response to hypercapnia reflected by an increase in the resting PaCO2 and displacement of the carbon dioxide response curve to the right - Response to hypoxia is less affected but administration of supplemental O2 may potentiate resp. depression - Pattern of respiration is typically with rate falling more than tidal volume. Pauses may occur between breaths due to interference with respiratory control centre. - “second peak” effect of resp. depression can occur after repeated doses of highly lipid soluble opioids such as fentanyl (lungs as store, possibly gut trapping ) - Neuraxial opioids can lead to phenomenon of delayed respiratory depression occurring greater than 2 hours after administration - Reflects a combination of cephalad migration and systemic absorption - Ciliary function is depressed - Loss of cough reflexes can reduce airway protection - Bronchoconstriction can occur due to direct effect on smooth muscle or secondary to histamine release Central Nervous System - Sedation may be an undesirable effect primarily mediated by kappa receptors - Euphoria (mu1) would be a desirable effect for most but increases the abuse potential - Dysphoria (kappa) occurs with increasing doses although is somewhat idiosyncratic Eye - Direct stimulation of the Edinger-Westphal nucleus leads to meiosis which can be undesirable in patients with head injuries in whom monitoring of pupil size is important - Pethidine can also cause corneal anaesthesia increasing the risk of eye trauma - Mydriasis with pethidine - Opioids (esp. sufentnil, alf and fent) may cause nystagmus Gastrointestinal Tract - Can produce spasm of smooth muscle leading to constipation, colic and delayed gastric emptying - Morphine decreases the peristaltic contractions and increases the tone of the pylorus, ileocecal valve and anal sphincter resulting in increased water absorption and constipation - Increased biliary pressure occurs as the gall bladder contracts against a narrowed sphincter of Oddi – may produce biliary colic Nausea and Vomiting - Direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle - Possibly due to partial dopamine agonism and stim of 5HT3 receptors - Increased GIT secretions and reduced gastric emptying may contribute - Morphine also depresses the vomiting centre in the medulla hence IV morphine causes LESS N&V than IM administration presumably because it reaches the medulla as rapidly as the CTZ Genitourinary - Increased tone and peristalsis of the ureter combined with increased detrusor muscle tone can contribute to urinary urgency - But, retention occurs due to increased vesical sphincter tone - ADH secretion is stimulated in the presence of painful stimulus – uncertain significance Pruritus - Generalised itching not associated with a rash or histamine release - Most marked with epidural and spinal administration of opioids - Paradoxically responds to antihistamines Cutaneous changes - Morphine causes cutaneous vessels to dilate - The skin of the face, chest, neck frequently becomes flushed and warm - Mostly attributable to histamine release - May contribute to loss of heat to the environment Endocrine - Morphine inhibits the release of ACTH, prolactin and gonadotrophic hormones - ADH secretion increased Skeletal Muscle - Truncal muscle rigidity can occur with high doses of opioids - Thought to be due to opioid receptor interaction with dopaminergic and GABA pathways in the substantia nigra - Can lead to impairment of mechanical ventilation - Myoclonus can occur that resembles seizure activity Fetal & Maternal Effects - Lipid soluble opioids can cross the placenta and lead to respiratory depression in the neonate - Pethidine crosses placenta readily and norpethidine accumulates in the foetus due to reduced clearance - Intrathecal and epidural morphine not used as it may lead to reactivation of herpes simplex virus Drug Interactions - Pethidine interacts with MAOIs via unclear mechanisms - Effects include coma, labile circulation, convulsions and hyperpyrexia Allergy - True allergy to opioids is rare but may occur |
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Pharm04-B4 Write short notes on tramadol. 50%
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General
* Centrally acting analgesic * Low affinity for µ receptors * 5-10 times less potent than morphine * analgesic effect reflected in its ability to inhibit noradrenalin and serotonin neuronal uptake * facilitates serotonin release * naloxone inhibits only 30% of its effects * chemical structure * synthetic 4-phenyl-piperidine analog of codiene * racemic mixture of 2 enantiomers * one inhibits noradrenalin uptake * other inhibits serotonin uptake and facilitates its release, also the µ effects * therefore the 2 isomers compliment each other Pharmacokinetics * Administration * Oral, IM or IV * Bioavailability about 70%, increases with subsequent doses, up to 100% * Dose 50-100mg every 4-6 hours max 400 mg * IV morphine is 1/10th as potent as morphine * Metabolism * Metabolised to by CYP2D6 to M1 (O-desmethyl tramadol), an active metabolite at opioid receptors. * ? may contribute to some of the analgesic effects * Proportion of population deficient in this enzyme, so may have reduced analgesia. Pharmacodynamics * Acts by acting at * the µ receptor * inhibits noradrenalin and serotonin uptake in the spinal chord, therefore activating spinal inhibitory pathways * Little respiratory depression than morphine, but still possible * Little sedation * Therefore not useful to prevent intraoperative awareness * High incidence of N&V * Less tolerance or addiction risk than morphine * agents, and other drugs that lower the seizure threshold * Minimal effects on GIT function * Tramadol may have direct LA effects on nerves * When added to regional local anaesthetic * provided a shorter onset of sensory block Adverse effects * Seizures esp if also on antidepressants * Esp MAOI, neuroleptic * Analgesic effects blocked by serotonin antagonists |
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Pharm-03A6 Explain how differences in the pharmacokinetics of alfentanil and fentanyl can influence the way they are administered intravenously. 51%
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Potency
Alfentanil is less lipid soluble than Fentanyl Hence Alfentanil is less potent (10-20%) than Fentanyl Onset of action and Timing of administration Effect-site equilibration Alfentanil: 1.4 mins Fentanyl: 6.8 mins Therefore Alfentanil has a more rapid onset of action than Fentanyl Due to low pKa (pKa Alfentanil 6.5 vs Fentanyl 8.4) ie nearly 90% of the drug exists in the non-ionized form at physiologic pH it is the non-ionized fraction that readily crosses the blood-brain barrier hence Alfentanil is useful to blunt response to a single brief stimulus eg tracheal intubation or performance of a retrobulbar block and should be given 1-2 mins before the stimulus Volume of distribution Alfentanil: 0.6 L/kg Fentanyl: 4.5 L/kg Volume of distribution of Alfentanil is 4 – 6 times smaller than Fentanyl Reflects lower lipid solubility (see octanol:H2O coefficient) ie less likely to store up in fat and muscle Protein-binding of alfentanil is greater Despite this lower lipid solubility, penetration of the BBB by Alfentanil is rapid because of its high degree of non-ionization at physiologic pH Time to peak effect Alfentanil reaches peak effect site concentration (hence peak effect) very shortly after bolus administration Also a rapid speed of offset because effect site concentrations begin to fall immediately after the rapid peak Fentanyl reaches peak effect slower than Alfentanil Duration of action Alfentanil has 1/3 the duration of action of Fentanyl (about 10 mins) because: Volume of distribution of Alfentanil is smaller than Fentanyl Fentanyl is long-acting because of distribution from the tissues back into the blood to be metabolised Clearance of Alfentanil is less than Fentanyl Hepatic extraction ratio of Alfentanil is 0.3-0.5 Hepatic extraction ratio of Fentanyl approaching 1.0 Fentanyl In small doses (1-2 μg/kg), its duration of action is short (about 30 mins)and there is rapid recovery In these conditions, plasma and CNS concentrations fall below an effective level during the rapid redistribution phase (due to its high lipid solubility) After multiple or large doses, the duration of action is significantly prolonged The distribution phase is complete while the plasma concentration of fentanyl is still high Recovery from the effects of the drug then depends on its elimination from the body Context-sensitive half-time As the duration of continuous infusion of Fentanyl increases beyond about 2 hours, the context-sensitive half time of Fentanyl becomes greater than Alfentanil This reflects Fentanyl’s larger VD Saturation of inactive tissue sites with fentanyl during prolonged infusions and return of opioid from peripheral compartments to the plasma This tissue reservoir of fentanyl replaces fentanyl eliminated by hepatic metabolism so as to slow the rate of decrease in the plasma concentration Alfentanil has a smaller VD The peripheral distribution of drug away from the plasma is not a significant contributor to the decrease in plasma concentration after discontinuation of alfentanil Dosing regimens Alfentanil may be administered either as: Bolus dose 1-2 minutes before the anticipated stimulus that is to be blunted (eg intubation) occurs Continuous infusion Loading dose of 25-50 μg/kg followed by infusion of 0.5-2.0 μg/kg/min eg as sole anaesthetic or for sedation in ICU pts Fentanyl Usually administered as a bolus dose 1-2 μg/kg for analgesia 50-150 μg/kg for sole anaesthetic agent (eg to attain cardiac stability during cardiac surgery) |
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Pharm-02B6 Write brief notes on tolerance and dependence in relation to opioid analgesics.
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Tolerance and dependence – with repeated administration - feature of all opioids - tolerance can occur without physical dependence - reverse seems not to occur
Tolerance - decreased receptor response to a given concentration of agonist, after repeated administration - decreased potency of agonist but maximum effect can still be attained - proportional to exposure - Propsed mechanisms include: - Down regulation of receptors – remains unproven - Up-regulation of cAMP system - Opioids inhibit adenylate cyclase (catalyzes synthesis of cAMP) - Long term opioid exposure → ↑synthesis of cAMP - Clearly demonstrated in locus ceruleus - NMDA receptor activation & increased glutamate - Prolonged exposure to opioids → activates NMDA receptors via 2nd messenger systems - Down regulation of spinal glutamate transporters → ↑synaptic glutamate concentration - ↑[glutamate] + activated NMDA receptors → tolerance & abnormal pain sensitivity - Uncoupling of receptor from intracellular messenger / reduced efficiency of this process (receptor desensitization) - Reduced affinity of receptor for agonist - Tolerance for a specific agonist – confined only to receptors agonist binds Affected by tolerance: - Analgesia - Euphoria - sedation - emesis - respiratory depression Less affected by tolerance: - Constipation - Miosis Cross tolerance develops between all opioids Dependence - characterised by ongoing reliance of dosing of a drug - Psychological – compulsive desire to use a drug even without dysphoric withdrawal symptoms - Physical – withdrawal of a drug produces unpleasant symptoms and signs - For morphine usually requires 25 days - Can occur sooner in emotionally unstable - Can occur more rapidly with frequent parenteral use – some degree of dependence after only 48 hours - Withdrawal abstinence syndrome - Initially yawning, diaphoresis, lacrimation, coryza - Insomnia, restlessness, dysphoria are prominent - Abdominal cramps, nausea, vomiting, diarrhoea - Peak 72 hours, decline over 7 to 10 days Onset (hours) Peak (hours) Duration (days) Morphine 6-18 36-72 7-10 Heroin 6-18 36-72 7-10 Fentanyl 2-6 8-12 4-5 Methadone 24-48 3-21 days 6-7 weeks Clinical significance - Tolerance and dependence seen in: - Chronic pain states – eg. on oral opiates - Prolonged acute pain states for which have received large doses of frequent parenteral opiates - Opiate abuse – eg. heroin/pethidine - These patients will require increased doses or peri-operative opiates for desired effects - Thankfully respiratory depression, sedation, euphoria also exhibit tolerance - Need to be weary of constipation – shows little tolerance - Sudden withdrawal (eg. during admission to hospital) will cause withdrawal abstinence syndrome - During withdrawal tolerance is rapidly lost – much decreased dose can terminate withdrawal symptoms |
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00A15 Describe the effects of opiods on the respiratory system.
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Mechanism of action
* effects of opiods are mediated by mu, kappa and delta receptors * Receptors are G-protein coupled * Majority of actions are at the Mu receptor: o Causes supra-spinal and spnal effects o Mu2 receptor is responsible for respiratory depression o Kappa and Delta receptors also contribute to respiratory depression o Direct brainstem depression Effects on ventilation: * dose dependent * decreased responsiveness to CO2 (? due to decreased ACh release from medullary neurons in response to CO2 stimulus) * increased CO2 -> cerebral vasodilation -> Raised Cerebral Blood Flow -> increased delivery of opioids to the brain. * interferes with pontne & medullary centres responsible for respiratory rhythm -> apnoea * Decreased frequency of breathing * Increased tidal volume * overall, decreased minute volume -> increased pCO2, decreased pO2, * CO2 response curve shifts right (higher pCO2 to get same respiratory response) * dose dependent decrease of ciliary function * truncal rigidity (makes ventilation more difficult) * cough suppression, eg. codeine * Resp. depression can lead to death, and is most common mode of opioid-related death (tolerance does not develop to respiratory depression) * sedation -> loss of airway reflexes * Therapeutic ratio is low: analgesic dose may be close to dose causing resp. depression. * Bronchospasm: o secondary to direct effects on bronchial smooth muscle. o Also secondary to effects of histamine release from mast cell degranulation. Confounding factors * sleep * old age * lack of CNS stimulus, eg. pain * other respiratory depressants, eg. Benzos, alcohol, anaesthetics, * hypothermia * route of administration: rapid IV bolus more likely to cause depression than IM Comparative pharmacology * pethidine causes more resp depression than morphine * fentanyl can cause depression and re-depression of respiration. o thought that fentanyl gets sequestered in gastric secretions, which are acidic, and trap the drug in ionised state. When it reches alkaline fluid in small intestine, it is reabsorbed -> re-sedation o also, sequetstered fentanyl in lungs during first pass is washed out as ventilation/perfusion relatiosnhips return to normal |
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Pharm-99A10 Write a brief outline on the pharmacology of remifentanil. 47%
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Introduction
Remifentanil is a relatively potent (15-20X as potent as alfentanil) selective μ opioid receptor agonist with a short duration of action Pharmaceutics A phenylpiperidine derivative, containing 2 ester bonds which is a weak base with a pKa of 7.1 Presented as a powder mixed with glycine, requiring reconstitution with water Pharmacokinetics Absorption Intravenous Rapid onset – effect-site equilibration time 1.1 min Distribution Predominantly ionised at body pH Moderately low lipid solubility compared to fentanyl 70% plasma protein-bound small distribution of volume (0.6L/kg) Metabolism/Biotransformation High clearance (40ml/kg/min) β elimination half life: about 10 mins Speed of offset due to clearance rather than distribution Short context sensitive half-life of about 4min, independent of the infusion time. Clearance is almost exclusively by hydrolysis of one of the ester bonds by "non specific" blood and tissue esterases (not by red cell esterase alone and not by "pseudocholinesterase") producing an almost inactive carboxylic acid derivative (i.e. non-cumulative effects) Another minor pathway of metabolism is by N-dealkylation in liver Excretion Inactive metabolites undergo renal excretion Pharmacodynamics Typical of a μ opioid receptor agonist CNS Analgesia and sedation depresses some brain stem regulatory centres (respiratory/cardiovascular), stimulate other centres causing: nausea pupillary constriction (action on Edinger-Westphal nucleus of oculomotor nerve) truncal rigidity (action on opioid receptors and interaction with dopaminergic and GABA responsive neurons) ICP and intraocular pressure are not changed CVS HR: Bradycardia secondary to effects on vagal nuclei and vasomotor centres Contractility: minimal direct effects on myocardium SVR: minimal direct effects on vasculature Decreased SVR secondary to effects on vagal nuclei and vasomotor centres normally no histamine release (cf. morphine) Resp decreased airway reflexes, (depression of ciliary activity) Resp Rate: decreased interferes with pontinine and medullary ventilatory centres that regulate rhythm, leading to prolonged pauses between breaths and periodic breathing apnoea at high doses Tidal volume: possibly compensatory increase Ventilatory response: decreased response to hypercapnia and hypoxia. GIT Increased tone in biliary tree, sphincter of Oddi, pyloric sphincter, ileocaecal valve, anal sphincter, ureter Decreased peristaltic contractions of GI smooth muscle, delay gastric emptying GUS Increased tone of ureter Clinical Use Indications Intraoperative analgesia of rapid onset/offset Neurosurgery in pt with raised intracranial pressure Blunt sympathetic response to direct laryngoscopy and tracheal intubation Rapid recovery to assess pt neurologically post-op ASAP Transient analgesic effect in performance of retrobulbar block Dose: optional preceding bolus of 1-2 microgm/kg. 0.1- 1.0 microgm/kg/min infusion precise and rapid titration to the desired effect is easily performed Need to make provision for postoperative analgesia before cessation of remifentanil Contraindications Spinal or epidural administration is not recommended because of neurotoxicity of glycine which acts as an inhibitory neurotransmitter Adverse effects Bradycardia and hypotension Truncal rigidity with high dose/rapid administration; "Neurotoxicity" due to glycine and immune mediated histamine release?? Nausea/vomiting and severe pain after cessation of administration in awake patients. Interactions Synergistic effect with hypnotics eg Midazolam |
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Pharm-98B11 Describe briefly the acute unwanted effects of the opioid agonist drugs 53%
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Opioid Agonists
- Drugs that act via the opioid receptors (mu, kappa, delta) - Morphine is prototype Acute Unwanted Effects Undesirable, potentially deleterious effects of drug administration that may be o An extension of therapeutic action o Side effect o Related to toxicity or idiosyncratic reactions “Acute” will, for the sake of this answer, be considered to be any effect occurring within approximately 24 hours following administration (does not include tolerance, dependence issues) Modifying Factors - Specific opioid receptor involved o Mu2 producing respiratory depression, bradycardia, inhibition of gut motility o Kappa producing sedation, meiosis and resp. depression - Specific opioid agonist and its unique spectrum of effects o Morphine producing histamine release o Pethidine toxicity via nor pethidine accumulation - Dose and rate of administration o Higher doses and more rapid administration typically lead to more acute complications as they are assoc. with higher peak concentrations of drug. - Route of administration o Intravenous administration is associated with rapid rises in plasma concentration o Complications related to the process of administration per se e.g. muscle haematoma from IM injection o Neuraxial opioids have unique and sometimes delayed side effects - Age of recipient and any pathophysiology o Elderly patients are typically susceptible to opioid effects and the therapeutic index is narrower o Pre-existing disease e.g. COPD may exacerbate consequences of respiratory depression Cardiovascular - Hypotension due to o Direct myocardial depression and venodilation o Secondary to histamine release (marked individual variability) o Baroreceptor response attenuated - Bradycardia through (effects more marked with fentanyl) o Vagal stimulation in the medulla and o Direct depressant effect on the sino-atrial node and o Slowing of AV conduction - CVS effects are typically exaggerated in presence of other depressant agents e.g. volatiles - Pethidine can cause o Tachycardia due to mild anticholinergic effects o Hypotension due to histamine and alpha 1 receptor blockade Respiratory Effects - All opioid agonists produce dose dependent depression of ventilation, primarily through agonist effect at mu2 receptors - Direct depressant effect on brainstem ventilation centres may lead to apnoea - Reduced response to hypercapnia reflected by an increase in the resting PaCO2 and displacement of the carbon dioxide response curve to the right - Response to hypoxia is less affected but administration of supplemental O2 may potentiate resp. depression - Pattern of respiration is typically with rate falling more than tidal volume. Pauses may occur between breaths due to interference with respiratory control centre. - “second peak” effect of resp. depression can occur after repeated doses of highly lipid soluble opioids such as fentanyl (lungs as store, possibly gut trapping ) - Neuraxial opioids can lead to phenomenon of delayed respiratory depression occurring greater than 2 hours after administration - Reflects a combination of cephalad migration and systemic absorption - Ciliary function is depressed - Loss of cough reflexes can reduce airway protection - Bronchoconstriction can occur due to direct effect on smooth muscle or secondary to histamine release Central Nervous System - Sedation may be an undesirable effect primarily mediated by kappa receptors - Euphoria (mu1) would be a desirable effect for most but increases the abuse potential - Dysphoria (kappa) occurs with increasing doses although is somewhat idiosyncratic Eye - Direct stimulation of the Edinger-Westphal nucleus leads to meiosis which can be undesirable in patients with head injuries in whom monitoring of pupil size is important - Pethidine can also cause corneal anaesthesia increasing the risk of eye trauma - Mydriasis with pethidine - Opioids (esp. sufentnil, alf and fent) may cause nystagmus Gastrointestinal Tract - Can produce spasm of smooth muscle leading to constipation, colic and delayed gastric emptying - Morphine decreases the peristaltic contractions and increases the tone of the pylorus, ileocecal valve and anal sphincter resulting in increased water absorption and constipation - Increased biliary pressure occurs as the gall bladder contracts against a narrowed sphincter of Oddi – may produce biliary colic Nausea and Vomiting - Direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle - Possibly due to partial dopamine agonism and stim of 5HT3 receptors - Increased GIT secretions and reduced gastric emptying may contribute - Morphine also depresses the vomiting centre in the medulla hence IV morphine causes LESS N&V than IM administration presumably because it reaches the medulla as rapidly as the CTZ Genitourinary - Increased tone and peristalsis of the ureter combined with increased detrusor muscle tone can contribute to urinary urgency - But, retention occurs due to increased vesical sphincter tone - ADH secretion is stimulated in the presence of painful stimulus – uncertain significance Pruritus - Generalised itching not associated with a rash or histamine release - Most marked with epidural and spinal administration of opioids - Paradoxically responds to antihistamines Cutaneous changes - Morphine causes cutaneous vessels to dilate - The skin of the face, chest, neck frequently becomes flushed and warm - Mostly attributable to histamine release - May contribute to loss of heat to the environment Endocrine - Morphine inhibits the release of ACTH, prolactin and gonadotrophic hormones - ADH secretion increased Skeletal Muscle - Truncal muscle rigidity can occur with high doses of opioids - Thought to be due to opioid receptor interaction with dopaminergic and GABA pathways in the substantia nigra - Can lead to impairment of mechanical ventilation - Myoclonus can occur that resembles seizure activity Fetal & Maternal Effects - Lipid soluble opioids can cross the placenta and lead to respiratory depression in the neonate - Pethidine crosses placenta readily and norpethidine accumulates in the foetus due to reduced clearance - Intrathecal and epidural morphine not used as it may lead to reactivation of herpes simplex virus Drug Interactions - Pethidine interacts with MAOIs via unclear mechanisms - Effects include coma, labile circulation, convulsions and hyperpyrexia Allergy - True allergy to opioids is rare but may occur |
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Briefly explain the factors which determine the duration of effect of intravenously administered bolus doses of fentanyl
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Briefly explain the factors which determine the duration of effect of intravenously administered bolus doses of fentanyl
Fentanyl is a synthetic phenylpiperidine μ opioid agonist It has a rapid onset of action due to its extremely high lipid solubility Duration of action is determined by its pharmacokinetic properties and dose. Factors that determine the duration of effect of IV Fentanyl: Redistribution half life t1/2 α = 3 mins determines offset of action and hence duration of smaller doses ie 1-2 mcg/kg duration of action 20-25 mins Volume of distribution VD 4 L/kg With high doses, ie as sole anaesthetic, 50-100 mcg/kg, tissue stores are saturated and offset of action is determined by clearance, Duration of action 4-6 hours Obesity increases VD (more fat depots), resulting in a longer elimination half life Elimination half life = 0.693 VD Clearance Clearance Clearance = 1 L/min t1/2 β = 3 – 4 hrs Hepatic extraction ratio approaches 1.0 Clearance determines offset of action when high doses saturate fat and muscle and provide a continued supply for distribution back into the central compartment In elderly patients, clearance will be reduced (due to decreases in hepatic blood flow, microsomal enzyume activity) and so effect is prolonged Context-sensitive half-time Context-sensitive half-time is the time necessary for the plasma drug concentration to decrease by 50% after ceasing a continuous infusion of a specific duration (context refers to the infusion duration) It considers the combined effects of Distribution Metabolism Duration of IV infusion It bears no constant relationship to the drug’s elimination half-time As the duration of continuous infusion of fentanyl increases beyond 2 hrs, the context-sensitive half time becomes greater. This reflects saturation of inactive tissue sites with fentanyl with prolonged infusions and return of the opioid from peripheral compartments to the plasma The tissue reservoir of fentanyl replaces fentanyl eliminated by hepatic metabolism so as to slow the rate of decrease in the plasma concentration of fentanyl when the infusion is ceased Pulmonary sequestration 75% first pass pulmonary uptake will provide a large inactive storage site for secondary release Secondary peaks in plasma concentration can occur after a bolus with possible prolongation/reoccurrence of effect. Possible mechanisms include: Sequestration into acidic gastric fluid where 99.9% Fentanyl is ionised then reabsorption occurs in the alkaline intestine Washout from pulmonary sequestration with post-op normalization of VQ relationships after a general anaesthetic |
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Pharm-96A11 Describe briefly the pharmacokinetics of pethidine. 60%
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Pharm-96A11 Describe briefly the pharmacokinetics of pethidine. 60%
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Describe briefly the mechanism of action of dantrolene. List its adverse effects and outline it’s uses in anaesthesia. 96A10
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Mechanism of action
• Produces skeletal muscle relaxation by blocking the electrical transmission from dihydropyridine receptor and ryanodine receptor, thus decrease the amount of calcium released from the sarcoplasmic reticulum thus prevent excitation contraction coupling. • No effect on neuromuscular transmission, nor does it have measurable effects on electrically excitable surface membrane Uses in Anaesthesia 1. Prophylaxis of anaesthetic induced Malignant hyperthermia 5mg/kg orally in 3 or 4 divided doses over 6 hours with last dose 4 hours pre-op or 2.4mg/kg IV over 30 minutes just before induction of anaesthesia and half the dose repeated in 6 hours Malignant hyperthermia – intrinsic abnormality of muscle tissue. It has been postulated that triggering agents induce a sudden rise in myoplasmic calcium either by accelerating the release of calcium by the sarcoplasmic reticulum or by preventing the reuptake of calcium back into the SR. The rise in myoplasmic calcium activates acute catabolic processes that lead to MH (hypermetabolism of skeletal muscle). Symptoms include tachycardia, tachypnoea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, fever, cyanosis and mottling of the skin. Dantrolene sodium may prevent the increase in myoplasmic calcium and the acute catabolism within the muscle cell by interfering with the release of calcium from SR to myoplasm. Thus the physiologic, metabolic and biochemical changes associated with the crisis may be reversed or attenuated. 2. Treatment of anaesthetic induced Malignant hyperthermia 2mg/kg IV with dose repeated until symptoms subside or cumulative dose of 10mg/kg IV is reached. NB: Dantrolene is not 100% effective, hence triggers for MH should be avoided even when dantrolene prophylaxis is used in susceptible individuals 3. Treatment of neuroleptic malignant syndrome (after chronic haloperidol, MAOI, lithium, phenothiazine) 4. Treatment of skeletal muscle spasticity due to upper motor neurone lesion or tetanus Dose: 100mg orally QID SE: skeletal muscle weakness which negates improvement in spasticity. Adverse effects 1. Available as 20mg sterile lyophilised powder, with 3g mannitol (to make solution isotonic), and NaOH to yield pH 9.5 when reconstituted with 60ml sterile water. Alkaline IV solution can cause phlebitis or tissue necrosis on extravasation Mannitol can cause osmotic diuresis therefore IDC is required 2. Skeletal muscle weakness – may be sufficient to interfere with adequate ventilation or protection of lungs from aspiration of gastric contents. Leg weakness, loss of grip strength 3. CNS - Blurred vision, drowsiness or dizziness 4. Resp – breathlessness, pleural effusion with chronic therapy 5. CVS – therapeutic doses have little or no effect on cardiac or smooth muscles 6. Uterine relaxation – can lead to uterine atony – increase risk of PPH 7. GIT – nausea diarrhoea Hepatitis in 0.5% of patients treated for > 60 days, fatal in 0.1-0.2% therefore monitor LFT 8. Hyperkalaemia 9. Anaphylaxis, urticaria, erythema Drug interactions 1. Increased risk of hyperkalaemia and VF in animal studies when given with verapamil 2. Potentiate vecuronium induced neuromuscular blockade |
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Briefly outline the acute management of malignant hyperthermia (during a relaxant general anaesthetic). Describe the important aspects of dantrolene pharmacology relevant to treating malignant hyperthermia.
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Equal marks were devoted to each half of the question. Inclusion of the following points would have scored a good pass mark.
Management: life-threatening emergency, call for help and dantrolene, cease triggers (e.g. volatile agents), hyperventilate with oxygen, maintain anaesthesia with non-triggering agents, give dantrolene 2.5 mg/kg, repeat up to 10 mg/kg, active cooling to <38 degrees. Pharmacology: skeletal muscle relaxant presented as orange powder containing dantolene 20 mg, mannitol 3g and sodium hydroxide to bring pH >9 with 60mls water. Difficult to mix. Metabolized by liver enzymes, eliminated in urine and bile with a half-life of about 10 hrs. Inhibits calcium release from sarcoplasmic reticulum. It can cause phlebitis, use of verapamil contraindicated. Most candidates who did not achieve a pass mark wrote very little on dantrolene pharmacology. Many candidates gave long, detailed accounts of the etiology and pathology of malignant hyperthermia but this was not asked in the question and attracted minimal bonus marks. |
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Pharm-07B4 A new clinical test called the "intubation score" has a reported 90% sensitivity and 70% specificity when used to predict difficult intubation. Describe how the accuracy, predictive value and clinical utility of this test can be evaluated. How will the incidence of difficult intubation affect the performance of this test?
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This predictive or screening test can be evaluated by using it on a sample of patients prior to intubation and then comparing the results of the test with the actual outcomes in a simple contingency table.
We must accurately define difficult intubation first eg >2 attempts by experienced anaesthetist or need for adjuncts Actual Difficult Intubation | Yes | No -------------------------------------------- Predicted Yes | True Positive (TP) | False Positive (FP) Difficult --------------------------------------------- Intubation No | False Negative (FN) | True Negative (TN) If a difficult intubation is predicted and is actually experienced then this is a true positive. If difficult intubation is predicted but intubation is not acutally difficult then this is a false positive. The sensitivity of the test is TP/(TP+FN) - gives proportion of actual difficult intubations that are accurately predicted The specificity of the test is TN/(TN+FP) - gives proportion of easy intubations that are accurately predicted The positive predictive value of the test is TP/(TP+FP) - gives proportion of positive results that are actually difficult intubations The negative predictive value of the test is TN/(TN+FN) - gives proportion of negative test results that are actually easy intubations The incidence of a condition is the number of individuals who develop a condition or number of new events that occur in a given time period. In this case it would be the number of difficult intubations that occur. As the incidence of a condition decreases, the proportion of positive results that will be false positives increases. This means that the positive predictive value will decrease, but the sensitivity and specificity will remain unchanged. Difficult intubation is a rare event, so this test will likely have a low positive predictive value despite its high sensitivity and specificity. Predicitive values are more useful that sensitivity and specificity because they take the population incidence into account and give us an idea of how our test result relates to the actual likelihood of difficult intubation. |
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Pharm-06A8 In a clinical trial, why is adequate power important? What factors affect the determination of an adequate sample size?
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Statistical Power:
- the probability of detecting an effect if there really is one. It is highly influenced by the size of the effect sought, and the size of the sample. It is important for clinical trials to have adequate power, because without it, finding no effect is meaningless. It could mean that there is in fact no effect, or that there is an effect and it was not detected. Power analysis allows sample size estimation- it allows estimation of how many patients will need to be studied in order to detect a difference between groups. It is more difficult to detect a small difference than a large difference, and therefore the investigator must decide what is a clinically significant difference. The simplest way to increase power in a study is to increase sample size, but power is not the only determinant of sample size. Errors: There are two types of errors which may be made when accepting or rejecting a hypothesis. * When the null hypothesis is rejected incorrectly, it is said to be a type I or alpha error. * When the null hypothesis is accepted incorrectly, it is said to be a type II or beta error. When designing a trial, the investigator sets a threshold for type I or alpha error - usually 0.05. The investigator also sets a threshold for the type II or beta error- usually between 0.05 and 0.20. The thresholds are different, because it is felt to be more serious to use a new drug on the basis of incorrect results, than to not use a new drug on the basis of incorrect results. Power is the probability of detecting an effect if there is actually an effect and it is equal to 1- beta. Therefore, the threshold set for beta error influences the power required for the trial. The higher the threshold for beta error, the more likely the null hypothesis is to be accepted, and the more power will be required to detect a difference. When designing a trial, two important questions are: 1. How large a sample is needed to allow statistical judgments that are accurate and reliable? 2. How likely is a statistical test able to detect effects of a given size in a particular situation? Sample size Sample size is important because if sample size is too small, the experiment will lack the precision to provide reliable answers to the questions being investigated. If sample size is too large, time and resources will be wasted for minimal gain. The difference between a sample mean and population mean is the sampling error. A larger sample size will decrease the sampling error. Factors which influence sample size are the values chosen for alpha and beta- a smaller alpha means a larger sample size, and a smaller beta means a larger sample size (esssentially, power). Other factors are the size of effect being sought, the number of study endpoints (rare events require larger sample size), measurement precision, and the variance in the underlying population. Sample size estimations assume a normal (Gaussian) distribution, and so if the study data are skewed or non-parametric, it is common to increase the sample size estimate by at least 10%. Currently, computer programs calculate sample size, and previously different formulas and nomograms were used. |
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Pharm-04B5 What are the strengths and weaknesses of the randomised controlled trial (RCT) study design? 49%
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RCT is the "gold standard" of clinical trial design.
It is a prospective trial that randomly allocates the subjects into the different treatment or control/placebo groups. The random allocation reduces bias and the effects of confounding variables. Strengths: * Prospective nature: can assign and administer Rx in a precise, controlled way (avoids different techniques). Size, funding, analysis all can be determined prior to starting. * Randomisation decreases selection bias and minimises confounders due to unequal distribution in a chosen population. * Mesurements, especially parametric data, can be precise, making it easier to make consistent observations. * Blinding is easier in RCTs, decreasing patient/observer bias, which improves trial credibility. * Controlling of group allocations enhances similarity of baseline features, so easier to form basis for statistical hypothesis. Having control group (no intervention) = more meaningful conclusions can be made RE: effects of Rx. Weaknesses: * Increased expense and time. * Difficult to organise/supervise if multiple sites. * Results may not always mimic real life situation or patient group. * Risk that treatments/subjects may involve invalid consent or unethical Rx. Also: * RCT = trial least exposed to bias. Randomisation balances known and unknown confounders. * Too specific a group or too stringent conditions may have high beta error (false negative). Especially if patients with medical conditions are excluded (less applicable to real-life patients). * Large, multi-centre RCTs tend to have greater applicability. |
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Pharm-03A5 Outline the important statistical issues in designing a study to compare the duration of analgesia of two drugs given for post-operative pain relief. 38%
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Examiner's report:
The principal points expected to pass would have included the following: * The setting of the study should be a randomised controlled clinical trial. * A statement defining the Null Hypothesis to answer the question raised, for example that the drug has no significant effect on post-operative duration of pain relief. * Discussion regarding the appropriate determination of sample size including power analysis and the setting of threshold for type one and two error. Power is only one of the issues in sample size estimation and a common mistake was to give too much emphasis to this point in candidate's answers. * The surgical procedure and anaesthetic technique must be standardised to reduce bias. * Other methods to reduce bias include blinding the person responsible for data collection. * The definitions of inclusion criteria for endpoints of analgesic effect are important and pain severity scores were mentioned by many candidates. Higher marks were given to answers which addressed which statistical test would be suitable and the reasons why it would be appropriate. The data may not be normally distributed so a non parametric test such as a Mann-Whitney U test might be preferred. Other tests were acceptable provided potential limitations were identified and data suitability was included. [edit] Comments The gold standard for a clinical trial is a randomised controlled trial, because it: * minimises bias and * minimises the effects of confounding variables. If possible, the trial should be double blinded to further reduce patient/observer bias. Sample data are estimates of population parameters. Sampling procedures (and inclusion criteria for the study) are therefore very important when selecting patients for study, so that they ultimately represent the population. The question should be defined, often as a hypothesis with a corresponding null hypothesis, eg H1- that the drug has a significant effect (eg 20% prolongation) on postoperative duration of pain relief; and H0- that the drug has no significant effect on postoperative duration of pain relief. The required power and sample size should be determined before starting the study. Thresholds for type one (alpha) and two (beta) error (usually 0.05 and 0.05-0.20) should be set as these will affect the sample size required. In addition, factors affecting sample size inclue variance in the population, the size of the effect sought, and the rarity of events being recorded. Power analysis is used to calculate the necessary sample size. A larger sample size will be required for small alpha and beta thresholds, a small effect, and for high variance. Surgical and anaesthetic technique should be standardised, to minimise confounding factors and bias. The primary endpoint of the study should be clearly defined, and the conditions in which it is to be measured and recorded, eg use of the same scale (eg VAS or pain score 1-10) in all patients to measure pain severity. When analysing the data, different statistical tests may be suitable. The choice of test depends on whether the sample fits a normal distributionn and on the type of data. For example, if the data is not normally distributed then a non parametric test such as a Mann-Whitney U test might be more suitable. |
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Pharm-01B16 Briefly describe correlation and simple linear regression, and explain their differences. What assumptions are common to both? 82%
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Key Points
- Correlation and regression are used to describe the relationship between two numerical variables - Correlation is a measure of association - Spearman rank order (rho) is a non-parametric version of the Pearson correlation coefficient - Regression is used for prediction - Main distinction between correlation and regression is the purpose of the analysis - Association between two variables does not imply causation Scatter Diagrams - Used to study two variables which are quantitative - Classically they are represented by a series of dots, each representing a pair of data (i.e. one x and one y co-ordinate for the two variables being studied) - Resulting graph is termed a scatter diagram - One variable is usually labelled the independent variable (x-axis) and the other the dependent variable (y-axis) Assumptions - The relationship between the independent and dependent variables is assumed to be linear - Data should be independent – each data point should represent a single observation from each patient. Multiple observations from each patient should not be analysed with simple correlation or regression analysis (tends to inflate value of “r”) - Assumes normal distribution of data Correlation - Attempts to describe the relationship or degree of association between two variables - Given as Pearson’s correlation coefficient (r) - Can have a value of between -1 and +1 o - or + 1 is a perfect correlation o 0.2 – 0.4 mild correlation o 0.4 – 0.7 moderate o 0.7 - 1.0 strong association o 0 is no association - Degree of uncertainty for value of r can be described by o the standard error of r and its 95% confidence interval o hypothesis testing (e.g. students t-test) gives a P value that determines if the correlation is significantly different to 0 o The coefficient of determination (r2 ) is an estimate of how much a change in one variable influences the other and therefore has clinical application - A partial correlation coefficient can also be determined: this is an adjusted r that takes into account a third variable (a covariate) - If multiple independent variables are used to describe a relationship with the dependent variable then a multiple correlation coefficient can be calculated (R) - Spearman Rank correlation (rho)used for o Non-parametric data o Small data sets (n<20) Regression - Analysis of data points on a scatter plot aiming to predict one variable from another - Describes a linear relationship between two numerical variables (e.g. body temp and VO2) - A line of best fit, called the regression line, can be drawn using the method of least squares o Where the perpendicular difference between each data point and the straight line (the residual) is squared and summed – the eventual line chosen is that with the smallest total sum - General formula is y = a + bx o A is the y intercept o b is the measure of the slope called the ‘regression coefficient’. It is NOT a measure of the strength of association - Uncertainty can be described by o The standard error of the slope (b) o 95% confidence interval can then be calculated using t table o (confidence intervals increase toward the extreme values hence the lines are curved) - Differences between the observed and predicted values are known as the residual. Residuals can be used to describe the ‘goodness of fit’ – i.e. how well the model predicts Non-linear Regression - Example is polyexponential curve of drug concentration vs. time - Modelling is done with computer to enable complex calculation - Quantal dose response curves are another example and need the use of probit or logit transformations Multivariate Regression - Used when there are several independent variables - No requirement for the independent variables to be normally distributed or even continuous -It is important to note that both correlation and regression do not indicate any causal relationships or any non-linear relationships. The assumptions common to both are: Both variables are normally distributed Both variables have a linear relationship That the relationship is only valid within the limits and cannot be extrapolated to values outside the limits Each value of Y (dependent variable) is independent of each other |
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Pharm-01A16 Describe the use of the null hypothesis and P-value in a drug trial 89%
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In a drug trial, the Null Hypothesis is the hypothesis that the drug has no effect compared with a control or other drug. Therefore it supposes that any difference seen between eg drug and placebo groups in a drug trial, is entirely due to chance. The Null Hypothesis is rejected or accepted on the basis of likelihood- it cannot be proved or disproved. Failure to reject the null hypothesis does not necessarily mean that the study groups are truly the same, only that a difference could not be detected. In logical terms, it is preferable to refute a hypothesis than to try to prove one. Therefore, many trials attempt to refute a Null Hypothesis (on the basis of probability). The alternative hypothesis is that the drug does cause some effect. If the Null hypothesis is rejected, the alternative hypothesis is generally accepted, even though it has not been proved. It is up to the researchers and readers to decide whether or not this is valid.
Probabilities are numbers ranging from 0 to 1.0, associated with the likelihood of events. A probability P(event)= 0 means that the event is impossible, and P(event) = 1.0 means that the event is certain. In a drug trial, the P-value indicates the likelihood that the result obtained (or a result more extreme) could have occurred randomly by chance, assuming that the null hypothesis is true. If P is less than an arbitrarily chosen value, known as or the significance level, then the null hypothesis is rejected. The value is often set at 0.05 (by convention) which means that there is a 5% probability that the result is due to chance. Rejecting the null hypothesis on the basis of a P-value of 0.05 will sometimes therefore be an incorrect rejection, and this is known as a type I (alpha) error. A type II (beta) error occurs when the null hypothesis is accepted incorrectly, and the probability of this occurring is termed . P-values are of use in a drug trial because they indicate the probability of the null hypothesis being correct. They are an indication of the statistical significance of the result. They do not give an indication of the magnitude of any observed differences and therefore no indication of the clinical significance of the result. Confidence intervals are often preferred when presenting results because they provide this additional information. |
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Pharm-99B9 What is meant by '95% confidence interval'? Explain the practical applications of confidence intervals and indicate why they may be preferred to P-values. 48%
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A Confidence Interval (=CI) is a range of values, the range having been selected to include a population parameter which is derived from a sample statistic. The 95% CI for any estimate gives a 95% probability that the true population parameter will be contained within that range. Alternatively, when used to describe outcomes in a clinical trial, Confidence Intervals give an indication of the magnitude of difference between the two groups. Confidence Intervals allow estimation of population parameters from sample statistics.
Confidence Intervals are derived from the Standard Error (SE). They define a range of values that are likely to include a population parameter, or the true difference between two study groups. The two ends of the range are called confidence limits. The width of the CI depends on the SE and the degree of confidence required (usually 95%, often 99%- but any % can be calculated). The range, 1.96 standard errors either side of the sample mean, has a 95% probability of including the population parameter (eg the mean) IN A LARGE SAMPLE SIZE. In a small sample size, the t distribution is applicable. The CI gives an estimate not only of the parameter itself, but also of precision. The wider the CI, the less precise the value derived from the sample. Confidence Intervals can be determined for not only the mean, but also proportion, median, risk ratios, and regression analyses. P-values are of use in a drug trial because they indicate the probability of the null hypothesis being correct. They are an indication of the statistical significance of the result- they do not, in comparison to confidence intervals, give any clinical information. They do not give an indication of the magnitude of any observed differences and therefore no indication of the clinical significance of the result. Confidence intervals are often preferred when presenting results because they provide information about statistical significance, and the accuracy of the sample estimates, and also the magnitude of effect. |
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Pharm-06A2 What is an isomer? Briefly write an account of the types of isomers and their significance in drugs used in anaesthesia.
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Isomers are compounds with the same molcular formula but different arrangement of the atoms
2 categories: structural and stereoisomers Structural Isomers • same molecular formula, but atoms arranged differently • may result in similar actions eg. isoflurane & enflurane • total dissimilar actions dihydrocodiene and dobutamine • pharmacokinetic and dynamics not neccesarily similar • Tautomerism : compounds that change structure depending on environmental mileau : pH, temperature • A subdivision of structural isomerism is dynamic isomerism (tautomerism) o Midazalam : ionized at pH4, but at pH 7.4 unionized ring opens which is lipid soluable and able to cross BBB Stereoisomerism • same chemical composition and chemical structure but arranged differently in space (ei 3D configuration) • atoms occupy different spatial arrangement • similar chemical properties, but different potencies, and other pharmacodynamic effects • 2 classes : Geometric and Optical • Geometric : described orientation of functional groups within the molecule o Eg atracurium : cis atracurium (but may others as well) o Eg mivacurium : trans-trans 58%, cis-trans 36%, cis cis 6% • Optical : same in everyway except being non-superposable mirror images • 3 different nomenclature systems: o optical rotation dextro (d) or levo (l), depending on direction of rotation of polarised light transmission o simple sugar spatial configuration D or L isomers, depending on configuration of D-glyceraldehyde NOT the same as d & l o absolute configuration describing drugs or other molecules international standard rules defining absolute configuration as right/rectus (R) or left/sinister (S) Stereoisomers usually separated into 2 groups: enantiomers & diastereomers. Enantiomers • Isomers that are mirror images of each other • Example: halothane (mix of R & S isomers) • Occurs due to chirality • Chiral centre is an atom with asymmetrical bonds Diastereomers • NOT simple mirror images • Arises when a drug has >1 chiral centre (so more rotational combinations are possible), also when cis & trans occur. • Example: methohexitone; atracurium (a mix of 10 isomers). Summary & relevance to anaesthesia • numerous nomenclature systems, NOT interchangeable • isomer may have different pharmacodynamic & pharmacokinetic properties • also may have diferent side efects (thalidomide was 2 isomers) • May have different physicochemical characteristics Examples • S(+) isomer of ketamine more potent than R(-) form • Bupivacaine: levo vs dextro o different pharmacokinetics o cardiotoxicity believed due mainly to dextro form • atracurium: cis vs trans o cisatracurium has less histamine-releasing potential than trans. |
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Pharm-03A4 Outline the potential problems associated with additives used to make medicines suitable for intravenous injection. 43%
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Addtives used to
1. solublize 2. pH modification 3. surfactant/emulsify 4. antioxidant, antimicrobial Problems Anaphylaxis - cremaphor Pain on injection - propylene glycol Thrombophelitis - glycerol Drug interactions -preciptation - thiopentonal -destruction - RBC |
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Pharm-00B15 Write brief notes on latex allergy 44%
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Introduction
- Latex is the name given to the sap of the rubber plant (Hevea brasiliensis) that is utilised in the manufacture of numerous medical products including: o Gloves o Tourniquets o Vial stoppers o Ventilator bellows o Elastic dressings o Urinary catheters - Allergy is common amongst healthcare workers and patients who are subject to repeated contact with latex e.g. spina bifida patients requiring catheterisation, surgeons using latex gloves - Increased in incidence since introduction of blood-borne pathogen standards to prevent transmission of HIV etc. - Those displaying atopic tendency are at increased risk - Estimated prevalence amongst healthcare workers is 5 – 17% - Incidence of latex allergy in children estimated at 1 in 10,000 - Frequently reactions to latex are confused with other administered drugs because the onset of symptoms may be delayed several hours from the time of exposure - Cross sensitivity to kiwi fruits and bananas Basic Immunology - Most serious latex allergy reactions are type 1 responses although some cases of contact dermatitis may be due to type 4 sensitivity Type 1 Hypersensitivity - Involves binding of allergens to IgE bound through its Fc segment to a mast cell - Cross linking and clustering of IgE receptors leads to release from the granules of mediators including histamine, leukotrienes, platelet activating factor and inflammatory mediators (including IL 3, IL-4, IL-5 and IL10) . This cross linking is important in precipitating anaphylactic responses - Occurs within 30 minutes but can occur immediately - Requires that an individual has had a previous exposure and the immune system is then ‘primed’ - Strong genetic susceptibility exists for Type 1 reactions and high levels of IgE are noted in atopic families. Type 4 Hypersensitivity - Delayed contact dermatitis type reactions. Onset typically 6 – 48 hours. - May be due to chemicals used in production of latex as well as latex itself. E.g. vulcanising agents and accelerators (thiurams) or antioxidants - Based on the interaction of antigen with primed T-cells and represents tissue damage resulting from inappropriate cell-mediated immunity reactions. - Soluble cytokines are released including IFN gamma which activate macrophages Irritant Dermatitis - Non immune mediated e.g. mechanical abrasion, pre-existing eczema, climate extremes Pathophysiology - Severity of reactions varies from local irritation to life threatening anaphylaxis - Acute reactions may present with: o Skin rashes, itching or redness o Nasal symptoms and coughing o Shortness of breath due to bronchiolar constriction o Anaphylaxis involving acute respiratory distress, circulatory collapse and angioedema Management of anaphylaxis - Discontinuation of contact or administration - Administration of 100% oxygen - Respiratory support considering intubation - Circulatory support including fluid administration and adrenaline (0.01 – 0.5mg/kgIV) - Attenuating the inflammatory response e.g. Hydrocortisone Investigations - Patch Test- drop of glove extract or piece of glove placed on the forearm and the reaction is checked in a specified length of time - RAST (radioallergosorbent test) measuring allergen specific levels of serum IgE. Reported to have 80% sensitivity and 100% specificity in non-atopic individuals - Skin-prick tests. Sensitivity is assessed by the response to intradermal challenge with antigen. The local release of histamine produces a wheal and flare reaction at the site. The immediate reaction usually subsides in 30 minutes and there may be a delayed reaction up to 24hours later mediated by cytokine release. Positive and negative controls are used (histamine and normal saline) - Mast Cell Tryptase within 1 – 4 hours after reaction. Clotted sample Prevention and Therapy - Allergen avoidance o Using latex free products in surgery - Modulation of immunologic response o Desensitisation programs may be useful - Mast cell stabilisation o Administration of sodium cromoglycate renders mast cells resistant to triggering - Mediator antagonism o Leukotriene antagonists, β2 agonists for broncho constriction etc - Pharmacological prophylaxis o Controversial administration of H1 and H2 antagonists and steroids may provide some protection. |
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Pharm-99B15 Briefly describe the preparation of oxygen for medical use. List the physical properties of oxygen. Outline the potential adverse effects associated with its medical use. 50%
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Preparation
Commercially by Fractional distillation of liquid air. -Free air is taken from the atmosphere -Compressed and passed through various filters and sieve to remove moisture, trace oils and CO2 -Air is compressed to 5 atmospheres and cooled to -181oC using reverse heat exchangers. -A two-stage distillation process yields 99.5% O2 (and 0.4% argon). -It is stored at 137 bar Other methods -Absorption of nitrogen by "artificial zeolite". Used for home use and remote locations. Physical properties Properties Colourless odourless gas Supports combustion. Molecular weight 32. Critical temperature - 119°C. Boiling point -182°C Melting point -218° Critical temperature -119°C Critical pressure 50 bar Potential adverse effects -Acute pulmonary toxicity -absorption atelectasis -decreased hypoxic respiratory drive in patients with hypercarbic respiratory failure -retrolental fibroplasia -hyperbaric effects including convulsions and pulmonary toxicity. |
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Pharm-92A1 Discuss the factors which influence the administration and dosage of drugs in the elderly.
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Pharmaceutics
• May have trouble reading labels, opening bottles, remembering whether drugs have been taken or not • May not be able to pay for high cost of drugs (eg gabapentin) • May have decreased compliance • More likely to be on more than one drug Physiology - CVS - Lower CO = slow circulation time = slower onset drugs (easy overdose). - Impaired baroreceptor reflexes and impaired B-adrenergic response (chronic high NA levels = receptor down-regulation) = poor response to hypotension (volatiles). - Resp - Multifactorial. - But, essentially decreased respiratory mechanics + decreased response to hypoxia and hypercapnoeia = worse with respiratory depressant drugs (opioids). - CNS - Increased sensitivity to CNS depressants (decreased neuronal mass) = lower doses. - Body compartments - Decreased TBW = proportionally more fat for drug absorption (diazepam, thiopentone). - Reduction in plasma proteins = more free drug. Pharmacokinetics • Linear decrease in cardiac, renal and respiratory function beginning at age 45 with large inter-individual variation Absorption • Reduced gastric emptying and bowel motility Distribution • Reduced lean body mass, reduced total body water, proportionate increase in fat • Reduced albumin, possible increase in α1 acid glycoprotein • Need to decrease loading dose esp. for acidic drugs Metabolism • Reduced phase 1 reactions • Reduced liver blood flow (esp. affects drugs with high extraction ratios) • Exacerbated by CCF (decreases metabolism and reduces liver blood flow) Elimination • Reduced renal clearance- requires dose reduction in renally excreted drugs • GFR decrease by 1-1.5% per year from the age of 30 • Increased V/Q mismatch and increased closing capacity has implications for inhalational anaesthesia Pharmacodynamics • Decreased responsiveness to β-blockers • Decreased baroreceptor function results in a propensity for orthostatic hypotension esp. when vasodilators are administered • Increased susceptibility to effects of anaesthetics/sedative-hypnotics ↓MAC • Increased susceptibility to the respiratory depressant effects of opioids • Other drugs may exhibit little pharmacodynamic differences esp. when the pharmacokinetic changes and the possible presence of active metabolites are taken into account. |
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Pharm-97A16 Discuss the possible effect of volatile inhalational agents on the liver
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Hepatic Blood Flow
• In general these agents reduce hepatic blood flow. • Halothane decreases both portal venous and hepatic arterial flow (results in increased susceptibility to the toxicity of this agent) • Isoflurane decreases hepatic portal venous flow but there is some increase in hepatic arterial flow (autoregulation) to compensate Drug Clearance • Decreased phase 1 oxidation • Decreased blood flow results in decreased clearance of drugs with a high hepatic extraction ratio Hepatotoxicity • Predisposing factors: liver disease incl viral hepatitis, septicaemia, severe burns, nutritional deficiency Halothane Self limited increase in LFTs • Occurs in 20% • Associated nausea and lethargy • May be related to the effects of reduced hepatic blood flow Halothane hepatitis • Incidence is 1:30000, less in children, increased incidence with previous halothane administration • If the microsomal enzymes associated with oxidative metabolism have been induced by administration of other drugs or by repeated exposure to halothane then the incidence is higher • Manifestations are fever, rash, peripheral eosinophilia • Halothane is oxidatively metabolised to a reactive trifluoroacetyl substance which is unstable and can bind covalently with certain proteins found in the endoplasmic reticulum. • These modified proteins can be expressed on the cell surface. • Antibodies are formed to these modified proteins which can cross react with endogenous substances- this immune mediated mechanism is thought to be the basis for the hepatic necrosis • Metabolism of enflurane (2%), isoflurane(0.2%) and desflurane can also produce this reactive intermediary in proportion to their degree of metabolism (only one case report or hepatotoxicity for desflurane in a patient who previously had halothane x 2) Chloroform • Manifestations are fatty infiltration, centrilobular necrosis, and elevated transaminase values • Can be delayed up to 24-48 hours after exposure • May be directly toxic • Has highly reactive metabolites CCl2 CCl3 which can also cause tissue damage |
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Pharm-96A9 Describe briefly the central nervous system effects of isoflurane
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Most important effects are those of general anaesthesia and potent analgesia at low doses. Others include:
1. EEG changes - no seizure activity on EEG and increased convulsion threshold * <0.4 MAC - increased frequency and voltage on EEG * 0.4 MAC - shift from posterior to anterior, decrease in cerebral metabolic requirements * 0.5 - 1 MAC - decreased frequency increased voltage * 1.5 MAC burst supression * 2.0 MAC can cause isolelectric EEG 2. Decreased cerebral metabolic rate and oxygen demand * starts at 0.4 MAC Isoflurane has the greatest decrease compared with others. 3. Increased CBF secondary to vasodilation (dose related). * occurs at >0.6 MAC * autoregulation is maintained at 1.0 MAC, but above this it is dose dependent. * increase is less than others 4. Increased ICP parallels increased CBF * maintains CO2 reactivity of vessels (unlike halothane or sevoflurane) * least increase in ICP therefore ideal for neurosurgery 5. Evoked potentials - dose related decreased amplitude increased latency 6. Altered CNS/respiratory response to hypoxia and hypercarbia 7. Production of CSF - normal CSF production, increased reabsorption |
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Pharm-96A12 Define MAC and outline the factors which influence it. Briefly explain MAC-hour, MAC-awake, MAC-bar and the applications of these terms 76%
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MAC = minimal alveolar concentration of anaesthetic agent that prevents movement in 50% of subjects when exposed to standardised surgical stimulus (skin incision).
All MAC figures are based on the assumption that there are no other drugs present. * o Factors decreasing MAC: * Age Peaks at 6 months, then declines. * Temperature: hypothermia * Pregnancy * Sodium Low Na = less MAC * Acute alcohol use * other drugs: opioids, clonidine, beta blockers, dexmedetomidine... * o Increasing MAC: Chronic alcohol use MAC-Hour: MAC x hours. If volatile given at 1.5 Mac for 2 hours = 3 Mac hours. If the volatile is very lipid soluble (eg. Halothane, B:G coefficient 225), then a large amount will be absorbed, and this prolongs recovery time. MAC-awake:concentration at which 50% of subjects will open eyes to verbal stimulus. About 0.3-0.5 MAC. Thought to be related to awareness, but this is disputed. MAC-BAR("Blocks Adrenergic Response"): concentration at which increase in BP/heart rate is absent in 50% of subjects during skin incision. Usually about 1.5 Mac. |
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Pharm-08A3 Describe the ideal pharmacokinetic and pharmacodynamic properties of agents used for sedation. Outline the pharmacology of midazolam and propofol with reference to these ideal properties.
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66% of candidates passed this question.
The main points expected for a pass included a description of the ideal pharmacokinetic and pharmacodynamic features of an agent specifically suited to the clinical situation of providing sedation. Therefore, pharmacokinetic features that result in a rapid onset and offset of effect with boluses or infusion is ideal. Also the effects of anxiolysis, amnesia and arousable sedation were considered desirable, with low propensity to inadvertently progress to general anaesthesia. A discussion about other ideal features such as analgesia and stable cardio-respiratory effects of the sedation agents were also expected. An outline of how midazolam and propofol fitted this ideal agent's features was also required. Extra marks were awarded for an opinion comparing the suitability of midazolam and propofol suitability [sic] for the provision of sedation, based upon the profiles generated above. A common error was to include pharmaceutic information that was not required, and factual pharmacokinetic information about each drug was given little credit when not applied to how it affected the agents profile with reference to the ideal agent. |
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Pharm-07A7 Describe the pharmacology of midazolam including its mechanism of action. 66%
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Better answers were well organized and outlined the important aspects of midazolam pharmacology including:
* Pharmaceutics, pH dependent “ring opening”, ampoule pH * Pharmacokinetics, administration, oral bio-availability, high lipid solubility and moderately fast onset, moderate hepatic clearance 7 mls/kg/min approx (cf diazepam), active metabolite, offset dependent on re-distribution and clearance, relatively short elimination half life * Mechanism of action (MOA), benzodiazepine receptor on alpha subunit of GABAa receptor, enhanced action of GABA, increased chloride entry and neuronal hyper-polarization * CNS effects, sedation, hypnosis, anxiolysis, amnesia, anti-convulsant, muscle relaxant * CVS effects, hypotension, vaso-dilatation Respiratory effects, respiratory depression, potential airway obstruction, hypoxemia, interaction with opioids * Clinical uses, pre-medication, sedation, induction agent, anti-convulsant, antagonized by flumazenil. Extra marks were awarded for an outline of; kinetics of offset including context sensitive half time, metabolism and excretion including CYP 3A4 and accumulation of metabolites, the GABA receptor and alpha sub-unit selectivity, effects on cerebral blood flow, oxygen requirements and the EEG, factors potentiating CVS and respiratory effects, dosages for particular clinical applications and clinically important structure activity. Common errors included; not mentioning MOA, describing MOA as direct activation of GABA receptor, describing NMDA or cyclic AMP effects, frequent citing of very inaccurate kinetic data with no mention of clinical implications and frequent omission of adverse effects. |
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Briefly describe the CNS effects of Volatile Inhalational Anaesthetics
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1. Induction and maintenance of Anaesthesia
• Mechanism is not completely understood. • It was previously thought a lipid site (ie membrane lipid bilayer) is likely since OGPC correlate well with potency = Myer Overton rule. • Cell membrane expansion hypothesis leading to compression of ion channels, hence reduced ion flux was the other old theory • Now, recent evidence suggests that GABAa receptor is a possible target for VIA GABA mediated effect is to cause increase Cl- influx cell hyperpolarisation and inhibition 2. Amnesia – at 0.4 MAC 3. CMRO2 • Dose dependent decrease in CMRO2 (greatest with isoflurane than equivalent MAC of halothane) down to isoelectric line at 2 MAC (except enflurane), which indicates CMRO2 decreased down to 55% • When EEG is isoelectric, additional concentration of volatiles does not produce further reduction in CMRO2 • Reduced CMRO2 -> reduced CO2 produced -> reduced vasodilatation, esp with isoflurane, thus minimize the rise in CBV and ICP 4. CBF • >0.6 MAC - cerebral vasodilatation (direct effect) -> reduced cerebrovasc resistance -> increase CBF -> increase ICP (worst with halothane, least with isoflurane) • Isoflurane/Des – preservation of reactivity to CO2 • Autoregulation of CBF in response to changes in MAP is retained with 1 MAC of isoflurane/Des/sevoflurane, but not halothane • Isoflurane posses greater capability to maintain global CBF relative to CMRO2 cf halothane and sevoflurane 5. Uncoupling of CMRO2 and CBF (worse with halothane, better with isoflurane) 6. Cerebral protection Isoflurane offers better global O2 supply demand balance than halothane, hence offers cerebral protection during induced controlled hypotension (eg clipping of cerebral aneurysm) 7. CSF • Enflurane increase rate of production, increase resistance to absorption -> increase ICP • Isoflurane does not alter production, reduce resistance to reabsorption, minimal changes in ICP 8. ICP • Increase ICP that parallels increase CBF • Hyperventilation to pCO2 < 30mmHg opposes the tendency of volatiles to increase ICP • (NB – enflurane has increase risk of seizure with low pCO2, seizure causes increase CMRO2, increase pCO2 -> vasodilation -> increase CBF -> increase ICP 9. EEG • MAC 0.4 – shift of high voltage activity from anterior to posterior portions of the brain • MAC 1 – EEG frequency drops, maximum voltage occurs • Isoflurane – burst suppression at 1.5 MAC, electrical silence at 2 MAC • Electrical silence does not occur with enflurane, and only at unacceptably high levels of halothane 10. Seizure activity • Enflurane produce seizure like EEG activity, which may be accompanied by tonic clonic twitching of skeletal muscle in the face and extremities, esp with >2MAC or with hyperventilation (pCO2<30mmHg), or with repetitive auditory stimuli • Isoflurane/Des/Sevoflurane – do not evoke seizure activity on EEG (can even suppress seizure activity) 11. Evoked potentials • Dose related decreased amplitude, and increase latency of cortical component of median somatosensory, visual, and auditory evoked potentials 12. Nausea and vomiting 13. Central respiratory centre depression leading to • decreased tidal volume leading to decreased minute ventilation and increase pCO2 (despite increase RR) • decrease ventilatory response to increase pCO2 • decrease response to hypoxia (via carotid body) 14. Halothane decrease central sympathetic outflow -> decrease HR, contractility and CO -> reduced BP (N2O increase central SNS outflow -> increase HR, SVR, BP) |
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Briefly describe the adverse effects of nitrious oxide.
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Nitrous Oxide
- N20 widely used alongside inhalational agents o MW 44 o Boiling Point -88 o SVP 5,200 o Container French blue cylinders 1kg = 542L o MAC 105% o Blood: Gas 0.47 o Oil: Gas 1.4 Potential Impurities - Manufactured by heating ammonium nitrate to 250°C - NH4NO3 N2O + 2H2O - Unless temperature controlled precisely may contain the following impurities with potential for adverse effects o NH3 o N2 o NO o NO2 o HNO3 Expansion of Closed Gas Spaces - Blood: gas coefficient of 0.47 is 34 times that of Nitrogen (0.014) - N2O can therefore leave the blood to enter an air filled cavity 34 times more rapidly than N2 can leave the cavity to enter blood - End result is an increase in volume or pressure of the air filled cavity with potentially adverse outcomes - Examples of compliant spaces: o Pneumothorax volume will double in 10 minutes with inhalation of 75% N2O o Air bubbles o Pulmonary blebs o Intestinal gas (questionable clinical significance) - Non compliant spaces o Middle ear – causing pain, nausea and vomiting if Eustachian tube blocked o Cerebral ventricles o Supratentorial space (note: N2O at 50% has no effect on the incidence or severity of venous air embolism) Diffusion Hypoxia - Occurs when inhalation of N2O is discontinued abruptly leading to a reversal of partial pressure gradients such that nitrous oxide leaves the blood to enter the alveolus - Poor solubility in blood means the nitrous pours into the alveoli faster than nitrogen can replace it in the blood - Dilution of alveolar contents occurs reducing PAO2 and then PaO2 causing hypoxia - In addition, dilution of PACO2 reduces stimulus to breathe compounding the problem Interference with DNA synthesis - Cobalt ion present in Vitamin B12 is oxidised by N2O so that it can no longer act as a co-factor for methionine synthase - N2O also directly inhibits methionine synthetase - Leads to reduced methionine, thymidine, tetrahydrofolate and DNA - Exposure of a few hours may result in megaloblastic changes in the bone marrow - Exposure of days may result in agranulocytosis - Long term exposure may result in neurological syndromes that resemble subacute combined degeneration of the cord due to chronic inactivation of B12 - No effect in scavenged environment with conc. < 50ppm - Recovery may be speeded by administration of folinic acid (alternative source of THF) - N2O has been shown to be teratogenic in rats – typically avoided in the first trimester of pregnancy Post operative Nausea and Vomiting - Administration of N2O is associated with increased incidence of PONV - Effect may in part be due to middle ear space changes and GIT distension - Possibly direct effect on chemoreceptor trigger zone Increased Cerebral Blood Flow - Increases in CBF may lead to undesirable increases in ICP - Usually avoided in neurosurgical cases Unexpected anaesthesia - Despite having a MAC of 105% its potential to cause anaesthesia in certain patients should not be ignored Cardiovascular Effects - Mild direct myocardial depressant effect usually offset by slight increase in sympathetic outflow - Depressant effect may be significant in patients with limited cardiac reserve Pulmonary Hypertension - Produces an increase in pulmonary vascular resistance that is exaggerated in patients with pre-existing pulmonary hypertension - Neonates are uniquely vulnerable to these effects - Patients with congenital heart defects may increase the right to left intracardiac shunting of blood jeopardising arterial oxygenation Combustion - Whilst not being flammable, N2O will support combustion |
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Pharm-09A5 Outline the effects of an opioid injected into the spinal intrathecal space.
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Opioids are drugs which have morphine like activity, bind and activate opiod receptors.
Intrathecal space is subarachnoid space, CSF bathing the spinal cord in the spinal canal. Medications injected into this space bypass the BBB. Common opioids injected into the intrathecal space include -morphine : 5-15ug/kg -fentynal : typically 15ug -sufentinal (not available in Australia) -often in combination with local anaesthetic drugs. Local Effects -Mu receptors are located in the substantia gelatinosa of the spinal cord (dorsal horn) -MuR: Gi protein linked, inhibit AD, decreased cAMP, decrease Na conductance, increased K conductance, overall : hyperpolarize neurons, decrease excitation and AP propagation. -mu1 produces analgesia -mu receptors located on C fibres, therefore analgesia for visceral pain, better than somatic pain (A delta transmission) -bypassed BBB, direct effect site delivery, lower dose, -urinary retention : mainly young males, more common than IV or IM admistration, inhibit parasympathetic outflow and detrusor muscle relaxation High centres in subarachnoid space -movement of opiod via bullk flow of CSF cephalid -depends on lipid solubility : -fentynal very lipid soluble hence redistributed into epidural fat and taken up by epidural veins, rarely reaches high centres -Morphine least soluble, therefore remains in CSF, lumbar delivery will reach cisterna magna in 1-2 hours and 4th ventricle in 3-6 hours. Coughing and straining can increase speed of migration. -mu2 receptor activation : respiratory depression, results in delayed onset of respiratory depression, up to 24 hours post delivery. -pruitis : common, localised to face, neck and upper thorax, more likely in term woman, is not associated with histamine release, migration of opioid to trigeminal nucleus, responsive to naloxone System Absorption -epidural space contains extensive network of venous plexus -lipid soluble -fentynal : peak plasma concentrations in 5-10 minutes -systemic effects of opoid administration : respiratory depression -addition of adrenaline into intrathecal space does not change systemic absorption, however activation of alpha 2 adrenoceptors produces additional analgesia Other Effects -viral reactivation : occur 2-5 days post delivery, herpes labialis (cold sores) |
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Pharm-07B3 Outline the important pharmacological considerations concerning choice of opioid and dosage when converting from intravenous morphine to oral opioid analgesia in the post operative period.
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48% of candidates passed this question.
The question asked about the science behind our choice and dosage of oral opioids. The other information in the question was that the patient had been on intravenous morphine in the post-operative setting. Good answers covered the rationale of what drugs we use, how and when we use them and why. Patient factors included the fact that acute pain is usually diminishing, the importance of the oral route and gut function returning, patient illness, type of surgery, age and previous opioid use. Dosage of the drugs can be calculated from intravenous morphine requirements in the previous period, usually using a prn (as required) dosing schedule and erring on a lower conversion dose and longer dosing interval for safety. Use of adjuvant drugs such as paracetamol and NSAIDs reduces the dose of opioid and use of sedative drugs increases the risk of side effects such as respiratory depression. Many candidates answered the question using a template; Pharmaceutics / Pharmacokinetics / Pharmacodynamics. In many cases it was possible to change the word "opioid" to any other drug and still have a correct statement. However, if this did not answer the question, no marks were awarded. |
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Pharm-06A7 Briefly outline the pharmacology of naloxone.
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Naloxone is a competitive opioid receptor antagonist, used to reverse unwanted effects of opioid receptor agonists, including respiratory depression, hypotension, sedation and pruritis. Has also been used in animal studies to reverse hypotension 2 to hypovolaemic/septic shock.
[edit] Pharmaceutics * substituted oxymorphone derivative: the tertiary amine methyl group of oxymorphone is substituted with an alkyl group, giving antagonist activity * OH group at the 3-carbon atom is retained. * pure mu, kappa and delta opioid receptor antagonist (competitive antagonism). * presented as clear solution for IV/IM injection, containing 20mcg/ml or 400mcg/ml naloxone hydrochloride. [edit] Pharmacokinetics absorption: oral: high absorption from the GIT (90%) but subject to high first pass metabolism- therefore not used orally (as opposed to naltrexone). IV: administered incrementally. 100 to 200mcg generally required for reversal of respiratory depression. Acts within 2 minutes when given IV. offset of effect may be within 45 minutes, and may necessitate continuous infusion (eg 5mcg/kg/hr) of naloxone if the opioid being reversed has a longer duration of action. IM/SC: onset of effect slower than IV but sometimes used in doses from 400mcg to 2mg. distribution: 46% protein-bound. Vd 2 litres/kg. highly lipid soluble. metabolism: hepatic, conjugated to glucuronide form, naloxone-3-glucuronide. excretion: clearance is 25ml/min/kg. elimination half time 60-90 min. [edit] Pharmacodynamics CNS: rapid reversal of opioid effects incl respiratory depression and sedation. also antagonises analgesic effects of opioid agonists. drowsiness at high doses. decreases pain threshold and antagonises placebo effect. CVS: increased SNS activity (?2 to sudden increase in pain) -> increased HR, BP, pulmonary oedema at high doses. Has reportedly been associated w cardiac dysrhythmias. has been used in animal studies to reverse hypotension of septic/hypovolaemic shock. GIT: reverses spasm of the sphincter of Oddi. associated w nausea and vomiting, esp with rapid IV administration. Obstetric/Paediatric: crosses the placenta. may cause acute withdrawal in the foetus or neonate after administered to an opioid dependent parturient. |
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Pharm-05A2 Outline the acute adverse effects of opioid receptor agonists. Describe the mechanism of the acute adverse effects of opioid receptor agonists.
Describe briefly the acute unwanted effects of the opioid agonist drugs |
Opioid Agonists
- Drugs that act via the opioid receptors (mu, kappa, delta) - Morphine is prototype Acute Unwanted Effects - Undesirable, potentially deleterious effects of drug administration that may be o An extension of therapeutic action o Side effect o Related to toxicity or idiosyncratic reactions - “Acute” will, for the sake of this answer, be considered to be any effect occurring within approximately 24 hours following administration (does not include tolerance, dependence issues) Modifying Factors - Specific opioid receptor involved o Mu2 producing respiratory depression, bradycardia, inhibition of gut motility o Kappa producing sedation, meiosis and resp. depression - Specific opioid agonist and its unique spectrum of effects o Morphine producing histamine release o Pethidine toxicity via nor pethidine accumulation - Dose and rate of administration o Higher doses and more rapid administration typically lead to more acute complications as they are assoc. with higher peak concentrations of drug. - Route of administration o Intravenous administration is associated with rapid rises in plasma concentration o Complications related to the process of administration per se e.g. muscle haematoma from IM injection o Neuraxial opioids have unique and sometimes delayed side effects - Age of recipient and any pathophysiology o Elderly patients are typically susceptible to opioid effects and the therapeutic index is narrower o Pre-existing disease e.g. COPD may exacerbate consequences of respiratory depression Cardiovascular - Hypotension due to o Direct myocardial depression and venodilation o Secondary to histamine release (marked individual variability) o Baroreceptor response attenuated - Bradycardia through (effects more marked with fentanyl) o Vagal stimulation in the medulla and o Direct depressant effect on the sino-atrial node and o Slowing of AV conduction - CVS effects are typically exaggerated in presence of other depressant agents e.g. volatiles - Pethidine can cause o Tachycardia due to mild anticholinergic effects o Hypotension due to histamine and alpha 1 receptor blockade Respiratory Effects - All opioid agonists produce dose dependent depression of ventilation, primarily through agonist effect at mu2 receptors - Direct depressant effect on brainstem ventilation centres may lead to apnoea - Reduced response to hypercapnia reflected by an increase in the resting PaCO2 and displacement of the carbon dioxide response curve to the right - Response to hypoxia is less affected but administration of supplemental O2 may potentiate resp. depression - Pattern of respiration is typically with rate falling more than tidal volume. Pauses may occur between breaths due to interference with respiratory control centre. - “second peak” effect of resp. depression can occur after repeated doses of highly lipid soluble opioids such as fentanyl (lungs as store, possibly gut trapping ) - Neuraxial opioids can lead to phenomenon of delayed respiratory depression occurring greater than 2 hours after administration - Reflects a combination of cephalad migration and systemic absorption - Ciliary function is depressed - Loss of cough reflexes can reduce airway protection - Bronchoconstriction can occur due to direct effect on smooth muscle or secondary to histamine release Central Nervous System - Sedation may be an undesirable effect primarily mediated by kappa receptors - Euphoria (mu1) would be a desirable effect for most but increases the abuse potential - Dysphoria (kappa) occurs with increasing doses although is somewhat idiosyncratic Eye - Direct stimulation of the Edinger-Westphal nucleus leads to meiosis which can be undesirable in patients with head injuries in whom monitoring of pupil size is important - Pethidine can also cause corneal anaesthesia increasing the risk of eye trauma - Mydriasis with pethidine - Opioids (esp. sufentnil, alf and fent) may cause nystagmus Gastrointestinal Tract - Can produce spasm of smooth muscle leading to constipation, colic and delayed gastric emptying - Morphine decreases the peristaltic contractions and increases the tone of the pylorus, ileocecal valve and anal sphincter resulting in increased water absorption and constipation - Increased biliary pressure occurs as the gall bladder contracts against a narrowed sphincter of Oddi – may produce biliary colic Nausea and Vomiting - Direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle - Possibly due to partial dopamine agonism and stim of 5HT3 receptors - Increased GIT secretions and reduced gastric emptying may contribute - Morphine also depresses the vomiting centre in the medulla hence IV morphine causes LESS N&V than IM administration presumably because it reaches the medulla as rapidly as the CTZ Genitourinary - Increased tone and peristalsis of the ureter combined with increased detrusor muscle tone can contribute to urinary urgency - But, retention occurs due to increased vesical sphincter tone - ADH secretion is stimulated in the presence of painful stimulus – uncertain significance Pruritus - Generalised itching not associated with a rash or histamine release - Most marked with epidural and spinal administration of opioids - Paradoxically responds to antihistamines Cutaneous changes - Morphine causes cutaneous vessels to dilate - The skin of the face, chest, neck frequently becomes flushed and warm - Mostly attributable to histamine release - May contribute to loss of heat to the environment Endocrine - Morphine inhibits the release of ACTH, prolactin and gonadotrophic hormones - ADH secretion increased Skeletal Muscle - Truncal muscle rigidity can occur with high doses of opioids - Thought to be due to opioid receptor interaction with dopaminergic and GABA pathways in the substantia nigra - Can lead to impairment of mechanical ventilation - Myoclonus can occur that resembles seizure activity Fetal & Maternal Effects - Lipid soluble opioids can cross the placenta and lead to respiratory depression in the neonate - Pethidine crosses placenta readily and norpethidine accumulates in the foetus due to reduced clearance - Intrathecal and epidural morphine not used as it may lead to reactivation of herpes simplex virus Drug Interactions - Pethidine interacts with MAOIs via unclear mechanisms - Effects include coma, labile circulation, convulsions and hyperpyrexia Allergy - True allergy to opioids is rare but may occur |
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Pharm04-B4 Write short notes on tramadol. 50%
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General
• Centrally acting analgesic • chemical structure : synthetic 4-phenyl-piperidine analog of codiene • Low affinity for µ receptors : 5-10 times less potent than morphine • naloxone inhibits only 30% of its effects • racemic mixture of 2 enantiomers • one inhibits noradrenalin uptake • other inhibits serotonin uptake and facilitates its release, also the µ effects • therefore the 2 isomers compliment each other • analgesic effect reflected in its ability to inhibit noradrenalin and serotonin neuronal uptake Pharmacokinetics • Administration : Oral, IM or IV • Bioavailability about 70%, increases with subsequent doses, up to 100% • Dose 3 mg/kg, 50-100mg every 4-6 hours max 400 mg • IV morphine is 1/10th as potent as morphine • Metabolism : Metabolised to by CYP2D6 to M1 (O-desmethyl tramadol), an active metabolite at opioid receptors. • ? may contribute to some of the analgesic effects • Proportion of population deficient in this enzyme, so may have reduced analgesia. Pharmacodynamics • Acts by acting at • the µ receptor • inhibits noradrenalin and serotonin uptake in the spinal chord, therefore activating spinal inhibitory pathways • Little respiratory depression than morphine, but still possible • Little sedation • Therefore not useful to prevent intraoperative awareness • High incidence of N&V • Less tolerance or addiction risk than morphine • agents, and other drugs that lower the seizure threshold • Minimal effects on GIT function • Tramadol may have direct LA effects on nerves • When added to regional local anaesthetic * provided a shorter onset of sensory block Adverse effects • Seizures esp if also on antidepressants • Esp MAOI, neuroleptic • Analgesic effects blocked by serotonin antagonists |
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Pharm-03A6 Explain how differences in the pharmacokinetics of alfentanil and fentanyl can influence the way they are administered intravenously. 51%
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Potency
Alfentanil is less lipid soluble than Fentanyl Hence Alfentanil is less potent (10-20%) than Fentanyl Onset of action and Timing of administration Effect-site equilibration Alfentanil: 1.4 mins Fentanyl: 6.8 mins Therefore Alfentanil has a more rapid onset of action than Fentanyl Due to low pKa (pKa Alfentanil 6.5 vs Fentanyl 8.4) ie nearly 90% of the drug exists in the non-ionized form at physiologic pH it is the non-ionized fraction that readily crosses the blood-brain barrier hence Alfentanil is useful to blunt response to a single brief stimulus eg tracheal intubation or performance of a retrobulbar block and should be given 1-2 mins before the stimulus Volume of distribution Alfentanil: 0.6 L/kg Fentanyl: 4.5 L/kg Volume of distribution of Alfentanil is 4 – 6 times smaller than Fentanyl Reflects lower lipid solubility (see octanol:H2O coefficient) ie less likely to store up in fat and muscle Protein-binding of alfentanil is greater Despite this lower lipid solubility, penetration of the BBB by Alfentanil is rapid because of its high degree of non-ionization at physiologic pH Time to peak effect Alfentanil reaches peak effect site concentration (hence peak effect) very shortly after bolus administration Also a rapid speed of offset because effect site concentrations begin to fall immediately after the rapid peak Fentanyl reaches peak effect slower than Alfentanil Duration of action Alfentanil has 1/3 the duration of action of Fentanyl (about 10 mins) because: Volume of distribution of Alfentanil is smaller than Fentanyl Fentanyl is long-acting because of distribution from the tissues back into the blood to be metabolised Clearance of Alfentanil is less than Fentanyl Hepatic extraction ratio of Alfentanil is 0.3-0.5 Hepatic extraction ratio of Fentanyl approaching 1.0 Fentanyl In small doses (1-2 g/kg), its duration of action is short (about 30 mins)and there is rapid recovery In these conditions, plasma and CNS concentrations fall below an effective level during the rapid redistribution phase (due to its high lipid solubility) After multiple or large doses, the duration of action is significantly prolonged The distribution phase is complete while the plasma concentration of fentanyl is still high Recovery from the effects of the drug then depends on its elimination from the body Context-sensitive half-time As the duration of continuous infusion of Fentanyl increases beyond about 2 hours, the context-sensitive half time of Fentanyl becomes greater than Alfentanil This reflects Fentanyl’s larger VD Saturation of inactive tissue sites with fentanyl during prolonged infusions and return of opioid from peripheral compartments to the plasma This tissue reservoir of fentanyl replaces fentanyl eliminated by hepatic metabolism so as to slow the rate of decrease in the plasma concentration Alfentanil has a smaller VD The peripheral distribution of drug away from the plasma is not a significant contributor to the decrease in plasma concentration after discontinuation of alfentanil Dosing regimens Alfentanil may be administered either as: Bolus dose 1-2 minutes before the anticipated stimulus that is to be blunted (eg intubation) occurs Continuous infusion Loading dose of 25-50 g/kg followed by infusion of 0.5-2.0 g/kg/min eg as sole anaesthetic or for sedation in ICU pts Fentanyl Usually administered as a bolus dose 1-2 g/kg for analgesia 50-150 g/kg for sole anaesthetic agent (eg to attain cardiac stability during cardiac surgery) |
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Pharm-02B6 Write brief notes on tolerance and dependence in relation to opioid analgesics.
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Tolerance and dependence – with repeated administration - feature of all opioids - tolerance can occur without physical dependence - reverse seems not to occur
Tolerance - decreased receptor response to a given concentration of agonist, after repeated administration - decreased potency of agonist but maximum effect can still be attained - proportional to exposure - Propsed mechanisms include: - Down regulation of receptors – remains unproven - Up-regulation of cAMP system - Opioids inhibit adenylate cyclase (catalyzes synthesis of cAMP) - Long term opioid exposure → ↑synthesis of cAMP - Clearly demonstrated in locus ceruleus - NMDA receptor activation & increased glutamate - Prolonged exposure to opioids → activates NMDA receptors via 2nd messenger systems - Down regulation of spinal glutamate transporters → ↑synaptic glutamate concentration - ↑[glutamate] + activated NMDA receptors → tolerance & abnormal pain sensitivity - Uncoupling of receptor from intracellular messenger / reduced efficiency of this process (receptor desensitization) - Reduced affinity of receptor for agonist - Tolerance for a specific agonist – confined only to receptors agonist binds - Affected by tolerance: - Analgesia - Euphoria - sedation - emesis - respiratory depression - Less affected by tolerance: - Constipation - Miosis - Cross tolerance develops between all opioids Dependence - characterised by ongoing reliance of dosing of a drug - Psychological – compulsive desire to use a drug even without dysphoric withdrawal symptoms - Physical – withdrawal of a drug produces unpleasant symptoms and signs - For morphine usually requires 25 days - Can occur sooner in emotionally unstable - Can occur more rapidly with frequent parenteral use – some degree of dependence after only 48 hours - Withdrawal abstinence syndrome - Initially yawning, diaphoresis, lacrimation, coryza - Insomnia, restlessness, dysphoria are prominent - Abdominal cramps, nausea, vomiting, diarrhoea - Peak 72 hours, decline over 7 to 10 days Onset (hours) Peak (hours) Duration (days) Morphine 6-18 36-72 7-10 Heroin 6-18 36-72 7-10 Fentanyl 2-6 8-12 4-5 Methadone 24-48 3-21 days 6-7 weeks Clinical significance - Tolerance and dependence seen in: - Chronic pain states – eg. on oral opiates - Prolonged acute pain states for which have received large doses of frequent parenteral opiates - Opiate abuse – eg. heroin/pethidine - These patients will require increased doses or peri-operative opiates for desired effects - Thankfully respiratory depression, sedation, euphoria also exhibit tolerance - Need to be weary of constipation – shows little tolerance - Sudden withdrawal (eg. during admission to hospital) will cause withdrawal abstinence syndrome - During withdrawal tolerance is rapidly lost – much decreased dose can terminate withdrawal symptoms |
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Pharm-00A15 Describe the effects of opioids on the respiratory system 75%
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Mechanism of action
* effects of opiods are mediated by mu, kappa and delta receptors * Receptors are G-protein coupled * Majority of actions are at the Mu receptor: o Causes supra-spinal and spnal effects o Mu2 receptor is responsible for respiratory depression o Kappa and Delta receptors also contribute to respiratory depression o Direct brainstem depression Effects on ventilation: * dose dependent * decreased responsiveness to CO2 (? due to decreased ACh release from medullary neurons in response to CO2 stimulus) * increased CO2 -> cerebral vasodilation -> Raised Cerebral Blood Flow -> increased delivery of opioids to the brain. * interferes with pontne & medullary centres responsible for respiratory rhythm -> apnoea * Decreased frequency of breathing * Increased tidal volume * overall, decreased minute volume -> increased pCO2, decreased pO2, * CO2 response curve shifts right (higher pCO2 to get same respiratory response) * dose dependent decrease of ciliary function * truncal rigidity (makes ventilation more difficult) * cough suppression, eg. codeine * Resp. depression can lead to death, and is most common mode of opioid-related death (tolerance does not develop to respiratory depression) * sedation -> loss of airway reflexes * Therapeutic ratio is low: analgesic dose may be close to dose causing resp. depression. * Bronchospasm: o secondary to direct effects on bronchial smooth muscle. o Also secondary to effects of histamine release from mast cell degranulation. Confounding factors * sleep * old age * lack of CNS stimulus, eg. pain * other respiratory depressants, eg. Benzos, alcohol, anaesthetics, * hypothermia * route of administration: rapid IV bolus more likely to cause depression than IM Comparative pharmacology * pethidine causes more resp depression than morphine * fentanyl can cause depression and re-depression of respiration. o thought that fentanyl gets sequestered in gastric secretions, which are acidic, and trap the drug in ionised state. When it reches alkaline fluid in small intestine, it is reabsorbed -> re-sedation o also, sequetstered fentanyl in lungs during first pass is washed out as ventilation/perfusion relatiosnhips return to normal |
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Pharm-99A10 Write a brief outline on the pharmacology of remifentanil. 47%
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Introduction
Remifentanil is a relatively potent (15-20X as potent as alfentanil) selective opioid receptor agonist with a short duration of action Pharmaceutics A phenylpiperidine derivative, containing 2 ester bonds which is a weak base with a pKa of 7.1 Presented as a powder mixed with glycine, requiring reconstitution with water Pharmacokinetics Absorption Intravenous Rapid onset – effect-site equilibration time 1.1 min Distribution Predominantly ionised at body pH Moderately low lipid solubility compared to fentanyl 70% plasma protein-bound small distribution of volume (0.6L/kg) Metabolism/Biotransformation High clearance (40ml/kg/min) elimination half life: about 10 mins Speed of offset due to clearance rather than distribution Short context sensitive half-life of about 4min, independent of the infusion time. Clearance is almost exclusively by hydrolysis of one of the ester bonds by "non specific" blood and tissue esterases (not by red cell esterase alone and not by "pseudocholinesterase") producing an almost inactive carboxylic acid derivative (i.e. non-cumulative effects) Another minor pathway of metabolism is by N-dealkylation in liver Excretion Inactive metabolites undergo renal excretion Pharmacodynamics Typical of a opioid receptor agonist CNS Analgesia and sedation depresses some brain stem regulatory centres (respiratory/cardiovascular), stimulate other centres causing: nausea pupillary constriction (action on Edinger-Westphal nucleus of oculomotor nerve) truncal rigidity (action on opioid receptors and interaction with dopaminergic and GABA responsive neurons) ICP and intraocular pressure are not changed CVS HR: Bradycardia secondary to effects on vagal nuclei and vasomotor centres Contractility: minimal direct effects on myocardium SVR: minimal direct effects on vasculature Decreased SVR secondary to effects on vagal nuclei and vasomotor centres normally no histamine release (cf. morphine) Resp decreased airway reflexes, (depression of ciliary activity) Resp Rate: decreased interferes with pontinine and medullary ventilatory centres that regulate rhythm, leading to prolonged pauses between breaths and periodic breathing apnoea at high doses Tidal volume: possibly compensatory increase Ventilatory response: decreased response to hypercapnia and hypoxia. GIT Increased tone in biliary tree, sphincter of Oddi, pyloric sphincter, ileocaecal valve, anal sphincter, ureter Decreased peristaltic contractions of GI smooth muscle, delay gastric emptying GUS Increased tone of ureter Clinical Use Indications Intraoperative analgesia of rapid onset/offset Neurosurgery in pt with raised intracranial pressure Blunt sympathetic response to direct laryngoscopy and tracheal intubation Rapid recovery to assess pt neurologically post-op ASAP Transient analgesic effect in performance of retrobulbar block Dose: optional preceding bolus of 1-2 microgm/kg. 0.1- 1.0 microgm/kg/min infusion precise and rapid titration to the desired effect is easily performed Need to make provision for postoperative analgesia before cessation of remifentanil Contraindications Spinal or epidural administration is not recommended because of neurotoxicity of glycine which acts as an inhibitory neurotransmitter Adverse effects Bradycardia and hypotension Truncal rigidity with high dose/rapid administration; "Neurotoxicity" due to glycine and immune mediated histamine release?? Nausea/vomiting and severe pain after cessation of administration in awake patients. Interactions Synergistic effect with hypnotics eg Midazolam |
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1991 Write short notes on narcotics administered via the epidural route
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• Epidural opioids are a good method of helping to control intraoperative and post-operative pain.
• Not often used on their own due to: tolerance, inability to control sharp pain, increased incidence of side effects due to higher quantities used when they are the sole agent. Pharmaceutics • Many preservatives and anti-microbials in opioids have been implicated in causing neurotoxicity and it is recommended that preservative free solutions be used. • Neurotoxicity may present as motor or sensory abnormalities, radiculitis, bladder/ bowel dysfunction Pharmacokinetics • Epidural opioids access nerve tissue by: o Diffusing to spinal nerve roots via the paravertebral spaces o Accessing nervous tissues past the end of the dural cuff o Diffusing across the dura o Via blood vessels leading to the cord • Opioids such as morphine are more hydrophilic and can distribute more widely than eg fentanyl • Fentanyl undergoes deposition in epidural fat and has a shorter duration of action Pharmacodynamics CNS • Presynaptic effects are a decrease in the release of Substance P and possibly glutamate from excitatory fibres (esp. C fibres which mediate dull pain). • Postsynaptic effects are a decrease in Ca entry and increased K entry as well as modulating cAMP levels. • Effects are achieved via G protein coupled receptors and μ,δ,κ are all present in the spinal cord with high numbers of opioid receptors in the sub gelatinosa. • There may also be direct ion channel effects- unclear. • Effect is to promote analgesia especially ↓dull pain mediated by C fibres but also sharp pain mediated by Aδ (although less effectively). • Vomiting and urinary retention are complications • Opioids may potentiate the effects of sedative drugs and therefore may lead to excessive sedation although the expected incidence is less than that with systemic administration.. Respiratory • Respiratory depression is a potential complication. • Respiratory depression may be worse with morphine due to an increased ability to distribute through the epidural space. • Caused by activating μ receptors on the floor of the fourth ventricle. • Respiratory depression is worse if concurrent systemic opioids (IV/ Oral etc) are given Cardiac • Foetal bradycardia has been reported- may be due to decreased maternal catecholamine levels with the sudden onset of analgesia Dermatological • Pruritus is a common side effect and the incidence may be as high as 40%-80% Other • You could mention all the problems of epidural anaesthesia/analgesia such as haematoma, cord infarction, paralysis, infection, death etc. • Tolerance will develop and the opioids cannot prevent wind up on their own. Consider using ketamine or clonidine or dexmetomidine- or even a local anaesthetic (now there is an original idea) |
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Pharm-96B9 Briefly explain the factors which determine the duration of effect of intravenously administered bolus doses of fentanyl. 70%
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Fentanyl is a synthetic phenylpiperidine opioid agonist
It has a rapid onset of action due to its extremely high lipid solubility Duration of action is determined by its pharmacokinetic properties and dose. Factors that determine the duration of effect of IV Fentanyl: Redistribution half life t1/2 = 3 mins determines offset of action and hence duration of smaller doses ie 1-2 mcg/kg duration of action 20-25 mins Volume of distribution VD 4 L/kg With high doses, ie as sole anaesthetic, 50-100 mcg/kg, tissue stores are saturated and offset of action is determined by clearance, Duration of action 4-6 hours Obesity increases VD (more fat depots), resulting in a longer elimination half life Elimination half life = 0.693 VD Clearance Clearance Clearance = 1 L/min t1/2 = 3 – 4 hrs Hepatic extraction ratio approaches 1.0 Clearance determines offset of action when high doses saturate fat and muscle and provide a continued supply for distribution back into the central compartment In elderly patients, clearance will be reduced (due to decreases in hepatic blood flow, microsomal enzyume activity) and so effect is prolonged Context-sensitive half-time Context-sensitive half-time is the time necessary for the plasma drug concentration to decrease by 50% after ceasing a continuous infusion of a specific duration (context refers to the infusion duration) It considers the combined effects of Distribution Metabolism Duration of IV infusion It bears no constant relationship to the drug’s elimination half-time As the duration of continuous infusion of fentanyl increases beyond 2 hrs, the context-sensitive half time becomes greater. This reflects saturation of inactive tissue sites with fentanyl with prolonged infusions and return of the opioid from peripheral compartments to the plasma The tissue reservoir of fentanyl replaces fentanyl eliminated by hepatic metabolism so as to slow the rate of decrease in the plasma concentration of fentanyl when the infusion is ceased Pulmonary sequestration 75% first pass pulmonary uptake will provide a large inactive storage site for secondary release Secondary peaks in plasma concentration can occur after a bolus with possible prolongation/reoccurrence of effect. Possible mechanisms include: Sequestration into acidic gastric fluid where 99.9% Fentanyl is ionised then reabsorption occurs in the alkaline intestine Washout from pulmonary sequestration with post-op normalization of VQ relationships after a general anaesthetic |
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Write short notes on danrolene.
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Mechanism of action
• Produces skeletal muscle relaxation by blocking the electrical transmission from dihydropyridine receptor and ryanodine receptor, thus decrease the amount of calcium released from the sarcoplasmic reticulum thus prevent excitation contraction coupling. • No effect on neuromuscular transmission, nor does it have measurable effects on electrically excitable surface membrane Uses in Anaesthesia 1. Prophylaxis of anaesthetic induced Malignant hyperthermia 5mg/kg orally in 3 or 4 divided doses over 6 hours with last dose 4 hours pre-op or 2.4mg/kg IV over 30 minutes just before induction of anaesthesia and half the dose repeated in 6 hours Malignant hyperthermia – intrinsic abnormality of muscle tissue. It has been postulated that triggering agents induce a sudden rise in myoplasmic calcium either by accelerating the release of calcium by the sarcoplasmic reticulum or by preventing the reuptake of calcium back into the SR. The rise in myoplasmic calcium activates acute catabolic processes that lead to MH (hypermetabolism of skeletal muscle). Symptoms include tachycardia, tachypnoea, central venous desaturation, hypercarbia, metabolic acidosis, skeletal muscle rigidity, fever, cyanosis and mottling of the skin. Dantrolene sodium may prevent the increase in myoplasmic calcium and the acute catabolism within the muscle cell by interfering with the release of calcium from SR to myoplasm. Thus the physiologic, metabolic and biochemical changes associated with the crisis may be reversed or attenuated. 2. Treatment of anaesthetic induced Malignant hyperthermia 2mg/kg IV with dose repeated until symptoms subside or cumulative dose of 10mg/kg IV is reached. NB: Dantrolene is not 100% effective, hence triggers for MH should be avoided even when dantrolene prophylaxis is used in susceptible individuals 3. Treatment of neuroleptic malignant syndrome (after chronic haloperidol, MAOI, lithium, phenothiazine) 4. Treatment of skeletal muscle spasticity due to upper motor neurone lesion or tetanus Dose: 100mg orally QID SE: skeletal muscle weakness which negates improvement in spasticity. Adverse effects 1. Available as 20mg sterile lyophilised powder, with 3g mannitol (to make solution isotonic), and NaOH to yield pH 9.5 when reconstituted with 60ml sterile water. Alkaline IV solution can cause phlebitis or tissue necrosis on extravasation Mannitol can cause osmotic diuresis therefore IDC is required 2. Skeletal muscle weakness – may be sufficient to interfere with adequate ventilation or protection of lungs from aspiration of gastric contents. Leg weakness, loss of grip strength 3. CNS - Blurred vision, drowsiness or dizziness 4. Resp – breathlessness, pleural effusion with chronic therapy 5. CVS – therapeutic doses have little or no effect on cardiac or smooth muscles 6. Uterine relaxation – can lead to uterine atony – increase risk of PPH 7. GIT – nausea diarrhoea Hepatitis in 0.5% of patients treated for > 60 days, fatal in 0.1-0.2% therefore monitor LFT 8. Hyperkalaemia 9. Anaphylaxis, urticaria, erythema Drug interactions 1. Increased risk of hyperkalaemia and VF in animal studies when given with verapamil 2. Potentiate vecuronium induced neuromuscular blockade |
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Pharm-09A7 Outline the subtypes of serotonin (5 hydroxytryptamine) receptors. Discuss pharmacological agents that act at these sites.
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Pharm-09A7 Outline the subtypes of serotonin (5 hydroxytryptamine) receptors. Discuss pharmacological agents that act at these sites.
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Pharm-08A5 Classify drugs that alter activity at serotonin receptors with examples. Describe their mechanisms of action and clinical indications.
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Pharm-08A5 Classify drugs that alter activity at serotonin receptors with examples. Describe their mechanisms of action and clinical indications.
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Pharm-08A4 Outline the pharmacologic management of bronchoconstriction in acute severe asthma. Include mechanisms of action and potential adverse effects.
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1. Beta 2 adrenoceptor agonists: They act on the β2-adrenergic receptor which is coupled to G-protein (Gs) thus activating adenyl cyclase mediated increase in cAMP. This hyperpolarises the smooth muscle cell via increased NA/K ATPase activity, and thereby causes smooth muscle relaxation resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin. Side effects such as insomnia, anxiety, and tremor occur in some patients. All β2 agonists are available in inhaler form (either metered-dose inhalers, which aerosolize the drug, or dry powder which can be breathed in). Higher doses have β1 activity with the common side effects of tachycardia, tremor etc. Remeber the ability of adrenaline to activate B2 in emergencies. Can also cause anxiety, metabolic effects such as increased BSL, increased lactate, decreased potassium.
Salbutamol also comes in a liquid form for nebulization, which is more commonly used in emergency rooms than inhalers. Salbutamol and terbutaline are also both available in oral forms. In addition, several of these medications are available in intravenous forms including both salbutamol and terbutaline. It can be used in this form in severe cases of asthma, also used to suppress premature labor because it also relaxes uterine muscle, thereby inhibiting contractions. 2. Anticholinergics eg. Tiotropium : intermediate-long acting inhaled Anti-Cholinergic; half-life 6 hours. eq. Ipratropium : short-intermediate acting inhaled Anti-Cholinergic; half-life 2 hours. Mechanism: 1. Muscarinic (M3) Receptors mediate smooth muscle contraction and glandular secretion. 2. G-Protein Coupled Receptor (Gq type) 3. Second Messengers are Phospholipase C (PLC), Inositol-3-Phosphate (IP3) leading to... 4. Increased intracellular Calcium. Therefore, M3 antagonists will cause bronchodilation. Adverse Effects are uncommon and mostly a result of accidental systemic absorption: 1. Dry mouth 2. Palpitations 3. Urinary retention & Constipation 4. Closed angle glaucoma 5. Allergic reactions 3. Steroids: inhaled/oral/IV Systemic glucocorticoids, eg. Methylprednisolone acetate (is a pro-drug that is hydrolysed to its active form by Plasma AChE; trivia) General effects of systemic glucocorticoids 1. Metabolic 2. Anti-inflammatory 3. Immunosuppressive Mechanism of Anti-inflammatory action: 1. As a steroid it binds to an intracellular receptor and then interacts with DNA to alter protein transcription. 2. Specifically, increased lipocortin, which inhibits Phospholipase A2. 3. Note Phospholipase A2 usually facilitates breakdown of membrane phospholipids to Arachadonic Acid (hence Prostaglandins, leukotrienes, plt aggregating factor). 4. Reduces tissue transudate and cell oedema. Other effects: 1. Permissive effect on vascular and bronchial smooth muscle (eg. action of catecholamines). 2. Adrenal suppression (longer term though) 3. Fluid Retention 4. Metabolic (increased BSL) 4. Mast cell Stabilisers (? incase the next question is asthma in general..not just acute severe) 5. Leukotriene antagonists 6. Phosphodiesterase inhibitors Methylxanthines Derivatives / Non-selective PDE-I, eg. Theophylline / Aminophylline. Multiple Mechanisms: 1. Inhibit all PDE isoenzymes leading to increased levels of intracellular cAMP. 2. Synergistic effect with circulating catecholamines. 3. Interfer with "the translocation of calcium into smooth muscle". 4. Inhibit degranulation of mast cells by Adenosine-Receptor blockade. 5. Potentiate Prostaglandin Synthetase. Note: 1. Metabolised by P450 - affected by inhibitors or inducers. 2. Saturable metabolism; can drop down from First order to Zero order kinetics. 3. Toxicity: Significant Cardiac and CNS toxicity, can cause tachycardia, arrythmogenic, CNS stimulation, and possible seizures in toxic levels. Ref. Peck & Williams 7. Inhaled anaesthetic agents - The halogenated volatile anaesthetic agents, such as sevoflurane, isoflurane, etc, can cause bronchodilation - by decreasing vagal outflow, and possible direct effects on vascular/bronchial smooth muscle (?) - adverse effects include hypotension, respiratory depression / apnoea - handy to use if already intubated and get bronchoconstriction 8. Ketamine - ketamine causes bronchodilation due to its sympathomimetic effect of increasing noradrenaline/adrenaline release - side effects include tachycardia, increased myocardial oxygen demand, dissociative anaesthesia, hallucinations, salivation - a good agent to use at induction for a person with severe acute asthma 9. Magnesium Role in Asthma: 1. Bronchodilation: Hypermagnesaemia causes smooth muscle relaxation. 2. Reduce neutrophillic burst in the Inflammatory Response. 3. Magnesium is safe and beneficial to use in severe' asthma, but evidence does not support routine use. Ref. Cochrane Database Syst Rev. 2000 10. Oxygen - tends to directly cause respiratory depression (decreased ventilatory sensitivity to CO2) and decreased cardiac output, coronary vasoconstriction - however, in a person who is hypoxaemic due to asthma, it will improve these parameters 11. Helium - decreased density of this helium/oxygen mixture decreases airway resistance (especially upper airways due to decreasing resistance to turbulent flow) - decreases WOB, and may improve oxygenation due to decreased airflow resistance - however, may need higher oxygen concentration in severe asthma, which offsets any benefits of the lower density gas |
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Pharm-06A4 Describe the pharmacodynamic properties of propofol and how this influences its clinical usage.
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69 % of candidates passed this question.
It was expected emphasis be placed on the central nervous system effects, followed by the cardiovascular and respiratory effects and marks were allocated accordingly. The question was specifically related to pharmacodynamics and a discussion of pharmacokinetic properties scored no additional marks. Candidates were expected to outline that Propofol is an intravenous anaesthetic agent used for both the induction and maintenance of anaesthesia or sedation. Reward was given to candidates who outlined potential mechanisms of action, the dose dependent nature of effects, the effects on the EEG and on cerebral metabolism. Further credit was given for describing how this might impact on its clinical use (e.g. neurosurgery). A description of the cardiovascular effects was expected to include reference to hypotension, reduced systemic vascular resistance and bradycardia with comment on those patients at risk. Respiratory effects include alterations in ventilatory response, reduction in airway reflexes and bronchial tone. Extra credit was given for discussion of other pharmacodynamic properties including; anti-emetic, anti-pruritic, non MH triggering, pain on injection, lipid/caloric load, reduction in intraocular pressure and risk of propofol infusion syndrome. It was expected that candidates would relate each pharmacodynamic effect to the impact on clinical use and failing to address this was a common omission (e.g. reduction of airway reflexes is useful for LMA insertion or airway manipulation). Well organised answers such as those with an ordered list with subheadings or a table were rewarded. |
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Pharm-05B2 Using opioids as examples, describe and illustrate with graphs what you understand by the terms "potency", "efficacy", "partial agonist", "competitive antagonist" and "therapeutic index". (83% pass rate)
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Pharm-05B2 Using opioids as examples, describe and illustrate with graphs what you understand by the terms "potency", "efficacy", "partial agonist", "competitive antagonist" and "therapeutic index". (83% pass rate)
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Pharm-04B1 Briefly describe how drugs produce their pharmacological effects. Illustrate each mechanism with examples. 67%
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Drug is any substance that, when absorbed into the body of a living organism, alters normal bodily function.
Targets are generally proteins (receptors, enzymes, ion channels, transporters (carriers) and DNA. Osmotic purgatives and antacids are examples of drugs which act without binding to receptors Enzymes Are biomolecules that catalyze (i.e., increase the rates of) chemical reactions eg cholinesterases, COX, cytoP450 Receptors A receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling (or "signal") molecule may attach Types 1. Ligand gated ion channels : eg nictonic AChR 2. G-protein couple receptors eg. adrenoreceptors 3. Tyrosine linked receptors eg insulin receptor 4. Intracellular receptors linked to DNA/RNA/protein synthesis : eg steroids, thyroid Mechanisms/ Drug receptor interactions All must have affinity : ei ability to bind to receptor or enzyme, usually have high affinity for other binding sites ( Efficacy : ability to initiate a response at the molecular, cellular or tissue level. No effect : antagonist : eg naloxone and mu recptors Full effect : agonist : eg morphine and mu receptors Partial effect: partial agonist : eg buprenorphine and mu receptors Competitive : drugs associate and dissociate readily at different rates, therefore effect can be antagonised with increasing antagonist eg most drugs Non-competitive : drugs which bind covelantly. Therefore cannot be antagonised. Usually require metabolism of receptor-drug complex eg. Organophosphates and cholinesterase Increase activity : eg heparin + antithrombin Decrease activity eg neostigmine and cholinesterase Other mechanisms: Direct chemical interaction with other drugs, eg. chelation, antacids. structural analogues (false substrates) which subvert normal metabolic pathways, eg. Folate and trimethoprim. Colligative properties: raising osmotic pressure, lowering vapour pressure. Due to number of particles of solute. Also: unknown, such as placebo effect and mechanism of inhaled anaesthetics. |
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Pharm-03B3 Outline GABA's role as a neurotransmitter and indicate how its actions may be modified by pharmacological agents. 63%
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GABA Receptors come in 2 main types; GABA-A and GABA-B
Also type c and non-A, non-B. Function unknown. GABA is found only in the brain, especially the nigrostriatal tract (with traces in other tissues). It is the main inhibitory neurotransmitter in the brain. Found largely in short interneurons and long GABA-ergic tracts to cerebellum and striatum. GABA thought to be involved in 30% of all synapses, with almost all neurons being sensitive. Made by: glutamate -------(glutamic acid decarboxylase)--> GABA GABA taken up mostly by astrocytes and GABA-ergic neurons by specific transporters (process inhibited by nipecotic acid and guvacine) Broken down by: GABA ------------------GABA transaminase-----> glutamate -oxyglutaric acid inhibited by vigabatrin GABA-A: * Postsynaptic ligand-gated Cl- channel with Selective permeability to Cl- that is Responsible for fast postsynaptic inhibition. * GABA binds to receptor, increasing the Cl- influx, hyperpolarising the cell, inhibiting its function. * Receptor: Pentameric structure with subunits- 2 α, β, γ, δ. Each has 3-6 subtypes each, so endless permutations. Drugs acting on GABAa receptors: At GABA binding site: * bicuculline antagonist * Muscimol agonist At modulatory site: * BZD binds with high affinity at subunit, increasing GABA binding. * Flumazenil (GABAA selective) inhibits GABA binding. * Barbiturates Steroid anaesthetics (neurosteroids): NOT on intracellular steroid receptor. Increases GABA action. Eg. alphaxolone. Some endogenous progesterone metabolites. At ion channel: picrotoxin blocks Cl- channel. Others: Propofol Etomidate Alcohol ?volatile anaesthetics GABA-B: * G-protein coupled receptor. * Pre&post-synaptic. * Similar to glutamate receptor. * Controls Ca++ and K+ flux. * Functional part of receptor = dimer of 2 different subunits. * Inhibits voltage-gated Ca++ channels, decreasing neurotransmitter release. * Opens K+ channels, decreasing postsynaptic excitability, via inhibition of adenylate cyclase. * Baclofen = agonist. Lipophillic GABA analogue. Little post-synaptic inhibitory effect. Selective GABAB agonist. * Phaclofen = antagonist. |
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Pharm-00B11 Describe the structure and function of G proteins 50%
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G-Proteins
G-proteins are heterotrimeric proteins involved the second messenger cascade guanine nucleotide-binding proteins Location on the intracellular surface of the plasma membrane Associated with receptors -metabotrophic receptors : 7 transmembrane molecules -eg M Ach R, Catecholamines, Histamine, Serotonin, Vasopressin. Structure 3 proteins Alpha: 2 domains, GTPase domain and effector domain Beta-Gamma : bound to membrane, upon activation, release alpha subunit Function Are important in signal transduction extracellular (receptor ligand binding) to intracellular. Due to activation of intracellular processes -amplication of response -increased duration of response (can persist for a longer duration that the ligand-receptor interaction) Large G-proteins Gi inhibit adenylate cyclase Gs stimulate adenylate cyclase Gq activation of phospholipase C Small G proteins -bind to GTP/GDP and produce cGMP |
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Pharm-97A9 Briefly describe the pharmacological role of the nicotinic cholinergic receptor 62%
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Nicotinic Acetylcholine receptors
-subtype of cholingeric receptors -ligand gated ion channels in the plasma membrane Activated by acetylcholine and nicotine Location : NMJ, autonomic ganglia, adrenal meddula and CNS Roles Structure Activation Role of alpha subunits Agonist Antagonists Effects |
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Pharm-09A4 Compare and contrast atropine and glycopyrrolate. Discuss the clinical implications of these differences.
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Pharm-09A4 Compare and contrast atropine and glycopyrrolate. Discuss the clinical implications of these differences.
Best Answered as a table Differences vs Similaries OR PC vs PK vs PD PC Both used for 1. vagolytic effects 2. protect against muscarinic effects of anticholinesterases 3. premedication as an antisialogogue Atropine used for 1. during CPR 2. cycloplegic 3. organophosporus poisoning 4. tetanus Chemical /structural Atropine : a naturally occurring alkaloid derivative of BellaDonna plant. It is an ester of tropic acid and tropine. Glycopyrrolate : synthetic quaternary ammonium containing mandelic acid Presentation Atropine comes as oral 600ug tablets and 600ug/ml ampoules for IV admin Glycopyrrolate : IV administration only 200mcg/ml PK Dosing Atropine : IV 20mcg/kg (average is one ampoule 1200mcg) Glyco : 400mcg (paediatric 5mcg/kg) Absorption Atropine : rapidly absorbed orally with bioavailablity 25% Glyco : erratic, poor bioavailability Distribution Atropine PPB 50%, Vd 3 L/kg, highly lipid soluble, crosses BBB and placenta Glyco Vd 0.5 L/kg, less lipid soluble, crosses placenta but not BBB Metabolism/Excretion Atropine : hydrolysed in liver to tropine and tropic acid, metabolites excreted by kidney, elim half life 2.5 hours Glyco : nil metabolism, renally excreted, elimination half life 1 hour PD Atropine Glyco Sedation + 0 Antisialagogue + ++ HR +++ ++ Relax SM ++ ++ Mydriasis + 0 Motion sickness + 0 Inhib Gastric Acid + + |
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Pharm-07A8 List the classes of drugs used clinically to treat chronic left ventricular failure. Outline their mechanisms of action. 65%
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Chronic LVF: The inability of the heart to produce sufficient output for the body's requirements due to impaired LV performance.
Manifested as inability too cope with preload or poor exercise tolerance. Decrease Afterload 1. ACE-I * block RAS by inhibiting AT1 to AT2 conversion by ACE in the lung - thus less aldosterone, less thirst, less direct vasoconstriction, less intravascular volume - results in a decrease in afterload - improved LV remodelling after AMI - shown to decrease mortality in CF associated with MI Decrease Preload 2. Diuretics * decrease intravacular volume, thus decrease preload - most act by direct effect on renal tubules * either Thiazides if good renal function (inhibit NaCl cotransporter in early Distal tubule so incr Na CL load to DT and so incr excretion of NaCl and water) * otherwise Loop (lasix) inhibit NaK-2Cl pump in ascending LoH resulting in impaired action of counter current multiplier system and increased diuresis. Also has effects on reducing preload well before this diuresis. Especially useful in pulmoary oedema * add spironolactone if severe - aldosterone antagonist - thus reduces eNaCS (epithelia na channels) and Na/K ATPase production, so decreased water resorption in collecting duct 3. Nitrates * Direct effect on smooth muscle causing vasodilation and increased capacitance, thsu decreased preload. - show tolerance if used >24-48 hours continuously Increased COntractility 4. Digoxin * weak positive inotrope, slows rate of conduction at AV node - inhibiting the Na K ATPase in cardiac muscle, thus higher [Na+]i which is exhcnaged for Ca2+ leading to higher [Ca2+]i - some positive inotropy - good for rate control in AF, allowing better disatolic filling and decreased heart rate - increases symptoms and performance but not mortality 5. PDE inhibitors (milrinone, amrinone) * decreases PDE activity, thus increasing cAMP and so increased [Ca2+]i - positive inotropes - used mainly acutely but oral prep is availbale. long term milrinone has an increased mortality Beta blockers * act by antagonising Beta 1 and Beta2 adrenoceptors. - Some are relatively selective for Beta 1 ("cardioselective") - Beta 1 antagonism - slows rate, decreases cardiac O2 reqt, - may be negatively inotropic but evidence of increased survival, espec post MI patients - may precipitate CCF in some patients, but helpful if rate control is an issue -Levosimendin(class IIa anti-arrhythmic) myofilament Calcium sensiitizer(does not increase cytosol calcium) improves LV and RV function Sympathomimetics - not used chronically The above classification seem very good and if I can add this: I.Drugs with inotropic action a) Non-Cardiac glycsides b) Cardiac glycosides eg Digoxin Non-cardiac glycosides ie:Sympathometic i)Natural occurring catecholaimes: adrenaline dopamine ii) Synthetic Catecholamines Dobutamine iii)PDE inhibitors:Milrinone Others:calcium, Glycagon and T3,Levosimendan II Drugs without inotropic action i)Loop diuretics ii)ACEI iii)Beta blockers(carvidolol) iv)Statins :improve LVEF,Reverse ventricular remodeling & reduce inflammatory makers. |
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Pharm-06B1 Describe the use of different sympathomimetics to treat hypotension occurring as a result of subarachnoid block. Outline the advantages and disadvantages of these agents. 73%
Pharm-98A14 |
Subarachnoid block is achieved by introduction of local anaesthetic into the epidural or subarachnoid space.
Hypotension is due to venodilation (venous pooling, resulting in decreased venous return, reduced preload, ventricular filling and thus cardiac output) Commonly used 1. metaraminol 2. ephedrine 3. phenylephrine Other sympathetomimetics include adrenaline, methoxamine, noradrenaline, dopamine, dobuatmine. These will not be discussed as they are not indicated for use in hypotension secondary to subarachnoid block. Vasopressin is not a sympthomimmetic. |
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Pharm-05A7 Outline the main biochemical events involved in noradrenergic transmission. Outline how these may be altered by the use of MAO (monoamine oxidase) inhibitors. 67%
Pharm-00A11 Pharm-97A11 |
67 % of candidates passed this question.
The main points expected for a pass were: * A schematic outline of norepinephrine (noradrenaline) synthesis from phenylalanine via tyrosine, DOPA, and dopamine, naming enzymes involved and the locations of these reactions * Function of the storage vesicle plus the calcium dependent exocytosis following the action potential * The biochemical interaction of the norepinephrine and the receptor * Breakdown by COMT in cleft (also intracellular) and other organs to form normetanephrine * Reuptake of norepinephrine at presynaptic and postsynaptic locations * MAO action in nerve terminal or sympathetic varicosities followed by COMT action to 3-methoxy-4-mandelic acid (VMA) * Inhibition of MAO resulting in decreased metabolism and subsequent increased activity and potential enhanced availability of norepinephrine plus epinephrine (adrenaline) and serotonin * Biochemical sequences explaining the adverse events when indirect or direct acting sympathomimetics, pethidine and derivatives, tyramine containing foods, and serotonin re-uptake inhibitors, are administered in the presence of MAO inhibition Credit was given for: * Mention of the MAO A and B sites along with their inhibitors * Noting of the reversibility of inhibition of MAO * Explanation of the role of false transmitters - MAO-induced e.g. octopamine * Mention of the biochemical rationale for the therapeutic use of the MAOIs * Receptor mechanisms and actions were outside the biochemical focus of this question. |
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Pharm-02A10 Outline the factors that determine recovery (offset of action) after ceasing a drug infusion. 43%
02A10 99B16 98A13 95B8 |
Recovery after ceasing a drug infusion if complex. For most drugs it is determined by the concentration at the biophase where the drug-receptor interaction no longer has a clinical effect.
Pharmacokinetic factors -removal of the drug from the biophase -requires diffusion from biophase/peripheral compartment to central compartment where it is cleared (down concentration gradient, following Fick’s Law of Diffusion) -CSHT : time taken to eliminate 50% of a drug following an infusion, balance between distribution and clearance. Smaller CSHT, generally shorter recovery. -Clearance : the volume of blood cleared of a drug per unit time. Hepatic and renal clearance, determines elimination of drug and therefore diffusion from biophase. Decreased clearance, longer recovery. Renal : RBF, GFR, tubular absorption, secretion, MW, solubility, degree of ionization Hepatic : ER, HBF, inducers, inhibitors Other : hypothermia, age -Vd : short infusion duration and large Vd, there may be continued redistribution (adipose tissue) after infusion ceased, along with clearance. Hence, plasma concentration falls, increasing the gradient for diffusion from the biophase. However, during long infusions and large Vd, there may be saturation of the peripheral compartment (adipose tissue), resulting in leak back into the central compartment maintaining a high plasma concentration. Vd is increased with drug lipid solubility Pharmacodynamic factors -cessation of interaction of drug at effect site -if reversible action, recovery is related to factors discussed above, when drug diffuses out of biophase -if irreversiable action may require resynethsis of receptors (cholinesterase and organophosphates) or enzymes (COX and aspirin) to regain normal function -genetic factors : increased sensitivity to drug :eg myasthesinia gravis -tolerance -active metabolites -drug interations : synergists, antagonists |
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Pharm-01A11 Define the term 'context-sensitive half time'. How does this differ from the elimination half life? Illustrate your answer by comparing thiopentone vs. propofol, and fentanyl vs. remifentanil 64%
73% in 2005; 64% in 2004 |
Pharm-01A11 Define the term 'context-sensitive half time'. How does this differ from the elimination half life? Illustrate your answer by comparing thiopentone vs. propofol, and fentanyl vs. remifentanil 64%
CSHT is the time taken to eliminate 50% of drug from plasma following a continuous infusion to maintain a steady plasma concentration for a specific duration. Determined by clearance, distribution and duration of infusion. While elimination half time is the time taken to eliminate 50% of drug after a single bolus. T1/2=0.693Vd/Cl Thiopentone and propofol are intravenous anaesthetic agents which have a rapid onset and offset after single bolus use. However after an infusion the offset of both differs. Thiopentone has a T1/2 of 11 hours while propofol has a T1/2 of 5 hours. Thio is highly lipid soluble with Vd 2.5L/kg and Cl 3.5ml/kg/min, as a result with increasing duration of infusion the CSHT increases. Propofol is also highly lipid soluble with Vd 2-10L/kg and high Cl 30-60ml/kg/min as a result increasing duration of infusion CSHT plateaus (due to redistribution into adipose and clearance. Hence, propofol (due to its rapid clearance) results in a shorter elimination half life and CSHT (at 8 hours thio 3 hours while propofol 40 min). Fentynal T1/2 3-5 hours CSHT 260 min after 4 hours Vd 3-5L/kg Cl 15ml/kg/min while Remifentanil T1/2 8-20 min CSHT 6 min Vd 0.5L/kg Cl 60ml/kg/min Due to the small Vd, the peripheral compartment is quickly filled. Combined with a large clearance results in a short CSHT and elimination T1/2 |
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Pharm-00A14 Discuss the roles of the plasma esterases on drugs used in anaesthesia 67%
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Overview
Plasma esterases: * Responsible for hydrolysis of ester bonds & subsequent inactivation of certain drugs * High capacity clearance enzymes produced in liver/RBCs * Non-organ dependent drug metabolism with generally inactive metabolites. Pseudocholinesterase (plasma cholinesterase): * Responsible for metabolism of succinylcholine (SCh, suxamethonium) and ester local anaesthetics. * Synthesised in liver. 4 subunits, each having catalytic site. Suxamethonium * Plasma ChE has large capacity to hydrolyse SCh at rapid rate (only a small fraction of dose reaches NMJ). Plasma ChE is not present at NMJ, so neuromuscular blockade by SCh is terminated by SCh diffusing away from NMJ into the ECF. Plasma ChE controls SCh duration of action by controlling amount ofdrug hydrolysed prior to reaching site of action (NMJ). * Congenital dysfunction of plasma ChE: a single ChE gene is present, and mutations account for variants in enzyme. * Dibucaine number reflects quality of plasma ChE (ability to hydrolyse SCh). Dibucaine is a local anaesthetic drug, which inhibits NORMAL plasma ChE by 80%. * Normal genotype in 96% of popolation. * In a patient with homozygous atypical gene and a dibucaine number of 20 (20% inhibition of enzyme by dibucaine), a normal dose of SCh may last 3 hours or more. * Heterozygous mutation leads to dibucaine number of ~ 40-60, meaning a slightly prolonged SCh duration of effect. * Acquired dysfunction can also occur, with similar effects to congenital dysfunction. * Severe liver disease can lead to decreased levels of plasma ChE, enough to prolong efects of SCh. Levels need to be <75% of normal to be significant. * Neostigmine causes profound decrease in plasma ChE activity. After 30min, enzyme activity is still only 50%. Anticholinesterases, such as insecticides, chemo drugs (cyclophosphamide) and metoclopramide may clinically prolong effcets of SCh. Mivacurium * Rapid onset, short duration non-depolarising NMJ blocking drug. * 3 stereoisomers * 2 isomers metabolised by plasma ChE, causing short duration of action. * 3rd isomer cleared at a rate similar to intermediate acting NMB drugs., but lacks significant effects at NMJ. * Hydrolysis rate depends on concentration. Higher conc = more rapid breakdown. * Duration of action prolonged in patients with atypical plasma ChE. Ester Local Anaesthetics * Hydrolysis of esters by plasma ChE, mainly in plasma. * Systemic toxicity inversely proportional to rate of hydrolysis. * Metabolites inactive. * Atypical plasma ChE may result in toxic LA drug levels systemically. Non-specific plamsa esterases * Metabolises atracurium, remifentanil * Atracurium: spontaneous degradation at certain temp/pH Hoffman degeneration, 1/3 of drug), and hydrolysis by non-specific esterases (other 2/3 of drug). Laudanosine is major metabolite of either pathway, is inactive at NMJ, and is cleared mainly by liver. * Remifentanil is unique among opioids: metabolised by non-specific plasma ChE and tissue esterases to inactive metabolites. Inactive metabolites excreted renally. * Duration of action of atracurium/remifentanil similar in normal patients and those with renal/liver dysfunction. May be affected by hypothermia (eg. in cardiac surgery). * Esterase metabolism appears to be well-preserved system with little variability between individuals, so allows predictability of drug efect when infusing remifentanil. * Context-sensitive half-time for remifentanil is independent of duration of infusion, and is about 4 minutes. High clearance, so a short half-life. RBC esterases * Responsible for metabolism of esmolol and possibly remifentanil. * Esmolol: Fast onset. Short elimination half-life (9 mins), due to rapid hydrolysis of plasma ChE and RBC esterases. This is independent of liver/renal function, so is easily titratable. |
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Pharm-96A13 Describe briefly the factors determining transdermal uptake of drugs and give some examples of drugs that can be administered by the transdermal route. Briefly outline the advantages and disadvantages of transdermal administration of drugs. 79%
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Pharm-96A13 Describe briefly the factors determining transdermal uptake of drugs and give some examples of drugs that can be administered by the transdermal route. Briefly outline the advantages and disadvantages of transdermal administration of drugs. 79%
Transdermal drugs -used for local effects : eg EMLA cream -used for systemic effects : eg fentanil patches, GTN, hyoscine Factors determining systemic uptake -Fick’s Law of Diffusion -passive process down concentration gradient -Diffusion is directly proportional to surface area, lipid solubility, concentration gradient, fraction unionized, and inversely proportional to MW and thickness -SA : relatively constant, determined by size of patch, greater SA, greater systemic delivery -Lipid Solubility : fentanyl is highly lipid soluble compared to other opiods therefore is used as it freely crosses cell membrane -Concentration gradient : larger the gradient, the larger the uptake -factors affecting gradient : concentration of patch, skin blood flow due to increased vascularity, cardiac output, (diluting affect locally, increases concentration gradient, increased uptake), decreased with hypothermia, shock. -Fraction unionized : determined by pKa and pH of patch, unionized fraction moves past lipid membrane. Weak bases are unionized above their pKa and weak acids are unionized below their pKa. Polar compounds are not lipid solube eg muscle relaxants -MW : increased size will reduce diffusion -Thickness : increased thickness will reduce diffusion. For example inflammation due to infection. Pros -increased compliance -easy to administer, non invasive -avoid first pass metabolism (GTN) -slow transfer, therefore sustained systemic absorption and steady state Cons -slow absorption long onset of effect -special preparations required -local irritation -systemic toxicity -variability in response due to changes in skin perfusion etc |
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Pharm-95B2 Describe the clearance of drugs by the kidney
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Pharm-95B2 Describe the clearance of drugs by the kidney
Renal clearance is the volume of blood cleared of a drug by the kidney per unit time. Renal clearance occurs by glomerular filtration, active tubular secretion or passive tubular reabsorption. Glomerular filtration depends on -MW : -free concentration : determined by concentration/dose, degree of PPB, displacement -charge/ionization : pKa and environmental malleiu -RBF -for example Gallamine is completely cleared at glomerulus, it is not secreted or reabsorbed, therefore Cl=GFR Secretion -involves active transport mechanisms, highly selective -weak acids secreted more readily -eg penecillins -Cl=RBF Passive Reabsorption -high lipid solubility results in greater reabsorbed -dependent on urine pH and pKA =>influencing degree of ionization -weak bases ionized where pH below pKa -> therefore excretion is increased by acidifying urine and vice versa -also dependent on rate of tubular flow, greater the flow, the less time to diffuse. |
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Pharm-95B3 Give a brief account of drug protein binding and outline its significance
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Pharm-95B3 Give a brief account of drug protein binding and outline its significance
Protein binding is reversible reaction, it obeys the law of mass action Drug + Protein DP complex Proteins include 1. Albumin : abundant, high capacity, low specificity, multiple binding sites (6 total), high capacity, low specificity, mainly weak acids 2. Alpha 1 acid glycoprotein : less binding site, mainly for weak bases 3. lipoproteins 4. Red Cells 5. other tissue proteins, enzymes, receptors Bond between complexes are weak bonds : hydrogen, van de waals and ionic and therefore readily reversible. Amount of binding is dependent on 1. free drug concentration 2. affinity for binding 3. concentration of plasma proteins There is competition for binding sites with endogenous agents such as bilirubin and free fatty acids, with drugs. Only unbound drug is available to 1. cross membranes and diffuse into various compartments, therefore affects distribution 2. exert an effect, ie be able to interact with a receptor 3. be available for heptatic metabolism 4. renally excreted A drug with high protein binding will be greatly affected if there is a change in protein binding. eg. PB of 99% to 98% doubles the unbound concentration. This is a particular concern for drug with a low therapeutic index, eg warfarin. |
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Pharm-95A3 Define Phase I and Phase II reactions in drug metabolism. Provide examples with drugs used in anaesthesia. 70%
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Phase I and Phase II refer to the hepatic metabolism of drugs.
Phase I reactions are non synthetic reactions which add or remove functional groups usually to inactive drug metabolites which are more polar to be renally excreted. They are cytochrome P450 dependent systems Types 1. Oxidation (add electrons) a) hydroxylation : addition of a hydroxyl group eg propranolol, phenobarbital, phenytoin b) dealkylation, remove an alkane eg morpine, codiene c) N-oxidation : add hydroxyl group to nitrogen eg paracetamol d) S-oxidation : eg cimetidine e) deamination eg amphetamine and diazepam f) desulfuration eg thiopental Reductions remove electrons, usualy by adding proton eg methadone, nalxone, dantrolene Hydrolysis esters eg prcaine, sux amides eg procainamide, ligonocaine Phase II reactions -synthetic reactions -conjugation of various bulky endogenous substances to yield a water soluable complex Glucuronidation eg morphine actylation eg sulfonamides glutathione eg paracetamol glycine eg aspirin sulfation eg paracetamol methylation eg adrenaline HD NO SODA DS 3G ASM |
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Pharm-04A5 Outline the effects of liver failure on drug kinetics and dynamics. 52%
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Pharmacokinetics
Absorption/bioavailability Some drugs are absorbed due to “first pass effect”: absorbed into hepatic sinusoids, metabolised, enters systemic circulation. The lipid-soluble drugs absorbed via the GIT are usually made more water soluble by a healthy liver, increasing their volume of distribution. In failure, they are less water-soluble, so have an increased Vd. Distribution All proteins except factor VIII and gamma globulins are made in liver, in rough endoplasmic reticulum of hepatocytes. Albumin’s half-life = approx. 23 days. If [albumin] < 2.5g/dL, increased unbound portion of drug, especially acidic drugs. Alpha-1 acid glycoprotein binds basic drugs. Its decreased production in liver failure means less binding. This can result in increased toxic effects of some drugs (eg. phenytoin, prednisolone). Metabolism Decreased enzymatic metabolism of drugs in liver. Less first-pass metabolism. Potential for increased effect of GIT administered drugs. Pseudocholinesterase deficiency results in prolonged neuromuscular block due to suxamethonium and mivacurium. Also, prolonged t½ of remifentanil and esmolol. Note that plasma cholinesterase has serum T½ of about 14 days. Thus, in acute liver failure, esterases will still be active for a while. Local anaesthetics: * Ester LAs are broken down by esterases in blood. * Amide LAs are broken down in liver (and some other sites). Hepatic failure prolonges the t½ of LAs. Increased bile salts in plasma causes decreased uptake of pancuronium/vecuronium. (No effects on atracurium/cisatracurium, as broken down by Hoffman degeneration). Excretion * Renal excretion by glomerular filtration is of unbound drug. The higher [free drug] means greater clearance by kidneys, eg. Penicillin is almost 100% cleared in a single pass. * Decreased hepatic blood flow. * Hepatic clearance is secondary to hepatic blood flow, not plasma protein binding, (eg. Ketamine clearance due to blood flow). * Biliary excretion of drugs is mainly of those over 400-500 Daltons. This includes some antibiotics. This requires active transport by hepatocytes, which decreases in liver failure. Pharmacodynamics * Acid Base: Decreased albumin = decreased plasma oncotic forces = pulmonary oedema, can lead to respiratory alkalosis]]. * Secondary hyperaldosteronism leads to Hypernatraemia and hypokalaemia, which causes [[metabolic alkalosis. * Hepatorenal syndrome: Can be worse or occur sooner if volume depleted. Decreases renal excretion of drugs. * Hepatotoxicity: Hepatic failure can produce metabolites which themselves are hepatotoxic. * Coagulation: Because coagulation factors (II, VII, IX, X and V and fibrinogen) are made in liver, anticoagulants may have exacerbated effect. Normal clotting can occur with as little as 1/3rd of normal factor levels. * Encephalopathy/sedation: Can be worse with analgesics/sedatives, because underlying pathology adds to sedative effect. * Some drug effects decrease over time by redistribution, eg fentanyl. The first dose, therefore, may not show any difference in liver failure. Subsequent doses may show a difference, due to the metabolism being more importance, after various compartments are starting to get saturated. |
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Pharm-02B2 Briefly describe the factors affecting the uptake of orally administered medicines 67%
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General: Uptake of an orally administered drug will be dependent on:
1. Drug characteristics Passive diffusion is the most common method of absorption from the GIT. Uptake from GIT is dependent on rate of diffusion, which follows Fick’s law of diffusion. - Proportional to surface area, solubility (degree of ionisation), and concentration gradient across the membrane (↓P1-2). - Inversely proportional to molecular weight according to Graham's Law (<1000 Da increases absorption) and thickness (not controlled). pKa - degree of ionisation determines solubility. - Only unionised pass readily. - Acidic drugs (eg aspirin) are unionised in the acid stomach, are absorbed rapidly - Weak bases (eg propranolol) are ionised in the stomach (↓uptake), relatively unionised in the duodenum (↑uptake). Formulation: - delay absorption → ↑size of molecule, binding agents (eg enteric coated), granulated - rapid absorption → liquids Physicochemical interaction (↓P1-2): - gut contents/food/other drugs → bind/inactivate drug eg tetracycline bound with Ca2+ from milk eg bile salts, bacterial degradation Pharmacokinetics: metabolism at the gut wall (eg GTN) (↓P1-2) 2. Pt characteristics - Compliance with medication - Mucosal blood flow (↓P1-2) - Vomiting (↓A)→ Insufficient/inadequate exposure to GIT to allow absorption - Malabsorption syndrome/↑transit time (↓A)→ Acquired (eg tropical sprue) or congenital (Coeliac disease) → ↓effective area of absorption - Gastric stasis (↓A) → Illness, trauma, drugs. For most drugs gastric stasis results in ↓absorption, except for aspirin, which is unionised in the stomach, and will continue to be absorbed from there in event of gastric stasis |
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Pharm-07A4 Discuss the suitability of ketamine as a total intravenous anaesthetic agent in comparison with propofol. 25%
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Ketamine and Propofol are both intravenous anaesthetic agents that are commonly used in total intraveous anaesthesia.
Pharmaceutics: Ketamine - long shelf life and high concentrations available - advantageous for remote environments Propofol - limited shelf life due to lipid emulsion, risk of bacterial contamination Pharmacokinetics: Ketamine - accumulates with long infusion giving delayed offset of action - kinetics during infusion less well defined and no computerised infusion devices available - longer duration of action following bolus so more suited to use by intermittent IV administration - may also be used IM Propofol - little accumulation with infusion (shorter CSHT) - well defined pharmacokinetics with computerised infusion devices available so well suited to long IV infusion Pharmacodynamics: CNS Ketamine - dissociative anaesthesia, high rate of emergence phenomena when used alone in high concentration, potent analgesic, high rate PONV Propofol - favourable emergence profile, antiemetic, no analgesic effects - important to have supplementary analgesia Resp Ketamine - stimulates respiration, maintains airway reflexes relatively well Propofol - potent respiratory depressant, early apnoea and loss of airway reflexes - more important to have airway managment skills and adjuncts CVS Ketamine - direct myocardial depressant but stimulates sympathetic nervous system, increases HR, CO and BP Propofol - vasodilation with mild cardiac depression causing hypotension, especially if hypovolaemic - must have access to other drugs for maintaining BP Overall: Ketamine well suited to TIVA in less skilled hands or adverse environments due to CVS/Resp stability and less requirement for other drugs (analgesics, vasopressors, IV fluids). Propofol drug of choice in controlled environment with adequte resources because of favourable emergence and predictable pharmocokinetics |
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Pharm-06A4 Describe the pharmacodynamic properties of propofol and how this influences its clinical usage. 69%
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It was expected emphasis be placed on the central nervous system effects, followed by the cardiovascular and respiratory effects and marks were allocated accordingly. The question was specifically related to pharmacodynamics and a discussion of pharmacokinetic properties scored no additional marks.
Candidates were expected to outline that Propofol is an intravenous anaesthetic agent used for both the induction and maintenance of anaesthesia or sedation. Reward was given to candidates who outlined potential mechanisms of action, the dose dependent nature of effects, the effects on the EEG and on cerebral metabolism. Further credit was given for describing how this might impact on its clinical use (e.g. neurosurgery). A description of the cardiovascular effects was expected to include reference to hypotension, reduced systemic vascular resistance and bradycardia with comment on those patients at risk. Respiratory effects include alterations in ventilatory response, reduction in airway reflexes and bronchial tone. Extra credit was given for discussion of other pharmacodynamic properties including; anti-emetic, anti-pruritic, non MH triggering, pain on injection, lipid/caloric load, reduction in intraocular pressure and risk of propofol infusion syndrome. It was expected that candidates would relate each pharmacodynamic effect to the impact on clinical use and failing to address this was a common omission (e.g. reduction of airway reflexes is useful for LMA insertion or airway manipulation). Well organised answers such as those with an ordered list with subheadings or a table were rewarded. |
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Pharm-05A3 What factors may explain the inter-individual variability in drug response seen with intravenous anaesthetic induction agents?
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Answers that were divided into pharmacokinetics and pharmacodynamics were usually more coherent than those that tried to present a single list of factors (age, liver disease, drugs etc) that was incomplete. The pharmacokinetic factors were those related to transporting the drug to the effect site and determining the concentration there. It was thus important to discuss regional blood flow, volumes of distribution and clearance that would determine the concentration gradients between the plasma and the effect site, and diffusion into the effect site. These would in turn be affected by genetic, physiological (e.g. age), pathological (e.g. hypovolaemia) and external factors (e.g. other drugs). Variations in drug metabolism were commonly mentioned, but few qualified this answer by noting that the offset of action was mainly by redistribution. Pharmacodynamic variability may be the result of differences in end-organ sensitivity, receptor regulation, or direct and indirect effects from various physiological, pathological and external factors including drug interactions. Genetic polymorphisms should have some effect, but they are not well characterized at present.
Although induction of anaesthesia (onset and duration) was the primary effect, it was important to remember that there are other common or idiosyncratic effects of the induction agents (e.g. hypotension, porphyria) that show inter-individual variability. Some candidates incorrectly wrote about differences between the various drugs, or used examples that were not relevant to intravenous induction agents. It was not sufficient to list factors without demonstrating an understanding of the concepts involved. For example, if changes in cardiac output and volume of distribution (etc.) were listed as factors, it was also important to indicate in which direction the drug response would be affected. |
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Pharm04-B7 Outline the factors which influence the elimination half life of propofol. 29%
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Propofol is 2,6 di-isopropyl phenol
Half life = 0.693 Vd/Clearance (The time taken to decrease the amount of drug in the body by half) Metabolism * Liver (& ? extrahepatic) conjugation with renal excretion of inactive metabolites Factors affecting Vd: * Vd = Dose in body / plasma concentration * Protein binding (Normally 90-98%) * Vd normally 4-5 l/kg. (some sources as high as 10) Increased Vd * higher body fat, females, children (larger central compartment per kg) Decreased Vd * elderly (initial Vd - give smaller initial dose, due smaller central compartment) Factors affecting Clearance: * Clearance = the volume of plasma irreversibly cleared of drug per unit time * Hepatic Clearance = hepatic blood flow x extraction ratio (Cl = Q x ER) * Has high hepatic extraction ratio (>1.0), so enzyme induction or protein binding do not significantly increase clearance - it is FLOW-dependent * about 30ml/kg (exceeds Hepatic blood flow) * Propofol also cleared in lungs (as shown during anhepatic phase of liver transplant). * Propofol clearance is "flow limited" so decreased hepatic blood flow will decrease clearance. Decreased clearance * Severe liver disease (also higher Vd) * Decreased Q due to: Shock, SNS stimulation, drugs (including fentanyl and propofol itself), low cardiac output (eg. due cardiac disease). * Old age * Hypothermia (either by decr Q or altered intercompartmental kinetics) Increased Clearance * Children have larger central compartment vol (50%) and higher clearance (25%), so need and tolerate higher dose/kg. Overall * Severe liver disease (incr Vd and decr HER thus prolonged elim half life) * Women have higher Vd and Clearance rates. Overall elimination T1/2 similar between sexes. * Critical illness: greater pharmacokinetic variability * Renal Clearance is 0.3% unchanged. Renal disease will slightly increase T1/2 * individual variability * hypothermia - increased t1/2 |
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Pharm-03B4 Describe how a computer-controlled infusion device targets and maintains constant blood concentrations of propofol. 33%
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Pharm-03B4 Describe how a computer-controlled infusion device targets and maintains constant blood concentrations of propofol. 33%
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Pharm-03A2 Outline the neuropharmacology of thiopentone, covering only its site of action, EEG changes, effects on cerebral blood flow and intracranial pressure. 80%
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1. Definition: an IV anaesthetic, barbituric acid derivative.
2. Structure : * diagram * sulphur group gives lipid solutbility * C5 substitutions give sedative and anticonvulsant activities. 3. Mechanism * increases duration of GABA dependent chloride channel opening; GABA being an inhibitory neurotransmitter widely distributed throughout the CNS; mostly postsynaptic (IPSPs) 4. PK * highly lipid soluble, protein bound 80%, pKa 7.9 * % free and unionised only approx 10% (or 12%) * But high lipid solubility of drug and high proportion of blood to brain (usually) means fast onset of action. * Zero order kinetics in prolonged infusions = prolonged sedation. 5. PD / Effects 1. Anaesthesia 2. Isoelectric EEG 3. Decrease CMRO2 4. Cerebral Vasoconstriction (due to decreased CMRO2 = Flow-Metabolism Coupling) 6. Adverse Effects 1. Prolonged sedation due to high CSHT after infusions 2. Inadequate Cerebral Blood Flow exacerbated by depressed blood pressure and cardiac output; may require vasopressors to maintain cerebral perfusion. 3. Active metabolite pentobarbitone (sedative anticonvulsant) NB: Please be aware that much of the above is not relevant to this question as the question only wanted information pertinent to: * site of action * EEG changes * effects on cerebral blood flow and ICP |
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Pharm-02A16 Briefly outline the pharmacology of flumazenil. 45%
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Structure: 1,4-imidazobenzodiazepine derivative.
Uptake: Rapid onset IV, but brief duration of action. PO dose rapidly absorbed, but ++ first pass metabolism = 25% reaches systemic circulation. Pharmacodynamics: Competetive, reversible BZD antagonist. High affinity for BZD receptors. May also stimulate BZD receptors (minimally). T1/2 approx 1 hour (shorter than BZDs), and duration of effect = 30-60 minutes, so drowsiness returns. . Binds to GABA receptor in A (active) and B (inactive) configurations, so is thought to antagonise effect of both agonists and inverse agonists. Metabolism: Mostly in liver, inactive metabolites. Dose: 0.2mg, then 0.1mg per minute until recovery. SFX: anxiety, may precipitate convulsions (possibly due to inverse agonist effect at GABA receptors, and more likely in patients on TCAs). Also reduces anterograde amnesia caused by BZDs. |
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Pharm-01A13 Outline the NON-ideal features as an intravenous induction agent of the current formulations of propofol 55% |
1. Pharmaceutics; complex formulation, possible bacterial growth, incompatibilities and difficulty of detection, glass packaging, expense |
