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827 Cards in this Set

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All of the following may occur in migraine headaches EXCEPT:
A. Vasoconstriction.
B. Cerebral ischemia.
C. Increased extracellular [K+], resulting in hyperpolarization and depressed cortical function.
D. Release of substance P and CGRP from sensory C fibers of the trigeminal nerve.
E. Vasodilation.
F. Plasma extravasation.
C
A, E. Cerebral blood flow typically undergoes a biphasic change during a migraine headache: an initial vasoconstriction → ↓cerebral blood flow (the hyporemia or oligoremia phase), followed by a secondary vasodilation (the hyperemia phase).
B. Ischemia (≡ obstruction of blood supply) is essentially synonymous with hyporemia/oligoremia.
C. Increased extracellular [K+] causes depolarization, not hyperpolarization. Note that this increase in extracellular [K+] is caused by the O2 deprivation that occurs during the initial hyporemia/oligoremia phase.
D. Sensory C fibers of the trigeminal nerve become sensitized during the hyporemia/oligoremia phase and release substance P and CGRP.
F. Substance P/CGRP cause additional vasodilation and plasma extravasation.
All of the following are true regarding the treatment of migraine headaches EXCEPT:
A. NSAIDs often can terminate mild headaches.
B. Ergotamine is the agent of choice for mild headaches because it has the fewest side effects.
C. Sumatriptan can terminate severe headaches in most patients.
D. Propranolol is useful as prophylactic therapy in patients with frequent migraines.
E. Verapamil is useful as prophylactic therapy in patients with frequent migraines.
B
B. Ergotamine can be effective in the treatment of migraine, but it is not the agent of choice because it can cause limb ischemia and other side effects. Since the introduction of the triptans, it is used primarily in resistant cases.
C. Sumatriptan can terminate migraine headaches in over 70% of patients!
D, E. Both β adrenergic antagonists (e.g., propranolol) and Ca2+ channel blockers (e.g., verapamil) can be used as prophylactic therapy in patients with frequent migraines. Other drugs that can be used prophylactically for frequent migraines include TCAs (e.g., amitriptyline), and antiepileptic drugs (e.g., valproic acid and topiramate).
A. 5-HT1 receptors
B. 5-HT2 receptors
C. 5-HT3 receptors
D. 5-HT4 receptors
E. All of the above
F. None of the above

Ligand-gated ion channels?
C 5-HT3 receptors are ligand-gated ion channels; the remaining 5-HT receptors are GPCRs.
A. 5-HT1 receptors
B. 5-HT2 receptors
C. 5-HT3 receptors
D. 5-HT4 receptors
E. All of the above
F. None of the above

Stimulation by sumatriptan accounts for its antimigraine effects?
A Sumatriptan is a 5-HT1B/D agonist; this agonist effect is believed to (1) block the release of substance P and CGRP from sensory C fibers of the trigeminal nerve (presynaptic effect); and/or (2) cause cerebral vasoconstriction, thereby counteracting the cerebral vasodilation that occurs in the hyperemia phase and that also is produced by substance P and CGRP.
A. 5-HT1 receptors
B. 5-HT2 receptors
C. 5-HT3 receptors
D. 5-HT4 receptors
E. All of the above
F. None of the above

Stimulation by ondansetron accounts for its antiemetic effects?
F The antiemetic effects of ondansetron result from blockade, not stimulation, of 5-HT3 receptors
A. Apomorphine
B. Cisplatin
C. Metoclopramide
D. Promethazine
E. Scopolamine

Causes emesis by stimulating 5-HT release from enterochromaffin-like cells in the intestinal mucosa?
B Cisplatin, a drug used in cancer chemotherapy, can increase 5-HT release from ECL cells in the intestinal mucosa. The 5-HT then stimulates 5-HT3 receptors on vagal afferents, thereby eliciting the vomiting reflex.
A. Apomorphine
B. Cisplatin
C. Metoclopramide
D. Promethazine
E. Scopolamine

Causes emesis by stimulating D2 receptors in the chemoreceptor trigger zone?
A Apomorphine stimulates D2 receptors in the chemoreceptor trigger zone (CTZ), which in turn stimulates the vomiting center.
A. Apomorphine
B. Cisplatin
C. Metoclopramide
D. Promethazine
E. Scopolamine

Inhibits emesis by blocking D2 receptors in the chemoreceptor trigger zone and by increasing the rate of gastric emptying?
C Both metoclopramide and promethazine block D2 receptors, but only metoclopramide also increases the rate of gastric emptying.
A. Apomorphine
B. Cisplatin
C. Metoclopramide
D. Promethazine
E. Scopolamine

Widely employed for the prevention of motion sickness?
E Remember the Transderm Scop® patch discussed in Winter POP! The antimotion sickness effect of scopolamine probably is due to its ability to block the mAChRs that are involved in mediating vestibular input to the CTZ.
All of the following are correct regarding the sensitivity to local anesthetics EXCEPT:
Less Sensitive , More Sensitive
A. Large fiber diameters, Small fiber diameters
B. Myelinated fibers, Unmyelinated fibers
C. A fibers, C fibers
D. Sympathetic preganglionic fibers, Sympathetic postganglionic fibers
E. Motor fibers to skeletal muscle, Sensory fibers from pain receptors
F. Higher frequency of depolarization, Lower frequency of depolarization
F D. Recall that autonomic preganglionic fibers always are myelinated, whereas autonomic postganglionic fibers always are unmyelinated.
F. Since local anesthetics (LAs) block Na+ channels by entering the open channel from the cytoplasmic side, a greater frequency of depolarization results in more frequent channel opening and therefore an increased likelihood of block.
Local anesthetics:
A. Typically have pKas below 6.0.
B. Are injected in acidic solutions to increase their solubility.
C. Only protonated molecules cross cell membranes.
D. Only unprotonated molecules block Na+ channels.
E. Block Na+ channels by a mechanism similar to tetrodotoxin.
B A. LAs are weak bases with pKas typically ≈ 8 to 9.
B. In an acidic solution, a weak base LA is more likely to be in the protonated (ionized) form and therefore is more soluble. Following injection into the ECF, the higher pH (7.4) favors the formation of the unprotonated, nonionized form, which is then able to cross cell membranes. The somewhat lower ICF pH (≈ 6.8) favors the formation of the protonated, ionized form, which then enters the Na+ channel from the cytoplasmic side and blocks it.
C. Only unprotonated, nonionized LAs cross cell membranes.
D. Only protonated, ionized LAs block Na+ channels.
E. Peptide Na+ channel blockers such as TTX and saxitoxin block Na+ channels from the outside.
Regarding local anesthetics:
A. Cardiovascular toxicity (e.g., decreased contractility, decreased conduction velocity) typically is seen at lower plasma concentrations than CNS toxicity (e.g., convulsions, coma).
B. A patient who develops a rash after using an OTC ointment containing benzocaine should not receive bupivacaine.
C. Vasoconstrictors such as epinephrine can be used to prolong the duration of action of local anesthetics administered by infiltration for hand surgery.
D. Procaine has a longer duration of action than bupivacaine.
E. Neurological complications are more common following intrathecal (subdural) administration than epidural administration.
E A. Cardiovascular toxicity is seen at higher plasma concentrations than CNS toxicity.
B. Benzocaine is an ester, so a patient is most likely to develop future hypersensitivity reactions to other ester LAs, such as procaine or tetracaine.
C. Vasoconstrictors can be used to prolong the duration of action of LAs administered by infiltration (intradermal injection in the immediate area of surgery), but are not used in appendages because of the danger of ischemia and tissue necrosis.
D. Procaine has a short duration of action (t1/2 ≈ 30 min, which is the shortest t1/2 of the ester LAs used clinically). Bupivacaine has a long duration of action (t1/2 ≈ 4 to 6 hr, which is the longest t1/2 of the amide LAs used clinically).
E. Neurological complications (e.g., CSF leakage, resulting in headaches) are more likely with intrathecal (subdural) administration (aka spinal anesthesia), since the dura mater is penetrated.
A. ACh L. Ca2+
B. Dopamine M. K+
C. GABA N. Na+
D. Glutamate O. Cl-
E. Serotonin P. μ
F. Substance P Q. κ
G. Brainstem R. δ
H. Dors. root gang. S. Depolarizing
I. Nodose ganglion T. Hyperpolarizing
J. Dorsal horn of spinal cord
K. Ventral horn of spinal cord
C fiber afferents transmit painful stimuli from the periphery to the CNS. The somas of these neurons are in the 7. . In the CNS, the fibers terminate in the 8. , where they release 9. . Opioids act at presynaptic 10. receptors on the C fiber that can inhibit the release of this neurotransmitter by blocking voltage-gated 11. channels. Opioids also can act at 12. receptors on second-order neurons in the 13. to inhibit the excitatory effects of 14. by increasing the 15. permeability, thereby 16. the neuron.
7. H
8. J
9. F
10. P
11. L
12. P
13. J
14. D
15. M
16. T
Which of the following volatile anesthetics has the most “ideal” properties?

MAC (%), PCfat/blood, PCblood/gas
A. 0.5 1.5 0.8
B. 3.0 4.0 6.5
C. 7.0 5.0 12.5
D. 50.0 20.0 10.5
E. 102.0 3.0 2.2
A The “ideal” volatile anesthetic would have a low MAC (high potency; therefore, not much gas is needed – and many of the volatile anesthetics are expensive to purify!), a low PCfat/blood (not much partitioning into fat), and a low PCblood/gas (i.e., a low solubility → rapid onset and recovery). Other qualities of an “ideal” anesthetic include analgesia, amnesia, muscle relaxation, non-toxic, non-explosive, inexpensive, rapid changes in depth of anesthesia, no excessive depression of cardiovascular and respiratory function, etc. It should be noted, however, that it is unlikely that a volatile anesthetic as “ideal” as the one described in choice A could be identified: a highly potent agent (MAC 0.5%) is likely (according to the Overton-Meyer hypothesis) to be quite lipid soluble and therefore would be expected to have a relatively high PCfat/blood (much greater than 1.5).
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 6 liters/min and a ventilation of 7 liters/min. The anesthetic has the following properties:
MAC = 2.0%
PCtissue/blood ≈ 1.0
PCblood/gas = 0.6
PCfat/blood = 5.0

38. The concentration of the anesthetic in blood at equilibrium is approximately:
A. 12%
B. 3.3%
C. 2.0%
D. 1.2%
E. 0.6%
F. None of the above
D PCblood/gas = cblood/calveolar, so cblood = PCblood/gas • calveolar = 0.6 • 2.0% = 1.2%. Regarding the % unit, you are familiar with this unit from the Respiratory Physiology section of OP; FIO2 = 0.21 or 21% is an example. In anesthesiology, the % unit is used not only for anesthetic concentrations in a gas phase (i.e., for calveolar), but also (somewhat inappropriately!) for cblood (as in this question), cfat (see question 39), etc.
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 6 liters/min and a ventilation of 7 liters/min. The anesthetic has the following properties:
MAC = 2.0%
PCtissue/blood ≈ 1.0
PCblood/gas = 0.6
PCfat/blood = 5.0

The concentration of the anesthetic in fat at equilibrium is approximately:
A. 60%
B. 16.5%
C. 10%
D. 6%
E. 0.24%
F. None of the above
D PCfat/blood = cfat/cblood, so cfat = PCfat/blood • cblood = PCfat/blood • PCblood/gas • calveolar = 5 • 0.6 • 2.0% = 6%.
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 6 liters/min and a ventilation of 7 liters/min. The anesthetic has the following properties:
MAC = 2.0%
PCtissue/blood ≈ 1.0
PCblood/gas = 0.6
PCfat/blood = 5.0

The time required for the anesthetic in arterial blood to equilibrate with alveolar gas (PPblood ≈ PPalveolar):
A. Can be shortened by administering the anesthetic at 2.0 MAC instead of 1.0 MAC.
B. Can be shortened by increasing the ventilation.
C. Is longer than for an anesthetic with a PCblood/gas = 6.0.
D. Is independent of the cardiac output.
E. Is approximately 7 min.
E
A. The anesthetic has a PCblood/gas less than 1.2 and is therefore a low solubility agent. Thus, equilibrium between alveolar gas and blood is achieved relatively quickly, and the time required for equilibration (PPblood ≈ PPalveolar) is approximately equal to the time required for a volume of blood equal to the total body water to pass through the pulmonary capillaries, i.e., the time required is independent of MAC or PPalveolar. Therefore, administering the anesthetic at a PP of 2.0 MAC instead of 1.0 MAC will not shorten the time required for equilibration and induction of anesthesia. However, with a high solubility agent (PCblood/gas > 1.2), the time required for equilibration is approximately equal to the time required to breathe in the volume of gas that is needed to fill the total body water with the anesthetic. In this case, administering the anesthetic at a PP of 2.0 MAC instead of 1.0 MAC (over pressure) can be used to speed equilibration and induction of anesthesia.
B. For a low solubility agent, the time required for equilibration and induction of anesthesia is rate-limited by the cardiac output, not ventilation. Thus, increasing the ventilation will not shorten the time required for equilibration.
C. The time required for equilibration of a low solubility agent is relatively short: as noted above (see answer to choice A), it is approximately equal to the time required for a volume of blood equal to the total body water to pass through the pulmonary capillaries. The patient in this question has a total body water of 42 liters (0.6 • 70 kg) and a cardiac output of 6 liters/min; hence, the time required for a volume of blood equal to the total body water to pass through the pulmonary capillaries is ≈ 7 min (42 liters ÷ 6 liters/min). Equilibration therefore will occur in ≈ 7 min. In contrast, for an anesthetic with a PCblood/gas = 6.0 (a high solubility agent), the time required for equilibration is approximately equal to the time required to breathe in the volume of gas that is needed to fill the total body water with the anesthetic. With a total body water of 42 liters and a PCblood/gas = 6.0, the volume of gas needed to fill the total body water is ≈ 252 liters (= 6 • 42 liters); with a ventilation of 7 liters/min, the time required to breathe in this volume of gas is ≈ 36 min (252 liters ÷ 7 liters/min). Equilibration therefore will occur in ≈ 36 min. Note that if this high solubility agent were used, the anesthesiologist would not want to wait 36 min for equilibration and induction of anesthesia! He/she would therefore start by administering the anesthetic at a higher PP (> 1.0 MAC) (over pressure; see answer to choice A), and then reduce the PP once anesthesia is induced.
D. As noted above (see answer to choice B), the time required for equilibration of a low solubility agent is rate-limited by the cardiac output.
E. This calculation was explained in the answer to choice C.
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 5 liters/min and a ventilation of 6 liters/min. The anesthetic has the following properties:
MAC = 1.4%
PCtissue/blood ≈ 1.0
PCblood/gas = 1.4
PCfat/blood = 48

The concentration of the anesthetic in blood at equilibrium is approximately:
A. 2.8%
B. 2%
C. 1.4%
D. 0.02%
E. None of the above
B PCblood/gas = cblood/calveolar, so cblood = PCblood/gas • calveolar = 1.4 • 1.4% ≈ 2%.
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 5 liters/min and a ventilation of 6 liters/min. The anesthetic has the following properties:
MAC = 1.4%
PCtissue/blood ≈ 1.0
PCblood/gas = 1.4
PCfat/blood = 48

The concentration of the anesthetic in fat at equilibrium is approximately:
A. 134%
B. 94%
C. 67%
D. 1.3%
E. 0.94%
F. None of the above
B PCfat/blood = cfat/cblood, so cfat = PCfat/blood • cblood = PCfat/blood • PCblood/gas • calveolar = 48 • 1.4 • 1.4% ≈ 94%.
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 5 liters/min and a ventilation of 6 liters/min. The anesthetic has the following properties:
MAC = 1.4%
PCtissue/blood ≈ 1.0
PCblood/gas = 1.4
PCfat/blood = 48

If the partial pressure of the anesthetic in the mask is 0.01 atm (≈ 1.4% of 1 atm), the partial pressure of the anesthetic in the fat at equilibrium is approximately:
A. 1.40 atm
B. 0.67 atm
C. 0.48 atm
D. 0.14 atm
E. 0.01 atm
F. None of the above
E At equilibrium, the partial pressure of the anesthetic in all body compartments is approximately the same as the partial pressure of the anesthetic in the mask!!
A volatile anesthetic is administered at 1.0 MAC to a patient weighing 70 kg, of which 60% is water and 15% is fat. The patient has a cardiac output of 5 liters/min and a ventilation of 6 liters/min. The anesthetic has the following properties:
MAC = 1.4%
PCtissue/blood ≈ 1.0
PCblood/gas = 1.4
PCfat/blood = 48

Assuming that fat gets approximately 6% of the cardiac output, the time that would be required for the anesthetic in fat to equilibrate with arterial blood is approximately:
A. 1 hr
B. 12 hr
C. 24 hr
D. 1½ days
E. 2 days
F. 3½ days
G. 5 days
F The time required for the anesthetic in a given tissue to equilibrate with arterial blood is approximately equal to three time constants (TCs) for equilibration of that tissue with arterial blood, where the TC is defined as the ratio of the capacity of the tissue for the anesthetic to the blood flow delivering anesthetic to that tissue. In this question, the capacity of fat for the anesthetic = Vfat • PCfat/ he capacity of fat is ≈ 500 liters (≈ 10.5 liters • 48). The blood flow to fat is 6% of the cardiac output = 0.06 • 5 liters/min = 0.3 liters/min. So the TC = capacity/blood flow = 500 liters ÷ 0.3 liters/min = 1667 min, and 3•TC = 5000 min ≈ 3.5 days, i.e., because fat has a large capacity for this anesthetic (which has a relatively high PCfat/blood) and a low blood flow, a very long time is required for this anesthetic in fat to equilibrate with arterial blood! Fortunately, such equilibration is not required to perform a surgical procedure!! Equilibration with the organs in the vessel-rich group (VRG), especially the brain, is most important!
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Least potent?
E Recall that potency is reciprocally related to the MAC.
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Most Potent?
B
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Can only achieve stage I or stage II of anesthesia?
E
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Most rapid onset and recovery of agents that can be used to achieve stage III of anesthesia?
D All agents listed except N2O can be used to achieve stage III (the surgical stage), but desflurane has the most rapid onset and recovery because of its low solubility (PCblood/gas = 0.45).
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Irritating agent that can form explosive peroxides?
A
MAC*(%), PCblood/gas, PCfat/blood
A. Ether 7, 12, 5
B. Isoflurane 1.4, 1.4, 45
C. Sevoflurane 2, 0.65, 48
D. Desflurane 6, 0.45, 27
E. Nitrous oxide 105, 0.47, 2.3

Approximately 0.02% of inhaled dose is metabolized by cytochrome P450?
D Desflurane undergoes the least cytochrome P450 metabolism (0.02%) of all halogenated hydrocarbon volatile anesthetics. This is important because the centrilobular necrosis that occasionally is seen with halothane, the first halogenated hydrocarbon volatile anesthetic, probably is caused by a free radical intermediate generated during P450 metabolism (approximately 20% of an inhaled dose of halothane is metabolized by cytochrome P450) and probably is the cause of halothane hepatitis (primarily for this reason, the use of halothane has declined markedly in recent years).
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Short-acting agent (due to
redistribution from brain to other tissues; metabolism actually is slow [metabolic t1/2 ≈ 24 hr]) that often is used for induction of anesthesia?
E Propofol also is a short-acting agent, primarily as a result of redistribution from brain to other tissues. But propofol has a metabolic t1/2 ≈ 30 – 60 min, so metabolism also contributes to its short duration of action. Because its metabolic t1/2 is so much shorter than that of thiopental (metabolic t1/2 ≈ 24 hr), propofol does not accumulate in adipose tissue as thiopental does.
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Related to phencyclidine; affects NMDA receptor?
B
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Should be avoided in patients with certain forms of porphyria?
E Barbiturates are contraindicated in patients with certain porphyries (variegate and intermittent) because they can induce ALA synthase.
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Can cause respiratory depression and rigidity of jaw, neck, and upper torso?
A Rigidity of the jaw, neck, and upper torso can be seen with other opioid analgesics as well and probably is due to a central effect of these agents
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Can cause emergence psychosis?
B Emergence psychosis can be avoided or minimized by prior administration of a benzodiazepine and allowing the patient to recover in a dark room.
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Can cause an increase in blood pressure?
B Ketamine is contraindicated in patients with hypertension
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Can have hyperalgesic effects?
E
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Used as a preanesthetic agent to reduce anxiety and produce amnesia?
C
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Administered in a fat emulsion that is easily contaminated?
D
A. Fentanyl
B. Ketamine
C. Midazolam
D. Propofol
E. Thiopental

Effects can be reversed by flumazenil?
C Flumazenil is a competitive antagonist at the BDZ binding site on the GABAA receptor
Important principles in anesthesia include:
A. A constant depth of anesthesia should be maintained throughout a surgical procedure.
B. Barbiturates such as secobarbital can be used as preanesthetic medications to decrease anxiety.
C. Atropine is an important preanesthetic medication because it decreases upper respiratory secretions.
D. Propranolol and other β antagonists should be discontinued prior to surgery to avoid cardiac depression and bradycardia.
E. Spinal anesthesia is safer than general anesthesia in patients taking anticoagulants.
F. All of the above.
G. None of the above.
G A. The depth of anesthesia is appropriately varied throughout a surgical procedure. For example, greater depth may be required during intubation or while making an incision.
B. Barbiturates are useful only for their sedative effects; they do not significantly decrease anxiety in a surgical setting (for example, they are much less anxiolytic than a visit from an anesthesiologist!). Even as sedatives they are not the agents of choice because barbiturates cause cardiovascular and respiratory depression and can have hyperalgesic effects.
C. When highly irritating general anesthetics such as ether were commonly used, atropine was routinely given as a preanesthetic medication to decrease upper respiratory secretions. With newer, less irritating anesthetics, atropine only is given as needed during a procedure to counteract major decreases in heart rate (e.g., due to opioids or vagovagal reflexes elicited by the surgical manipulation of abdominal viscera).
D. β Antagonists such as propranolol should not be discontinued immediately prior to surgery, because abrupt withdrawal can cause arrhythmias (probably because up-regulation of β receptors occurs when a patient takes β antagonists chronically). However, the dose of the β antagonist should be reduced prior to surgery if possible.
E. In patients taking anticoagulants, spinal anesthesia is much more dangerous than general anesthesia.
A. Depolarizing agents
B. Competitive agents
C. Both
D. Neither

Can cause two phases of block?
A
A. Depolarizing agents
B. Competitive agents
C. Both
D. Neither

Action can be terminated by the administration of an anti-ChE?
B An anti-ChE will potentiate the neuromuscular blockade produced by depolarizing agents.
A. Depolarizing agents
B. Competitive agents
C. Both
D. Neither

Class includes drugs that can be inactivated by BuChE?
C The depolarizing agent succinylcholine and at least one competitive agent (mivacurium) can be hydrolyzed by BuChE (aka plasma cholinesterase). The competitive agent atracurium is hydrolyzed by plasma esterases (not cholinesterases) and also can undergo spontaneous hydrolysis in plasma.
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Analgesic with a toxic metabolite that may cause seizures?
D The metabolite normeperidine may be responsible for the seizures caused by high doses of meperidine.
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Neuromuscular blocking agent with most rapid onset of action?
I Rocuronium also has a rapid onset of action, but not as rapid as succinylcholine.
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Neuromuscular blocking agent with shortest duration of action?
I Mivacurium also has a short duration of action, but not as short as succinylcholine
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Neuromuscular blocking agent that is hydrolyzed spontaneously as well as by plasma esterases?
B
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Neuromuscular blocking agent that is contraindicated in patients with soft tissue injuries or burns?
I Succinylcholine can cause life-threatening hyperkalemia (by causing prolonged opening of the ion channel of the NM receptor), particularly in patients at risk for developing hyperkalemia. It is therefore contraindicated in patients with soft tissue injuries or burns, since these conditions also can cause a loss of K+ from cells
A. Aspirin
F. Mivacurium
B. Atracurium
G. Morphine
C. Dantrolene
H. Rocuronium
D. Meperidine
I. Succinylcholine
E. Midazolam
J. Thiopental

Must be available in all operating rooms?
C Dantrolene blocks Ca2+ release from the sarcoplasmic reticulum in skeletal muscle and is used to treat malignant hyperthermia, a life-threatening condition induced by halogenated hydrocarbon volatile anesthetics and by succinylcholine in a small number of patients (who apparently have a mutation in their skeletal muscle RyR1 receptors or L-type Ca2+ channels). Dantrolene also can be used to treat the neuroleptic malignant syndrome.
Concerning seizures and their therapy, all of the following are true EXCEPT:
A. Absence seizures occur primarily in children.
B. Only generalized seizures result in a loss of consciousness.
C. Seizures can be treated by drugs that block Na+ channels, such as phenytoin and carbamazepine.
D. Seizures can be treated by drugs that potentiate or facilitate GABAergic transmission, such as benzodiazepines, barbiturates, and gabapentin.
E. Seizures can be treated by drugs that reduce glutamatergic transmission, such as lamotrigine.
B B. Complex partial seizures also result in a loss of consciousness.
Concerning seizures and their therapy, all of the following are true EXCEPT:
A. A drug eliminated by first-order kinetics should be given approximately every t1/2 to avoid large fluctuations in plasma concentration.
B. When starting therapy with a drug eliminated by first-order kinetics, a steady-state plasma concentration is reached after approximately 4 to 5 half-lifes.
C. First-generation AEDs have clearly defined therapeutic ranges for plasma concentrations that can be used to decide if the patient is receiving the appropriate dose.
D. First-generation AEDs have teratogenic effects.
E. Most AEDs can cause nystagmus (involuntary spasmodic motion of the eyeballs).
F. For most AEDs, doubling the plasma concentration doubles the rate of elimination.
C A, B. These general pharmacokinetic principles were discussed in the POP Mini-Course.
C. Therapeutic ranges of AEDs are useful as guidelines only; there is much individual variability.
D. Teratogenicity is an important problem with first-generation AEDs; not enough data are yet available on the effects of fetal exposure to second-generation AEDs.
E. Nystagmus actually is a useful side effect, because it represents a good sign that the patient is in the therapeutic range.
F. Since most AEDs are eliminated by first-order kinetics, doubling the plasma concentration will double the rate of elimination: -dc/dt = kecp. Note that first-order kinetics of elimination often is referred to as linear kinetics, since a plot of average cp vs dose is linear (as predicted from the equation for the calculation of the maintenance dose: MD = Clearance • cpss/Bioavailability). Non-linear kinetics include zero-order kinetics (phenytoin) and kinetics in which the clearance increases as cp increases (carbamazepine).
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Specifically blocks T-type Ca2+ channels in thalamic neurons?
B
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Metabolized by zero-order (dose-dependent) kinetics?
F Note that zero-order kinetics of elimination often is referred to as dose-dependent kinetics: at low doses (before the elimination mechanism is saturated), elimination often is first-order¬; as the dose increases (and the elimination mechanism becomes saturated), elimination becomes zero-order.
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Eliminated entirely by renal excretion?
C
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Used only for absence seizures?
B
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

First choice broad spectrum agent?
G
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Can cause gingivitis (gum hypertrophy) and hirsutism (heavy growth of hair) with long-term use?
F
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Can cause alopecia (hair loss) and weight gain with long-term use?
G
A. Carbamazepine
B. Ethosuximide
C. Gabapentin
D. Lamotrigine
E. Phenobarbital
F. Phenytoin
G. Valproic acid

Can cause blurred vision and diplopia at high doses?
A
In the CNS, dopamine is:
A) Less abundant than NE
B) localized primarily in neurons with a diffuse pattern of innervation
C) metabolized to 5-HIAA
D) primarily an agonist at ionotropic receptors
E) released from nerve terminals by amphetamine
E
In a neuron that receives glutamatergic and GABAergic input, NMDA receptor activation is most likely to occur when:
A) glutamate release is decreased, GABA release is decreased, glycine is absent
B) glutamate is decreased, GABA release is decreased, glycine is present
C) glutamate is increased, the membrane potential is held constant, glycine is present
D) glutamate release is increased, GABA release is increased, glycine is present
E) glutamate release is increased, GABA release it decreased, glycine is present
E
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

which one is an indoleamine?
L
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

most abundant transmitter in CNS?
F
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

Most abundant catecholamine is the CNS?
D
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

NT whose effects are terminated primarily by enzymatic degradation?
A
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

Blocks ion channel?
K
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

Blocks GABA binding site?
C
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

blocks glycine binding site?
M
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

precursor is a major excitatory neurotransmitter in the CNS?
E
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

Metabolized to a neurotoxin?
H
A. ACh
B. Baclofen
C. Bicucculine
D. Dopamine
E. GABA
F. Glutamate
G. glycine
H. MPTP
I. NMDA
J. Norepinephrine
K. picrotoxin
L. serotonin
M. strychnine

Metabolized to HVA in the CNS?
D
Conventional antipsychotic drugs as a class:
A) show clinical potency that correlated with affinity for D1 dopamine receptors
B) cause postural hypotension due to blockade of mAChRs
C) increase the seizure threshold
D) inhibit prolactin secretion due to blockade of dopamine receptors in the tuberoinfundibular pathway
E) none of the above
E
Advantages of the atypical antipsychotic drug risperidone over conventional antipsychotics include:
A) alleviation of negative symptoms
B) lower addiction potential
C) lower cost
D) more rapid onset of action
E) no risk of EPS
A
The SSRI antidepressants as a class:
A) block presynaptic 5-HT2 receptors
B) cause insomnia
C) inhibit DA uptake
D) lack major CV side effects
E) take effect more rapidly than the TCAs
D
SSRIs inhibit a larger percentage of NE or 5-HT at a given dose?
Inhibit much more NE reuptake than 5-HT at a given dose.
Calculate the amount of ethanol consumption (i.e. the dose in grams) by a 60kg male patient whose blood ethanol level is 70mg%. Assume ethanol has a Vd of 0.65L/kg and a bioavailability of 1.0
27.3 gm.
Cp = Dose/VD; the dose must be multiplied by the bioavailability (F) if the drug is not administered IV (in this problem, as in many calculations with ethanol, bioavailability is assumed to be 1.0). Therefore Dose = Cp • VD = 700 mg/liter • 0.65 liters/kg = 455 mg/kg = 0.455 g/kg. So for this 60 kg patient, the dose is 0.455 g/kg • 60 kg = 27.3 gm.
True or False?
in acute alcohol toxicity, owing to high levels of ingested ethanol, P450 induction can lead to increased blood levels of acetylaldehyde?
False Cytochrome P450 is induced in chronic alcoholism, not acute alcohol toxicity.
True or False?
disulfiram must be metabolized by glutathione-S-transferase and S-methyltransferase before it can inhibit ALDH
false
Disulfuram must be metabolized by glutathione reductase and S-methyl transferase to form the active inhibitor of ALDH, diethylthiomethylcarbamate.
True or False?
Ethanol enhances hepatic triglyceride synthesis partly via induction of alpha methyl phosphate acyl transferase
false
Ethanol enhances hepatic triglyceride synthesis partly via induction of α-glycerol-phosphate acyl transferase.
True or False?
mild daily ethanol consumption (about 40ml) is associated with reduced plasma ratios of HDL:LDL and protection against coronary artery insufficiency
false
Mild daily ethanol consumption is associated with increased plasma ratios of [HDL]:[LDL].
True or False?
Reductive storage, a biochemical condition associated with ethanol consumption, can lead to lactic acidemia
true
True or False?
folate administration will increase intracellular levels of formic acid in patients suffering from methanol poisoning
false
Folate reduces intracellular levels of formic acid by accelerating its non-enzymatic conversion to CO2 and H2O.
True or False?
In the CNS, during acute elevations in blood ethanol, neuronal kainate and GABAa receptor activity are attenuated
false
During acute elevations in blood ethanol, neuronal kainite receptor activity is attenuated, but neuronal GABAA activity is enhanced.
True or False?
In the CNS, during acute elevations in blood ethanol, neuronal membrane fluidity and adenosine uptake are elevated
false
Membrane fluidity is increased, but adenosine uptake is inhibited.
True or False?
In the CNS, during acute elevations in blood ethanol, neuronal NMDA and Ca receptor activity are augmented
false
Neuronal NMDA and Ca2+ receptor activity are inhibited.
True or False?
In the CNS, during acute elevations in blood ethanol, vasomotor depression leads to cutaneous vasodilation
true
the pharmacokinetic properties that differ amongst the BDZs include all the following except:
A) biologic half-life
B) conversion to biologically active metabolites
C) glucuronidation as a required step in metabolism
D) extent to which the drug accumulates with successive doses
E) rate of entry into the brain
C
In choosing a sedative hypnotic for sleep therapy, it is important to recognize theat:
A) the available drugs are not effective inless used for a few weeks
B) daytime sedation is not a concern if the parent drug is rapidly metabolized
C) efficacy for more than a few months has not been proven with most agents
D) OTC hypnotics are safer and can be as effective as the BDZs
E) none of the above
C
list representative drugs that are classified as mu, delta, and kappa agonists.
μ agonists: morphine, meperidine, methadone, fentanyl, codeine (partial agonist) buprenorphine (partial agonist), β-endorphin (endogenous peptide)

δ agonists: leu- and met-enkephalin (endogenous peptides), β-endorphin (endogenous peptide)

κ agonists: butorphanol, dynorphins (endogenous peptides)
discuss the intracellular coupling of the mu opioid receptor
The μ opioid receptor is a GPCR that couples to Gi/Go, resulting in the inhibition of adenylyl cyclase, activation of K+ channels → membrane hyperpolarization, and inhibition of voltage-gated Ca2+ channels → ↓neurotransmitter release.
discuss the primary sites of action at which opioids act to produce analgesia
The primary sites at which opioids act to produce analgesia are the amygdala, substantia nigra, periaqueductal gray area (PAG), rostroventral medulla, and spinal cord. Of these sites, the mechanisms for analgesia in the PAG and spinal cord are best understood (see Figures 9 and 10 in the syllabus). In the PAG, opioid binding to presynaptic μ receptors on the nerve terminals of interneurons in the PAG → inhibition of voltage-gated Ca2+ channels →↓GABA release → reduced inhibition of PAG projections to the medulla → increased activation of bulbospinal projections (from medulla to spinal cord) → ↑5-HT and/or NE release in spinal cord → inhibition of spinal pain input. In the spinal cord (dorsal horn), opioid binding to presynaptic μ receptors on the terminals of C fibers activated by painful stimuli → inhibition of voltage-gated Ca2+ channels →↓release of peptide transmitters (e.g., substance P) from C fibers; also, opioid binding to μ receptors on second order neurons in dorsal horn → activation of K+ channels → membrane hyperpolarization → ↓excitability of second order neurons.
indicate the cardiac effects of morphine
The cardiovascular effects of morphine include (a) increased excitation of parasympathetic nerves that innervate the heart (vagus) → ↓heart rate (atropine-sensitive); and (b) release of histamine from mast cells → peripheral vasodilation and hypotension. Note that because opioids are typically well tolerated from a cardiovascular perspective, they are widely used as induction agents in cardiac surgery (especially fentanyl).
what is the WHO ladder?
The World Health Organization (WHO) ladder (Figure 24 in the syllabus) provides a model for graded analgesic therapy. It emphasizes starting with weak opioids and then progressing to stronger opioids for more severe pain states, using combination analgesic therapy (e.g., NSAIDS + opioids), and using adjuvants to manage side effects (e.g., laxatives, antiemetics, and stimulants).
Define tolerance, dependence, and addiction
Tolerance: a decrease in effectiveness of a drug over time with repeated administration; thus, an increased dose is required to yield an equivalent response after successive doses. With opioids, tolerance can be extreme, e.g., 10 mg PO is a high dose in a naïve individual, while 3 gm IV might produce only minor sedation in an extremely tolerant individual.
Dependence: state of adaptation to a specific drug such that abrupt cessation (e.g., by drug abstinence) and/or administration of a specific antagonist → withdrawal syndrome.
Addiction: drug-seeking behavior motivated by a strong desire to acquire a drug for non-therapeutic self-administration; an extreme form of dependence.
what is the origin of the pain associated with migraine?
While the origin of migraine pain is not completely understood, one proposed mechanism is as follows: A primary vasoconstriction (triggered by stress, anxiety, exercise, hunger, and/or various unidentified factors) causes a mild ischemia and results in sensitization of sensory afferents (C fibers) in the trigeminal nerve (CN V). This sensitization may lead to the local release of substance P (SP) and/or calcitonin gene-related peptide (CGRP); these peptides → local cranial vessel dilation, extravasation of plasma from the vessel, and the activation of mast cells. The vasodilation and products from the mast cells → stimulation of the sensitized trigeminal C fibers → pain.
what is the mechanism by which the triptan-like drugs are thought to relieve migraines?
The triptans are 5-HT1B/D agonists. They act at (a) presynaptic 5-HT1B/D receptors on the sensory afferents in the trigeminal nerve → ↓release of SP and/or CGRP; and (b) postsynaptic 5-HT1B/D receptors on the intracranial vessels → vasoconstriction.
what is the receptor at which the ondansetron-like drugs act?
Ondansetron and related drugs (the setrons) are 5-HT3 antagonists.
list two drugs that would be useful in treating the nausea arising from motion sickness
Nausea arising from motion sickness can be treated with anticholinergics (muscarinic antagonists) such as scopolamine [Transderm Scop®] and antihistamines (H1 antagonists) such as dimenhydrinate [Dramamine®] (dimenhydrinate is a salt of diphenhydramine). Note that the effectiveness of antihistamines in treating the nausea arising from motion sickness probably is due primarily to their anticholinergic activity.
what is the mechanism by which metoclopramide controls nausea?
Metoclopramide [Reglan®] controls nausea by blocking D2 receptors in the CTZ of the medulla (area postrema). Metoclopramide also has prokinetic effects in the GI tract (e.g., it increases gastric emptying) by acting as an agonist at 5-HT4 receptors on neurons in the enteric nervous system (ENS) → ↑ACh release.
Why would administration of methoxyflurane to an obese person for a long surgical procedure not only be expensive, but risky?
To understand why the administration of methoxyflurane (PCblood/gas = 12, PCfat/blood = 61; see Table 1 in the syllabus) to an obese person for a long surgical procedure would be both expensive and risky, one needs to calculate the amount of methoxyflurane that would accumulate in the body. During a long procedure, the anesthetic would equilibrate not only throughout body water, but also throughout the body fat. Assume that the patient weighs 80 kg, 50% of which is water and 30% of which is fat; thus, the patient has 40 kg = 40 liters of body water and 24 kg ≈ 24 liters of fat. The volume of gas needed to fill the body water = PCblood/gas • volume of body water = 12 • 40 = 480 liters of gas. The volume of gas needed to fill the body fat = PCfat/blood • PCblood/gas • volume of fat = 61 • 12 • 24 = 17,568 liters of gas (!) Thus, the total volume of gas needed to fill body water plus fat is over 18,000 liters (!!). This would be expensive!! If it is assumed that the anesthetic is eliminated exclusively by ventilation, then the time required to eliminate the anesthetic is ≈ volume of gas (liters) ÷ ventilation (liters/min). [Note that this calculation is very approximate, as it assumes a zero-order elimination process (constant rate); in actuality, the elimination process will be first-order.] If ventilation = 6 liters/min, then the time required to eliminate ≈ 18,000 liters of gas is ≈ 18,000 ÷ 6 = 3,000 min = 50 hours (!!). This would be very risky for the patient!! Thus, a volatile anesthetic with a high PCblood/gas and high PCfat/blood should not be used for a long surgical procedure, particularly in an obese person! [Note that because of its high PCblood/gas and high PCfat/blood, methoxyflurane no longer is used in anesthesiology.]
why does the duration of thiopental anesthesia increase with each successive dose?
With thiopental, as long as the fat, and to some extent the muscle, compartments are not filled with thiopental, the duration of action depends on the redistribution of thiopental from high blood flow areas (e.g., brain) to low blood flow areas (especially fat and to a lesser extent resting muscle), not on the metabolism of thiopental (which actually is relatively slow: t1/2 ≈ 12 hr!!). Following a single bolus, a patient typically will emerge from anesthesia in 10 min as a result of such redistribution. With successive thiopental doses, the fat and muscle compartments become filled, and as they do, redistribution no longer represents a potential mechanism for lowering the concentration of thiopental in blood. Therefore, the body must rely on metabolism to lower the plasma concentration of thiopental, and when the surgery is over, metabolism must eliminate not only the thiopental in plasma, but the relatively large amount of thiopental that accumulated in fat. Because thiopental metabolism is so slow, a patient may require more than a day to emerge from anesthesia after a long thiopental infusion.
whay is nitrous oxide less efficacious in Denver than in San Diego?
The partial pressure is the driving force for equilibration of anesthetics, and the partial pressure of anesthetic PA = PTotal • XA , where PTotal is the total barometric pressure and XA is the mole fraction of the anesthetic gas (i.e., the fraction of the total gas molecules that are molecules of anesthetic). Since N2O is not a potent anesthetic, concentrations up to 80% (XA = 0.80) must be used during induction to obtain the desired PA. At high altitudes, where PTotal is lower, it is not possible to use a higher XA to obtain the desired PA since oxygen demands would be compromised (i.e., if XA > 0.80, then XO2 would have to be less than 0.20, resulting in a very low PO2 ).
What is the desired mode ot elimination of volatile anesthetics?
The newer volatile anesthetics are halogenated hydrocarbons, the metabolism of which (by cytochrome P450) can result in the formation of free radical intermediates that can cause liver necrosis or high output renal failure. Thus, a volatile anesthetic that is eliminated by respiration and not by metabolism is preferred. Note that of the halogenated hydrocarbons, halothane undergoes the most P450 metabolism (≈ 20%), while desflurane undergoes the least (≈ 0.02%); enflurane (≈ 2%), isoflurane (≈ 0.2%), and sevoflurane (≈ 3%) are in between.
What is the mechanism of anesthetic action of volatile anesthetics?
Although the Meyer-Overton relationship (Figure 6 in the syllabus) suggests a general interaction of volatile anesthetics with lipid membranes, additional data (e.g., the fact that stereoisomers show different potencies; see Figure 7) suggest a more specific membrane action, probably involving interactions with the GABAA receptor. Volatile anesthetics have been shown to increase GABAA–mediated Cl- influx in a stereospecific manner, and anesthetic action is diminished when expression of the functional form of this receptor is reduced (e.g., in KO mice).
what is MAC and what is MAC-sparing?
MAC represents the minimum alveolar concentration of a volatile anesthetic that blocks the response to a noxious stimulus (e.g., incision) in 50% of patients. A “MAC sparing” agent is a drug that can be given in combination with a volatile anesthetic to reduce the anesthetic requirement (e.g., opioids, neuromuscular blocking agents).
what is the component of the action potential that is blocked by the local anesthetics?
The local anesthetics block the voltage-gated Na+ channels; thus, they block the spike of the action potential.
whay are the clinically useful anesthetics referred to as use-dependent blockers?
The clinically useful local anesthetics are referred to as use-dependent blockers because they enter the open Na+ channel (from the cytoplasmic side). More frequent depolarization → more frequent channel opening → ↑opportunity for the local anesthetic to block the channel.
describe the two structural components and the linkages of the common local anesthetics
The commonly used local anesthetics consist of a hydrophilic domain (tertiary or secondary amine) linked to a hydrophobic domain (aromatic residue); an ester or amide alkyl chain links the two domains.
discuss the sensitization that can occur with local anesthetics
Some individuals can develop hypersensitivity reactions to local anesthetics. The reaction most commonly consists of an allergic dermatitis, but asthmatic or anaphylactic reactions can occur. Hypersensitivity reactions most commonly are seen with local anesthetics of the ester type; if an individual develops a hypersensitivity reaction to one ester local anesthetic, he/she usually will have a hypersensitivity reaction to other ester local anesthetics. Sometimes, such allergic reactions are provoked by preservatives or other solutes (e.g., methylparaben, sulfite) in the local anesthetic solution rather than by the local anesthetic itself.
what is the principal morbidity associated with local anesthetic action and what is its mechanism?
The systemic toxic reactions associated with local anesthetics are a function of the blood level. As the blood level increases, CNS effects are seen first (in the following order: numbness of lips/tongue, lightheadedness, restlessness, tremors, unconsciousness, convulsions, coma, respiratory arrest) followed by cardiovascular depression (in the heart: ↓myocardial excitability, ↓conduction velocity, ↓firing rate, ↓force of contraction; in the blood vessels: arteriolar dilation). Although cardiovascular toxicity typically is seen at higher blood concentrations than CNS toxicity, occasionally low doses of local anesthetics → cardiovascular collapse and death, probably due to the sudden depression of cardiac pacemakers or ventricular fibrillation.
What are steps 1,2,3, and 4 of anesthesia?
(I) analgesia, amnesia, stupor, no loss of consciousness, desynchronized EEG. (II) excitement or delirium (III) surgical anesthesia, inconsciouness, regular respiration, HVSW-EEG = high voltage slow wave electro- encephalogram (IV) medullary depression, respiratory/CV depression, flat EEG
Classes of anesthetics?
Injectable (barbiturates, propofol, etomidate, BDZs, ketamine, opiods), and volatile (chloroform, ether, nitrous oxide, halogenated hydrocarbons)
How to deliver inhalation anesthetics?
Anesthetic plus inhaled gas (air/O2). Dosing is based on % anesthetic in inhaled gas plus total gas flow (ventilatory rate/volume)
Concentration or partial pressure more important for effects of inhaled anesthetics on brain?
Depth of anesthesia is directly related to partial pressure at equilibrium, PPbrain = PPalveolar = PPinhaled gas. Volatile anesthetic dose is aveolar concentration (expressed as % alveolar gas) associated with PP that produces a given degree of anesthesia. Also, movement of volatile anesthetics from one body compartment to another is a function of PP, not concentration. Furthermore, the concentration of the drug in a particular tissue is directly related to its solubility in that tissue, so if want to increase concentration in a 3x less soluble tissue, need to increase PP of the drug 3x to get equal concentration. Values are based on partition coefficient (PC). Drugs will diffuse between tissue until equilibrium is reached (equal PP).
What indexes of potency are used to describe inhalation anesthetics?
MAC = minimum alveolar concentration of anesthetic required to block purposeful somatic movement otherwise evoked by a noxious stimulus in 50% of patients. MACBAR is min alveolar conc that blocks autonomic response evoked by stong stimulus in 50% of patients.
What affects MAC and MACBAR?
Age and anesthetic agent. MAC is maximal at 6mo of age, and decreases 6% each decade (so half in 80yo). Also, agents differ in potency. Methoxyflurane MAC is 0.16%, all the way up to nitrous oxide which is 105%
Movement of inhaled anesthetic into alveoli?
Anesthetic mixes with the gas, is removed by diffusion into alveolar blood, and will continue to do so until PP of avleolar gas is same as PP pulmonary blood
How does inhaled anesthetic move from alveoli into blood?
Rapid process, but thr rate depends on anesthetic solubility in the blood (different than solubility in air or tissues). Agents with PCblood/gas >1.2 have high solubility in blood, e.g. isoflurane versus desflurane, and are more rapidly cleared from alveolus. So desflurane will equilibrate faster because blood can’t hold as much (less soluble).
High versus low solubility is ventilation- or blood flow-limited?
High solubility is ventilation-limited because need a lot of gas to “fill up” the blood with the gas. Low solubulity is blood flow-limited because blood fills up fast, and gas just waits for more blood to come along to fill up
What dictates how fast/well anesthetics get delivered from blood to tissues?
PPblood in blood, volume blood (flow) received by tissue, mass of the tissue, anesthetic solubility in that tissue. Isoflurane has 1.4, 48, 26 tissue/blood partition, while desflurane has 0.45, 2.3, 1.3 (blood, muscle, brain)
How fast does brain equilibrate?
It has low solubility and high blood flow, so rapid (similar to kidney and liver). These are opposite of fat, which is high solubility and low blood flow, so it’s slow equilibration.
Ideal anesthetic?
Low fat PC(blood/gas), low PC(fat/blood), and low MAC. (high PC leads to accumulation and long recovery times),
What is the prodrome of migraines?
Vague changes in mood or appetite
What is the aura of migraines?
Visual disturbances (positive and negative symptoms), motor or sensory disturbances, N/V
Description of the headache of migraines?
Throbbing over one eye, or can be occipital pain. Pain accompanied by malaise, N/V, gastric stasis, light/sound sensitivity, pallor, diuresis
What is the resolution phase of migraines?
HA resolves after 3-4 hrs, but can last 24 hrs or more
What is the class of migraine called classic migraine?
Migraine with aura, has all four aspects (prodrome, aura, HA (with associated pains), and resolution
What is the class of migraine called common migraine?
Migraine without aura
Clinical manifestation of basilar migraine?
Aura, no motor disturbance, originate at brainstem and/or from both hemispheres. Most common in young women and children.
Clinical description of familial hemiplegic migraine?
Rare, aura-associate migraine with unilateral motor weakness and sensory loss. Autosomal dominant inheritance
Who most commonly has basilar artery migraine?
Young women and children
What is the inheritance pattern of familial hemiplegic migraine?
Autosomal dominant
Clinical description of ophthalmologic migraine?
Localized around one eye, followed by unilateral CN III, IV, VI nerve palsy
What is a cluster headache?
Not generally classified as a migraine. It is brief (1-2hrs), rapid, intense, episodic pain around one eye. It can be associated with lacrimation, nasal congestion
Clinical description of tension headache?
Bilateral, diffuse, felt as a band of pressure or constriction. Has no aura or systemic of neurological disturbances.
Common headache triggers?
Emotional stress, tyramine (cheese, chocolate, red wine), bright lights, loud noise, exercise, hunger
Smoking and contraceptive use and risk of migraines?
Smoking and contraceptive use by migraine sufferers raises risk of stroke by 34X.
What is the referred pain theory of migraines?
The brain parenchyma is insensate, but mechanical and chemical stimulation of meninges and cranial vessels (sensory is CN V), produces focal referred pain
What is the “vasomotor instability” or “modified vascular theory” of migraines?
Vasoconstriction or abnormal A/V shunting leads to mild ischemia→increased extracellular K→cortical spreading depression (and correlated to aura). The initial vasoconstriction sensitizes the trigeminal sensory afferents innervating meningeal blood vessels, which leads to release of SP and CGRP and therefore vasodilation and plasma extravasation, which leads to increased activity in trigeminal sensory afferents, and so referred pain in cranial area innervated by that afferent.
How do ergot alkaloids treat migraines?
Bind 5-HT receptors, leading to potent intracranial veno- and arterio-constriction and inhibition of excitability of C-fiber terminals, possibly by binding to 5-HT1B/D (so pain sensation is decreased).
What are side effects of ergot alkaloids as treatment for migraines?
Limb ischemia, gangrene. Potency of the agents can lead to rebound headaches.
What are four contraindications for ergot alkaloids for treatment of migraines?
Peripheral vascular disease, CAD, THN, renal disease
What is ergotamine? Other drug(s) in this class?
An ergot alkaloid for migraines. Due to alpha1 agonism, it can cause intense peripheral vasoconstriction, limb ischemia, gangrene Another ergot alkaloid is dihydroergotamine. It is also an oxytocin receptor agonist, so can help with uterine contractions to treat bleeding immediately after birth.
What is dihydroergotamine? Other drug(s) in this class?
An ergot alkaloid for migraines. Another ergot alkaloid is ergotamine
What is route of administration of ergot alkaloids?
Sublingual, oral, nasal.
Difference in affinities for 5-HT receptors between ergot alkaloids and triptans?
Ergot alkaloids have high affinity for 5-HT receptors, but less selectivity for 5-HT1B/D than triptans
How do triptans work to treat migraines?
Selectively agonizes 5-HT1B/D receptor, which is Gi coupled to inhibit AC. That leads to inhibition of excitability of peripheral trigeminal nerve terminals supplying intracranial vascular and meningial structures, decreasing SP and/or CGRP and decreasing vasodilation
Route of administration of sumatriptan?
SQ, PO, nasal
Efficacy of sumatriptan in migraines?
70-77% patients improve in 1 hr following SQ injection, but more effective earlier in attack.
What type of migraines can sumatriptan not treat?
Basilar or hemiplegic headache
How is sumatriptan metabolized?
Liver, but metabolites cleared renally
Contraindications for sumatriptan use?
Ischemic heart disease, uncontrolled HTN, Prinzmetal’s angina (focal spasm or angiographically normal coronary arteries)
How are COX inhibitors analgesics?
Inhibit PG synthesis, so less pain
How does ASA/APAP/caffeine treat migraines?
Caffeine causes vasoconstriction. This plus analgesics might work to treat migraines
What categories of drugs to treat mild migraine attacks?
NSAIDS, antiemetics
What categories of drugs are used to treat mild to severe migraines?
Triptans, antiemetics
What categories of drugs are used to treat severe migraines?
SQ triptans, or SQ, IM, IV, or nasal dihydroergotamine in resistant cases, or opioid analgesics as a last resort for pain-free sleep.
What can be used to prevent migraines?
Beta antagonists, antiepileptic drugs, Ca channel blockers, TCAs, Botox (although not FDA approved)
Muscles used in vomiting?
Simultaneous contraction of inspiratory and expiratory muscles, co-contraction of the diaphragm and abdominal muscles increases pressure on the stomach. Glottis is closed to prevent aspiration
Medical problems that can be causes by vomiting?
Weight loss, electrolyte imbalance, inability to complete therapeutic regimen, impair healing (open sutures, etc), risk of aspiration, prevent absorption of drugs
How is vomiting controlled/triggered?
By the emetic center of the 4th cerebral ventricle, which is the final receiving pathway from many stimuli. The chemoreceptor trigger zone (CTZ) is on the floor of the 4th ventricle outside the BBB. Other contributors include the cerebral cortex, the GI tract via CN X to the NTS, and the vestibular apapratus.
How does ipecac cause vomiting?
Activates the CTZ and peripheral vagal afferents
What does apomorphone do, and how does it work?
Induces vomiting by acting on D2 receptors in CTZ
How does motion sickness occur?
Conflicting inputs between visual and vestibular systems ot between 2 vestibular systems.
How are 5-HT3 receptors involved in emesis? Two main locations of these receptors?
Systemic toxins such as cisplatin and radiation increase 5-HT release from enterochromaffin cells in intestinal mucosa, which binds to and opens 5-HT3 ligand-gated cation channels on vagal afferents, leading to depolarization and vomiting reflex. There are also 5-HT3 receptors in the CTZ and medullary emetic center.
Why do 5-HT3 antagonists suppress emesis?
They bind to 5-HT3 receptors on both vagal nerves and the CTZ and medullary emetic centers, to prevent action of 5-HT released from the stimulus of toxins like cisplatin or radiation to induce emesis
In what conditions will 5-HT3 antagonists not prevent emesis?
In the presence of apomorphine, morphine, or motion sickness. They are not universal antiemetics
How are DA receptors involved in emesis?
Visual and vestibular input increase DA released to CTZ, so stimulates the medually emetic center. This is why D2 antagonists can have antiemetic effects and why apomorphine (a D2 agonist) can cause emesis
How are mAChRs involved in emesis?
ACh is released by vestibular input to CTZ, which activates mACh receptors in CTZ, causing emesis. That is why scopolamine can prevent motion-induced nausea
What is scopolamine and how does it work to treat motion sickness?
mAChR antagonist and H1 blocker, so it blocks input to the central emesis center by the vestibular area (good for motion sickness)
At what point in the process of nausea are antiemetics most effective? When should antiemetics be given?
Best when given before onset. Should be given on a scheduled basis, around the clock, throughout the period of anticipated emetic response.
How to improve efficacy of antiemetic therapy?
Combo therapy helps to target multiple transmitter systems. The more neurotransmitters that are blocked from producing emesis, the more effective.
What would happen at equilibrium if the blood was exposed to 1atmosphere of isoflurane, nitrous oxide, and ether?
The PP of a gas in a tissue (or blood) is a function of the solubility of the gas in that tissue. So, based on their solubilities in blood, 1.14L isofluorane, 0.47L nitrous oxide, 12 L ether
The amount of anesthetic delivered to a tissue depends on what 4 properties?
PP(blood) in that tissue, the volume of blood received by the tissue (% cardiac output), mass of the tissue, and anesthetic solubility in that tissue
How does blood flow affect clearance of anesthetic?
High blood flow tissues clear anesthetic faster, but they also come to equilibrium faster when anesthetic is administered.
What are the neuronal effects of gas anesthetics?
Block excitation and spontaneous activity. Block excitatory brainstem and spinal reflexes, and depress cortical EEG (all these due to membrane hyperpolarization)
What is the Meyer-Overton relationship?
Potency (MAC) is inversely proportional to Oil/gas partition coefficient, even across species and 5 log units.
What is the limit to the Meyer-Overton rule of anesthetics interacting with lipid membranes?
Agents with carbon chains greater than 8-10 show no anesthetic activity, giving evidence for a specific pocket in the lipid bilayer for anesthetics to act. Also, stereoisomers show different potencies
What is the role of GABA A receptors for volatile anesthetics?
GABA-activated Cl- channel leads to hyperpolarization. The Cl- current is enhanced by volatile anesthetics, and is a stereospecific effect. The anesthetic action is diminished in KO mice in which the functional GABA is knocked out.
Solubility and potency of nitrous oxide as an inhaled anesthetic?
Low blood solubility (S=0.47), and low potency. Even at 70% (max because O2 has to be given too), can only achieve 2nd stage of anesthesia. Note, stage 1 and 2 are: (I) analgesia, amnesia, stupor, no loss of consciousness, desynchronized EEG. (II) excitement or delirium.
A good use for nitrous oxide?
Good for analgesia, and also in combo with isoflurane, especially to reduce concentration of other anesthetics needed compared to their use alone. It has low solubility and low potency.
Effect of nitrous oxide on BP?
Maintains blood pressure through sympathetic discharge
Effect of nitrous oxide on skeletal muscle?
No skeletal muscle relaxation
Possible complication from nitrous oxide?
Pockets of trapped gas may reside after anesthesia
Solubility of ether, and implications of that?
High solubility (12). So, it has to be administered at high doses at first in order to speed induction, but slow recovery because so much accumulation.
Effect of ether on cardiovascular system?
Circulatory stability, no CV depression.
Side effects of ether?
Irritating, produces N/V
Stages of anesthesia induced by ether?
Has a classic timeframe for each stage of anesthesia
Efficacy of ether for muscle relaxation?
Very good
Efficacy of ether for analgesia?
Very good
Possible problems with ether?
Peroxides formed by ether evaporation are explosive. It causes irritation to respiratory tract, increases secretions and bronchoconstriction. Ether is not used in U.S. and other developed countries, but mainstay in third world countries. It has high solubility
Solubility of halothane?
2.3. no longer used, but is standard to which all other gas anesthetics are compared.
Effect of halothane on analgesia?
Poor analgesia.
Effect of halothane on CV system?
Depresses myocardium and baroreceptor reflexes, sensitizes ventricular tissues to catecholamines (but does not stimulate sympathetic output). Circulatory depression
What is the most important risk of halothane?
1:10,000 cases it can cause halothane hepatitis. 15-20% of halothane is metabolized by P450, and a free radical intermediate is formed from that.
Solubility of isoflurane?
Intermediate solubility (1.4). has more rapid onset and recovery than halothane
Effect of isoflurane on CV system?
Less cardiac depression than halothane
Effect of isoflurane on skeletal muscles?
Good muscle relaxation
Problems with isoflurane?
Can cause uterine contractions, is slightly irritating, and stimulated airway reflexes.
Solubility of desflurane?
0.45, most rapid onset and recovery. Good in outpatient setting. Recovery is 5-10 minutes after discontinuation
Effects of desflurane on CV system?
Same as isoflurane (less cardiac depression than halothane), may have some benefit in CAD pts
Effect of desflurane on skeletal muscle?
Good muscle relaxation (like isoflurane and ether, but not Nitrous oxide)
Metabolic degradation of desflurane?
Very little. Only about 0.02%, which is similar to isoflurane (0.2%).
Problems with desflurane?
More irritating on the airways, induction more difficult. It’s use is increasing in the U.S.
Solubility of sevoflurane?
0.65, so it has rapid onset and recovery like desflurane.
Advantage of sevflurane over desflurane?
Less irritating.
Metabolic degradation of sevflurane?
3% (as opposed to 0.02% for desflurane and 0.2% for isoflurane)
Problems with sevflurane?
Chemically unstable in the presence of absorbants of CO2
How do anesthetic agents reach their site of action?
Local diffusion (after direct delivery), or movement though the IV route
Consistency of structure between volatile and injectable agents?
Injectable agents have consistent structure similarity, which is an independent predictor of bioactivity. But volatile agents have no EVIDENT structure similarity.
GABA receptors for injectable anesthetics?
They are highly concentrated in neuraxis. They are inhibitory at virtually every neuron in the CNS, and inhibition can be mediated by specific subclasses of receptors
GABA A and GABA B receptors ionotophic or metabotrophic?
GABA A is ionotrophic. GABA B is metabotrophic. Anesthetics target the GABA A receptors
Structure of GABA A receptors?
Pentamer of subunits, creating a gated Cl- channel. Each subunit has 4 transmembrane regions. There are four families of subunits, alpha, beta, gamma, and delta. And several versions of each subunit
What happens at the GABA-A receptor when GABA binds?
Opens the channel to Cl-conductance, which either depolarizes or hyperpolarizes the membrane depending on the Cl equilibrium potential
what’s thiopental?
A barbiturate like phenobarbital. It targets the GABA-A receptor to increase affinity for GABA and Cl conductance
What is alphaxone?
A steroid that targets the GABA-A receptor
What is midazolam?
A BDZ, like alprazolam that targets the GABA-A receptor. Short duration of action
What is alprazolam?
A BDZ like midazolam that targets the GABA-A receptor.
What is propofol?
IV Anesthetic that targets the GABA-A receptor to increase its affinity for GABA and increase Cl conductance
What is etomidate?
IV anesthetic than targets the GABA-A receptor to increase its affinity for GABA and increase Cl conductance. It can cause post-op N/V and temporary Addison’s.
Ethanol and GABA-A?
Ethanol targets the GABA-A receptor to increase its affinity for GABA and increase Cl conductance.
Effect of GABA-A-targeted drugs at low vs. high concentration?
At low conc, they increase the receptor’s affinity for GABA and therefore increase Cl conductance. At high concentration, they alone increase Cl conductance at GABA receptors
Onset and duration of thiopental?
10-20sec and 20-30 minutes. Short duration due to redistribution of drug from brain to other tissues like fat (not because of metabolism)
What is the half-life of thiopental?
Very fast, but not due to metabolism. It has a “context-sensitive half-life” because chronic exposure can lead to accumulation and extended recovery.
What is thiopental good for?
Induction (fast onset), followed by other, longer-acting agents.
Effects of thiopental on pain?
No analgesia, in fact, causes hyperalgesia (like other barbiturates) during recovery.
Effects of thiopental on CV system?
Minimal CV effects
Effects of thiopental on respiratory system?
Depressed respiratory response to to hypercarbia/hypoxia, bronchospasm
Contraindication for thiopental?
Porphyrias
Onset and duration of propofol?
Rapid acting IV anesthetic, more rapid emergence than thiopental after bolus. Duration depends on how long pt has been exposed. Immediately half-life is 2-4 minutes. After 1 hr, 5 minutes. After 10 hrs, 7 minutes.
CV effects of propofol?
Initial apnea and fall in BP. (causes vasodilation and reduced myocontractility). These are the same effects as for etomidate.
What’s propofol good for?
Good for induction of anesthesia, (same as etomidate)
Problems with propofol?
Prepared in fat emulsion base, associated with bacteremia. Dose is reduced in elderly
Onset and duration of etomidate?
Rapid acting IV anesthetic. But, recovery is less affected by prolonged exposure than with propofol
CV effects of etomidate?
Initial apnea and fall in BP. (causes vasodilation and reduced myocontractility). These are the same effects as for propofol. However, there are “minimal effects upon CV, no hypotension, best for cardiac stability”
What’s etomidate good for?
Good for induction of anesthesia, (same as etomidate)
Which injected anesthetic is best for cardiac stability?
Etomidate
Problems with etomidate?
N/V, stongly suppresses adrenocortical stress response
Utility of BDZs in anesthetics?
Diazepam and midazolam are good for preanesthetic agents or anesthesia supplements.
Onset of BDZs compared to barbiturates?
BDZs slower than barbiturates, and drowsiness continues after plasma levels fall. Midazolam has the shortest duration of action
Problems with BDZs in anesthesia?
All except midazolam cause vascular irritation if injected rapidly, will not produce anesthesia alone, but good for diagnostic procedures not requiring analgesia (“conscious sedation”)
What’s flumazenil?
Competitive antagonist at the BDZ binding site, used to reverse BDZ-induced sedation.
Use of opioids in anesthesia?
Opiates like fentayl and sufentanil are used widely as induction agents. And as supplements to general anesthetics to reduce anethetic requirements. Has a MAC-sparing effect
Cardiac effects of opioids in anesthesia?
Bradycardia, but CO and organ perfusion still maintained.
Respiratory effects of opioids in anesthesia?
High doses result in respiratory depression and significant chest wall and jaw rigidity, so severe that usually requires muscle relaxant to permit intubation
Which glutamate receptor do some anesthetics target?
NMDA (as opposed to AMPA and Kainate, which are also ionotropic), and not metabotropic glutamate receptors either.
Structure of the NMDA receptor?
Transmembrane, glutamate-activated, calcium channel, a pentamer of NR1 (2) and NR2 (3) subunits.
How do anesthetics targeted at NMDA receptor control pain?
They are antagonists at the NMDA receptors which are associated with many systems including learning and memory, and in spinal cord, help pain transmission.
What clinical effects to NMDA antagonists have in anesthesia?
Sedation, immobility, amnesia, analgesia, feeling of disociation from environment. Hence the name “dissociative anesthetics”
What is Ketamine?
IV anesthetic. A dissociative anesthetic (NMDA antagonist, like PCP). Has pressor effects, and only IV total anesthetic.
Onset and duration of action of ketamine?
NMDA antagonist. 45 seconds, lasting 10-15 minutes. Analgesia lasts 40 minutes and is accompanied by amnesia.
Cardiac effects of Ketamine?
Increased BP, cardiac output.
Side effects of Ketamine?
Amnesia, pupillary dilation, emergence delirium, bad dreams, hallucinations.
Effect of Ketamine on skeletal muscle?
Maintains muscle tone
Use of Ketamine?
Dissociative anesthetic. Loss of response to commands, used in kids due to no hypotension or bronchospasm.
Contraindications for Ketamine?
HTN (due to increased BP and CO), psychiatric conditions (due to hallucinations and dreams(, eye surgery (due to dilation)
Why use neuromuscular blocking agents in anesthesia?
Muscle tone can be bad in chest wall and jaw rigidity (such as from opiates) which can prevent intubation. motor function, airway closure. Tissue injury (surgery/trauma) increases muscle tone. So, management of muscle tone in surgery is critical.
How do depolarizing agents work as neuromuscular blocking agents?
Activates post-synaptic nicotinic receptors, leading to long depolarization, which greatly prolongs repolarization of end plate. If short exposure (phase I), removal of agent results in relatively rapid reveral, but with prolonged administration (phase II), a more profound block occurs (loss of endplate function), and has slower rate of recovery.
How do competitive neuromuscular blocking agents work?
Bind competitively to Nm receptor on motor end plate to block binding of ACh, and do not depolarize the end plate (but actually prevent depolarization). Duration of action is as long as the drug occupies the receptors
What is succinylcholine?
Depolarizing agent, neuromuscular blocker. Can cause two phases of block.
Onset and duration of succinylcholine?
1-1.5 minutes and 5-8 minutes. (very fast)
Problems with succinylcholine?
Causes fasiculations, may trigger malignant hyperthermia in susceptible patients, and is dangerous to use in hyperkalemia or if plasma cholinesterase is reduced (such as in pregnancy, liver/kidney disease, burns, anemia, oral contraceptives, glucocorticoids, organophosphate insecticides, or genetically deficient enzyme).
What is d-tubocurarine?
Natural alkaloid (poison darts), a competitive neuromuscular blocking agent (like vecuronium and rocuronium)
What is onset and duration of d-tubocurarine?
Slow (4-6 min), and 80-120 minutes
Problems with d-tubocurarine?
Hepatic metabiolism, renal elimination (just like vecuronium)
What is vecuronium?
A competitive neuromuscular blocking agent (like d-tubocurarine and rocuronium)
Onset and duration of vecuronium?
Faster than d-tubocurarine. 2-4 minutes and 60-90 minutes
Problems with vecuronium?
Hepatic metabolism and renal elimination (just like d-tubocurarine
What’s rocuronium?
Competitive neuromuscular blocking agent (like d-tubocurarine and vecuronium)
Onset and duration of rocuronium?
Very fast (>vecuronium>d-tubocurarine). 1-2 min, 30-60 minutes
Problems with rocuronium?
Hepatic metabolism
What’s atracurium?
Competitive neuromuscular blocking agent (like d-tubocurarine, vecuronium, rocuronium).
Onset and duration of atracurium?
Fast. 2-4 minutes, and 30-60 minutes.
How atracurium eliminated?
Renally. Inactivated by plasma esterases.
Problems with atracurium?
Same problems as succinylcholine if low blood cholinesterase. Potential histamine release, hypotension, tachycardia, bronchospasm.
Electrophysiology of neuromuscular junction?
ACh binds to Nm receptor, causes short depolarization, cation flow through the open channel (Na and Ca in, K out)
Rank neuromuscular blocking agents in order of fastest to slowest (onset and duration)?
Succinylcholine, rocuronium, atracurium, vecuronium, d-tubocurarine.
Which neuromuscular blocking agents are metabolized hepatically?
Rocuronium, vecuronium, d-tubocurarine. The others are metabolized by serum esterases (succinylcholine and atracurium)
Which neuromuscular agents are metabolized by blood esterases?
Succinylcholine and atracurium. The others are hepatically metabolized.
What is used in anesthesia to block the rigidity caused by opioids, in order to permit intubation/induction?
neuromuscular blocking agents
Use of neuromuscular blocking agents intra-operatively?
Anesthetics may give anesthesia, but not muscle tone block at current dose. So, can give muscle blockade with blockers without increasing dose of anesthetic and extending recovery time. (atracurium and vecuronium used commonly)
How are neuromuscular blockers used in recovery?
Dose is reduced near end of surgery (so muscle relaxation is reduced to allow extubation). Recovery can be shortened by adminstration of Achesterase inhibitor like neostigmine. Pt is monitored for twitch response
What is neostigmine?
ACHesterase inhibitor, used to reverse neuromuscular blockade of a competitive agent, but at high doses can prolong the blockade. If given after succinylcholine, can also prolong the blockade
Porphyria?
Inherited disorders, giving problems with heme synthesis. Can cause problems with skin, blisters, itching, swelling, sun sensitivity, CNS pain, numbness, tingling, paralysis, cramping, vomiting, constipation. Barbiturates can induce P450 and stimulate porphyrin synthesis. So, barbiturates are contraindicated for porphyria pts
Q: For which drug does alveolar gas equilibrate with inspired gas more rapidly, methoxyflurane or desflurane? Why?
Desflurane-PCblood/gas=0.45. Methoxyflurane-PCblood/gas= 12. Gas will continue to be absorbed from the alveolar space until PP alveolar = PP blood). Higher blood capacity for MF than desflurane, requires more methoxyflurane to be delivered. e.g. it will take longer for methoxyflurane to come to equilbrium.
what can the anesthesiologist do to decrease the induction time for methoxyflurane? Will that procedure work equally well for desflurane?
For MF: Deliver a higher concentration of inhaled gas. Blood gas will rise rapidly to a PP necessary for MF to produce anesthesia. “over pressure”. For desflurane, low solubility make its absorption time dependent upon cardiac output…. increasing ventilation or concentration will have less effect.
What will be the effect of an increase in cardiac output on the alveolar concentration of desflurane?
Time required for arterial blood to equilibrate with alveolar gas (PPblood ≈ PPalveolar) is time required for a volume of blood equal to the total body water to pass through pulmonary capillaries. Therefore, the higher the cardiac output, the faster will be equilibration.
If sevoflurane in fat has equilibrated with arterial blood (PPfat ≈ PPblood), how much more sevoflurane is present in a ml of fat than in a ml of blood? Given this result, why is it that the distribution of sevoflurane in fat only becomes significant in a long surgery?
At equilibrium, PCbrain/blood = 1.7; PCfat/blood = 48. Therefore the ratio of these two numbers will indicate the relative amounts of Sevo in fat as in brain at equilibrium, i.e 48/1.7 = 28. Time required to come to equilibrium depends upon perfusion solubility in tissue and volume of tissue. Fat receives only 6% of CO and is 2X mass of the VRG (brain, kidney and liver which constitute only 10% of BW). So equilbrium time will be much longer for fat than brain. Time constant for sevoflurane in VRG = 3.3 min Time constant for sevoflurane in Fat = 2240 min.
What will be the impact on onset and offset of anesthesia of increasing fat from 15% of a 70-kg body weight (lean individual) to 40% of a 100-kg body weight (obese individual)?
Onset of Anesthesia: Fat: large reservoir, but poorly perfused…comes to equilibrium slowly. With short exposure, amount of drug which distributed into the fat will be only modestly affected by body/ fat mass. Principal up take will initially be into vessel rich group, and onset of anesthesia will be unaltered. Offset of anesthesia: With long surgery, fat stores are filled. The larger the fat pool, the greater the anesthetic store that must be washed out Washout of anesthetic from brain will be slowed by clearance from fat and delay emergence from anesthetic as compared to a lean patient.
What factors do obese patients have which may compromise their anesthesia?
(1) Decreased functional residual capacity (a measure of lung function), (2) Decreased compliance (increased difficulty to fill and empty lungs), (3) Increased atlectasis (partial or complete collapse of lungs)
Basic outline of how to induce anesthesia?
Goals are start anesthesia, tracheal intubation, invasive lines. Premedicate with midazolam, give IV anesthetic (fentanyl, thipental, propofol, etomidate), then give neuromuscular blocking agents (succinylcholine, rocuronium, atracurium, vecuronium, mivacurium)
What are BMI classes?
Underweight is <18.5. Normal is 18.5 to 24.9. overweight is 25-29.9. obese is >30.
Basic protocol for maintaining anesthesia?
Induction by IV (fentanyl, thiopental, propofol, etomidate), and then volatile anesthetic to achieve desired depth (isoflurane, desfluraen, enflurane)
What is safety factor?
When discussing the local anesthetics, the term safety factor is used to describe how easy/difficult it is to block nerve conduction. If it's more difficult to block conduction in a given nerve fiber, that fiber is said to have a larger safety factor. Increases in fiber diameter and myelination correlate with an increase in safety factor.
3 important properties of the nerve membrane Na channel?
Voltage-dependent opening, voltage-independent closing (inactivation), and voltage-dependent reactivation
Na channel location on myelinated versus unmyelinated axons?
On myelinated fibers, Na channels are only on the nodes, but in unmyelinated fibers, Na channels are evenly distributed over the membrane
How does transmission resistance (in an axon) relate to speed of transmission and safety factor?
More resistance (Rt) causes the depolarizations to spread further and faster down the axon. The greater the spread, the greater the safety factor. (greater diameter and more myelination also increase speed, and therefore safety factor)
How does axon diameter relate to speed of conduction and safety factor?
Larger diameter means faster speed, and therefore higher safety factors
What is the term to describe depolarization jumping from one node of Ranvier to the next?
Saltatory conduction. Each depolarization travels up to 3-5 nodes (not just from one node to the next). This is how myelination speeds up conduction
From largest to smallest, what are the axon fiber types in order of size (and therefore speed of conduction)?
A-alpha, A-beta, A-gamma, A-delta, B, C. A and B types are myelinated, C are not. A-alpha are motor efferents and muscle/joint afferents (for motor and propioception). A-beta are sensory tactile and muscle/joint afferent (for light touch and propioception. A-gamma are efferents to muscle spindles for muscle tone. A-delta are sensory afferents for first pain (sharp pain/temp/touch). B are preganglionic sympathetics. C are sensory for second pain (dull/temp) and postganglionic sympathetics
Describe the properties of the Na channel?
Three subunits (alpha, beta1, beta2). Alpha is most important, has 4 homologous domains, each with six membrane-spanning regions (S1-S6).
Subunits of Na channel: A) S5/S6 subunits, B) S4 transmembrane region in each domain, C) transmembrane loop between domains III and IV, D) Loop between domains I and II. Which one, if phosphorylated leads to channel inactivation?
C and D. Phosphorylation of loop between either loop I and II, or II and IV (the inactivation gate) leads to channel inactivation.
Subunits of Na channel: A) S5/S6 subunits, B) S4 transmembrane region in each domain, C) transmembrane loop between domains III and IV, D) Loop between domains I and II. Which one forms the walls of the pore?
A. S5 and S6 of each of the four domains forms the wall of the pore
Subunits of Na channel: A) S5/S6 subunits, B) S4 transmembrane region in each domain, C) transmembrane loop between domains III and IV, D) Loop between domains I and II. Which one is the voltage sensor?
B. S4 of each domain is the voltage sensor (for activation and reactivation of the channel, but not inactivation)
Which Na channel types are TTX sensitive versus resistant? Which ones activate at -40mV, and which ones at -60mV?
All TTX Na channels activate at -40 (Nav 1.1-1.4, 1.6, 1.7) and all TTX-resistant Na channels activate at -60 (Nav 1.5, 1.8, 1.9).
What types of Na channels are in cardiac myocytes?
TTX sensitive: 1.1, 1.3, and TTX resistant: 1.5. Skeletal muscle has 1.4. 1.8 and 1.9 are in small DRG, nociceptors (these are TTX-resistant)
What types of Na channels are in small DRG (nociceptors)?
1.8 and 1.9 (TTX resistant)
Where, in the cell, do local anesthetics exert their effect?
They diffuse through the cell membrane (go into the cytosol), and enter and block OPEN Na channels from the cytosolic side, binding to hydrophobic AA residues. The exception to this is peptide Na chanel blockers, such as saxitoxin or TTX that block Na channels from the outside. Most local anesthetics block all subtypes of Na channels.
Factors that influence action of local anesthetics?
Potency is increased by membrane depolarization (neuron being used). Enters through an open channel, binds with greater affinity to inactivated channel, so channel-block is use-dependent. More frequent depolarization also increases anesthetic occupancy (example 30hz depolarization facilitates anesthetic potency and occupancy more than 3hz).
How do different sizes of fibers compare in sensitivity?
Small diameter fibers more sensitive to local anesthetics than large fibers. Unmyelinated fibers also show more sensitivity than myelinated (so safety factor is higher for myelinated and large). Because of these differences, autonomic function is lost before motor function.
What senses are susceptible to blockage by local anesthetics (in order of most to least susceptible)?
Pain (A-delta C-fibers) >cold>warmth (A-delta fibers)>touch>deep pressure (A-beta fibers)
General structure of local anesthetics?
Hydrophylic end (tertiary or secondary amine) bonded (ester or amide) to lipophic end (aromatic residue)
Chemical properties of local anesthetics that help their pharmacology?
They are weak bases, protonated form is the active form because free base (unprotonated) form is poorly soluble in water. Formulated in acidic solution to increase water solubility. In the body, buffers increase pH, leading to more free base form, which can penetrate axon membrane. Then, inside the neuronal cytosol, pH is slightly lower, so more protonation and ion trapping. The protonated form binds the ion channel.
What metabolic action determines duration of action of local anesthetics?
For ester anesthetics (benzocaine and tetracaine), plasma and liver esterases cleave them. For amide anesthetics (Lidocaine and Bupivacaine), N-dealkylation followed by conjugation in the liver metabolizes them.
Co-administration of what drug class can prolong the duration of action of local anesthetic?
Vasoconstrictors. It localizes the agent at the site of action, it slows redistribution to systemic circulation, so reduces systemic side effects. But, it is contraindicated for extremity blocks due to risk for tissue necrosis
Toxicity of local anesthetics?
A function of blood concentration. With increasing dose, get local anesthetic effect, then CNS effects (visual, auditory disturbances, twitching, convulsions, coma, respiratory arrest), then CV depression
As blood level of local anesthetic increases, what CNS sxs of toxicity manifest?
Restlessness, tingling/numbness in lips and tongue, tremors, convulsions, CNS depression, respiratory failure, death
CV effects of local anesthetic toxicity?
Decreased myocardial excitability, conduction rate, force of contraction, then arterial dilation (low increases contraction, high concentrations inhibit). Small amounts of local anesthetics can occasionally cause CV collapse and death due to pacemaker depression or ventricular fibrillation.
Why are some local anesthetics more cardiotoxic than others?
Due to use-dependence and dissociation of the drug. Bupivicaine is more cardiotoxic than lidocaine because bupivicaine dissociates more slowly. In other words, both agents block Na channels during systole, but during diastole, more Bupivicaine is still hanging around, while lidocaine has dissociated fast. Slow dissociation leads to cardio-depression.
Which type of local anesthetics are more likely to cause hypersensitivity reaction?
Ester (benzocaine, tetracaine) more than amide (lidocaine, bupivacaine). There is also cross-sensitivity
Considerations for topical administration of local anesthetics?
OTC sprays (like benzocaine) can sensitize the nerves to other ester anesthetics. Exposure to mucous membranes (pharynx, respiratory tract, urinary tract, cornea, anus, mouth, denuded skin) can increase systemic absorption and lead to toxicity
When can infiltration administration (intradermal injection at site of injury) of local anesthetics be used?
Good for biopsies, orthopedic surgery, dentistry. The action of lidocaine and tetracaine (the amides) can be prolonged with epinephrine, but avoid it in the digits and appendages due to ischemia
In what settings is specific nerve or nerve plexus block (by local anesthetics) used?
Dentistry, general surgery, orthopedic surgery. Lidocaine or bupivacaine with or without epinephrine are used.
What is a Bier block with local anesthetics?
Also called a dense block. It is an IV local anesthetic into a limb with proximal inflated cuff
What are the advantages and limitations to epidural and intrathecal anesthesia with local anesthetics?
Dense blocks decreases autonomic response to stimulus. With catheters, can achieve controllable continuous blocks. Muscle relaxation. Patients maintain airway reflexes. The limitations are that the patient remains conscious, it is like a sympathectomy, there is spinal neurologic deficit, and other misc. effects.
Where is intrathecal anesthesia injected, what area does it cover, and what is the order of functional blockade?
Usually bolus (sometimes continuous catheter) into L3/5 interspace, blocks from sacral to T2. Blocks preganglionic autonomic, sensations, then somatic motor function
What factors influence the distribution of intrathecal anesthesia?
Anesthetic volume, posture (supine vs sitting), specific gravity of CSF (isobaric versus hyperbaric), vasoconstrictors. The duration is influenced by the venous drainage since there is no esterase activity in the CSF. Vasoconstrictors double the duration of intrathecal anesthetics
CV complications of intrathecal anesthesia?
Sympathetic block decreases BP, CO, PVR, and is worse in hypovolemia and increased age
Respiratory complications of intrathecal anesthesia?
Usually little or no effect on respiration, PO2 and PCO2 unaltered
Neurologic complications of intrathecal anesthesia?
CSF leakage leads to headaches, and is related to needle gauge and number of punctures (good technique helps this). Cauda Equina syndrome and chronic progressive adhesive arachnoiditis can occur rarely
Characterisitics of epidural anesthesia?
Given as bolus or through catheter. Provides highly segmental block, has slower onset (15-30 minutes) and requires higher doses than intrathecal.
Complications of epidural anesthesia?
Similar to intrathecal (CV depression, no respiratory effect, CSF leakage and HA), but fewer neurologic effects and higher systemic effects (due to higher dose).
What is unique about cocaine as a local anesthetic?
Has additional CNS effects (block reuptake of catecholamines) that other local anesthetics do not have. Produces hypertension (centrally and peripherally). Used in ophthalmic procedures, but can cause corneal damage
Characteristics of Procaine (Novocaine)?
Used in infiltration, nerve block, and spinal anesthesia. Not typically effective. Has short duration of action (~30 minutes). It is hydrolyzed in vivo to PABA, which antagonizes the antibacterial effects of sulfonamides.
What is unique about tetracaine?
10x more potent than procaine (novocaine) due to high hydrophobicity. It is used topically for spinal
What is unique about chlorprocaine?
Short duration, used for infiltration and nerve block
What is unique about benzocaine?
Topical, widely used OTC
Difference between lidocaine and bupivacaine?
They are both used in all forms of local anesthesia. Bupivacaine has long duration (4-6hrs), and lidocaine is more potent and longer lasting than procaine (novocaine)
What is an important peptide Na channel blocker we learned about?
Tetrodotoxin (TTX). It is not used as a local anesthetic. Used only in experimental studies
What type of activity is blocked by increasing dose/concentration of anesthetic?
Loss of voluntary activity, loss of escape response to pain (MAC for volatile anesthetics), loss of somatomotor reflexes, loss of spontaneous respiration, loss of autonomic response to pain (MACBAR for volatile anesthetics)
Goals of anesthesia?
Reduce anxiety, produce sedation, permit induction/intubation, reduce anesthetic requirements (MAC-sparing)
What drugs can be used to treat anxiety in anesthesia?
Phenothiazines (but can cause hypotension due to alpha antagonist activity) and respiratory depression. Butyrophenones is used in neuroleptic anesthesia. BDZs most commonly used, minimal respiratory depression when given alone.
Utility of opioids in anesthesia?
Smooth induction (rapid sequence induction) prior to transition to volatile anesthetics. Allow easier maintenance of analgesia with less potent side effects (N2O) and lower doses of anesthetics (MAC-sparing). Side effects include prolonged awakening time, promote colic, bronchiolar narrowing, vagotonic effects, major truncal and jaw rigidity
Utility of antiemetics and anticholinergics in anesthesia?
Indication for routine use of antiemetics is reduced with less irritating anesthetics. Anticholinergics (atropine) are used to counteract the vagotonic effects, like bradycardia, of anesthetics (especially opioids).
Rationale for decreasing stomach acidity and secretions during anesthesia?
Protects against pulmonary aspiration of gastric contents. Use H2 blockers (+ metoclopramide)
What are examples of MAC-sparing agents that can be administered with volatile anesthetics?
Other anesthetics (propofol), N2O, Opioids bolus + infusion (up to 75% reduction of MAC with opioids)
Utility of NM blocking agents in anesthesia?
Permit intubation (opioid-induced muscle rigidity), and reduce muscle tone to permit surgery and dissection
What NM blocking agent causes hyperkalemia?
Depolarizing agenst like succinylcholine and decamethonium. Hyperkalemia is particularly bad in patients on digitalis, or on K-sparing drugs (ACEIs, ARBs, diuretics), or with soft tissue injuries or burns
Considerations for anesthesia for patient on propanolol?
Aggravates myocardial depression caused by anesthesia, so need to reduce dose. If stop medication, can lead to arrhythmias.
What anesthetic agent causes malignant hyperthermia?
Depolarizing agents and halogenated hydrocarbon anesthetics. They release Ca in skeletal muscle. Treat with Dantrolene
What are the phases of a seizure?
Aura (immediately prior), Ictal (the seizure), and Post-Ictal (time after the seizure). Typically last seconds to minutes
What are the types of partial (focal) seizures?
Also known as local seizures. (1) Simple partial (do not lose consciousness), and (2) complex partial or psychomotor (dream-like, mentally impaired, compulsive purposeless bahavior or movements). A secondary generalized seizure starts as a partial seizure and then spreads to whole cortex and becomes a GTC seizure. Complex partial seizures are the most common of any seizure.
What is an absence seizure?
One of the generalized seizures. It is an abrupt loss of consciousness associated with staring. “petit mal”, usually lasts <30sec. It is the ONLY seizure that does not cause brain damage. It is also the only seizure that does not involve excitation, it is only due to too much inhibition
What are the types of primary generalized seizures?
(1) absence or “petit mal” (zone out, stare, then come back to normal), (2) myoclonic or “minor motor”, (3) clonic or “grand mal”, (4) Tonic Clonic, or “grand mal”, and (5) Atonic or “akinetic/drop/minor motor”
What is a myoclonic seizure?
One of the primary generalized seizures. A brief (~1sec), shocklike contraction of muscles that may be restricted to part of one extremity or generalized.
What is a Tonic Clonic seizure?
One of the primary generalized seizures. Sometimes referred to as grand mal seizures. Involve an initial contraction of the muscles (tonic phase) which may involve tongue biting, urinary incontinence and the absence of breathing. This is followed by rhythmic muscle contractions (clonic phase). A tonic seizure alone is just sustained contraction of muscles, typically 1-3 minutes.
What is an Atonic seizure?
One of the primary generalized seizures. Involve the loss of muscle tone, causing the person to fall to the ground. These are sometimes called 'drop attacks' but should be distinguished from similar looking attacks that may occur in narcolepsy or cataplexy
Preferred AEDs for primary generalized tonic clonic (GTC) seizures?
Valproic acid, phenytoin (avoid in children), lamotrigine, others (except ethosuximide)
Preferred AEDs for partial seizures?
Carbamazepine, phenytoin (avoid in children), others (except ethosuximide)
Preferred AEDs in absence seizures?
Ethosuximide, valproic acid, lamotrigine. However, if patient has GTC or myoclonic seizures, valproic acid is 1st line for absence seizures too.
What is 1st line therapy for atypical, atonic, myoclonic seizures?
Valproic acid, lamotrigine. Valproic acid is part of the list of 1st line therapy for any kind of seizure. Lamotrigine is 1st line also for partial seizures, but 2nd line for primary GTC seizures.
What is the basic mode of action of 1st generation AEDs?
They block action potential and/or release of NT from terminal. Phenytoin, Carbamazepine, and valproic acid are 1st gen AEDs that block Na channels. Ethosuximide and valproic acid (which are 1st line for absence seizures) inhibit T-type Ca channels. So, notice that valproic acid has two modes of action
How does stimulation of GABA receptors inhibit action potential propagation?
When GABA (which is synthesized in axon terminals from carboxylation of glutamate) binds to the GABA receptor, the Cl channel opens, hyperpolarizing the membrane, and thus preventing excitability of the membrane to depolarization.
How to BDZs and barbiturates affect the GABA receptor differently?
BDZs increase the frequency of opening time. Barbiturates increases the duration of open time.
The Na channels and Ca channels inhibited by 1st gen AEDs are located where?
Na channels are along the membrane of axons. Ca channels (high voltage ones) are on axon terminals to control NT release. Low voltage T-type Ca channels are mainly in the thalamic-cortical pathway.
What are the glutamate receptors (excitatory, and involved in epilepsy)?
NMDA (fluxes Ca and Na) and AMPA/Kainate (fluxes Na only)
What three AEDs block both Na channels AND Ca channels?
Valproic acid, zonisamide, and lamotrigine (which also antagonizes the glutamate receptors). Ethosuxamide also blocks Ca channels, but not Na channels.
What AEDs block Na channels?
Phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate, oxcarbazepine, Zonisamide. But gabapentin and pregablain do not.
What AEDs produce GABA potentiation?
Gabapentin and Topiramate.
What AEDs induce P450s?
Phenytoin, phenobarbital, primidone, oxcarbazepine, carbamazepine (self induces), and topiramate (can compromise BCP effectiveness if ≥ 200mg/day)
Which AED induces its own metabolism?
Carbamazepine. It is the only one that does this. The effect wears off after a few weeks (max 4 weeks), but returns if ever dose is changed. It is metabolized in the liver (just like all the 1st gens), to an active metabolite
Which three AEDs are most highly protein bound?
Phenytoin, Primadone, Valproic acid.
Due to the high level of protein binding with phenytoin (as well as primdone and valproic acid), how to calculate the phenytoin level based on patient’s albumin?
Adjusted phenytoin=(measured phenytoin)/[(0.9*albumin/4.4) + 0.1]
Which AEDs are cleared exclusively hepatically?
All 1st gen + lamotrigine
What are the 1st gen AEDs?
Phenobarbital (and primdone), phenytoin (and fosphenytoin), BDZs, carbamazepine, ethosuximide, valproic acid
What are the 2nd gen AEDs?
Gabapentin, pregabalin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide
Which AEDs are cleared only renally, and therefore should be avoided in renal disease?
Gabapentin and pregabalin (both are 2nd gen). All the 1st gen + lamotrigine are cleared only hepatically, and all the other besides these have mixed metabolism
Considerations for drug levels in epilepsy?
Effective levels vary from patient to patient, so treat the patient and the symptoms, not the level. Optimal levels depend on the patient. Start low, and increase slowly
What AEDs can cross react to stimulate hypersensitivity reaction?
Phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine (?). they are either hydantoins or similar to them (carbamazepine is a Tricyclic, but similar). Avoid switching between these agensts.
Important distinguishing characteristics of carbamazepine?
1st gen AED. Blocks Na channels. Induces own metabolism (to an active metabolite). Can cause blood dyscrasias (like agranulocytosis, other hemotological depression). Can cause neural tube defects like valproic acid. Can cause SIADH→ hyponatremia. One of the hypersensitivity drugs (along with phenytoin, phenobarb, ethosuximide, lamotrigine). It is used most often for GTC and partial complex seizures
Distinguishing characteristics of Phenytoin as an AED?
1st gen AED. Blocks Na channels . Ataxia is an important side effect, as well as visual and ocular problems, and sedation. It leads to acne, hirsutism, and gingival hyperplasia, and in kids, can lead to facial coursening. Like carbamazepine, it can cause blood dyscrasias and Steven-Johnson’s. It is one of the hypersensitivity drugs (along with carbamazepine, phenobarb, ethosuximide, lamotrigine)
Compare IV phenytoin with fosphenytoin?
Phenytoin is cheap, has been used a long time, and can be stored at room temp. But, it contains propylene glycol, stable in NS for one hour only (and can only be by itself), has pH of 12 (caustic), and can lead to soft tissue damage, hypotension, cardiac arrythmias, and absorption is erratic. Fosphenytoin lacks propylene glycol, it is water-soluble, it is compatible with other IV solutions, is at pH 8.5, can infuse it faster, and has less reactions (still some pruritis). However, it is expensive, must refrigerate, has confusing dose conversion, and requires conversion from prodrug into phenytoin (which takes about 15 minutes in the body).
Distinguishing characteristics of valproic acid?
1st gen AED, inhibits Na channels and T-type Ca channels. Good for all types of seizures. It can cause a dose-dependent tremor, alopecia, pancreatitis, weight gain, and neural tube defects (like carbamazepine)
Distinguishing characterisitics of phenobarbital as an AED?
Can induce P450s, is one of the hypersensitivity drugs, can cause blood dyscrasias, steven-johnsons, rash, sedation. It can cause hyperactivity, aggression.
Two metabolites of Primidone?
Mostly phenobarbital, but also some PEMA (phenylethylmalonamide)
What is Ethosuximide?
1st gen AED. One of the hypersensitivity drugs. One of the 1st line treatments for absence seizures (along with valproic acid). It is only used for absence seizures. Can cause rash, hiccups, aggression, night terrors, lethargy, sedation
What is gabapentin? Unique about it?
2nd gen AED. GABA potentiation (along with Topiramate). Can also treat neuropathic pain. It can cause ataxia, weight gain. And in children, can cause behavioral problems, aggression, developmental delay, ADHD
Most common side effect of lamotrigine?
Rash. Start with low dose, and not with valproate. It is the only 2nd gen AED that is metabolized only in the liver.
Distinguishing characteristics of Topirimate?
2nd gen AED. ≥200mg/day induces metabolism of BCPs. Causes cognitive impairment (“Dopamax”, patients get dopy), kidney stones
What is unique about oxcarbazepine?
Carbamazepine without an epoxide. 2nd gen AED. Causes hyponatremia in up to 25% of patients (more than carbamazepine), but mild. Need to monitor Na. Rash is less than carbamazepine, and it lacks the auto-induction of carbamazepine.
Distinguishing characteristics of Levetiracetam?
“Keppra”. 2nd gen AED. has no DDIs. Low rash incidence. Somnolence, fatigue, uncoordination wears off after a month. Can cause hallucinations, agitation, anxiety, depression, dizziness.
What is Zonisamide?
“long-acting Dopamax”. It is a sulfonamide, so contraindicated in sulfa allergy, and rash is common for that reason. It also causes kidney stones in a small percentage of patients.
What’s unique about pregabalin?
2nd gen AED. It is water soluble and structurally related to GABA.
Definition fo status epilepticus?
Seizure that persists at least 5 minutes or 2 or more discrete seizures, between which, there is not complete recovery of consciousness (in about 20 minutes).
Fastest and most reliable way to administer AEDs?
IV. Also, the greater the lipid solubility, the faster it diffuses across tissue membranes.
Important differences between BDZs for status epilepticus?
Lipophilicity: Diazepam>Lorazepam>Midazolam. However, even though lorazepam is just barely slower at diffising into the brain than diazepam, it stays in brain longer. Lorazepam is the only of the three without an active metabolite, and is the only one metabolized by glucuronidation instead of P450s. It also has the longest distibution half-life.
For which AEDs does rash occur?
Common with all, but lamotrigine is much more rash-producing in kids.
Which AEDs cause highest behavioral changes?
Phenobarb, topiramate, zonisamide. Carbamezepine and Valproate are the least
Which AEDs are most likely to cause kidney stones?
Topiramate, Zonisamide. Drink lots of water
Which AEDs commonly cause visual disturbances?
Phenytoin, phenobarb, carbamazepine, oxcarbazepine
Which AED causes taste disturbances?
Remember… “Taste Topirimate”. It commonly causes metallic taste and rarely alcohol intolerance
Which AEDs cause weight gain?
Valproate and gabapentin.
Which AEDS cause hair loss?
Valproate, topiramate. Phenytoin can cause increases body hair (hirstusism)
Which AED most commonly causes blood dyscrasias like aplastic anemia?
Carbamazepine
Which AEDs inhibit excitatory neurotransmission?
Lamotrigine (blocks glutamate), and topiramate (blocks AMPA). Topiramate also potentiates GABA on GABAa receptors
Which AEDs enhance GABAergic activity?
BDZs, phenobarb, topiramate, Gabapentin
Three mechanisms topiramate uses for AED effects?
Blocks Na channels, potentiates GABAergic transmission, and blocks AMPA receptors
Oral bioavailability of AEDs?
Most are very highly bioavailable (90%). The exception id gabapentin, which is about 60%
Elimination kinetics of AEDs?
All first order except phenytoin, which is zero order.
Which AEDs have an active metabolite?
Primidone (phenobarb), Carbamazepine (CBZ-10, 11-epoxide). Both of those involve oxidation reactions. Oxcarbazepine is a prodrug of MHD, and the conversion is done by a reductase, not P450.
Considerations for AED therapy?
Don’t suddenly stop or change drugs. Need to taper off. If therapy is inadequate, can add one drug and taper off the other, or keep both on board. Choose the drug for the right type of seizure. Two 1st gens are tried before 2nd gen, because most were approved initially as adjunctive therapy.
Best use for valproic acid and lamotrigine?
All seizure types, lamotrigine may be an exception for some types
For AEDs without anti-absence activity, which has broadest efficacy?
Topiramate.
Most important dose-related side effect for phenytoin, carbamazepine, valproate, topiramate?
Phenytoin=ataxia. carbamazepine=blurred vision and diplopia. Valproate=tremor. Topiramate=cognitive impairment, word-finding difficulties “dopy”
Problem with valproic acid in kids?
Can cause liver failure, especially if preexisting metabolic disorder. It can also cause pancreatitis
Teratogenicity of AEDs?
Major malformations for all 1st gens, but neural tube defects with valproic acid and carbamazepine. 2nd gens, not enough data yet.
Consequences of generalized convulsive status epilepticus?
Physical exhaustion, renal failure due to myoglobin ppt in kidneys, cardiotoxicity due to elevated lactate, brain damage due to anoxia or prolonged ictal activity (glutamate toxicity)
Difference between dependence and addiction?
Addiction is just more extreme form of dependence, and involves the alteration of the normal awards system. In addiction, need higher dose to give desired effect. In both cases, there is want, need, complusion, and withdrawal symptoms (which are the opposite effects of the drug)
What is psychological dependence?
Plays a significant role in degree of dependence. Factors include genetics, environmental cues, and the act of remembering feeling of withdrawal symptoms
What is physical dependence?
Sxs of withdrawal. It is only one of the parts of addiction
What is drug tolerance?
It is a sign of extent of addiction. Need higher dose to get desired effect. Can be PK (like barbiturates) or PD (like opiates). It also occurs in non CNS drugs. Cross-tolerance also occurs for drugs that act on same receptor
What factors contribute to drug addiction relapse?
Environment, small priming dose, withdrawal sxs, stress. Environment may even produce withdrawal sxs
What percentage of drug users become addicted?
3% of illegal drug users, and 0.5% of prescription drug users (of scheduled drugs)
What are the most commonly abused drugs (in order)?
Caffeine, EtOH, Nicotine, marijuana, amphetamines, cocaine, opiates
Two things that drugs of abuse have in common?
Reinforcing effects when taken, and aversive effects upon withdrawal.
What do amphetamines and methamphetamines do?
Increase monoamines (NE, DA, 5HT) present in synapse. Methamphetamines are more potent. They enter terminals through monoamine transporters (NET, SERT, DAT), displace NTs from vesicles, which then go into the synapse. They also compete for reuptake since they use the same transporters.
What does cocaine do?
Blocks the reuptake of monoamines from synapse. Produces euphoric effects, increased energy and decreased fatigue, enhanced performance of simple tasks (but not complex tasks), and decreased appetite
What is the role of the dopaminergic system in euphoria that is associated with drug abuse?
Rats will self-administer cocaine, but not w/o DA system intact, because it is the dopaminergic system that is responsible for the euphoric effects (more glucose consumption in nucleus accumbens), even in drugs that don’t act directly on the DA system (nicotine, opiates, EtOH). Withdrawal of stimulants leads to lower levels of DA than were present before stimulants were started.
What are some of the unwanted effects of stimulants?
High doses cause stereotypy (repetitive, meaningless movements like swaying, or picking at one’s clothes), high doses cause seizures. CV effects (high NE at synapses) like high BP, HR, arrhythmias
What is the sensitization that occurs with stimulants?
It is the opposite of tolerance, but only occurs for some effects. It can cause stimulant psychosis (identical to schizophrenia, and treated with DA agonists). It also “kindles” seizures, making them more likely.
What does methylphenidate do?
Ritalin. It blocks DAT and NET, and slightly blocks SERT. How it works in ADHD is unknown, but may be due to increased DA to increase focus and attention. The time-release form is less addictive, but still only a little addictive.
What do MDMA and MDA do?
“Ecstasy”, they increases release of 5-HT (and small amount of DA). They are called enactogens due their mood altering effect. Low doses produce well-being. High doses cause hallucinations. There is evidence of neurotoxicity (decreased CSF metabolite concentration), and possibly decreased memory.
What does LSD do?
Very similar structure to 5-HT, it suppresses 5-HT neurons via presynaptic autoreceptors, but is a direct agonist at post-synaptic 5-HT_1A and 5-HT_2A, which are probably responsible for hallucinogenic effects. LSD has very rapid tolerance and loss of tolerance. Users are aware that their hallucinations are not “real”, and often are synesthesias (seeing smells or hearing smells). Good or bad trip depends on the environment
What does PCP do?
Phencyclidine, angel dust, designed as anesthetic, but causes hallucinations and sxs of schizophrenia. It is similar to ketamine, and non-competitively inhibits NMDA receptor, so blocks effects of glutamate. Since glutamate is so ubiquitous in the CNS, the effects of PCPP can include altered body image, inability to distinguish self from others, feeeling isolated, disorganized thought, hostility, euphoria, dream-like state, and superhuman strength.
What does marijuana do?
Has tetrahydrocannabinol (THC), which binds to cannabanoid receptors. The natural ligand is anadamide. Marijuana produces sense of well being, relaxation, increased appetite, impaired short-term memory, dry mouth, increased HR. Therapeutically, it can reduce intraocular pressure and have antiemetic effects.
What factors contribute to the abuse potential of opioids?
Low addiction incidence in neoplastic disease, trauma, or post-surgery pain. It increases if a psychogenic or recurrent component is attached to its use (e.g. lower back pain, stress-induced pain, peripheral neuropathies, migraine)
What are the three responder types to methadone treatment for opioid addiction?
Stables (totally functional in social and work), Loners (sequestered from society), and Junkies (use other opioids when can, just use methadone to prevent withdrawals)
Primary effects of opioids in abusers?
Facial flush, pleasureable rush, then dreamy indifference, sedation, reduced aggression, decreased sex drive, and analgesia. The only rage and crime that is associated with its use is in avoidance of abstinence syndrome (withdrawal effects).
Tolerance potential in opioids?
Among highest of any drugs. Effect of 10mg in naïve person will require as much as 2g every 3 hrs to avoid abstinence syndrome in tolerant person. (400x)
What is abstinence syndrome of opioids?
Purposive: Complaints, pleas, demands, manipulations in order to obtain drug, Non-purposive: yawning, rhinorrhea, lacrimation, sweating, GI hypermotility, restless sleep, dilated pupils, gooseflesh, irritability, shivering, tremors, muscle spasms. Major symptoms subside after about a week. Seldom life threatening, unlike barbiturates (including alcohol)
Common causes of death in opioid abusers?
Loss of tolerance is major cause. But also anaphylaxis, infections, AIDS, low resistance, and embolism.
Signs of opioid overdose?
Respiratory depression, pinpoint pupils. Victims are “on the nod”, not totally out, but sedated and can be aroused. It is treated with naloxone.
Symptoms of barbiturates and BDZs abuse?
BDZs have less overdose tox than barbs. Stupor, confusion, slurred speech, irritibility (and LACK OF AROUSAL). Some tolerance is seen, but less than opiates. Abstinence syndrome is tremors, insomnia, seizures, delirium, muscle cramps, reflex twitching, hypotension
What are gamma-hydroxybutyrate and Flunitrazepam?
Date-rape drugs. They are sedative hypnotics like barbs and BDZs. GHB is an analog of GABA that causes sleep, amnesia, CNS depression. Flunitrazepam is a potent BDZ that produces anterograde amnesia, not sold legally in U.S.
How fast is nicotine delivered to the brain from a cigarrete?
From pulmonary system to brain in about 7 seconds. Repetitive drug delivery (200 times per day) leads to psychological imprinting and psychological dependence.
How does nicotine exert its effects?
Stimulates presynsaptic receptors to increase release of DA and glutamate. DA release causes euphoria in nucleus accumbens area (limbic). Increased glutamate produces clarity of thought. Receptors desensitize but upregulate. Absorption is increased by free-basing, using treatment with alkali in preparing the tabacco.
What is abstinence syndrome for nicotine?
Irritibility, hostility, anxiety, dysphoria, restlessness, decreased HR, increased appetite and weight gain
What is buprenorphine used for?
Alternative to methadone for addiction treatment. It is a partial agonist (but more potent than morphine), so overdose is impossible or at least less likely. However, withdrawal symptoms may be more severe.
Three major groups of CNS depressants?
Benzodiazepines, barbiturates, ethanol
6 effects of CNS depressants, in the order of their effect from smallest to largest dose?
Sedation, induction of sleep (hypnosis), unconsciousness, sugical anesthesia, coma, fatal depression of respiration and CV function. (however, BDZs and newer selective sedative-hypnotics cannot produce anesthesia or coma, so no fatal risk)
What about psychomotor effects of CNS depressants?
CNS depressants can cause psychomotor impairment, for which warning labels are required
How do CNS depressants affect memory, sleep, and cognition?
Can cause anterograde amnesia (inability to acquire new memory while under influence of the drug), drowsiness, and confusion
Do users of CNS depressants become more sensitive to their effects, or tolerant?
Tolerant, even cross-tolerant (so a heavy drinker will need a bigger dose of a BDZ to get same effect, unless of course, they use them concomitantly which creates a larger, synergistic effect)
What kind of dependence do users of CNS depressants develop?
Physical dependence, which means they have withdrawal sxs (which are opposite of the effects of the drug) upon discontinuation after chronic use
What are 3 causes of insomnia that are NOT appropriate to treat with sedative-hypnotics?
1) Depression and other psychiatric disturbances, 2) Drug abuse of stimulants, sleeping pills, or ethanol, and 3) Physical disorders like pain and sleep apnea
What are three causes of insomnia that ARE appropriate to treat with sedative-hypotics?
All short-term: 1) Body-clock disturbances, 2) External disturbances like noise, and 3) Stress-associated, like bereavement
What is difference in onset of action between sedative-hypnotics and antipsychotics and antidepressants?
Sedative-hypnotics work immediately, but antipsychotics and antidepressants take time to start working (weeks or more)
What are three criteria for effectiveness and five criteria for safety that the ideal sedative-hypnotic should have?
Effectiveness: 1) reduce sleep latency and increase duration of sleep, 2) produce minimal changes in normal sleep cycle, and 3) not give hangover effect of sedation or rebound anxiety. Safety: 1) Not fatal on overdose, 2) No serious drug interactions, 3) No physical dependence, 4) No rebound insomnia upon d/c, 5) low abuse potential
How do barbiturates work?
Bind to allosteric site (a different one than BDZs) on GABAA receptor, which increases its affinity for GABA, so Cl channels remain open for longer, which leads to increased magnitude of GABA-mediated IPSPs
As opposed to the ideal sedative-hypnotic, what properties to barbiturates have?
Tolerance (partly due to induction of CYPs), Physical dependence (due to life-threatening withdrawal sxs of tremor, insomnia, hypotension, delirium, seizures), Highly Addictive, Low therapeutic index (so can be fatal on overdose), Induce glucuronyltransferase (which messes up kinetics of other drugs), Mess up the sleep cycle (by decreasing REM and slow-wave sleep), have long half-life (so daytime sedation)
What problems (non-ideal characteristics) do BDZs have as sedative hypnotics? And what advantages do they have over barbiturates?
Like barbiturates, they have Tolerance, Physical dependence, abuse potential, and affect sleep cycle (but quality of sleep is better than with barbiturates), However, hay fewer drug interactions and do not induce or inhibit CYPs, safe on overdose (when used alone)
How to BDZs work?
Binds to GABAA receptors allosterically to increase affinity of GABA to its receptor (so without GABA, BDZs don’t work). It causes more frequent ion channel opening. It binds between the α and γ subunits of which there are subtypes that are responsible for the different effect. α1 and γ2 mediate sedative-hypnotic effects, while α2 mediates anxiolytic and muscle realxant effects. Interestingly, no endogenous ligands have been found which bind to the BDZ binding site
What are the four effects of BDZs that they are used therapeutically for?
1) anxiolytic (α2), 2) sedative-hypnotic (α1 and γ2), 3) anticonvulsant, and 4) muscle relaxant (α2 ), which is a CNS effect, not a skeletal muscle effect
4 significant side effects of BDZs?
(1) drowsiness, (2) confusion, (3) anterograde amnesia, and (4) psychomotor impairment
Which route are BDZs administered?
IV and oral (not IM)
Triazolam?
“Halcion” Along with flurazepam, is the most rapidly absorbed BDZ. So, it is abused more than alternatives like chlordiazepoxide (20hr half-life) Short duration, so doesn’t accumulate, and effect is gone by morning. Metabolite is hydroxylated.
Flurazepam?
“Dalmane”. Along with triazolam, is the most rapidly absorbed BDZ. It has a long biological half-life, so can accumulate in body. Metabolite is N-dealkyl.
Alprazolam?
“Xanax”. Rapidly absorbed BDZ, most often prescribed as anxiolytic (not as hypnotic due to long half-lide of 12hrs). metabolite is hydroxylated. (Intermediate duration)
Temazepam?
A BDZ, “Restoril” absorbed slowly. Intermediate Duration, so some effects still left in morning. Only metabolized by glucuronidation.
Diazepam?
BDZ “Valium”, absorbed more rapidly than chlordiazepoxide. Metabolite is N-dealkyl. Has long half life
Oxazepam?
BDZ. “Serax” Intermediate Duration, like alprazolam and temazepam. Slow absorption, and metabolized only by glucuronidation.
Midazolam?
BDZ. “Versed” Short duration. Metabolite is hydroxylated. Administered IV for anesthesia
Phase 1 metabolites of BDZs?
Microsomal oxidation by CYPs produce N-dealkyl metabolites and hydroxylated metabolites. The N-desalkyl metabolites (of diazepam, chlordiazepoxide, and flurazepam) are ACTIVE and have LONG half-life. The hydroxylated metabolites (of triazolam, midazolam, and alprazolam) are ACTIVE and have SHORT half-life
Phase 2 metabolites of BDZs?
Glucuronidation is the last step in ALL BDZ metabolism, and is the ONLY step for some BDZs (oxazepam, lorazepam, temazepam). So, the conjugated BDZs are excreted into bile. Liver dysfunction affects glucuronidation less than CYP function
How do drugs and age affect metabolism of BDZs?
Microsomal oxidation by CYPs can decrease with impaired liver function, such as in the elderly. Also, drugs that use or inhibit CYPs like cimetidine and SSRIs increase the effects of BDZs. However, BDZs that are metabolized only by glucuronidation (oxazepam, lorazepam, temazepam), are less affected by hepatic insufficiency.
What is “biological” half-life?
It means half life of the parent drug and active metabolites
What is advantage and disadvantage to BDZ having short or long half-life?
Short half-life means less hangover effect and psychomotor impairment, but are more likely to cause rebound of original sxs (anxiety, insomnia)
Advantage and disadvantage to BDZs with long half-life?
Cleared more gradually, so withdrawal is tapered (less rebound sxs). But, can cause progressive psychomotor impairment
BDZs with what half-life are better for anxiety?
Usually short half-life, because less psychomotor impairment, but the need for frequent dosing can cause anxiety
What is the Halcion (triazolam) controversy?
DC’d in UK due to studies showed it was associated with confusion, amnesia, abnormal behaviors, but not that other agents lacked these. In U.S., FDA-recommended dose decreased to 0.125 – 0.25mg (not yet demonstrated to be effective). It does appear to have high anterograde amnesia.
Which BDZ to use for anxiety versus insomnia?
All can be used for both
Selection criteria for BDZs?
Rate of absorption, how metabolized, half-life, etc
Duration to use BDZs?
Short-term. If more than a few days, taper off. If more than a month they are not effective to treat chronic anxiety or insomnia
How can BDZ antagonists be used?
Flumazenil is a BDZ antagonist that competitively binds to the BDZ binding site to decrease affinity of GABA for its receptor. It can be used to treat BDZ overdoses and to reverse BDZ effects after surgery or diagnostic procedures
Zolpidem?
“Ambien”. Like Zaleplon and Eszopiclone. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 30 min onset and 2 hr half-life. Also comes in CR formulation
Zaleplon?
“Sonata”. Like Zolpidem and eszopiclone. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 10-20 min onset and 1 hr half-life.
Eszopiclone?
“Lunesta”. Like zolpidem and zaleplon. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 30 minute onset, 6 hr half-life. A side effect is bitter aftertaste. Approved for long-term use (like Ramelteon)
Ramelteon?
Melatonin agonist (a sub-category within non-BDZ sedative-hypnotic). More selective for MT1 and MT2 receptors than melatonin, so more effective too. Onset 15-25 min, half-life 1-3 hrs. Only hypnotic that is not scheduled.
Buspirone?
A non-BDZ anxiolytic. It has NO sedative-hypnotic, anticonvulsant, ot muscle relaxant effects. That is because it doesn’t bind GABA receptors. It is a partial agonist at 5-HT1A receptors. Takes 1-4 weeks to work, and is a good choice if BDZ abuse is a concern
What is preferred agent for tx of long-term severe anxiety?
SSRIs. But some, like fluoxetine, can sometimes produce anxiety. Severe anxiety may include general anxiety, OCD, social phobia, panic disorder, and agoraphobia. Performance anxiety can also be treated with propanolol (a β antagonist)
Modafinil?
“Provigil” is used to treat excessive sleepiness, caused by shift work, sleep apnea, and narcolepsy. It is potentially a drug of abuse for persons wishing to extend productive working hours. It causes minimal CV and CNS effects.
Phenobarbital?
barbiturate
What increases the risks for side effects of BDZs?
>65yo, EtOH, using >1 BDZ, highly soluble BDZs
Rules of thumb for when and how to taper off BDZs?
If use >2 weeks, then taper off over 2+ weeks. Give 2-4 doses per day, taper 25% over first 3 days, then slower during second half of tapering period. Also provide support and family help.
What are pt factors that increase risk of BDZ abuse?
Substance abuse hx, psychiatric hx, (however, social and demographic factors are no indicator at all)
Long term use of sedative-hypnotics (>2 weeks) increase what risks?
Side effects, misuse, abuse, dependence (this also includes Lunesta and Ambien)
What does “opiate” mean as opposed to “opioid”?
Opiate is the drugs, opioid is all structures related to opium, including the endogenous opiod peptides. Or more precisely, any substance that acts at the opioid receptor to produce respiratory depression, somnolence, analgesia, and decreased GI motility, and can be reversed with Naloxone
What are the three opiod receptor types?
Mu (μ), agonized by morphine and β-endorphin; delta (δ), agonized by DPDPE and leu-enkephalin and β-endorphin; and kappa (κ), agonized by butorphonol and dynorphin 1-17. All are antagonized by naloxone
What are sigma (σ) and orphan opioid receptor-like receptors?
Once thought to be types of opioid receptors. Sigma can be stimulated by opioids (but probably through PCP), but not blocked by naloxone. ORL is not stimulated by opioids nor blocked by naloxone
How are the mu, kappa, and delta opioid receptors the same?
All from their own single gene (with >75% homology), all are GPCRs, have external N-terminus, and most importantly, they are all negatively coupled to adenylyl cyclase via Gi. Hetero-oligomerization can occur to make pairs of the types, but no clinical relevance exists for these different complexes
How does pertussis toxin (PTX) affect opioid receptors?
It can block the receptor-mediated effects of opioids
How do opioid receptors mediate their action?
Agonist binding leads to inactivation of the neuron. It starts with inactivation of adenylyl cyclase and inactivation of Ca channels (depress NT release, which is either inhibitory or excitatory depending on the particular neuron). Also, activation of G-protein-activated inwardly rectifying K channels (GIRK), leads to hyperpolarization, so reduced excitability of soma.
How does opioid receptor internalization (desensitization) occur?
Agonist binds, internal carboxy terminus gets phosphorylated by g protein coupled receptor kinases (GPRKs), increasing receptor affinity for arrestin, which then recruits c-Src adaptor (AP-2), which links arrestin with clathrin, causing endocytosis. Arrestin binding uncouples the transducing G-protein, so signaling is inhibited. For the mu receptor, etorphine and methadone doe this much greater than morphine and DPDPE. For the delta receptors, DPDPE does this much more than morphine. Side note: receptors are recycled, so new ones don’t have to be transported all the way from the nucleus and ER
Butorphanol
No effect
Morphine
Agonist
Naloxone
Antag
Three endogenous opioid peptides and their prohormones?
Enkephalins (from proenkephalin), dynorphins (from prodynorphin), and endorphins (from pro-opiomelanocortin or POMC). Each are cleaved post-translationally by trypsin-like enzymes into the active peptide. The prohormones contain either leu-enkephalin or met-enkephalin, which are pentapeptides offset by arginines and lysines
Proenkephalin?
Prohormone to enkephalins. Contains mutliple met-enkephalins and one leu-enkephalin. Found in brain in multiple populations of interneurons. Made mostly in adrenal chromaffin cells
POMC?
Pro-opiomelanocortin, the prohormone to endorphins. POMC contains sequences for ACTH, β-lipotropin (β-LPH), α-melanocyte-stimulating hormone (α-MSH). Found in pituitary
Prodynorphin?
Prohormone for dynorphins. Has multiple copies of leu-enkephalin. Found in pituitary and adrenals in small amounts
Differences in affinity of endogenous peptides for opioid receptors?
Met- and leu-enkephalin have most affinity for delta. B-endorphin has most for mu, and some for delta. Dynorphin 1-13 has only (a lot) for kappa
Role of endogenous opioids?
Released during stress and exercise from pituitary and adrenals. Give “runner’s high”, decrease pain, and modulate respiration and CV function. Naloxone has no measurable affect on endogenous peptide activity (probably because it is subtle)
Where do opioids exert their analgesic effects?
On mu receptors, primarily in the following regions of the brain: amygdala, substantia nigra, periaqueductal gray area (PAG), rostroventral medulla (RVM), and spinal cord. The PAG is best characterized, and maybe the most important
How do opioids produce analgesia in the PAG?
Bind mu receptors on interneurons, block release of GABA from tonically active interneurons (so inhibits the inhibitory action of GABA on the PAG). That permits PAG projections into the medula to activate bulbospinal projections which release 5-HT and/or NE at spinal level. There, 5-HT and NE act through α2 and 5-HT receptors to inhibit spinal pain input.
How do opioids effect analgesia in the spine?
Depresses discharge of spinal dorsal horn neurons activated by small afferents (high threshold). Intrathecally, it attenuates stimulation of sensory afferents. There are several mechanims: hyperpolariazation by activating K channels, block Ca chanels (so small NTs like substance P can’t be released), reduce release of NTs from C-fibers in the substantia gelatinosa
What are the effects of opioids on sleep/wakefulness?
mu and delta receptors. they reduce arousal and promote sedation, via inhibition of ascending excitatory drive from the mesencephalic reticular activating systems.
What are the effects of opioids on respiration?
Mu receptors. Reduce respiratory drive by depressing the brainstem response to high CO2. It is useful in patients with “air hunger”
What are the GI effects of opioids?
Mu and kappa receptors. Reduce biliary, pancreatic, and intestinal secretions. Increase tone in intestines, leading to non-propulsive contractions. It leads to increased viscosity, slower passage time, constipation. Mediated by inhibition of Ach in myenteric plexus. Increased biliary tone can also lead to colic
What are the emetic effects of opioids?
Mu, kappa, and delta receptors. Cause nausea and emesis by agonizing receptors in the chemoemetic trigger zone (CTZ)
What are the effects of opioids on euphoria/reward?
Mu receptors. Strong reward, euphoria. Receptors in the nucleoid accumbens inhibit inhibitory GABAergic interneurons, so release more dopamine. Heroine does this fastest because it’s so lipid soluble.
How do opioids affect pupillary caliber?
Mu receptors. Induce constriction (Miosis), due to excitation of p.symp nerves (via inhibition of inhibitory GABAergic interneurons) to contract pupillae constrictor.
How do opiods affect CV function?
Mu receptors. Typically well-tolerated. Increased excitation of vagus, leading to atropine-sensitive decrease in HR. Morphine releases histamine from mast cells, so produces vasodilation and hypotension
How do opioids affect the neuroendocrine system?
Mu and kappa receptors. Inhibit hypothalmic release of GnRH and CRF, but increase release of prolactin by reducing dopamine (an inhibitor of prolactin). Mu agonists increase ADH secretion (so decreases urine flow). But kappa agonists inhibit ADH secretion, so increase urine flow.
Morphine?
μ agonist (and patial κ agonist). For chronic pain (slow release) and for post-operative pain. Half-life 3 hrs. significant 1st pass metabolism oral. Metabolized by glucuronidation (which is still active at 6-position, but not 3-), undergoes hepatic circulation. Side effects are release of histamine from mast cells, so pruritis and hpotension
Meperidine?
μ agonist. “Demerol”. Oral or IM. Shorter duration of action than morphine. IM for fast pain relief. Metabolized by demethylation to give normerperidine which has a longer half life, can accumulate if repeated doses, and is a convulsant
Methadone?
μ agonist. Oral, IM. High oral availability. Crosses BBB slower than morphine. Long duration, so useful in chronic pain and suppressing opioid withdrawals. Metabolized by N-demethylation in liver. Side effects: repeated dosing proteins binding and accumulation in tissues. Has long half-life. Crosses BBB slower than morphine
Fentanyl?
μ agonist. “Sublimaze”. High potency (more than morphine). Used for anesthesia, or for acute pain in chronic pain patients. Half-life is 3-4 hrs, but effect wears off after 30 minutes. Metabolized by liver → then liver and renal excretion of metabolites. Side effects are extreme rigidity at high doses
Oxycodone?
μ agonist. “Oxycontin”. For moderate to severe pain, frequently in combo with NSAID. Effect enhanced by cimetidine which inhibits its metabolism
Codeine?
μ agonist. High oral bioavailability. Frequently given with NSAID. Must be activated (3-O-demethylated) by CYP2D6 to become morphine. 10% of caucasian population has deficient 2D6, so no analgesia in these patients. Has ceiling effect because “weak” opioid, but it crosses BBB faster than morphine and is more orally available than morphine
Butorphanol?
κ agonist. Opioid analgesic. Oral or intranasal. For moderate to severe pain. Has significant first-pass metabolism.
Buprenorphine?
μ PARTIAL agonist, but more potent than morphine. For post-operative pain or maintenance drug for opioid-dependent patients. Long duration of action (more than serum half-life due to slow release from receptor). Excreted in feces. Can be used as antagonist to full agonists
Naloxone?
Opioid receptor antagonist. IM or IV. Onset immediate, duration short (half-life 1 hr, which is less than morphine), metabolized by liver conjugation. Can antagonize all effects of agonists
Tramadol?
Weak μ agonist, but also weakly inhibits NET and SERT (to block NE and 5-HT reuptake). Half-life 5 hrs, extensice metabolism by N- and O-demethylation and glucuronidation and sulfation. SHOULD NOT BE CO-ADMINISTERED WITH MAOI or TCA
Rules of thumb for DDIs with opioids?
Slowing of hepatic blood flow (e.g. cimetidine,) or inhibit CYPs (cimetidine, ketoconazole, grapefruit), incease action of opioids. Inhibitors of 2D6 (like fluoxetine, quinidine) block activation of codeine. CNS depressants synergize with opioids.
What are the two dimensions of pain?
Sensory-discriminative (quantifiable and relates to a sensory input), and Affective-motivational (emotional context of the pain, e.g. suffering)
What is an acute pain stimulus?
Activation of small, high threshold sensory afferents (Aδ and C fibers) sends transient input into spinal cord, then to neurons contraleterally to the thalamus, and to the somatosensory cortex. (needle stick, hot cup, etc)
What is a tissue injury pain stimulus?
Local release of mediators (bradykinin, prostanoids, potassium causes persistent activation of small sensory afferents, which activates ascending pathways and leads to “spinal sensitization” (so more sensitive to small stimuli (burns, post-incision, abrasion, etc.)
What is nerve injury pain stimulus?
Nerve damage causes anatomical and biochemical changes in nerve and spinal cord to give spontaneous dysesthesias (shooting, burning pain) and allodynia (light touch hurts). Maybe occurs via low threshold afferents (nerve trauma, diabetic neuropathy, neuralgia
What kind of pain are NSAIDS most effective for?
Tissue injury really well, but not acute stimuli or nerve injury
What kind of pain are opioids most effective in treating?
Tissue injury and acute stimuli better or the same as nerve injury
What kind of pain are anticonvulsants and tricyclic antidepressants most effective in treating?
Nerve injury, but not tissue injury or acute stimulus (gabapentin, tipiramate)
what should be used to treat mild or moderate pain?
Mild = NSAIDS, moderate = NSAIDS and/or weak opioids (Buprenorphine and Codeine)
What should be used to treat severe pain?
NSAIDS plus strong opioids, anticonvulsants. Also, adjuvants like laxatives, antiemetics, stimulants, antidepressants
Rules of thumb for combining pain releievers?
Use drugs with non-overlapping MOAs, don’t mix partial agonists with full agonists
What are typical rescue pain meds?
Fentanyl patch or IV PCA
Possible mechanisms or explanations for tolerance?
1) higher clearance or metabolism 2) loss of receptors or receptor coupling 3) increased pain over course of disease, 4) development of non-opioid-sensitive pain (i.e. neurologic pain), 5) don’t block “suffering”, only nociceptive pain
What is dependence?
Withdrawal will produce drug-specific withdrawal symptoms (usually exaggerated symptoms that are supressed by the opioid, like hyperalgesia, diarrhea, agitation)
What is addiction?
Drug-seeking behavior for non-therapeutic purpose, continued use despite harm, craving, and illegal behavior to get drugs.
What drugs are used to treat opioid addiction?
Methadone, buprenorphine (with ot without naloxone)
How common is addiction to opioids after therapeutic use?
Relatively rare, but abuse and diversion are more common
Which endogenous peptide has highest affintity for kappa recerptor?
Dynorphins
Which endogenous peptide has highest affintity for mu recerptor?
Beta-endorphins
Which endogenous peptide has highest affintity for delta recerptor?
Met- and leu-enkephalins
Loperamide?
Mu agonist at ALL opioid receptors (mu, kappa, delta). Treats diarrhea. Very poorly absorbed (that’s good)
Gabapentin?
“neurontin”. Anticonvulsant like topiramate (Topamax). Used to treat neuropathic pain, only side effect is some drownsiness
Topirimate?
“Topamax”. Anticonvulsant like gabapentin (Neurontin), used in treatment of neuropathic pain
Amitriptyline?
Tricyclic antidepressant. Tertiary amine. Inhibits reuptake of NE and 5-HT. Side effects are dry mouth, CV effects. Used to treat neuropathic pain and also as antidepressant iin chronic pain
Duloxetine?
“Cymbalta” 5-HT and NE reuptake inhibitor or “SNRI” (like venlafaxine), but not a tricyclic. Inhibits NET at lowe doses than venlafaxine. Can inhibit 2D6. Causes nausea, sedation, but less sex dysfunction. Approved for diabetic neuropathy, to treat neuropathic pain and as an antidepressant in chronic pain
Trihexyphenidyl?
Like Benztropine, a mAChR antagonist used in the treatment of Parkinson’s disease and in combination with antipsychotic drugs to control EPS. Just like all anti-Ach, it can cause constipation, urinary retention, dry mouth, tachycardia, precipitation of attacks of acute narrow-angle glaucoma in susceptible individuals, confusion, and drowsiness
L-Dopa?
precursor of DA used in the treatment of Parkinson’s disease; generally administered in combination with carbidopa. Alone, it can cause severe nausea and vomiting because L-dopa is converted to dopamine in the periphery by aromatic L-amino acid decarboxylase. The dopamine then stimulates the chemoreceptor trigger zone (CTZ) in the area postrema in the medulla; this region of the brain is not protected by the blood-brain barrier
Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase, the enzyme that converts L-dopa to dopamine. It is used with L-dopa because it inhibits the peripheral formation of dopamine (neiher carbidopa nor dopamine crosses the blood-brain barrier, but Dopa does), thereby reducing the nausea and vomiting and increasing the fraction of the administered L-dopa that is available for transport across the blood-brain barrier
Sinamet?
Combination levadopa carbidopa
What is a possible side effects of sinamet after chronic use such as in parkinson’s?
Sinemet is combo carbidopa + L-dopa. Psychosis, caused by the extra dopamine. In Parkinson’s patient, need drug that has no EPS (only one is clozapine. Chronic sinamet use can also lead to dyskinesias, which mechanism is not known. Only recourse is to lower Sinamet dose. The effects of Sinament can also decrease over time probably due to progression of the disease in which there are fewer dopaminergic neurons available to convert L-dopa to dopamine.
Benztropine?
Like Trihexyphenidyl, a mAChR antagonist used in the treatment of Parkinson’s disease and in combination with antipsychotic drugs to control EPS. Just like all anti-Ach, it can cause constipation, urinary retention, dry mouth, tachycardia, precipitation of attacks of acute narrow-angle glaucoma in susceptible individuals, confusion, and drowsiness.
Ropinirole?
Like Pramipexole, a DA agonist used in the treatment of Parkinson’s. DA agonists are first line in parkinson’s to avoid AEs of Dopa.
Pramipexole?
Like Ropinirole, a DA agonist used in the treatment of Parkinson’s. DA agonists are first line in parkinson’s to avoid AEs of Dopa
Selegiline?
Relatively selective MAO-B inhibitor used in the treatment of Parkinson’s, especially for tremor.
Entacapone?
COMT inhibitor used in the treatment of Parkinson’s. Gives DA a longer half-life. (one formulation is a combination with L-dopa and carbidopa).
How does degeneration of dopaminergic neurons lead to dyskiniesia in Parkinson’s?
ACh stimulates and DA inhibits (and stimulates) GABAergic neurons, so when DA neurons degenerate, the DA influence decreases, and leads to both bradykinesias, rigitity, and tremors
How does L-dopa therapy lead to psychosis?
Extra DA in the mesolimbic pathway causes psychosis
Rank the amount of EPS that will be induced by atypical antipsychotics (in general), risperidone, chlorpromazine, haloperidol, and clozapine?
Haloperidol is the worst (high potency conventional), then chlorpromazine (low potency conventional), then respiridone (the most EPS of the atypicals), then atypical antipsychotics (D2 antagonists). Haloperidol is high potency. Clozapine causes no EPS, but can cause agranulocytosis
What are the sxs of early, middle, and late alzheimer’s?
Early is difficulty remembering converstions, date, losing things, social withdrawal, depression, poor judgement and planning. Middle can be anger, violent, paranoia, problems with personal care and communication, as well as motor impairment, 24hr supervision needed. Late is minimal verbal communication, not even basic personal care, can’t recognize people, places, things, can’t walk, smile, and maybe can’t swallow.
Two cellular pathological components to cause of alzheimer’s?
Extracellular neuritic amyloid plaques (can be due to h synthesis of Aβ plaques or decreased clearance), and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. These lead to degeneration of primarily cholinergic neurons projecting from nucleus basalis to cortex and hippocampus
How does choline supposed to work for alzheimer’s?
A precursor to ACh. Since cholinergic neurons extending from the nucleus basalis to the cortex and hippocampus are degenerated in alzheimer’s, increasing ACh might possibly help. It is limited by the ability of choline to cross both the BBB and get taken up by neurons via (probably) an already saturated uptake receptors.
Donepezil?
Tertiary amine Cholinesterase inhibitor used in the treatment of Alzheimer’s. Possible side effects include p.symp stimulation of GI, increase sweating, and other cholinergic responses. To treat these effects, a quaternary amine mAChR antagonist can be given (does not cross BBB)
Besides ACh esterase inhibition, what other strategies can be used to increase ACh transmission in Alzheimer’s?
mAChR agonists that are selective for M1 and M3 (M2 would decrease ACh release due to presynaptic effect. Or, nAChR agonists, at presynaptic effects to increase ACh release.
Memantine?
NMDAR antagonist; used in the treatment of Alzheimer’s disease. Works, possibly by decreasing neuroexcitatory stimulation by NMDA, which otherwise might lead to neuronal degradation. In effect, this means that “noise” that normally has to be overcome to produce memory, is erased, so memories can form with less dramatic excitation
Which part in the sequence of steps in Alzheimer’s progression does Memantine possibly inhibit?
After injury caused by amyloid plaques, memantine might prevent disruption of metabolic and ionic homeostasis, which normally leads to oxidative damage and then neuronal dysfunction
What potential therapies might be explored for treatment of alzheimer’s?
Inhibition of secretase (which protealyzes APP to make Aβ amyloid). Or immunotherapy against the Aβ amyloids
What are the “strong” opioids? “weak” opioids?
Morphine, meperidine, oxycodone, methadone. Weak = codeine and buprenorphine
What is the problem with using multiple short-acting opioids?
They cause tolerance much more than other regimens.
acamprosate
Related to GABA, increases glutamatergic transmission. And diminishes neuronal hyperexcitability during withdrawal from alcoholism; used in the treatment of chronic alcoholism
Aripiprazole?
Newest atypical antipsychotic drug (SDA, with partial agonist effects at D2 receptors and 5-HT1A receptors) “functional selectivity”. Little or no weight gain, metabolic changes, prolactin, lipids, hyperglycemia, or QT changes
Baclofen?
GABAB agonist (GPCR), muscle relaxant that works in spinal cord
Bicuculline?
Competitive GABAA antagonist, binds at GABA-binding site, which is on the beta subunit
Bupropion?
atypical antidepressant drug; postulated mechanism: NE/DA reuptake inhibitor (NDRI). No weight gain, sedation, sex dysfunction (can treat sex dysfunction), helps with nicotine withdrawal, more likely to cause seizures, but good effectiveness to safety profile.
Chlorpromazine?
conventional (typical) antipsychotic drug like thioridazine. (D2 antagonist); phenothiazine derivative, low potency, causes less EPS than haloperidol, but more than atypicals. Treats pos sxs (hallucinations, delusions, and disorganized thinking), but not neg sxs (withdrawal, loss of motivation)
Citalopram?
SSRI, has the most SERT/NET inhibition (but paxil has most SERT block). Has least p450 inhibition and CNS stimulation. Remarketed as escitalopram “lexapro” with no demonstratable advantage except more potent.
Clozapine?
Atypical antipsychotic (SDA). Has the highest affinity for 5-HT2A/D2. Selective for mesocortical/limbic. In striatum, presynaptic 5-HT2A is blocked, so increase DA release, so no effect in nigrostriatal. Best for EPS, but can cause agranulocytosis, seizures, wt gain, metabolic changes, hypersalivation, orthostatic hypotension (alpha1). The %-HT2A antagonism can’t explain lack of EPS though, because chlorpromazine has this too, but still EPS. Works in 60% of pts refractory to other meds. Was 1st to inprove neg sxs, doesn’t increase prolactin.
Despiramine?
tricyclic antidepressant drug; 2º amine
Disulfram?
“antabuse”. An inactive prodrug; converted to diethylthiomethylcarbamate, which suicide inhibits aldehyde dehydrogenase (ALDH); used in the treatment of chronic alcoholism. Chelates zinc to inhibit ADH directly, causes neurotoxicity by increasing Ni and Pb. It gives the pt acetylaldehyde syndrome N/V/HA
Divalproex?
Anticonvulsant used as a mood stabilizer
Fluoxetine?
“prozac”, prototype SSRI. Very selective for SERT. Has small mAChR, α1, H1 effects and cardio effects. Long half-life (50hrs), plus an active metabolite (10hr half-life), so less discontinuation syndrome. It can cause agitation, suicide tendencies, irritability, insomnia, akasthesia, inhibits 2D6. Also used for premenstrual dysphoric syndrome.
Fomepizole?
competitive inhibitor of alcohol dehydrogenase (ADH); used in the treatment of methanol poisoning
Lamotrigine?
Anticonvulsant used as a mood stabilizer
Lithium?
Mood stabilizer. Good for mania, but not mixed state or rapid cycling. Good response for 3 or fewer cycles per lifetime, and for mild illness. May patients are unresponsive to it, has low compliance, narrow therapeutic window, and side effects include tremors rash, GI upset, weight gain, cognitive impairment, teratogenic
Mirtazapine?
atypical antidepressant drug; postulated mechanism: antagonist at presynaptic α2 receptors → ↑NE and 5-HT release (NSSA = noradrenergic and specific serotonergic antidepressant). Has high H1 side effects (sedation), increases appetite and weight gain
MPTP?
toxin that is converted (by MAO-B) to MPP+, which destroys dopaminergic neurons
Muscimol?
GABAA agonist. Binds at same site as GABA (the beta subunit)
Naltrexone?
Long-acting Opioid antagonist, inhibits rewarding effects of EtOH to treat chronic alcoholism
Nefazodone?
atypical antidepressant drug; postulated mechanism: 5-HT2A antagonist with weak SSRI activity (SARI = serotonin 2A antagonist/reuptake inhibitor). 5-HT antagonism is not enough to cause antidepression, so SERT activity is essential. By blocking 5-HT2A, more activity occurs at 5-HT1A. has H1 side effects, and sometimes liver failure
Olanzapine?
Atypical antipsychotic (SDA). Along with quetiapine, has weight gain, DM, lipid profile worsening
Paroxetine?
“paxil”, SSRI. Most potent SERT inhibitor, highly inhibits 2D6, causes more weight gain, sex dysfunction, less CNS stimulation (maybe sedating), and has longer half-life than fluoxetine
PCP?
Phencyclidine. Blocks NMDA receptor ion channel
Picrotoxin?
Noncompetitive GABAA antagonist. Blocks GABAA receptor ion channel
Quetiapine?
Atypical antipsychotic (SDA)
Risperidone?
Atypical antipsychotic (SDA). First atypical after clozapine. More potent D2 blocker, less H1, alpha1, and mAChR effects. Of the atypicals, it is the worst for EPS and prolactin.
Sertraline?
SSRI, used mostly for OCD, not depression. Less P450 inhibition and CNS stimulation than prozac or paxil
Strychnine?
Glycine receptor antagonist. Strychnine is the GABA of the spinal cord
Thioridazine?
Conventional antipsychotic like chlorpromazine. (D2 antagonist), phenothiazine derivitive, low potency. Can cause retinitis pigmentosa and QT elongation
Tranylcypromine?
MAO inhibitor used as antidepressant
Venlafaxine?
Atypical antidepressant, the first SNRI. Is SNRI at low doses and NET inhibitor at high doses. Minimal effects on 5-HT. causes nausea, sedation, sex dysfunction, but more effective than SSRIs
Ziprasidone?
Atypical antipsychotic (SDA). Little or no weight gain, but can cause QT elongation like thioridazine (black box)
5 steps to tx of methanol poisoning?
Manage respiration, infuse ethanol (to compete for ADH), infuse bicarb for acidosis, give folate to get rid of formate, give FOMEPIZOLE to inhibt ADH (probably better than EtOH)
What are the four major effects of methanol poisoning?
Acidosis, respiratory depression, minor CNS depression, blindness (due to formic acid → retinal hyperemia, edema, and demylenation of optic nerve). It is also renally toxic
How is methanol metabolized?
NAD+-dependent enzymes (ADH and ALDH) to form formaldehyde (rate-limiting step) and then formic acid. this increases the NADH/NAD+ ratio, which increases lactate. The formic acid is turned to formate in a pH-dependent process. Formate gives off CO2 and H20, but requires folate (that’s why give folate)
What makes an antipsychotic clinically atypical?
Reduced EPS, but also possibly effective in pts refractory to standard agents, efficacy against negative sxs, and efficacy against cognitive sxs
How/when are 1st generation antipsychotics used?
Acute ot adjunctive therapy, but used less and less
All atypical antipsychotics are what class?
SDAs. They cause less EPS than 1st gen, and work better on negative sxs
Side effects of 1st gen vs atypical antipsychotics?
1st gen have EPS (acute dystonia, parkinsonian tremor bradykinesia rididity, akasthesia, tardive dyskinesia). They also have little or no hematological effects, weight gain, sedation, cardiac conduction probs, retinal probs, orthostasis. Atypicals can cause weight gain, drooling, sedation, seizures, and clozapine causes no EPS except akasthesia, but may cause agranulocytosis
Parkinsonian sxs and dyskinisias are most similar to pos or neg sxs?
Parkinsonian is like neg sxs. Dyskinesias are like pos sxs
What does 4-7 tremor cycles indicate?
Parkinson’s
Compare dystonia, parkinsonism, and akasthesia?
Dystonia is sustained muscle contraction, occurs within 1-2 days of therapy, in 2-10% of pts. Acute is more likely in young pts. Treatable with anticholinergics. Parkinsonism is bradykinesia, tremors, rigidity. Occurs within weeks of therapy, 50-60% of pts. More common in elderly. Flexed posture, shuffling steps, no swinging arms, mult steps to turn around. Akasthesia is voluntary movement to try to relieve inner discomfort. 50% of pts, more common in elderly. Difficult to treat.
How to treat seizures from EtOH withdrawal?
BDZs
Chronic GI effects of EtOH?
Intestinal malabsorption, vitamin deficiency, liver disease, stimulation of CYP2E1 leads to tolerance to EtOH and drugs that are metabolized with 2E1. The increased O2 use by 2E1 also decreased ATP production and depletes NAD+ stores. Increased acetylaldehyde, producing protein adducts and giving an immune response.
Chronic CV effects of EtOH?
Cardiomyopathy, degenerative changes, CHF
Chronic effects of EtOH on CNS?
hNMDA, hCa chanels, iGABA, all leading to increased output, which leads to dependence
Acute GI effects of EtOH?
Increase acid secretion and gamma-amino-levulinic acid synthase (makes porphyria worse)
Acute effects of EtOH on CV?
Dilates cutaneous vessels (flushing) via central vasomotor depression. Acetylaldehyde directly dilates sm musc. Increases catecholamine release from adrenal medulla
Acute CNS effects of EtOH?
Depressant. Increase 5-HT action, and GABA leading to inhibition activity. Also decreases NMDA, Kainate, Ca channels, and adenosine uptake. It perturbs membrane fluidity and electrical activation, blocks nerve conduction. Inhibits secretion of ADH from post pit. Hangovers caused by fusels, which are contaminants of formulation process.
What’s reductive storage?
NADH:NAD+ ratio increases from 1:4 to >1 as a result of EtOH consumption, due to build up of NADH, acetate, pyruvate, NADPH, lactate, acetyl CoA. Causes increased blood lactate (acidosis from competition with ureate production), increases ketones from fat, hyperlipidemia due to high FA synthesis intermediates, fatty liver from hepatocyte FA synthesis and decreased VLDL export. But increases HDL/LDL ratio with moderate alcohol
Primary and secondary pathway for EtOH metabolism?
Primary (75%): EtOH goes to acetylaldehyde by ADH, followed by conversion to acetate by acetylaldehyde dehydrogenase (ALDH). ADH is zn-containing, and is inhibited by pyrazole. ALDH is inhibited by disulfram, and is deficient in 30-50% of asians. Secondary (25%): induced in chronic alcoholism. First step is CYP2E1, which is part of the microsomal ethanol oxizing system (MEDS) in smooth ER. Second step is acetylaldehyde to acetate by ALDH or a non-specific aldehyde oxidase
How fast is EtOH metabolized?
About 10g (10mL) per hour in 70kg person
How does EtOH distribute in body?
Goes everywhere, in proportion to blood flow (so brain is high). Vd is lower in elderly and women due to less water per kg body mass
How to calculate amt EtOH consumed based on blood level?
Weight (kg) x Vd (L/kg) x 1000ml/L x % (g/100mL) = amt (g).
How is absorption and bioavailability of EtOH?
0.8 to 1.0. 1st order absorption (so faster at first), takes 1-4 hrs to complete. Food slows absorption by slowing gastric emptying.
St John’s Wort for depression?
Not more effective than placebo, can interact with drugs in many ways
How often need to use combo therapy or augmenting agents for antidepressants?
About 50% respond to monotherapy. Augmenters not to be used alone, only in combo with antidepressant
Side effects of MAOIs?
Change BP, insomnia, increased appetite. Potentiate effects of sympathomimetics and tyramine and TCA and SSRIs. Can cause Serotonin syndrome which is too much 5-HT, causing GI sxs, CNS toxicity, hyperthermia, CV collapse. It can also occur when switching between MAOI and SSRI
How do MAOIs work?
Block metabolism of NE, 5-HT, so leak out into sysnapses. Mechanism unknown because amine levels increase immediately, but effects take weeks. Can be reversible or irreversible and selective and nonselective
Which SSRIs can be used for kids?
Sertraline and fluoxetine.
Side effects of SSRIs?
GI: N/V/D, cramps, bleeding. CNS: HA, anxiety, motor restlessness, insomnia, sexual dysfunction. Inhibit P450s, if stopped, cause discontinuation syndrome. Can cause serotonin syndrome with MAOIs, which is altered mental state, agitation, tremor, ataxia, fever, GI upset
How do SSRIs work, and compare to TCAs?
Block SERT, as well as NET a little. Less anti-ACh, alpha1, and H1 effects than TCAs, and safer on oerdose than TCAs.
What are the 2nd gen TCAs and what are the advantages, problems?
Amoxapine, maprotiline. Less sedation, less anti-ACh, less cardiac tox. But, can cause seizures and amoxapine can cause EPS (they are not drugs of choice)
Triad for TCA toxicity?
Coma, seizures, and ECG abnormalities. They are highly lipid-soluble, so accumulate in tissues. Tx is supportive care
What are the side effects of TCAs?
In additionto blocking NET (how they work), they block mAChR, alpha1, and H1 (like conventional antipsychotics). Alpha1 efects are postural hypotension. Sinus tachycardia, conduction delays, arrhythmias (hallmark of TCA tox), esp amitriptyline
Major DDIs of TCAs?
Block NET, so potentiate catecholamines, block sympathomimetics
What is endogenous versus reactive depression?
Endogenous can manifest as guilt, sad, appetite, weight, sleep, ambition, sex desire, devaluation, hopelessness (not “real events”). Reactive is related to life events, so antidepressants not usually used because those probs go away
Worst antipsychotic for EPS and increasing prolactin?
Respiridone
Worst antipsychotics for weight gain and metabolic changes (2)?
Clozapine and olanzapine. Black box warning. Should take familiy hx of DM, obesity, lipids, BP, etc…
Which antipsychotic changes QT interval?
Ziprasidone
Which antipsychotic is worse for sedation?
clozapine
Atypicals in elderly?
Can cause strokes and increase mortality. (black box)
Compare side effects of low vs. high potency conventional antipsychotics?
Low = more alpha1, mAChR, and H1 effects, but mAChR effects are beneficial to balance out anti D2 in striatum, so less EPS. High = low mAChR blocking, but that means more EPS
What is neuroleptic malignant syndrome?
Rare, dangerous form of EPS that resembles PD, and is especially likely with high doses of high potency agents. 10% fatal. Can be treated by D/C drugs, give muscle relaxants, and hydrate
What is the late EPS caused by antipsychotics?
Tardive dyskinesias. Very common, can happen months so years after starting therapy, usually upon withdrawal. It consists of face convulsions, and is more common with high doses, long duration, and elderly. Can be reversible. Caused by increased DA receptor sensitivity. mAChR blockers make it worse.
What is the acute EPS caused by antipsychotics?
Due to D2 blockage in nigrostriatal pathway. Has three forms (dystonia, akasthesia, parkinsonian). Dystonia is sudden uncoordination, muscle spasms. Akasthesia is inner restlessness. Parkinsonian is rigidity, bradykiniesia. Acute (but not late) dyskinesias can be treated by mAChR blockers (balance), or just give lower dose of antipsychotic.
Three classes conventional antipsychotics?
Phenothiazines (chlorpromazine, thioridazine, fluphenazine), thioxanthines (thiothixene), butyrophenones (haloperidol). Flu and halo are high potency. Chlor and Thoir are low potency
Contraindications for antipsychotics (based on common side effects)?
BPH, glaucoma, urinary retention (due to anticholinergic), other effects are orthostatic hypotension (alpha1), and sedation (H1). Other side effects are lower seizure theshold, weight gain, sun sensitivity, retinitis pigmentosa (thior), QT elongation, esp thior
How do conventional antipsychotics work? What is effect on CTZ? How affect pos or neg sxs? High or low potency antipsychotics have more side effects?
Block D2 receptors. Antiemetic due to effect on CTZ. Don’t help neg sxs. Low potency have more side effects because need higher dose (lose specificity). They can also increase prolactin and cause EPS
What is the EP system for? The meso-cortical and limbic? The tuberofundibular?
EP for motor, meso-cortical and limbic for cognition and emotion, the tuberofundibular inhibits prolactin by ant. Pit. All these systems are mediated by DA, so when D2 antagonists are used to treat the extra DA in schizophrenia, they also block the D2 in the other pathways, leading to increased prolactin and EPS
Antipsychotics like neuroleptics and respiradone have antipsychotic effects, but what else?
Like all antipsychotics (except clozapine), these produce EPS, but in risperidone and neuroleptics, maybe when 50% have antipsychosis, 15% already have EPS
How does NMDAR stimulation proposed to cause neuronal damage?
Decreased blood flow, O2, glucose (anything that leads to decreased ATP production) leads to more glutamate in synapse. Also, dying cells release glutamate and K+, which depolarizes cells, leading to NMDAR activation, increased Ca concentration, and neuron death. (a lot of Ca is bad, a little is good)
How is NMDAR involved in memory?
Repetitive or prolonged depolarization due to activated GluRs→ activates NMDARs. This causes Ca to enter the cell causing a permanent change via p’lation of ion channel (puts more receptors on membrane). The strength of the signaling increases with repetitive use, and may last for hours, and is associated with memory
Compare the relative roles of NMDAR, AMPA, and kainate?
NMDAR are usually only activated secondary to prolonged loss of inhibitory signaling, such as occurs from GABAergic degeneration or blocked Cl channels. The continued depolarization leads to open NMDAR channels, which sustains spiking and spreads activity. Seizures can result, so treated by increasing GABAergic transmission.
How are NMDARs permeable to Na and Ca, but GluRs (AMPA) only to Na?
A point substitution of R instead of Q in the GluR subunit makes AMPA impermeable to Ca. As long as the Q isn’t there, it is permeable, such as asparigine in NMDAR
What are the two types of GluRs? How are they different in their activation from NMDAR?
AMPA and kainate. They conduct Na to produce EPSPs, and they don’t require glutamate binding to do this. However, NMDARs require glutamate binding to conduct both Na and Ca. NMDAR can be clogged up by Mg when polarized. Must be depolarized to open up.
What substances other than glutamate and NMDA affect NMDARs?
PCP and ketamine plug up the channel like Mg to decrease excitation. Glycine is REQUIRED as a coagonist with glutamate on NMDA. Polyamines bind several sites to potentiate agonism, but can inhibit at high conc.
What are the four types of glutamate receptors?
Ionotropic: AMPA, kainate, NMDA. Metabolic: mGluRs. The mGluR is named for glutamate as substrate even though they all use glutamate as a substrate. The ionotropic ones are named for their synthetic ligands.
Characterize glutamate as an NT, its synthesis and metabolism?
It is the major excitatory NT in CNS (75-80%), and it’s nonessential because it is synthesized from glucose in the CNS and doesn’t cross the BBB. It is terminated by reuptake via Na-dependent glutamate transporters (EAAT)= excitatory AA transporter
Characterize the glycine receptors?
Similar to GABAA. Ionotropic, ligand-gated. They increase Cl conductance to create IPSPs. Strychnine is a glycine receptor agonist, so blocks inhibition, giving more motor output (skeletal and facial muscle convulsions)
Characterize glycine NT?
Glycine is the GABA of the spinal cord (major inhibitor). Glycine is synthesized from serine via hydroxymethyltransferase (SHMT). It is highly concentrated in synapse, low in vesicles. It is reuptaken by astrocytes and neurons
What is difference between GABAA and GABAB receptors?
GABAA is ligand-gated and ionotropic, increases Cl conductance. It has thousands of combos of subunits. GABAB is GPCR and metabotropic. They both activate K channels to hyperpolarize (which inhibits NT release)
Where does GABA bind to GABA receptor?
Beta subunit.
Where effect do steroids have on GABA receptors?
Increase GABAergic transmission
How does GABA inhibit motor activity?
Increase Cl conductance→ IPSP, which prevents excitatory signals from reaching threshold
How is GABA involved in Huntington’s disease?
Decreased EP GABAergic function in nigrostriatal pathway leads to huntington’s (less GABA→ more motility)
How prevalent is GABA in CNS? How is it synthesized? How is it terminated?
The major inhibitory NT (15-20% of synapses). Made from glutamate via glutamic acid decarboxylase. Interestingly, glutamate is the major excitatory NT, and is made from glucose in brain. Terminated by GABA-T, which is GABA transaminase, found in GABAergic neurons to make succinate and glutamate. In astrocytes, transported by GAT, and products recycled
ACh in memory?
Nucleus basalis (basal forebrain) to cortex and hippocampus.
ACh in vestibular control (balance)?
Involved, but not explained how. It explains the amnesia from scopalamine.
How is ACh involved in motor control?
In nigrostriatal pathway, ACh is balanced against DA, so if DA is degenerated (like in Alzheimer’s), antiACh can help restore chemical balance and motor control
How is DA implicated in Parkinson’s?
Dopaminergic neuron degeneration in nigrostriatal pathway leads to movement problems.
How is HVA related to Parkinson’s?
HVA (the breakdown product of DA) in CSF is associated with Parkinson’s.
MPTP and Parkinson’s?
A contaminant of heroin. It is converted by MAO-B to MPP+, which kills dopaminergic neurons in nigrostriatal pathway and gives parkinson’s sxs
How is DA involved in schizophrenia?
Decreased (or increased?) DA in meso-limbic and meso-cortical pathways affects cognition and emotion.
How can amphetamines cause psychosis?
Increase DA release, leading to psychosis similar to schizophrenia
What is the biogenic theory of mood disorders?
That the availability of amines at synapses underlies depression. For example, reserpine, which blocks VMAT-2, depletes NE and 5-HT, causing depression
What is the problems with the biogenic amine theory of mood disorders?
Not all uptake blockers are antidepressants (e.g. cocaine), and time course is slower than increase in synapse amine conc.
Where and how much is 5-HT found outside the CNS?
90% of 5-HT is made in gut by enterochromaffin cells. It is released by stretch, vagal stimulation, toxins, drugs. It helps with peristalsis, secretion, release of other NTs. Platelets also have SERT and VMAT-2, and release 5-HT when aggregate to help hemostasis and thrombosis
Nature of serotinergic pathways in the brain?
Diffuse like NE, except originate in raphe nuclei. All 5-HT receptors are GPCRs except 5-HT3, which is ligand-gated (the only monoamine receptor that is ligand-gated). 5-HT mediates mood, sleep, anxiety, sexual function, appetite, and also vascular effects for migraine
How is serotonin synthesis like DA synthesis?
Tryptophan goes to L-5-hydroxytryptophan, then to serotonin with the exact same enzymes that tyrosine goes to dopa then to dopamine. Those enzymes are hydroxylase and then aomatic-L-AA-decarboxylase. Serotonin can also be made into melatonin in the pineal gland. It is broken down by MAO or reptaken by SERT (the target of SSRIs)
What is the effect of amphetamine and antipsychotics on mesolimbic, mesocortical pathways?
These pathways are involved in emotion and cognition. Amphetamines increase DA output, while antipsychotics decrease D2 activity.
What does the nigrostriatal pathway do, and how do psych drugs affect it?
Voluntary movement. Antipsychotics cause EPS, while DA agonists and L-dopa inprove EP function
How is prolactin controlled?
DA on D2 receptors in ant. Pit. Antipsychotics that block D2 increase prolactin secretion
How is emesis mediated by D2 receptors?
In CTZ, which is unprotected by BBB, D2 agonists cause emesis
How is pleasure mediated by D2 receptors?
In the nucleus encumbens, D2 agonists increase activity
What are the three main pathways of dopaminergic transmission in the brain?
Nigrostriatal (substantia nigra to striata) responsible for voluntary movement, mesocortical and mesolimbic (midbrain to cortical and limbic areas) responsible for cognition and emotion, tuberoinfundibular (hypothalamus to median eminence (DA goes to ant pit to prevent prolactin secretion).
Distribution and effects of NE transmission in brain?
Nuclei in locus coeruleus, and is diffuse. It mediates mood, reward, arousal, and BP
What is most abundant catecholamine in brain? Ho is NE and DA broken down in brain compared to periphery?
DA is most abundant, more than NE and EPI (but all play small role overall). DA is transported into vesicles by VMAT-2, then beta-hydroxylated to NE. in brain and periphery, DA is metabolized into HVA. NE is broken down to MOPEG in brain, but VMA in periphery. DA and NE are both reuptaken by DAT and NET respectively
What are two kinds of pharacologic placticity?
P’kinetic: a drug inhibits or induces its own metabolism (less than 5x changes). Or P’dynamic, in which cells adapt (can be >1000x changes)
What ion channels mediate IPSP, EPSP, and AP?
IPSP = Cl in or K out, EPSP= Na in, AP=large depolarization secondary to EPSP (rapid Na in)
What are the ligand gated receptors in the brain?
5-HT3, nicotinic ACh, glutamate (NMDA, AMPA, kainate), and GABAA.
what are the monamines in the brain? What are the AA NTs in the brain?
5-HT and DA. Glutamate (at 75-80% of receptors) and GABA
What is Aprepitant?
NK1 antagonist used as antiemetic. NK1 receptors are located on the CTZ and vagal affernents in gut. NK1 is similar to substance P. This is a new agent, used as adjunct therapy, usually with 5-HT3 antagonists (ondansetron) and corticosteroids.
What is chloroprocaine?
Local anesthetic (ester), short duration of action
What is dantrolene?
Blocks Ca release from sarcoplasmic reticulum in skeletal muscle. Used to treat malignant hyperthermia (side effect of succinylcholine + halogenated volatile anesthetic in persons with mutated ryanadine receptor), and neuroleptic malignant syndrome (hyperthermia, rigidity, and autonomic dysregulation from antipsychotic drugs).
What is desipramine?
TCA, 2nd gen
What is dexamethasone?
High potency corticosteroid used as an antiemetic. It works by stimulating corticosteroid receptors on the CTZ. Dexamethasone if used for CINV, not effective against motion sickness. (can remember its use by thinking of symptoms of Addison’s disease which causes N/V)
How does Ondansetron work?
“Zofran” 5-HT3 antagonist. 5-HT3s are located on CTZ and vagal afferents in gut. So, Ondanstron is effective for CINV, post-op, and post-radiation N/V. Not good for motion sickness. Side effects can be HA, diarrhea, fever
What do phenothiazines do?
They are typical antipsychotics (block D2), and include chlorpromazine, thioridazine, fluphenazine. But they also are used as antiemetics (prochlorperazine, promethazine, and metoclopramide) because they block H1 and muscarinic receptors. Good for all purpose nausea (because H1s and muscarinic receptors are on central emesis center, and D2 is on CTZ). Side effects include EPS, alpha-1 blockade, antimuscarinic
How do BDZs treat nausea?
Since they are GABAa agonists (increases freq of opening), and GABA receptors are located in the cortex (which signals the central emesis center), it can decrease centrally-induced nausea, especially anticipatory. It can cause profound sedation, perceptual disturbances, urinary incontinence.
How does Dronabinol treat Nausea?
“Marinol”. It is a cannabanoid agonist (receptors on CTZ), good for CINV and motion sickness. Can cause orthostatic hypotension, sedation, dry mouth, psychoactive effects.
How do diphenhydramine and dimenhydrinate treat nausea?
H1 blockers (and antimuscarinic), so block vestibular input to central emesis area. Good for motion sickness
How does prochlorperazine treat nausea?
It is a phenothiazine (D2 antagonist), but also blocks mACh and H1 receptors. Good for general nausea. Side effects are orthostatic hypotension, EPS, contrainidcated in parkinson’s. Other phenothiazines are promethazine and metoclopramide.
How does promethazine treat nausea?
It is a phenothiazine (D2 antagonist), but also blocks mACh and H1 receptors. Good for general nausea. Other phenothiazines are prochlorperazine and metoclopramide.
How does metoclopramide treat nausea?
It is a phenothiazine (D2 antagonist), but also blocks mACh and H1 receptors. Good for general nausea. It is also used to increase gastric emptying and GI tone. Other phenothiazines are promethazine and prochlorperazine.
What is fluphenazine?
Conventional (typical) antipsychotic (D2 antagonist), a phenothiazine, and high potency
What is mivacurium?
Nm blocker (competitive), short duration of action. It is hydrolyzed by BuChE
What are the ligand-gated excitatory receptors?
NMDA, kainate, AMPA, nicotinic, 5-HT3. The inhibitory ligand-gated are GABA and glycine
Single drugs that treat migraine and another problem simultaneously?
Propanolol is for migraine and HTN. Amitrityline is for migraine and neuropathic pain and depression. Valproic acid and topirimate can treat migraine, bipolar, seizures, and neuropathic pain. Botox can treat migraines and wrinkles, sweating.
What are the non-depolarizing Nm blockers, and their durations of action?
The benzylisoquinolones are atracurium and mivacurium. The ammoniosteroids are rocuronium and vecuronium. And the natural alkaloid is d-tubocurarine. The middle ones (ammoniosteroids) and atracurium are intermediate duration. Miva is short and d-tubocurarine is long.
Which non-depolarizing Nm blocker is broken down by spontaneous hydrolysis (Hofmann elimination)?
Atracurium. It has a middle duration of action. (like vecuronium and rocuronium)
Which Nm blocker has two phases of action?
Succinylcholine. Phase one is depolarization blockade (channel is stuck inactivated, and open to K leakage). Second phase is desensitization in which the channel has no succinylcholine present, but is resisitant to excitation.
Problems with barbiturates as anesthetics?
Cause hyperalgesia, sedation (concerned about combining with other sedatives), and distributes to fat leading to very long half life.
Which volatile anesthetics are perfusion or ventilation limited?
If high solubility (PCb/g >1.2), it is ventilation limited, because need to deliver more air to get to saturation. If low solubility (PCb/g <1.2), it is perfusion limited because pulmonary capillary blood fills up fast, so if blood moves faster, it will all get filled faster.
What is PC blood/gas equal to?
PCb/g = conc.blood/conc.gas = conc.blood/conc.alveoli = conc.blood/MAC
What two drugs cannot be broken down normally if patient is deficient in BuChE (plama cholinesterase)?
Succinylcholine and Mivacurium
carbidopa?
Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase, the enzyme that converts L-dopa to dopamine. It is used with L-dopa because it inhibits the peripheral formation of dopamine (neiher carbidopa nor dopamine crosses the blood-brain barrier, but Dopa does), thereby reducing the nausea and vomiting and increasing the fraction of the administered L-dopa that is available for transport across the blood-brain barrier
Acamprosate?
Related to GABA, increases glutamatergic transmission. And diminishes neuronal hyperexcitability during withdrawal from alcoholism; used in the treatment of chronic alcoholism
What agonist activity do morphine, butorphanol, and buprenorphine have at which opioid receptor subtype?
The only effect buprenorphine has is partial agonist at mu. the only effect butorphanol has is agonist at kappa. morphine is a mu agonist and a kappa partial agonist
A terminal cancer patient on chemotherapy is taking morphine to control pain. Appropriate adjuvants might include all of the following EXCEPT:
A. Ondansetron.
B. Laxatives.
C. Phenobarbital.
D. Amphetamine.
E. Fluoxetine
C A. Ondansetron is a 5-HT3 antagonist that is highly effective in controlling the nausea that often accompanies chemotherapy.
B. Constipation is a common side effect of morphine.
C. Phenobarbital, like morphine, can cause respiratory depression and is therefore contraindicated. Barbiturates also can be hyperalgesic.
D. Amphetamine can be given as a stimulant if a patient is oversedated by morphine.
E. Antidepressants often can be helpful for terminal patients.
A. Aspirin
G. Morphine
D. Meperidine
E. Midazolam

Analgesic with a toxic metabolite that may cause seizures?
D The metabolite normeperidine may be responsible for the seizures caused by high doses of meperidine. This question asked about analgesics, but note that the neuromuscular blocking agent atracurium can form a metabolite (laudanosine) that can potentially cause seizures, although this effect has primarily been observed in animals.
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra Primary location of somas of serotonergic neurons?
D
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra Primary location of somas of noradrenergic neurons?
C
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra Primary location of somas of the neurons that degenerate in Parkinson’s disease?
E
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra The therapeutic effectiveness of trihexyphenidyl in Parkinson’s disease is due to the blockade of mAChRs in this location?
A The net activity of GABAergic projection neurons with somas in the corpus striatum is determined by a balance between inhibitory input from nigrostriatal dopaminergic neurons (mediated by D2 receptors) vs excitatory input from striatal cholinergic interneurons (mediated by mAChRs; designated as M in the figure): In Parkinson’s disease (PD), the degeneration of the inhibitory nigrostriatal dopaminergic neurons leads to increased excitation of the striatal GABAergic projection neurons: mAChR antagonists such as trihexyphenidyl can block the mAChRs on these GABAergic projection neurons and thereby help restore the balance between inhibition and excitation of the projection neurons.
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra The therapeutic effects of thioridazine are due to the blockade of D2 receptors in this location?
B Thioridazine is a conventional (typical) antipsychotic drug; like chlorpromazine, it is a low potency member of the phenothiazine class. Like all conventional antipsychotics, its therapeutic effects are believed to be due to the blockade of D2 receptors in the limbic forebrain.
A. Corpus striatum B. Limbic forebrain C. Locus coeruleus D. Raphe nuclei E. Substantia nigra The extrapyramidal symptoms caused by fluphenazine are due to the blockade of D2 receptors in this location?
A Fluphenazine is a conventional (typical) antipsychotic drug; it is a high potency member of the phenothiazine class. Like other high potency antipsychotics, it frequently causes extrapyramidal symptoms due to the blockade of D2 receptors in the corpus striatum.
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Agonist at GABA binding site on the GABAA receptor?
D
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Antagonist at GABA binding site on the GABAA receptor?
C
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Increases Cl- conductance by binding to an allosteric site on the GABAA receptor?
B A barbiturate would represent another possible answer for this question.
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Blocks ion channel of GABAA receptor?
E
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Agonist at GABA binding site on the GABAB receptor?
A
A. Baclofen D. Muscimol B. Benzodiazepine E. Picrotoxin C. Bicuculline F. Strychnine Antagonist at glycine binding site on glycine receptor?
F
A. AMPA receptors B. Kainate receptors C. NMDA receptors D. All of the above E. AMPA and kainate receptors only Glutamate binding opens an ion channel that is primarily permeable to Na+?
E
A. AMPA receptors B. Kainate receptors C. NMDA receptors D. All of the above E. AMPA and kainate receptors only Glutamate binding opens an ion channel that is permeable to Ca2+ and Na+?
C Glutamate binding will open the NMDA receptor ion channel and allow Ca2+ and Na+ to enter the cell only if the membrane is depolarized (to a potential less negative than ≈ -50 mV) by nearby synaptic activation of AMPA and/or kainate receptors; in the absence of depolarization, Mg2+ blocks the NMDA receptor ion channel.
A. AMPA receptors B. Kainate receptors C. NMDA receptors D. All of the above E. AMPA and kainate receptors only Glycine binding to a modulatory site is required for ion channel activation?
C
A. AMPA receptors B. Kainate receptors C. NMDA receptors D. All of the above E. AMPA and kainate receptors only Phencyclidine (PCP) blocks ion channel?
C
A. AChE E. Glutamic acid decarboxylase B. COMT F. MAO C. Dopamine β hydroxylase G. Tryptophan hydroxylase D. Dopa decarboxylase H. None of the above Found almost exclusively in the CNS?
E Glutamic acid decarboxylase (GAD) also is found in the β cells of the pancreas!
A. AChE E. Glutamic acid decarboxylase B. COMT F. MAO C. Dopamine β hydroxylase G. Tryptophan hydroxylase D. Dopa decarboxylase H. None of the above Biosynthetic enzyme found in all catecholaminergic neurons?
D Tyrosine hydroxylase would be another example of a biosynthetic enzyme found in all catecholaminergic neurons (tryptophan hydroxylase catalyzes the first step in 5-HT biosynthesis). Note that while dopamine β hydroxylase (choice C) is found in neurons that release NE and EPI, it is not found in dopaminergic neurons.
A. AChE E. Glutamic acid decarboxylase B. COMT F. MAO C. Dopamine β hydroxylase G. Tryptophan hydroxylase D. Dopa decarboxylase H. None of the above Inhibitors are used in the therapy of Alzheimer’s disease?
A Examples would be donepezil, galantamine, and rivastigmine, as discussed in Winter POP.
A. AChE
E. Glutamic acid decarboxylase
B. COMT
F. MAO
C. Dopamine β hydroxylase
G. Tryptophan hydroxylase
D. Dopa decarboxylase
H. None of the above

Inhibition ameliorates the symptoms of Parkinson’s disease?
F Selegiline, a MAO-B inhibitor, can be used in the therapy of Parkinson’s disease. It presumably decreases the degradation of DA in dopaminergic nerve terminals in the corpus striatum.
A. AChE
E. Glutamic acid decarboxylase B. COMT
F. MAO
C. Dopamine β hydroxylase
G. Tryptophan hydroxylase
D. Dopa decarboxylase
H. None of the above

Inhibition increases the efficacy and decreases the side effects of an important drug used in the therapy of Parkinson’s disease; therefore, inhibitors of this enzyme are routinely administered in combination with this important drug?
D Carbidopa, a dopa decarboxylase inhibitor, is administered with L-dopa to decrease the peripheral conversion of dopa to DA, thereby (1) increasing the fraction of administered dopa that is available to enter the brain; and (2) decreasing the nausea and vomiting resulting from stimulation of D2 receptors in the chemoreceptor trigger zone (CTZ) in the area postrema by DA formed in the periphery (the CTZ is not protected by the blood-brain barrier). Note that a COMT inhibitor (e.g., entacapone) also can be administered with L-dopa to increase its efficacy, but it is not routinely administered in combination with L-dopa (also, COMT inhibitors will not decrease the side effects of L-dopa).
A. AChE
E. Glutamic acid decarboxylase
B. COMT
F. MAO
C. Dopamine β hydroxylase
G. Tryptophan hydroxylase
D. Dopa decarboxylase
H. None of the above

Inhibitors are used as first choice agents in the therapy of depression?
H Although MAO inhibitors can be used in the therapy of depression, they are not first choice agents (the first choice agents are generally SSRIs).
Evidence for the biogenic amine theory of depression is provided by the effects of all of the following drugs EXCEPT: A. Cocaine. B. Desipramine. C. Paroxetine. D. Reserpine. E. Tranylcypromine.
A Although cocaine inhibits NET (like the TCAs, e.g., desipramine), it is not an antidepressant. One possible explanation is that while the main peripheral effects of cocaine are due to the blockade of NET, in the CNS cocaine mainly blocks DAT.
Conventional (typical) antipsychotics commonly cause all of the following EXCEPT: A. Increased appetite and weight gain. B. Increased prolactin secretion. C. Lowering of the seizure threshold. D. Nausea and vomiting. E. No effect on negative symptoms such as withdrawal and flat affect.
D B. Conventional antipsychotics cause increased prolactin secretion by blocking D2 receptors in the tuberoinfundibular pathway. C. Conventional antipsychotics increase the incidence of seizures, but primarily in patients with pre-existing seizure disorders (in contrast, the atypical antipsychotic clozapine can cause seizures in patients with no prior history of seizures). D. Conventional antipsychotics have an antiemetic effect! In fact, phenothiazines such as promethazine and chlorpromazine are used as antiemetics. E. The inability of conventional antipsychotics to ameliorate negative symptoms is an important limitation of these agents; in contrast, the newer atypical antipsychotics can improve negative symptoms.
Extrapyramidal symptoms due to therapy with antipsychotic drugs: A. Are seen only after several months to years of therapy. B. Are most commonly seen with low potency agents. C. Are less likely to be seen with agents that also block 5-HT2A receptors. D. Can be treated with donepezil. E. Generally disappear when drug therapy is terminated.
C A. Acute EPS can occur within the first week, even within hours after drug administration. B. EPS are most common with high potency agents; autonomic side effects are most common with low potency agents. C. The newer (atypical) antipsychotics, the 5-HT2A - D2 antagonists (SDAs), are less likely to cause EPS, possibly because their ability to block 5-HT2A receptors → disinhibition of dopaminergic transmission in the nigrostriatal pathway (the reduced likelihood of EPS also may be related to the ability of at least some atypical antipsychotics to block D4 receptors, which appear to be present in mesolimbic but not nigrostriatal dopaminergic pathways). D. Donepezil is an anti-ChE and would make the symptoms worse; a mAChR antagonist such as benztropine can help ameliorate acute EPS. E. Although acute EPS typically disappear when therapy is terminated, late EPS (tardive dyskinesias) are irreversible in up to 50% of patients.
26. Advantages of clozapine over haloperidol include decreased: A. Time to onset of therapeutic effects. B. Risk of seizures. C. Risk of tardive dyskinesias. D. Weight gain. E. Anticholinergic effects.
C A. Both atypical antipsychotics (e.g., clozapine) and conventional antipsychotics (e.g., haloperidol) require weeks to months to be effective. B. Both clozapine and haloperidol can increase the risk of seizures. Although conventional antipsychotics such as haloperidol increase the risk of seizures primarily in patients with a prior history of seizures, clozapine can cause seizures even in patients with no prior seizure history. C. This is a big advantage of clozapine! The decreased likelihood of acute or tardive EPS with the atypical antipsychotics probably can be attributed to their ability to block 5-HT2A receptors (and possibly their ability to block D4 receptors) (see answer to question 25, choice C). Note that clozapine produces the fewest EPS of all of the atypical antipsychotics (essentially none!), possibly because of its significant anticholinergic (mAChR antagonist) activity. D. Both clozapine and haloperidol can cause weight gain. E. As a high potency antipsychotic, haloperidol has few anticholinergic (mAChR antagonist) effects at usual therapeutic doses. As noted above (choice C), clozapine has significant anticholinergic effects (except that it paradoxically causes excess salivation!), more than other atypical antipsychotics.
A. Amitriptyline B. Chlorpromazine C. Both D. Neither

High therapeutic index?
B Conventional (typical) antipsychotics such as chlorpromazine have a high therapeutic index; in contrast, TCAs such as amitriptyline have a low therapeutic index.
A. Amitriptyline B. Chlorpromazine C. Both D. Neither

Therapeutic response typically requires several weeks?
C
A. Amitriptyline B. Chlorpromazine C. Both D. Neither

Characteristic features of overdose include coma, seizures, and ECG abnormalities?
A The combination of coma, seizures, and ECG abnormalities represents an important diagnostic triad for TCA overdose.
A. Amitriptyline B. Chlorpromazine C. Both D. Neither

Can cause postural hypotension?
C Both amitriptyline and chlorpromazine can cause postural hypotension by blocking α receptors (3o amine TCAs such as amitriptyline and low potency antipsychotics such as chlorpromazine are especially likely to block α receptors at therapeutic doses).
Which of the following is FALSE? Tricyclic antidepressants (TCAs): A. Cause sedation. B. Cause sinus tachycardia. C. Are contraindicated in patients who are susceptible to attacks of acute narrow-angle glaucoma. D. Block the effects of α-methyldopa. E. Potentiate the effects of tyramine.
E A. TCAs can cause sedation primarily as a result of their ability to block H1 receptors. B. TCAs can cause sinus tachycardia as a result of (1) their ability to block mAChRs receptors; (2) their ability to cause postural hypotension (see answer to question 30 above), resulting in reflex sinus tachycardia; and (3) their ability to inhibit reuptake of NE into sympathetic nerve terminals by NET (uptake 1) in the SA node. C. TCAs could precipitate an attack of acute narrow-angle glaucoma in susceptible individuals as a result of their ability to block mAChRs → mydriasis. D. α-Methyldopa must be taken up into the nerve terminal in order to be converted to α-methylNE; this uptake would be blocked by TCAs. E. Tyramine must be taken up into the nerve terminal to displace NE into the junctional space; this uptake would be blocked by TCAs.