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93 Cards in this Set
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- Back
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Pain transmission Modulation of pain |
Nociceptors in periphery respond to pH, ligand, ATP and send a signal Signal is conducted to the doral root ganglia --> dorsal horn --> brainstem --> thalamus, hypothalamus and cortex Modulated at all levels by GABA, glycine, NE and opioids |
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Difference between opiate and opioid Examples of opioid peptides What are the opioid receptors What are their actions on the brain, brainstem, spinal cord and peripheral sites |
Opiate = natural, opioid = synthetic b-endorphin, enkephalins, dynorphins Mu, delta, kappa 1. Alter mood in response to pain 2. Stimulate release of inhibitory signals 3. Inhibit primary afferent (sensory) activity 4. Inhibit afferent (sensory) response |
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Types of pain (3) Complex regional pain syndrome previous name Symptoms Final treatment |
1. Acute - severe but transient 2. Transitional - in-between acute and chronic, not easily diagnosed 3. Chronic - long-lasting, continuous pain Reflex sympathetic dystrophy Peripheral sensitization - allodynia (pain from light touches) and hyperalgesia (high pain sensitivity) Amputation of non-functional limb |
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Neuropathic pain cause Common in what group of people |
Injury to CNS or PNS nerves with pathway changes during regeneration - intense, shock-like pain Diabetics but with no known cause |
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Opioid receptor agonists
2. Addictive? 3. Metabolism 4. Side effects and dosage 5. All derived from what compound |
1. Mu receptors in brain, brainstem, spinal cord, and peripheral terminals 2. Physical and psychological dependence - develops very quickly3. Liver; oral intake reduced by first-pass metabolism 4. Many side effects, lots of ways to administer 5. Morphine - many metabolized to morphine |
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Non-steroidal antiinflammatories drugs (NSAIDs) 1. Mechanism of action 2. Side effects |
1. Inhibit COX-1, COX-2 enzymes Reduce prostaglandin production and release in dorsal horn- analgesia Reduce recruitment of leukocytes - reduces inflammatory mediator production 2. Gastric hemorrhage, platelet dysfunction, renal toxicity |
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Classes of antidepressants used in analgesia (3) 1. Mechanism of action 2. Used in what cases |
Tri-cyclics, SSRIs, Serotonin norepinephrine re-uptake inhibitors 1. Increase NE and 5 HT activity in spinal cord 2. Depressed chronic pain patients Diabetic neuropathy (nerve damage) Post-herpetic neuralgia |
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Anticonvulsants 1. Mechanism of action 2. What type of pain 3. Used in what cases 4. Side effects |
1. Reduce neuronal excitability 2. Chronic pain management 3. Diabetic neuropathy, trigeminal neuralgia 4. Dizziness, somnolence (extreme drowsiness), confusion, ataxia (loss of body control) |
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NMDA receptor antagonists 1. Mechanism of action 2. Used in what cases |
1. Reduced central sensitization due to increased NMDA - receptor inactive 2. Occasionally for labour and analgesia prior to surgery |
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Alpha2 - agonists 1. Routes of administration 2. Side effects |
1. Orally or neuraxially (CNS direct; spinal cord, CSF) 2. Sedation, severe postural hypotension (low BP when getting up), very dry mouth |
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5HT1 - agonists (Sumatriptan) 1. Mechanism of action 2. Used in what cases 3. Administration 4. Side effects |
1. Vasoconstriction and prevention of central sensitization 2. Treatment of migraine headaches 3. Self-administered by syringe and needle 4. Vasoconstriction can result in vascular problems in other areas - cardiac malfunctioning |
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Local anesthetics 1. When are they used 2. Two classes 3. Administration routes 4. Side effects Modes of delivery (5) |
1. In conjunction with opiates to reduce amount of opioid needed
2. Esters and amides 3. Neuraxial, sub-arachnoid space (spinal), epidural 4. Loss of sensation, muscle weakness, hypotension 1. Oral 2. Rectal 3. IM or IV 4. Neuraxial 5. Percutaneous |
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Obstetrical pain 1. Labour pain scale, delivery pain scale 2. Psycho-prophylaxis 3. Nitrous oxide 4. IV Narcotics 5. Ketamine 6. IM Narcotics 7. Epidural 8. Other treatment |
1. t10 to I1, intermittent, increasing in intesnity S2, S3, S4 - continuous or nearly continuous 2. Breathing, relaxation 3. Only used during contraction - effective but only intermediate potency - sedation and confusion 4. Different effects on mom and babe - potential for respiratory depression 5. Effective in small doses, short-lived; larger doses can cause psychiatric effects 6. Same as IV but longer lasting 7. Continuous infusion of local diluted anesthetic and opioid - loss of urge to push (muscle weakness) - slows down early stages of labour but quickens entire labour time 8. Massages, baths, acupuncture |
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Goals of anesthesia (3) Excitatory neurotransmitters Inhibitory neurotransmitters - which is most important Mechanism of action |
Amnesia (memory), analgesia (pain), anesthesia (sensation) ACh (nicotinic), NMDA, glutamate GABA, glycine - GABA Cl- channels Upregulation of inhibitory channels 1. GABAa - chloride channel 2. Strychnine-sensitive glycine - chloride channel Downregulation of excitatory channels 1. 5HT3 - NaCa in, K+ out 2. Neuronal nicotinic - ACh activated NaCa in, K+ out 3. Glutamate NMDA/AMPA - glutamate activated NaCa in, K+ out |
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Anesthesia induction Stage 1 characteristics (3) Stage 2 characteristics (3) Stage 3 Factor to consider for maintenance and emergence Alpha stage vs beta stage |
Analgesia 1. Reduced response to painful stimuli 2. Loss of voluntary control of eyeball movements 3. Eyelash reflex preserved - muscle tone normal Excitatory phase 1. Patient tense and appears restless 2. Cough gag and breath holding - risk of vomiting 3. Loss of eyelash reflex and pupild dilated 4. Reflex response to painful stimuli Surgical anesthesia Relaxed, excited, super super relaxed, deds Context sensitive half-time - time taken for [ ] in plasma to decline by 1/2 after infusion has stopped A = distribution, B = elimination |
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Mechanism of action and biotransformation 1. Propofol 2. Ketamine 3. Benzodiazepines |
1. Inhibitory neurotransmission via GABA (rapid) Conjugation in liver results in inactive metabolites 2. NMDA antagonist --> increases catecholamines and 5HT; dissociates thalamus from limbic cortex In liver - metabolites have renal anesthetic activity 3. Enhances effects of inhibitory neurotransmitters (GABA) Liver |
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Mechanism of action and biotransformation 1. Opioid 2. Remifentanil |
1. Bind to mu, kappa, delta, sigma Liver - beware of meperidine Renal failure during excretion risk 2. Ultra short acting opiod (3 min regardless of infusion duration) Rapid ester hydrolysis by esterases in blood and tissue |
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Minimum alveolar concentration |
Amount of alveolar anesthetic that prevents movement in 50% of patients in response to a standardized stimulus Decreases with age |
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Inhalational agents 1. Mechanism of action 2. Effects on heart, lungs, brain 3. Contraindications Malignant hyperthermia mechanism and treatment |
1. GABA channels activate and hyperpolarize membranes
Inhibits CA2+ channels and prevents NT release; inhibits glutamate channels 2. Heart: decrease BP Lungs: bronchodilation, increase breathing rate Brain: increase pressure, blood flow, decrease metabolic rate 3. Severe hypervolemia (lack of fluid in blood) Distributive shock Intracranial hypertension Malignant hyperthermia (whole body contracts - rapid use of ATP and O2) Abnormal RyR receptor - causes Ca2+ release from SR after anesthesia Dantrolene - binds ryanodine receptor |
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Nitric oxide properties Desflurane properties Sevoflurane properties |
Colorless, odorless, non-explosive, non-flammable Nonflammable, ethereal odor Rapid release can cause catecholamine release - heart rate does not decrease Short half life regardless of dose duration Non-pungent, longer duration if dose duration is higher, low blood solubility - rapid inhalation inductions Potential nephrotoxicity - breaks down into Compound A when taken with barium hydroxide lime (soda lime) |
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Reasons to use IV vs. Inhalational anesthetics Advantages and disadvantages for both |
Common, requires for rapid sequence intubation A: rapid induction, minimal excitatory phase D: IV access, rapid loss of airway control, risk of extravasation (fluid leakage) Pediatrics (needle phobia) A: maintains spontaneous ventilation until intubated D: slow, increased excitement phase, volatility and facemask irritation, risk of apnea or obstructed airway |
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Structural components of local anesthetics (3) Example of each type Chemical properties that determine activity (2) |
1. Aromatic ring 2. Connecting group (ester, amide) 3. Ionizable amino group Novocaine/procaine - ester Lidocaine/xylocaine - amide 1. Lipid solubility - potency, plasma protein binding, duration of action Higher solubility - longer duration, more plasma protein bound 2. Ionization constant (pK) - free base enters nerve fibre (crosses membrane) - ionized form blocks conduction of Na+ channels on the intracellular side Lower pK - faster onset of action |
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Mechanism of action of local anesthetics Similar toxins - how are they different |
Bind to open Na+ channel from the cytoplasmic side of neuronal membrane Prevents depolarization and action potentials and slows down the opening of the inactivation gate Tetrodotoxin, saxitoxin (shell fish) - bind to extracellular side of channel |
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Functional effects of Na+ channel blockage on nerves, vascular smooth muscle, heart and CNS |
Nerves: reduced or stopped conduction Smooth muscle: vasodilation Heart: decreased excitability (Reduced pacemaker) CNS: increased excitability followed by depression |
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Effects of local anesthetics on nerves Differential nerve blockade Reasons for differential nerve susceptibility to local anesthetics (3) |
All nerves have Na+ channels - anesthetics at high enough levels can completely block conduction and AP Small, non-myelinated neurons (eg. pain) are more susceptible (Type B, Type C)Large myelinated fibres are less susceptible (Type A least a > b > g > d most) 1. Depo current moves along nodes - 2-3 successive nodes must be blocked to impair conduction Small fibres have smaller internodal distances - shorter length of nerve needs to be blocked 2. Use-dependence: the more a nerve is used, the more easily it is blocked - High stimulation frequencies increase # of Na+ channels in the active form (pain, pacemaker) 3. Longer action potentials mean that the probability that an Na+ channel is open is increased - local anesthetics only target open form - pain fibres and pacemakers have longer APs |
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Effect of local anesthetics on vascular smooth muscle Consequences (2) How to prevent poor side effects Consequences (3) |
Vasodilation 1. Enhanced rate of removal from administration site - decreased duration of action, increased toxicity risk 2. Hypotension - compounded with cardiodepression from anesthetic Administration of a vasoconstrictor 1. Prolonged anesthetic action - adding very small amount of E means duration of anesthetic is increased significantly 2. Decreased toxicity risk 3. Decrease in bleeding from surgical manipulations |
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Effects of local anesthetics on the heart (4) Side effects |
1. Reduce myocardial excitability 2. Reduces pacemaker activity 3. Prolongs refractory period of myocardial tissue 4. Antiarrhythmic effects Myocardial depression along with hypotension can lead to cardiovascular collapse and death |
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Effects of local anesthetics on CNS |
At toxic doses, produce excitation followed by depression (biphasic) Excitatory phase: preferential blockade of inhibitory neurons at first Depressive phase: can lead to cardiovascular collapse and death |
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Applications of local anesthesia (5) + most common use Order of nerve blocking Inflammatione ffect |
1. Nerve block* - dental/minor surgery 2. Topical application - skin -analgesia, mucous membranes (benzocaine) - diagnostics 3. Spinal anesthesia - major surgery/childbirth 4. Local injection - at end of surgery - long lasting analgesia (reduces narcotics need) 5. IV infusion - control of cardiac arryhtmias (lidocaine) Pain - temperature - touch and pressure - motor function; recovery in reverse Reduced susceptibility - lowered local pH means more of the drug is in the charged form |
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Common causes of local anesthetic toxicity (2) Manifestations (3) |
1. Accidental intravascular injection while nerve blocking - always aspirate before injection 2. Rapid absorption following spraying of mucous membrane (respiratory tract) 1. Allergic reactions (esters only) - metabolized to p-amino benzoic acid (PABA); amines preferred for nerve block 2. Cardiovascular effects - cardiodepression, hypotension (anesthetic), hypertension, tachycardia (vasoconstrictor) 3. CNS effects - excitability (agitation, increased talking, convuslions) followed by depression Convulsions treated by CNS depressants may worsen the later depressive phase |
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Normal blood sugar level vs diabetes level Insulin release in response to high glucose |
< 140mg/dL > 200mg/dL 1. Glucose enters beta cells of the pancreas through GLUT-2 transporter 2. Glucose is broken down via glycolysis to pyruvate 3. Pyruvate is broken down via OxPhos to ATP 4. ATP closes an ATP-sensitive K+ channel - increases intracellular K+ 5. Depolarization opens a VG-Ca2+ channel that allows insulin to be released from the cell |
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Type I diabetes cause When does the pancreas secrete insulin Speeds of insulin - colours |
Lack of insulin release - needs external insulin Risk of ketoacidosis Half as bolus after a meal - needs fast, short acting insulin Half gradually during day and night - long acting insulin Rapid-acting (clear), short-acting (clear), intermediate (bedtime, twice a day; cloudy), long-acting (once or twice a day; clear and colourless) |
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Type 2 Diabetes characteristics Progression to type 2 diabetes Pancreatic cell dysfunction in T2DM |
Insulin resistance, b-cell dysfunction (long term apoptosis), no ketoacidosis 1. Predisposing factors for insulin resistance (obesity, sedentary aging, genetic factors) 2. Insulin resistance 3. High plasma glucose - impaired tolerance 4. Increased b-cell production of insulin 5. Beta cell exhaustion 6. Inadequate insulin for the degree of insulin resistance Beta cells are underfunctional (less insulin), alpha-cells are overfunctional (more glucagon) |
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Treatments of T2DM Peroxisome proliferator-activated receptors Effect of PPARy |
Lifestyle 1. Exercise - mere attempt 2. Diet Pharmacological management 1. Sulfonylureas - increase insulin release from b cells 2. Biguanides - insulin sensitizers for body tissues 3. Alpha-glucosidase inhibitors - inhibits pancreatic a-glycosidase; prevent carbs in diet from being converted into sugars 4. Thiazolidinediones - insulin sensitizer through activating PPARs (specifically gamma) Nuclear receptors that bind to DNA and activate specific genes Activation increases storage of FA in adipocytes - reduces fat in circulation - cells require glucose more often for energy - decreases glucose circulation |
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Incretin mechanism of action Two primary incretins DPP-4 inhibitors - why use them over GLP agonist |
Hormone that decreases blood glucose levels Released from the jejunum and ileum upon ingestion of food 1. Stimulates insulin secretion 2. Suppresses glucagon secretion 3. Slows gastric emptying - reduces food intake 4. Improves insulin sensitivity Long term effects 1. Increased b-cell mass and maintains b-cell function 1. Glucagon-like peptide (GLP 1) - L cells in ileum - analogs are used for T2DM treatment 2. GIP - K cells in jejunum - act on b-cells in pancreas, sometimes on adipocytes DPP-4 enzyme found in all major organs - degrade incretins Inhibitors increase incretin action - increase insulin release and sensitivity without weight gain or hypoglycemia side effects Oral instead of injection, no weight loss, cheaper, doesn't lower glucose as much |
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Systolic vs diastolic pressure What factors determine arterial pressure |
Systolic: BP when heart contracts Diastolic: BP when heart is resting Arterial pressure = cardiac output x peripheral resistance (constriction) |
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Renin-angiotensin-aldosterone system (RAAS) Overall effects |
1. Kidney releases renin in response to sympathetic stimulation, hypotension, or decreased sodium dlievery 2. Angiotensinogen released from the liver is converted by renin into angiotensin I 3. Angiotensin I is converted by ACE released by epithelial cells in lung and kidnehy to Angiotensin II Angiotensin II increases aldosterone secretion, sympathetic activity, vasoconstriction and water retention Aldosterone leads to pathogenic remodelling - artherosclerosis and fibrosis Overall increases blood pressure and blood volume Decrease in NO by production of free radicals |
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Thiazide diuretics mechanism of action b-adrenergic receptor antagonists Angiotensin receptor inhibitors ACE inhibitors mechanism of action Contraindications |
Increases sodium and water excretion 1. Short term - decreases blood volume, decreases cardiac output - decreases blood pressure 2. Long term - decreases sodium content of smooth muscle which decreases sensitivity to vasopressors decreasing peripheral vascular resistance Prevent kidneys from secreting renin Prevents angiotensin II effects on the body - no aldosterone production and no vasoconstriction 1. Prevents angiotensin II synthesis - prevents BP increase effects 2. Prevents breakdown of bradykinin into inactive kinins Bradykinin causes vasodilation which decreases BP Pregnancy - can't be used in preeclampsia |
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Angina pectoris definition - types (4) Medications and where they act (3) |
Recurring acute chest pain due to lack of blood supply to the heart - O2 demand exceeds supply 1. Stable - during exertion 2. Unstable - at rest or exertion in crescendo 3. Variant - comes in cycles at rest 4. Microvascular - lasts for a much longer time 1. Nitrates (amyl nitrate, nitroglycerin) - increases coronary blood flow; decreases preload ventricular volume and pressure 2. B-blockers - decreases HR and contractility (decrease demand) 3. Calcium channel blockers - increase coronary blood flow, decreases HR and contractility, decreases afterload ventricular volume and pressure |
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Two basic types of arrhythmia Where do cardiac action potentials occur Five phases of fast potentials Classes of anti-arrythmic drugs (4) |
Tachydysrhythmia - HR increased Bradydysrhythmia - HR decreased His-Purkinje fibres and in atrial and ventricular muscle 0 - depolarization 1- partial repolarization (dip) 2 - plateau 3 - repolarization 4 - stable potential 1. Class I: fast sodium channel blockers - prevent depolarization 2. Class II: beta blockers - prevent Ca2+ channels from opening - blocks plateau in muscle, depolarization in pacemaker 3. Class III: K+ channel blockers - prevent repolarization - increase refractory period 4. Class IV: calcium channel blockers - decrease HR and contractility |
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Congestive heart failure definition and key symptoms Digitalis mechanism of action Drugs that treat heart failure (6) |
Inability to pump enough oxygenated blood with each contraction - shortness of breath (dyspnea) and fluid retention; caused by chronic heart damage Digoxin blocks Na/K pump causing buildup of sodium within the cell after an action potential Sodium then exits the cell down its [ ] gradient; Ca2+ gradient now favours influx - causes contraction Slightly increases stroke volume per contraction but not to healthy levels 1. Diuretics 2. Inhibition of RAAS system 3. B-blockers 4. Digoxin and other cardiac glycosides 5. Inotropic agents 6. Vasodilators |
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Basic functions of the kidney Nephron definition and function (3) Sites of sodium and water reabsorption in the nephron |
1. Cleansing ECF and maintenance of volume and composition 2. Maintenance of acid-base balance 3. Excretion of metabolic wastes and foreign substances Functional unit of the kidney 1. Filtration - occurs at glomerulus 2. Reabsorption - 99% of water, electrolytes and nutrients undergo reabsorption 3. Active tubular secretion - proximal convoluted tubule of urea, antibiotics etc. 1. Proximal convoluted tubule - 65-70% of Na+ 2. Ascending loop of Henle - 20-25% 3. Distal convoluted tubules - 5-10% 4. Collecting duct - 1-5% Every Na+ absorbed is accompanied by H2O - iso-osmolality |
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Mechanism of urine production Na+/K+/H+ transporter in DCT special notes Two primary uses of diuretics |
1. ECF is filtered into the glomerular capillaries where it enters the proximal convoluted tubule 2. Na+, H2O and HCO3- are reabsorbed from the filtrate in the PCT into the kidney cortex 3. The tubule descends into the kidney medulla and becomes narrower (loop of Henle) - water is reabsorbed and the urine becomes more concentrated 4. The thick ascending limb becomes impermeable to water and transports Na+, K+ and Cl- back into the interstitial fluid 5. The filtrate travels to the distal convoluted tubule which is also impermeable to water and contains a Na/Cl transporter 6. Tubule dives back into the medulla as the collecting duct where it exchanges Na+ for K+ and H+ which are excreted into the urine 7. Water is reabsorbed in the collecting duct through pores regulated by ADH 1. Tubular [Na+] controls reaborption - if high, more Na is absorbed and more K+ and H2O are excreted 2. Regulated by aldosterone - increase in aldosterone stimulates reabsorption of Na+ - increases loss of K+ and H2O into the urine 1. Hypertension 2. Managing edema |
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Carbonic anhydrase inhibitors 1. Mechanism of action 2. Uses 3. Toxicities |
1. Inhibits CA in the proximal tubule - causes recycling of H+ into the lumen in exchange for Na+ - increases H2O in the tubule
CA - H2CO3 --> CO2 + H2O 2. Weakest diuretic - rarely in CV disease, mainly in eye surgery and glaucoma treatment 3. Kidney stones |
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Osmotic diuretics 1. Mechanism of action 2. Uses 3. Toxicities |
1. Act at proximal tubule - small inert molecules filtered into the glomerulus and not reabsorbed Increases osmolarity of the tubule - H2O is drawn in and urine output increases 2. Acute renal failure, decreasing intracranial pressure, decreasing intraocular pressure 3. None |
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Loop diuretics 1. Mechanism of action 2. Uses 3. Toxicities |
1. Acts on thick ascending limb of loop of Henle and decreases Cl- and Na+ reabsorption Strong but brief - within 1 hour, lasts 4 hours 2. Moderate to severe fluid retention Hypertension Edema from congestive heart failure, or liver/kidney disease 3. Loss of K+ (Ca2+ and Mg2+), hypotension, volume loss, dose related hearing loss Drug interactions (digoxin, NSAIDs, anti-hypertensive agents) |
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Thiazides 1. Mechanism of action 2. Uses 3. Toxicities |
1. Inhibits reabsorption of Na+, Cl-, K+ in distal convoluted tubules Most widely used diuretic, medium potency 2. Hypertension (common), mild heart failure, edema 3. Loss of K+ (hypoalkemia), enters breast milk Dehydration (hypotension), hyponatremia (low sodium) K+ loss potentiates digitalis toxicity |
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Potassium-sparing diuretics 1. Mechanism of action - two variants 2. Uses 3. Toxicities |
1. Blocks aldosterone in distal portion of distal tube - aldosterone normally promotes absorption of Na+ in exchange of K+ Reduces reabsorption of Na+ and H2O that is usually induced - retention of K+ Aldosterone receptor antagonists - slow onset Epithelial sodium channel blockers - quick onset 2. Modest diuresis, used with more potent diuretics to reduce K+ loss 3. Hyperkalemia (high K+), gynecomastia (aldosterone antagonist), gastric problems (ulcers) Drug interactions with ACE inhibitors - potentiate hyperkalemia NSAIDS - reduced diuretic efficacy |
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Define endocrine gland Hormone Exocrine gland |
Produce and secrete hormones directly into the circulatory system
Substance that travels through the bloodstream to reach target tissues and cause effects there Produce and secrete substances onto an epithelial surface via ducts |
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Steroid hormone list - derived from what 1. Circulating form 2. Clearance 3. Half-life 4. Receptor type 5. Mechanism of action |
Testosterone, estrogen, cortisol, progesterone, aldosterone Derived from cholesterol 1. Bound to carrier protein in circulation - sex - globulin, corticosteroids - globulin 2. Slow breakdown - large fraction of pool bound to carrier proteins - large pool that takes a long time to be excreted 3. Long half life 4. Intracellular receptors - can permeate cell membranes due to hydrophobic structure Glucocorticoid receptor, estrogen receptor, thyroid hormone receptor 5. Steroid hormone diffuses through membrane and binds an intracellular receptor Receptor-hormone complex enters the nucleus and binds a specific DNA region Binding initiates transcription of gene which leads to protein synthesis |
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Peptide hormone list - derived from what 1. Circulating form 2. Clearance 3. Half-life 4. Receptor type 5. Mechanism of action |
Insulin, glucagon, parathyroid hormone, growth hormone, luteinizing hormone, oxytocin 1. Free hormone, soluble in plasma - circulating concentration represents active concentration 2. Very fast - specific enzymes cleave peptide hormones leading to rapid inactivation of these signals 3. Short 4. Cell surface receptors (transmembrane proteins) that alter signal transduction pathways A) G-protein coupled Eg. Glucagon receptor, TSH receptor, FSH receptor B) Tyrosine kinases Eg. Insulin receptor, GH receptor 5. A) Dissociation of heterotrimeric G proteins and activate signalling cascades (catecholamines also activate) B) Dimerization, autophosphorylation then recruitment of downstream signalling molecules |
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Feedback mechanisms 1. HPA axis 2. Control of insulin by circulating glucose 3. Control of lactation by oxytocin and prolactin |
1. Hypothalamus releases CRH in response to stress, circadian rhythm and blood levels of cortisol This prompts ACTH release from the anterior pituitary ACTH prompts release of cortisol from the adrenal cortex Cortisol negatively feedbacks to inhibit ACTH and CRH release 2. Elevation of blood glucose leads to insulin secretion in b-cells Insulin release reduces circulating glucose which reduces the stimulus for further insulin release 3. Suckling by infant triggers oxytocin release leading to milk ejection as well as prolactin release leading to milk production More milk = more suckling = more oxytocin and prolactin release (positive feedback) |
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Classification of endocrine disorder based on underlying defect position |
Primary: defect in gland that directly produces the hormone Secondary: defect in an upstream control gland Tertiary: defect in a further control gland Eg. Hypercortisolism 1 = high CRH, ACTH, low cortisol 2 = high CRH, low ACTH, cortisol 3 = Low CRH, ACTH, cortisol |
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Potential treatment for hypersecretion with examples Potential treatment for hyposecretion with examples (3) |
Typically caused by tumor or other defect in gland Could be treated with blocking hormone receptor or reducing hormone synthesis but not practical Most common to surgically remove gland Eg. Hyperthyrodisim - inhibits synthesis of thyroid hormones or radiation to destroy thyroid cells Hyperaldosteronism - surgical removal of adrenal gland - sometimes use mineralocoritcoid receptor antagonists Hormone replacement therapy 1. Hypoinsulinism (diabetes) - parenteral delivery of insulin with special delivery methods (pumps, b-cell transplants) 2. Growth hormone deficiency (pituitary dwarfism) - replaced with synthetic/recombinant forms of hormone 3. Hypocortisolism (Addison's, adrenal deficiency) - administering exogenous glucocorticoids (prednisone, hydrocortisone) |
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Ovarian/menstrual cycle phases (4) Effect of oral contraceptives |
1. Follicular phase - estrogen released by developing follicle - negative feedback on GnRH and FSH 2. Ovulation - estrogen levels cross a threshold and start to exert positive feedback on LH and FSH (LH surge) promoting release of egg 3. Luteal phase - follicule develops into corpus luteum and secretes high levels of estrogen and progesterone 4. Diminishing levels of FSH and LH causes shedding of uterine lining Releases combination of progesterone and estrogen, progesterone alone also effective - Progesterone reduces GnRH, LH and FSH secretion - reduced follicular development and no LH surge (no ovulation) - Estrogen reduces FSH - also prevents follicular development - Prevents normal release of estrogen and progesterone from luteum because it never develops |
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Glucocorticoid drug side effects |
Used for powerful anti-inflammatory and immunosuppressive actions Immediately stopping glucocorticoid release leaves the body with low circulating CRH and ACTH which means endogenous glucocorticoids are reduced Farquharson phenomenon: application of exogenous hormone suppresses natural production and atrophy in the producing organ Tapering is needed when stopping long-term hormone therapy |
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General properties of psychiatric drugs |
1. Cross the blood brain barrier 2. Affect neurotransmission by modulating action of NTs 3. Only decrease or relieve symptoms, don't cure 4. Many side effects 5. Takes weeks for effects to be seen 6. Often administered orally 7. Lipid soluble, metabolized in liver and eliminated by renal excretion |
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Demographics of depression Defining symptoms of depression |
8% of population, more in women, average age 30 One of: depressed mood, apathy/lack of interest 4+ of 1. Weight/appetite changes 2. Sleep disturbances 3. Fatigue 4. Guilt and worthlessness 5. Executive dysfunction 6. Suicidal ideation |
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Monoamine oxidase inhibitors (MAOIs) - last in line treatment 1. Mechanism of action 2. Contraindication 3. New form (moclobemide) |
1. Inhibits MAO in the pre-synaptic neuron - increases amount of NE and 5HT available for neurotransmission 2. Tyramine consumption - MAO also breaks down tyramind; excess tyramine can cause hypertensive criss 3. MAO-A breaks down 5HT and NE, dopamine and tyramine MAO-B breaks down dopamine and tyramine and phenethylamine Older MAOIs are non-selective, double dip in preventing tyramine breakdown Newer ones only block MAO-A - reduces risk of tyramine induced hypertensive crisis |
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Tricyclic antidepressants (TCAs) 1. Structure and examples 2. Mechanism of action 3. Side effects |
1. Three rings - imipramine, clomipramine, doxepin, amitriptyline, notriptyline 2. Prevent 5HT and NE reuptake by inhibiting SERT and NET - increases NE and 5HT available for neurotransmission High affinity for many receptors (low selectivity; M, a1-adreno, H1 histamine) 3. Anticholinergic effect, orthostatic hypotension, sedation, weight gain, cardiac arrythmias |
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Selective serotonin reuptake inhibitors (SSRIs) 1. Examples 2. Mechanism of action 3. Side effects Serotonin norepinephrine reuptake inhibitors (SNRIs) 1. Examples |
1. Prozac (fluoxetine), Paxil (paroxetine), Zoloft (sertraline) 2. Selectively inhibits SERT to increase 5HT levels in synapse 3. Nausea, headache, drowsiness, sexual dysfunction 1. Effector-XR, Cymbalta |
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Atypical antidepressants 1. Bupropion 2. Mirtazapine 3. Trazodone |
1. Inhibits NET and DAT 2. Blocks presynaptic a2-adrenergic receptors and postsynaptic 5HT2C receptors to enhance NE and 5HT release Also affects 3. Blocks postsynaptic 5HT2A and 5HT2C receptors and inhibits SERT - also affects a1-adrenergic and sometimes H1 histamine receptors |
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Schizophrenia demographics Positive and negative symptoms Dopamine hypothesis Mesolimbic pathway Mesocortical pathway |
Early adulthood (late teens to early thirties) Positive - hallucinations, delusions, disorganized thinking Negative - lack of motivation, social withdrawal, poverty of speech Positive symptoms of schizophrenia associated with excess dopamine signalling in the mesolimbic system Ventral tegmental area --> nucleus accumbens VTa --> cortex Both dopamine pathways |
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Antipsychotic uses - common features Typical antipsychotics |
Treat schizophrenia and manic phase of bipolar disorder Affect dopamine and/or 5HT NT systems Block D2 receptor First gen - positive symptom treatments D2 receptor antagonists - cause extrapyramidal or neurological side effects (abnormal involuntary movements) Chlorpromazine (Thorazine), Haloperidol (Haldol) |
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Atypical antipsychotics 1. Mechanism of action 2. Uses 3. Side effects 4. Examples |
1. Dopamine D2 and 5-HT2A receptor antagonists - block serotonin and some dopamine activity 5HT inhibits release of dopamine via activation of 5HT2A receptors on doapmine neurons Reduced dopamine in mesocortical associated with negative symptoms Antagonists increase dopamine release - reduces negative symptoms 2. Treats both positive and negative symptoms of schizophrenia Also treats bipolar disorder 3. Metabolic - weight gain, insulin resistance 4. Clozaril (clozapine), Seroquel (quetiapine) |
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Treatments for bipolar disorder Treatments for anxiety disorders |
Typical/atypical antipsychotics, lithium, anticonvulsants SSRIs, SNRIs, TCAs, MAOIs, atypical antidepressants, benzodiazepines, azapirones |
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Role of the GI tract (3) Modulation by nervous system (3) Microscopic anatomy (3) - inside to outside Three major players of gastric pharmacology |
1. Digestion - mechanical and chemical 2. Absorption 3. Compaction 1. Parasympathetic - excitatory, ACh 2. Sympathetic - inhibitory, NE 3. Enteric - monitors and regulated tract tone, motility, secretion and blood flow Excitatory and inhibitory - localized minute to minute regulation 1. Mucosa - epithelium, lamina propria, Muscularis mucosae 2. Submucosal plexus (Meissner) 3. Myenteric plexus 1. Mucous cells - secrete mucus and bicarbonate ions 2. Parietal cells - secrete HCl, canaliculi in apical surface to increase SA 3. Enterochromaffin-like (ECL) cells - in mucosa below epithelium, near parietal cells |
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Mechanism of stomach acid secretion Stimulation effect |
ECL cells release histamine in response to gastrin and ACh Histamine activates H2 receptors on parietal cells increasing cAMP and Ca2+ H+/K+ ATPase on apical membrane brings K+ into the cell in exchange for H+ Passive diffusion of Cl- along with active transport of H+ out results in HCl secretion Neurocrine release of ACh activate M3 receptors to increase secretion Endocrine release of gastrin (enteric) activate CCK to increase secretion |
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How does the stomach protect itself from acid (5) Prostaglandin derived from what - what inhibits them |
1. Mucus layer resists acid and enzyme action on mucosa 2. Mucus layer secretes bicarbonate ions that get trapped in the mucus 3. Tight junctions in epithelial cells prevent acid from entering further 4. Continuous epithelial cell replacement maintains this barrier 5. Prostaglandins (E2 and I2) produced by mucosa bind receptors on parietal cells to inhibit H+/K+ ATPase and also receptors on mucus cells to promote release of mucus and bicarbonate Membrane phospholipids - inhibited by NSAIDs (ASA, ibuprofen) |
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Peptic ulcer disease Main principles of treatment |
Acid-induced inflammation of the stomach - erosion of lining due to pepsin and HCl activity Small association with malignant tumors Can also occur in duodenum and esophagus 1. Existence of H. pylori (80%) - existence doesnt cause but people with ulcers have it PPI, clarithromycin, amoxicillin/metronidazole for two weeks - antibiotics + PPI more efficacy 2. NSAIDs (10%) - risk with chronic therapy (anticoagulant, arthritis therapy) Discontinue NSAID use Misoprostol used traditonally - PPIs now used (better dosing, fewer side effects, longer effect) Reduce or neutralize H+, strengthen protective forces |
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Antacids 1. Mechanism of action 2. Chemical structure 3. Examples 4. Side effects |
Earliest form of treatment -- over the counter 1. Direct chemical neutralization of acid without receptors - mainly used between meals 2. Hydroxide or carbonate salts with Al, Mg, Ca or Na 3. Gaviscon (AlOH), Milk of Magnesia (MgOH2), Tums (CaCo3), Alka-seltzer (Na/K(HCO3) 4. Altered pH can affect solubility of other drugs Carbonate based - belching Al salts produce constipation Mg salts produce diarrhea Mixture of antacids necessary to preserve bowel function |
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Histamine H2 Receptor antagonists 1. Mechanism of action 2. Uses 3. Examples 4. Side effects |
1. Selectively block histamine H2 receptors in epithelial parietal cells - reduce signalling to reduce effectiveness of H+/K+ ATPase 2. Primary treatment of peptic ulcers until 90s, first ever blockbuster drug - long-term treatment Most effective for constitutive/nocturnal acid secretion - food induced partially bypasses histamine pathway Sometimes used for uncomplicated ulcers 3. Cimetidine, ranitidine, nizatidine, famotidine - first is standard, others more potent all OTC 4. Low profile (<3%) - diarrhea, headache, drowsiness - crosses placenta and enter breast milk |
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Proton pump inhibitors 1. Mechanism of action 2. Uses 3. Examples 4. Side effects |
1. Ingested as prodrug, absorbed in intestine, diffuses into acidified compartments Irreversible inactivation of H+/K+ ATPase enzyme via sulfenamide covalent bonding 2. Most effective suppressors of acid release - 98% Short serum half-life but lengthy effect - requires new synthesis of cells and membrane insertion (18-24 hr) - can be prolonged if accumulated in canaliculi Primary treatment 3. Omeprazole (main), Lansoprazole 4. Diarrhea, headache, abdominal pain in 1-5% Long-term use increases risk of gastric polyps - benign but not sure effect on health |
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Misoprostol 1. Mechanism of action 2. Uses 3. Side effects |
1. Prostaglandin E1 analogue that acts on EP3 receptors (same as PGE2) Inhibits parietal cells to reduce H+ release Stimulates mucus cells to increase mucus and HCO3- secretion 2. Enhancement of natural gastric defences - particularly useful in NSAID induced ulcers as it inhibits natural protection by endogenous prostaglandins 3. Due to effects on smooth muscle Diarrhea in up to 30% Abortion risk |
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Sucralfate 1. Mechanism of action 2. Uses 3. Side effects |
1. Aluminum hydroxide sulfacted sucrose complex Acid exposure releases anionic sucrose molecules that crosslink and polymerize with charged groups This forms a viscous, sticky protective gel that prevents degradation by pepsin 2. 4X daily dosing on empty stomach Mainly for prophylaxis rather than treatment 3. Reduces absorption of certain drugs (antibiotics, amitriptyline) Constipation - likely due to Al ions |
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Gastroesophageal Reflex Disease (GERD) pathophysiology Mild and chronic cases Rationale of treatment (3) |
Reflux of stomach contents into lower esophageal sphincter - low pH chyme with lack of mucus puts this at high risk for inflammation
Mild/acute: heartburn and mild regurgitation Chronic: requires long term therapy - epithelial cells in esophagus change from stratified squamous to simple columnar (Barrett's metaplasia) - risk for adenocarcinoma 1. Lifestyle changes - smaller meals, lying down after a meal 2. Reduction of acid release - both chronic and acute 3. Stimulation of enteric nervous system to facilitate gastric emptying (prokinetic drugs) |
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Acid reduction to treat GERD Prokinetic drugs to treat GERD |
Acute: antacids with algininates - creates foam raft that floats on stomach to prevent reflux Chronic: PPIs shown to reverse Barrett's metaplasia Stimulate enteric NS to facilitate gastric emptying/intestinal motility Eg. Domperidone (dopamine receptor antagonist) Limited efficacy in GERD when used alone |
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Function of large intestine - mediated by what Bristol stool chart Constipation treatment theory (3) |
Last chance for isotonic water/salt absorption - enteric NS mediates, distension is a signal Type 1 (most hard) - Type 7 (most watery) 1. Diet management 2. Tweaking current pharm regime 3. Stimulate enteric NS to produce a bowel movement |
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Bulk laxatives Osmotic laxatives Stimulant/contact laxatives |
Indigestible, water-absorbing molecules produce distension in colon stimulating a bowel movement - no adverse effects Eg. Methylcellulose (Citrucel), psyllium husk (Metamucil) Uses poorly absorbed salts, FAs, or carbs instead of fibre - increases colon volume by osmosis Eg. Magnesium sulfate/hydroxide (saline) - lactulose, sorbitol, mannitol Side effects: cramps, diarrhea Senna preparations - anthracene compounds directly stimulate myenteric plexus (smooth muscle activity) Eg. sennosides (Ex-Lax), castor oil |
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Why are anti-infective agents not necessary in diarrhea treatment Anti-motility agents |
Viral Antivirals have limited efficacy and most cases of diarrhea resolve before drugs begin to take effect Side-effect profile is often more severe Bacterial Most cases will self-resolve even faster Repeated treatment of antibiotics leads to resistance Emergency - erythromicin/azithromycin, rifaximin or ciprofloxacin among common options Opiates - act on u receptors in ENS within myenteric plexus Diminish propulsive activity - more water absorption Eg. Loperamide, diphenoxylate - more selective for digestive tract than other opiates Side effects: constipation Antimuscarinic agents and adsorbents also good treatments |
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General routes to new drugs (3) Molecular targeting (3) Why are Alzheimer's disease drugs less likely to succeed |
1. New uses for old drugs 2. Exogenous, endogenous sources 3. Systematic drug design - molecular targeting, disease targeting (less favoured) Protein involved in a disease process 1. High throughput screening - detects interactions between many molecules and macromolecular target 2. Combinatorial chemistry - rapid synthesis of multitude of molecules to feed HTS machines 3. Molecular modelling - create the best drug in silico and in vitro No well characterized models available - no effective control drugs, regulatory guidance Long duration of trial for animals - poor correlation with clinical activity, poorly characterized models |
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Stages of clinical development (7) with descriptions |
1. Discovery of drug 2. Preclinical - animal studies of toxicity ---- Investigational new drug application ---- 3. Phase I: small group of healthy volunteers safe dosage range, PD and PK, side effects, sometimes early signs of effectiveness 4. Phase II: first test of efficacy in patients with target condition - determine dosage and short-term side effects, best regimen and endpoints for phase III (few hundred) 5. Phase III: RCT to confirm efficacy, safety, side effects - necessary information for product labelling (hundreds to a thousand) -------- Submit New Drug Submission (NDS) ------ 6. FDA review and approval 7. Phase IV (post marketing): safety surveillance to detect rare or long-term adverse effects - can result in recall |
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Define the genetic variations that affect drug response (2) |
1. Single nucleotide polymorphisms (SNPs)- single nucleotide base pair differences among individual DNA sequences (more common) 2. Copy number variants - difference in the number of copies of a large block of base pairs within DNA (less common) Most people are 99.9% genetically identical |
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Why do adverse drug reactions occur Pharmacogenetics - how does this help Example of a biomarker |
Age, sex, associated diseases, drug interactions, dosage, genetic variation Identifies common genetic variations in relation to ADRs Pharmacokinetics - drug transporters and metabolizing enzymes Pharmacodynamics - drug targets and intracellular signalling pathways |
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Herceptin (tratuzumab) - biomarker |
Anticancer drug that binds a specific protein, if protein is lacking then it doesn't work HER-2 protein is overexpressed in some tumors - if it isn't there then treatment will have no effect |
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CD44 gene |
Causes acute liver injury if tylenol is taken |
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VKORC1 gene mutation Cytochrome P450 mutations |
Poor metabolization of Warfarin (blood thinner) - smaller dose needed to minimize effects Affects 37% white, 14% black Over/under expression changes dosing since 90% of drugs are metabolized by this in the liver Majority of genomic tests look at this activity Poor metabolizer uses active drug, ultra-rapid uses prodrug |
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Cisplatin - biomarker |
Anticancer drug used for a wide variety of tumor locations Deafness in children linked to mutation in COMT gene |
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Doxorubicin - biomarker |
Highly effective anticancer drug - blood, breast, childhood ABCC2 transporter genetic testing can show with 75% accuracy if it will be cardiotoxic |
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Xalkori (Crizotinib) - biomarker |
Shrinks or stabilizes tumors in non-small cell lung cancer Defective gene product of ALK (enzyme) is the target |
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Kalydeco - biomarker |
Cures cystic fibrosis Defect in CFTR gene results in defective CFTR protein Kalydeco binds to one of the defective versions found in 3-5% of people with cystic fibrosis |
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BRCA1 gene |
Expressed in breast tissue and ovaries - codes for protein that repairs damaged DNA or triggers apoptosis Mutation can lead to defective BRCA1 protei that leads to unchecked cell proliferation - 60% breast, 40% ovarian cancer Jolie |
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Impacts of therapeutics initiative (2) |
1. Physicians prescribed more drugs that were found to be more beneficial and prescribed less drugs that were found to be less beneficial based on evidence-based trials 2. Reference based pricing - least expensive drugs of a class were fully covered, more expensive ones were covered up to the cost of the least expensive - no adverse effects in hospitalizations, increased savings on drug spending |
