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Pharmacology 2060A/B final summary.doc

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Pharmacology 2060A/B
Angela Nissen

MODULE 12: CHOLESTEROL • Cholesterol – precursor to steroids and bile salts. 80% cholesterol is from endogenous synthesis in liver. • Lipoprotein: outer hydrophilic shell of phospholipids, core composed of hydrophobic cholesterol & triglycerides o Transport cholesterol (hydrophobic) in the blood. Allows it to be soluble in blood. o Have apolipoproteins embedded in the phospholipid shell. 1) Recognition by different cells 2) Activate enzymes that metabolize lipoproteins 3) Increase structural stability of lipoproteins o Apolipoprotein A-1: transport cholesterol from non-hepatic tissue to liver o Apolipoprotein B-100: transport cholesterol to non-hepatic tissue. • P- higher density than lipid • 3 classes of lipoproteins: 1. Very Low Density Lipoproteins (VLDL): triglyceride rich core, almost all of triglyceride content in blood, high VLDL → atherosclerosis, contain 1 B-100 apoliop- so they deliver triglycerides from liver to adipose/muscle, allows them to bind to cells and transfer their triglyceride content to cells 2. Low Density Lipoproteins (LDL): cholesterol rich core, 1 B-100 apolipop- deliver cholesterol to non-hepatic tissue. Higher LDL → coronary heart disease. BAD CHOLESTEROL 3. High Density Lipoproteins (HDL): cholesterol is main core lipid, contain multiple apolipop- (A-1) deliver cholesterol back to liver out of blood, more HDL → decreased risk for coronary disease. GOOD CHOLESTEROL LDL CHOLESTEROL IN ATHEROSCLEROSIS DEVELOPMENT  LDLs promote the initiation of atherosclerosis. Damage to the endothelium (hypertension, smoking) → LDL cholesterol move from blood into sub endothelial space → LDLs become oxidized → recruit monocytes (converted to macrophages – immune cell) → macrophages take up/ingest oxidized LDL (become larger and vacuolated) – now called foam cells → accumulate beneath the endothelium to form plaque → fatty streak appears → platelet adhesion, smooth muscle migration and collagen synthesis (form a fibrous cap over the plaque) → atherosclerotic lesion with lipid core and a tough fibrous plaque. o Smooth muscle cells multiply, move to surface of plaque → form fibrous cap covering plaque.  If fibrous cap is weak, moving blood can cause it to rupture → thrombus (aggregation of platelets) will form → block BF  Plaque builds up, artery narrowed, blocks BF to heart. Blood cholesterol is a factor for developing heart disease  Atherosclerosis is primarily an inflammatory process. LDL penetration of the arterial wall → mild injury to arterial endothelium → inflammatory response that mediates the development of atherosclerosis • Report cholesterol in mmol/L. Diabetes, heart disease, hypertension, smoke, inflammatory or renal disease → screen cholesterol • Cardiovascular risk assessment of developing cardiovascular disease → Framingham Risk Score (FRS): uses gender, age, total blood cholesterol, smoking status, HDL cholesterol, systolic BP. Represents patient’s 10 year risk of developing coronary heart disease. o Underestimates risk in youth, women and patients with metabolic syndrome o Separate tables for male and female. Points are different. Add up total # of points to get FRS • Patients with diabetes and heart disease – high risk for heart disease. • Moderate risk when significant inflammation is present (blood test) • Metabolic Syndrome: 3 or more of: central obesity, elevated triglycerides, low HDL (good) cholesterol, hyperglycemia, hypertension. Cause increased risk of coronary heart disease and type 2 diabetes. Treat by decreasing risk for coronary heart disease and type 2 diabetes. Elevated LDL cholesterol → lifestyle changes first to decrease LDL cholesterol 1. Change diet (eliminate high fat from diet, decrease cholesterol intake, eat soluble fiber and sterols) 2. Weight loss lowers LDL cholesterol and ↓ risk of coronary heart disease 3. Exercise decrease LDL cholesterol, increase HDL cholesterol, decrease insulin resistance and BP 4. Smoking decreases HDL cholesterol and increases LDL cholesterol, ↑ risk for heart disease. CLASSES OF DRUGS TO ↓ blood LDL cholesterol Hepatic cholesterol synthesis occurs by the mevalonic acid pathway: acetyl CoA → HMG CoA → mevalonic acid by HMG CoA reductase**RLS – site of action for statins → cholesterol (synthesis greatest during the night) 1. STATINS: decrease hepatic synthesis of cholesterol by inhibiting enzyme HMG CoA reductase ↓ chol synthesis a. Inhibition of HMG CoA reductase → upregulation of hepatic LDL receptors, liver removes more LDL cholesterol from blood → into bile acids. Decreased LDL cholesterol in blood b. ↓ LDL cholesterol, ↑ HDL cholesterol, ↓ triglycerides in blood c. Highest prescribed drugs in the world b/c they prevent onset and progression of CV disease. Primary prevention studies: prevent development of CV disease. Statins decrease incidence of coronary events in low risk patients with no history of heart disease. Secondary prevention studies: prevent recurrence of CV events in higher risk patients. Atorvastatin: (Lipitor) low oral bioavailability, large fraction of dose extracted by liver (site of drug action), distribution to liver (primarily) and to spleen, adrenal, muscle, metabolized by CYP3A4 (metabolizes most drugs), eliminated through bile into feces (minimal renal excretion) High extraction ratio Rosuvastatin: low oral bioavailability, large fraction of dose extracted by liver, distribution primary to liver, also to skeletal muscle, not extensively metabolized, eliminated in feces, minimal renal excretion - Plasma levels 2x higher in Asians! Initial dose should be 5mg (lowest dose) d. Well tolerated, adverse effect: myopathy (muscle injury, aches, weakness) e. Rhabodomyolysis: muscle lysis with severe muscle pain. Measure blood levels of muscle enzyme creatine kinase (elevated in rhabodomyolysis). Accompanied by large increase in blood K+ (hyperkalemia) may cause acute kidney failure. Preserve kidney fxn by IV administration of fluids. f. Low incidence of hepatotoxicity. Liver fxn tests should be done. g. Statins shouldn’t be used in pregnant females or trying to become pregnant (cholesterol required for synthesis of PM and hormones), potentially teratogenic drug. 2. NICOTINIC ACIDS (niacin) inhibit hepatic secretion of VLDL. LDL is a by-product of VLDL degradation, they reduce both VLDL and LDL, increase HDL. Reduce triglycerides and LDL cholesterol in blood. a. Side effects → facial flushing, hepatotoxicity, hyperglycemia, skin rash, increase uric acid levels 3. BILE ACID SEQUESTRANTS - Bile acids are –vely charged, produced in liver by CYP cholesterol metabolism. Secreted into intestine via bile duct, aid in absorption of dietary fats and fat soluble vitamins. Bile acids undergo enterohepatic recycling - reabsorbed from intestine back into liver via the portal vein. a. Large +vely charged molecules, bind bile acids (-ve) in intestine and prevent their absorption back into body (excreted in feces). ↑ demand for bile acid synthesis in liver → more LDL cholesterol required to make more bile acids → liver cells increase # LDL receptors → ↑ uptake of cholesterol from the blood to the liver → decrease in plasma LDL cholesterol b. Holds onto cholesterol in the intestine c. Adverse effects → not absorbed at all, don’t have any systemic side effects. GI tract → constipation/bloating. May decrease absorption of some –vely charged drugs (thiazide diuretics, digoxin, warfarin, antibiotics) – drugs interact with bile acid sequestrants. 4. CHOLESTEROL ABSORPTION INHIBITORS inhibit absorption of cholesterol from intestine. Inhibit transport p- (NPC1L1), lower blood cholesterol. a. Ezetimibe blocks transporter, decrease intestinal chol absorption → compensatory increase in hepatic cholesterol synthesis. So its prescribed as an adjunct therapy along with a statin 5. FIBRIC ACID DERIVATIVES (FIBRATES) most effective class of drugs for lowering plasma triglyceride levels. Increase HDL, no effect on LDL. Activate intracellular receptor in liver called PPARα (peroxisome proliferator activated receptor-alpha). a. Drug receptor complex into nucleus, ↑ synthesis of enzyme lipop- lipase (degrades triglycerides in liver), enhances clearance of triglyceride rich lipop-. b. Decreased apolipop- C-III production (inhibitor of lipop- lipase), increased lipop- lipase activity c. Increase apolipop- A-1 and A-2 levels → increased HDL levels. d. Adverse effects → gallstones, myopathy (↑ risk if combined with statin), hepatotoxicity MODULE 13: HYPERTENSION - Elevated systemic arterial BP (force against the walls of arteries), measured with a sphygomomanometer. o Seated for 5min, no caffeine/nicotine, feet on floor, arms @ heart level, 2 measurements in each arm 5min apart, repeated 3 times 2 weeks apart to diagnose - Systolic P/Diastolic P. - Majority of patients – primary hypertension, no known cause. - Secondary hypertension – identifiable cause (kidney disease, hyperthyroidism, pregnancy, taking erythropoietin drug, pheochromocytoma (tumor on adrenal gland → excess E release → vasoconstriction → hypertension), sleep apnea, oral contraceptive use. - Hypertension → increased morbidity and mortality. Can cause myocardial infarction, kidney failure, stroke, retinal damage. Can have high BP for years before symptoms - Amount of H2O, salt, condition of kidney, levels of hormones → determine BP - Risk factors for hypertension: obesity, stress, smoking, high salt diet, diabetes, African descent, NSAIDs, oral contraceptives, cold meds that contain pseudoephedrine. - ↓BP ↓morbidity/mortality ↓ stoke, myocardial infarction, heart failure - CO: determined by HR, contractility, BV, venous return. Increase in these ↑CO, ↑BP - Peripheral resistance: determined by arteriolar constriction → ↑BP - Meds ↓BP by ↓CO or ↓TPR - Systems that regulate BP 1. SNS: responds to stress (fight/flight), always active to keep BP in homeostasis, reflex circuit called the baroreceptor reflex (keeps BP at set level). Activation of SNS → pupils dilate, ↑HR 1. Baroreceptors in aortic arch and carotid sinus sense BP → info to brainstem 2. Low BP → sympathetic neurons stimulate heart to ↑CO + vasoconstriction → ↑BP 3. High BP → sympathetic activity ↓, ↓CO + vasodilation. 4. Set point in hypertensive patients is high. Responds rapidly (sec/min) to ΔBP 2. RAAS: series of hormones and enzymes, regulate BP, BV, electrolyte balance, affects kidney and vascular smooth muscle to control BP, hours/days to influence BP 1. Angiotensinogen → (RENIN) → Angiotensin I (inactive) → (ACE) → Angiotensin II (active); vasoconstrictor → stimulates release of aldosterone (from adrenal cortex) and ADH (from post pit) 2. Renin: enzyme, rate limiting step, secreted by juxtaglomerular cells of kidney. Stimulated by:  Decreased BV, low BP, stimulation of beta 1 receptors on JG cells of kidney  JG cells sense amount of Na+ and BP around glomerulus 3. AngII binds to AT1 receptor to produce vasoconstriction to ↑BP. 4. ADH causes H2O retention by the kidney ↑BV ↑CO ↑BP 5. Aldosterone acts on kidneys to ↑Na+ and H2O retention ↑BV, CO, BP 6. RAAS ↑CO and TPR to ↑BP. Causes vasoconstriction and renal retention of H2O and Na+ (↑BV) 3. Renal regulation of BP: low BP → kidney retains H2O ↑BV ↑CO ↑BP st Lifestyle Δ 1 ! ↓body weight, restrict Na+ intake, exercise, K supplementation, DASH diet, stop smoking, restrict alcohol 1) Obesity α Hypertension. Obese have ↑insulin secretion → tubular reabsorption of Na+, water follows ↑BV↑BP. Obese have increased activity of SNS ↑contractility + vasoconstriction ↑CO ↑TPR ↑BP 2) Restrict Na+ (salt) intake. High Na+ → water reabsorbed from kidney into blood ↑BV ↑BP 3) Exercise ↓ECFV/BV ↓BP & circulating levels of plasma catecholamines (cause vasoconstriction normally) 4) Potassium supplementation. High potassium → lower BP by ↑Na+ excretion ↓renin release and vasodilation. Source: fresh fruits and vegetables. ***patients taking ACE inhibitors shouldn’t be on high K diet 5) DASH diet: fruits, vegetables, low fat dairy, lean meats (poultry and fish), whole grains, nuts, legumes, exclude food high in saturated fat, total fat and cholesterol. Achieve lower BP without lowering salt intake. Diet helps activity of medications 6) Stop smoking → smoking elevates BP b/c of nicotine. Smoking and hypertension are risk factors in developing CV disease 7) Restrict alcohol → excessive alcohol consumption ↑BP, ↓response to antihypertensive meds. • Targets for BP lowering medications: vascular smooth muscle (Ca+ channel blockers, Thiazide diuretics), RAAS (beta blocks, direct renin inhibitors, ACE inhibitors, ARBs – angiotensin receptor blocks, aldosterone receptor antagonists), brainstem (alpha 2 receptor agonists), heart (beta blockers, Ca+ channel blockers), kidney (thiazide diuretics, loop diuretics, potassium sparing diuretics) 1. DIURETICS: mainstay therapy for hypertension. 3 main classes of diuretics. Block Na+ and Cl- ion reabsorption from the nephron, prevents reabsorption of water, excretion of water and Na+/Cl- ions (↓ECFV, CO, BP) Water follows Na+ a) Loop Diuretics act in LoH, majority of Na+ reabsorbed here. Largest ↓BP (most effective) b/c high Na+ reabsorption here. Block Na+/Cl- reabsorption in thick ascending limb of LoH a. Reserved for rapid loss of fluid → edema, severe nonresponsive hypertension, severe renal failure b. Gets rid of extra TBW, ECFV quickly c. Adverse effects → hypokalemia (↓potassium in blood → dysrhythmia), hyponatremia (low Na+ in blood), dehydration, hypotension b/c very effective at removing H2O from body b) Thiazide Diuretics → most commonly used class of drug to treat high BP. Block Na+/Cl- reabsorption in the DISTAL tubule and ↓vascular resistance. Max amount of diuresis is less than loop diuretics a. Adverse effects → hypokalemia, dehydration, hyponatremia c) Potassium Sparing Diuretics/Aldosterone Antagonists; block aldosterone receptors in the COLLECTING DUCT, minimal lowering of BP. Prevent Na+ reabsorption but not as effective to ↓BP b/c less Na+ reabsorbed here. Block actions of aldosterone, never used alone to ↓BP a. Aldosterone normally causes Na+ reuptake into blood and K+ secretion into nephron b. Causes increased Na+ excretion and K+ retention in blood c. In combination with thiazide and loop diuretics to counteract the hypokalemia side effect d. Shouldn’t be used with ACE inhibitors of ARBs (also conserve potassium) e. Adverse event → hyperkalemia → dysrhythmia. Elevation in potassium levels 2. BETA BLOCKERS: a. Binding of catecholamines (E, NE) to cardiac beta receptors ↑CO. Beta blockers block cardiac beta 1 receptors on heart to ↓HR, CO and BP b. Catecholamines → beta 1 receptors → JG cells release renin → RAAS → vasoconstriction ↑BP. Beta blockers block beta 1 receptors on JG cells → decrease renin release ↓RAAS mediated vasoconstriction c. BETA BLOCKER DRUS: SUFFIX "OLOL” d. 1STgeneration beta blocker produce non-selective blockade of beta receptors. Inhibit both beta 1 (heart, JG cells) and beta 2 (lung) receptors (problematic for asthmatics). Lower risk of heart problems. i. Adverse effects → also, bronchoconstriction b/c blocking of beta 2 receptors in lung, inhibition of hepatic and muscle glycogenolysis (dangerous in diabetics if they take too much insulin) e. 2ndgeneration beta blocker produce selective blockage of beta 1 receptors. i. Adverse effects → bradycardia, ↓CO, heart failure, rebound hypertension if withdrawn abruptly, must be tapered slowly to prevent this. 3. ACE INHIBITORS: block RAAS, ↓BP a. ↓production of ANG2 (vasoconstrictor) → vasodilation ↓BV ↓CO, TPR b. Inhibit breakdown of bradykinin peptide (elevated levels cause vasodilation − ↓TPR) c. SUFFIX: “PRIL”. ACE breaks down bradykinin normally d. Well tolerated. Adverse effects b/c of: i. Decreased ANG2: 1 dose hypotension (1 few doses should be low), hyperkalemia (↓Ang2 ↓aldosterone release → potassium retention). Potassium supplements and use of potassium sparing diuretics should be avoided with ACEI ii. Elevated bradykinin: persistent cough, angioedema, using NSAIDs may ↓effect of ACEI, BP lowering effect is lower when taking NSAID (DRUG INTERACTION!) 4. ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) a. Similar to ACEI b/c ↓action of ANG2. Act by blocking binding of ANG2 to its AT1 receptor; block actions of ANG2 but don’t affect its synthesis b. Cause vasodilation by blocking the action of ANG2 on arterioles. Also decrease aldosterone release from adrenal cortex causing ↑Na+ and water excretion from body ↓BP c. SUFFIX: “SARTAN” d. Adverse effects → don’t inhibit bradykinin breakdown (don’t produce persistent cough with ACEI). Don’t cause hyperkalemia and incidence of angioedema is lower than ACEI 5. DIRECT RENIN INHIBITORS (DRIs) inhibit renin (rate limiting step), DRIs influence the whole RAAS pathway. Its BP lowering effect is the same as other classes of drugs (ACEI, ARBs) a. Adverse effects → hyperkalemia (elevated K), shouldn’t be used with drugs that cause kyperkalemia (potassium sparing diuretics, ACEI) and potassium supplements, low incidence of persistent cough and angioedema (lower than ACEI), diarrhea. 6. CA+ CHANNEL BLOCKERS a. Block entry of Ca+ into heart and smooth muscle cells → ↓ contraction. Subclasses: 1) Dihydropuridine Ca+ channel blockers ↓ Ca+ influx into arteriolar smooth muscle cells. Relaxation of the muscle around arteries → vasodilation. At therapeutic doses → don’t act on heart a. SUFFIX: “DIPINE” b. Adverse effects → flushing, dizziness, headache, peripheral edema, reflex tachycardia, rash 2) Non-dihydropyridine Ca+ channel blockers block Ca+ channels in both heart and smooth muscle of arteries. Produce vasodilation and ↓ CO a. Adverse effects → constipation, dizziness, flushing, headache, edema, compromise cardiac fxn (used with caution in patients w/cardiac failure) 7. CENTRALLY ACTING ALPHA 2 RECEPTOR AGONISTS a. Activate alpha 2 receptors in the brain stem → decreases sympathetic outflow to heart and vascular smooth muscle (↓CO, TPR, BP). Sympathetic activity normally causes increased CO and vasoconstriction b. Adverse effects → drowsiness, dry mouth, rebound hypertension if withdrawn abruptly (taper dose) Patients with severe renal disease → thiazide diuretics are ineffective so loop diuretics should be used (more potent) High risk for developing heart disease, controlling BP more difficult Moderate renal disease or diabetes → thiazide diuretic ACEI, ARB, BB, CCB can be added if thiazide diuretic is insufficient. MODULE 14A: NEUROPHARMACOLOGY; neurological diseases • How drugs affect fxn of CNS, CNS disorders b/c biochemical imbalance in brain. Drugs treat biochemical imbalance, treat symptoms not the cause • Neurons → excitable cells, transmit info by electrical and chemical signalling, AP causes NT release from nerve terminal → next neuron • RMP = -70. Depolarization: Na+ enter through VG Na+ channels. Close, then K+ channels open so K+ can leave during repolarization. Hyperpolarization: overshoots RMP b/c excess K+ leaves. Then back to RMP • AP @ presynaptic nerve terminal → influx of Ca+ into terminal via VG Ca+ channels. Ca+ causes vesicles to fuse and release NTs into synaptic cleft (b/w neurons) → bind to receptors on post synaptic neuron o NTs recycled, repackaged into vesicles to be used again • Receive depolarizing stimulus → opens some Na+ channels → threshold → more Na+ channels open → Na+ channels close, K+ channels open → K+ out of cell → MP↓ to RMP → overshoots due to excess K+ leaving → K+ channels close → RMP - NTs are chemicals that transmit signal across synapse. - Monoamines: NE (depression, anxiety), E (anxiety), dopamine (Parkinson’s and schizo), serotonin (D, A) - Amino acids: excitatory: glutamate and aspartate (both Alzheimer’s). inhibitory: GABA & glycine (anxiety) - Other: acetylcholine (Alzheimer's and Parkinson’s) - Drug action: 1) Replacement: drugs replace NTs low in disease (Parkinson's) 2) Agonists/antagonist: drug directly binds to receptor on postsynaptic membrane to activate neuron 3) Inhibiting NT breakdown: elevate amount of NT around, longer effect 4) Blocking reuptake: of NT into presynaptic membrane 5) Nerve stimulation: drug stimulates nerve to release more NT PARKINSON’S DISEASE  Neurological disease. Caused by progressive loss of dopaminergic neurons in the substantia nigra in brain o Progressive loss of dopaminergic neurons is a normal process of aging. o Drugs can reduce progress of this chronic movement disorder  Symptoms: tremor in extremities, rigidity b/c of increased muscle tone, bradykinesia (slowness of movement), masklike face, postural instability, dementia later on.  Normally, balance b/w dopamine and ACh, controlled release of GABA o Dopaminergic neurons fire ↓GABA release. Cholinergic neuron fire ↑GABA release  Caused by an imbalance between ACh (too much) and dopamine (little) in brain → abnormal ↑ release of GABA  Symptoms b/c: treat symptoms by trying to balance dopamine and ACh (↑dopamine or ↓ACh) o Dopamine release is ↓, not enough dopamine to inhibit GABA release o Excess ACh compared to dopamine → increase GABA release (inhibitory NT) o Excess GABA → movement disorder with PD, disturbed movement  Cause of PD (etiology) is idiopathic (unknown) 1) A by-product of illicit street drug synthesis produce MPTP (irreversible death of dopaminergic neurons → PD) 2) Mutation in 4 genes (alpha synuclein, parkin, UCHL1, DJ-1) predisposes patients to PD 3) Environmental toxins (pesticides) associated with PD 4) Brain trauma from injury linked with increased risk for PD 5) ROS cause degeneration of dopaminergic neurons: link between diabetes induced oxidative damage and PD 5 classes of drug that ↑dopamine neurotransmission 1. DOPAMINE REPLACEMENT: Levodopa (L-dopa) → Most effective drug to treat PD, effects decrease as disease progresses (not good long term) → L-dopa enters presynaptic nerve terminal → Crosses BBB by an active transport p-. Inactive on its own but converted to dopamine in dopaminergic nerve terminals by decarboxylase enzymes that use cofactor vitamin B6/pyridoxine. → Increase amount of dopamine present in dopaminergic neurons, more dopamine released when AP arrives → Adverse effects: nausea, vomiting (dopamine activation of chemoreceptor trigger zone in medulla), dyskinesias (abnormal involuntary movements), cardiac dysrhythmias (conversion of L-Dopa to dopamine in periphery → activation of cardiac beta 1 receptors), orthostatic hypotension (drop in BP when stand up), psychosis (hallucinations, vivid dreams/nightmares, paranoid thoughts) → Small amount of total L-Dopa reaches the brain, remaining is metabolized in peripheral tissue (intestine) before reaching the brain. Decarboxylase enzymes metabolize most of L- dopa to dopamine in peripheral tissue ∴ given with carbidopa (decarboxylase inhibitor that inhibits the peripheral metabolism of L-Dopa), when combined, more L-dopa reaches brain, less is metabolized in peripheral tissue o Allows a lower dose of L-dopa, ↓ incidence of side effects (dysrhythmias, etc.) Dopamine doesn’t cross BBB; can’t get into dopaminergic nerve terminals. Has a very short ½ life in blood. ∴ L-Dopa 2 types of loss of effect: Wearing Off – gradual loss of effect over time, occurs at end of dosing interval, indicates drug level is low - Minimized by: shortening dosing interval of L-dopa, give drug that inhibits L-dopa metabolism (carbidopa) and add a dopamine agonist to therapy On-Off – abrupt loss of effect (unpredictable), can occur even when drug levels are high. - Minimized by: dividing medication into more doses/day, use controlled release formulation, move p- meals to evening 2. DOPAMINE AGONIST ↑dopamine levels in brain → Cross BBB, directly activate dopamine receptors on post synaptic cell membrane. → Not as effective as L-Dopa but are used as 1 line treatment for mild symptoms → Adverse effects: hallucinations, daytime drowsiness, orthostatic hypotension 3. DOPAMINE RELEASER stimulates 1) release of dopamine from dopaminergic neurons and 2) blocks dopamine reuptake into presynaptic nerve terminals. Blocks NMDA receptors too (minor effect): ↓dyskinesia side effect of L-Dopa → Rapid response to dopamine releasers; within days of taking drug ↓symptoms → Not as effective as L-Dopa so used in combination with L-Dopa or alone in mild PD → Adverse effects: dizziness, nausea, vomiting, lethargy, anticholinergic side effects 4. CATECHOLAMINE-O-METHYLTRANSFERASE INHIBITOR (COMT inhibitor) → COMT enzyme adds methyl group to both dopamine and L-Dopa to inactivate them (can’t activate dopamine receptors) → Inhibit COMT → greater fraction of L-Dopa available to convert into dopamine → Only moderately effective in treating symptoms, often combined with L-Dopa → Adverse effects similar to L-Dopa: nausea, orthostatic hypotension, vivid dreams, hallucinations 5. MONOAMINE OXIDASE-B (MAO-B) INHIBITOR ↑ brain levels of dopamine. Similar to COMT → MAO-B enzyme oxidatively metabolizes dopamine and L-Dopa, inactivating them (unable to activate receptor) o Present in both periphery and brain → Inhibit MAO-B, inhibit oxidative metabolism of L-Dopa → more conversion to dopamine in the brain. Inhibition of dopamine metabolism in the brain allows more dopamine to remain in nerve terminals and be released following AP → Only moderately effective in treating symptoms, often combined with L-Dopa → Adverse effects: insomnia, orthostatic hypotension, dizziness → At therapeutic doses, MAO-B inhibitors used to treat PD don’t inhibit MAO-A in the liver, don’t cause hypertensive crisis when eat tyramine containing foods. MAO-A inhibitors treat depression Relative excess of ACh in PD causes diaphoresis (excess sweating), salivation, urinary incontinence. ANTICHOLINERGIC DRUGS (cholinergic antagonists): block binding of ACh to its receptor. May ↑ effectiveness of L-Dopa. These drugs ↓ incidence of diaphoresis, salivation and incontinence b/c block ACh and its effects → Adverse effects: dry mouth, blurred vision, urinary retention, constipation, tachycardia. Elderly may experience severe CNS side effects: hallucination, confusion, delirium. ∴reserved for younger patients only ALZHEIMER’S DISEASE  Irreversible form of progressive dementia (most common), mostly women. Enlarged ventricles, ↓ size of brain  Symptoms: memory loss, problems with language, judgement, behaviour, intelligence.  Early symptoms: confusion, memory loss, problems conducting routine tasks  Disease progresses → hard to eat, bathe, speak, bowel fxn, etc.  Affects frontal cortex (intelligence, judgement, behaviour), memory (hippocampus)  Degeneration of cholinergic neurons in hippocampus early in disease, then degeneration of neurons in cerebral cortex. Decreased cholinergic nerve fxn (↓ACh release). Very little cholinergic fxn  Definitive diagnosis of Alzheimer's not until death (brain sample analyzed). Hallmarks of Alzheimer’s are: 1) Neurofibrillary Tangles: inside neurons when MT arrangement is disrupted → abnormal production of tau p-(form cross-bridges between MTs to keep their structure) 2) Neuritic plaques: outside of neurons, composed of a core of p- fragments called beta amyloid (kills hippocampal cells, causes Alzheimer’s like symptoms  Cause of Alzheimer’s disease unknown, run in families, mutation in DNA can predispose to Alzheimer’s o Patients with 2 copies of apolipoprotein E4 are at increased risk for developing Alzheimer’s b/c it promotes formation of neuritic plaques by binding to beta amyloid and promoting deposition o Increased incidence of Alzheimer’s in patients with mutation in the amyloid precursor p- gene (involved in production of beta amyloid, component of neuritic plaques) o Head injury is also a risk factor for developing Alzheimer’s  Drug treatment of Alzheimer’s → minimal improvement in symptoms. 2 classes of drugs to treat: 1) CHOLINESTERASE INHIBITORS: inhibit metabolism of ACh by acetylcholinesterase enzyme. - Allows more ACh to remain in synaptic cleft for longer to exert its actions, greater effect - Only able to enhance cholinergic neurotransmission in remaining few healthy neurons - Display minimal benefit on memory, only effective in a small number of patients - Adverse effects: nausea, vomiting, diarrhea, insomnia 2) NMDA RECEPTOR ANTAGONISTS: - NMDA receptor is a Ca+ channel blocked by Mg at rest. Glutamate from presynaptic binds to NMDA receptor, Mg dissociates, allowing Ca+ to enter post synaptic neuron. Glutamate leaves receptor, Mg blocks entry of Ca+ again. Normal Ca+ influx imp in learning and memory - Alzheimer’s: excess glutamate released from presyn neurons so NMDA receptor remains open allowing excess Ca+ to enter postsyn neuron. o Detrimental to learning and memory (overpowers the normal Ca+ signal received by neurons) o Causes degradation of neurons (too much Ca+ is toxic) - NMDA receptor antagonists block excess Ca+ influx into post synaptic neuron. Fills in pore. Prevents degradation of cholinergic neurons - Well tolerated. No significant adverse effects SCHIZOPHRENIA  Hard to tell b/w real and unreal experiences, think logically, behave normally in social situations. Don’t have multiple personalities, not violent. Low incidence, begins in adolescence/early adulthood  Positive Symptoms: exaggerate or distort normal neurological fxn → delusions, hallucinations, agitation, paranoia, combativeness, disorganized speech, disorganized thinking  Negative Symptoms: loss of normal neurological fxn → social withdrawal, poverty of speech, poor self care, poor insight, poor judgement, emotional withdrawal, blunted affect, lack of motivation  Direct cause is unknown. Factors that increase risk: o Family history, genetic component. 2 parents → greater risk o Drug abuse with crystal meth, angel dust, LSD → cause schizophrenia o Low birth weight, increased risk o Low IQ, greater risk  Basal ganglia: movement and emotion. Schizo: paranoia and hallucinations  Frontal lobe: problem solving and insight. Schizo: difficulty planning actions and organizing thoughts  Limbic system: emotions. Schizo: agitation  Auditory system: processes sounds. Overactivity contributes to hallucinations  Occipital lobe: processes visual info. Schizo: interpreting images, reading emotion on faces, recognizing motion.  Hippocampus: mediates learning and memory (decreased in schizo)  A disorder with increased dopaminergic nerve transmission (opposite to Parkinson’s; too little) o Excess dopamine released, more binds to D2 receptor, mediates symptoms of schizo. Drugs that block dopaminergic nerve fxn ↓ some +ve symptoms o Drugs used to treat Parkinson’s may cause Schizophrenic like side effects  Other NTs also play a role b/c blocking dopamine doesn’t treat all symptoms o 5-HT (serotonin): schizophrenic symptoms → decreased # of 5-HT 2Areceptors and an increased # of 5-HT 1Aceptors in the frontal cortex o Glutamate: activates NMDA receptor. Angel dust is an antagonist of NMDA receptor, causes symptoms of schizophrenia. Schizophrenia → decreased # of NMDA receptors in some brain regions  No definitive diagnostic test. Diagnosis after interviewing patient and family, evaluate: o Changes in function from before illness symptoms o Developmental background o Family history o Response to medication, start on medication then evaluate o Brain scans; enlarged ventricles, decreased frontal lobe brain activity.  Treatment of symptoms → block dopamine, glutamate and/or serotonin neurotransmission in brain.  2 classes of drugs to treat schizo; differ in mechanism of action and side effects. Both used. o Conventional Antipsychotics: block binding of dopamine to D2 receptor in mesolimbic area of brain. Also block receptors for ACh, histamine, NE (lesser degree)  The potency of these drugs is directly α to their ability to inhibit D2 receptors  More effective at treating +ve symptoms than –ve  Initial effect of drug in 1-2days, substantial improvement of symptoms → weeks  Only a little dopamine can bind to D2 receptors b/c most are blocked by antipsychotics. Doesn’t allow dopaminergic nerve transmission to proceed  Adverse effects: extrapyramidal symptoms, sudden high fever, anticholinergic side effects, orthostatic hypotension, sedation, skin rxns o Atypical Antipsychotics: block both dopamine D2 receptors and 5-HT1A/2A receptors (serotonin)  Therapeutic action attributed to blockade of 5-HT receptors, only some activity to block D2 receptors b/c affinity is very low. Compared to conventional, these have: 1. Same efficacy against +ve symptoms of schizo 2. Much greater efficacy against –ve symptoms 3. Lower risk of developing extrapyramidal symptoms, esp tardive dyskinesia b/c of decreased D2 receptor blocking activity (b/c of low affinity)  Adverse effects: sedation, orthostatic hypotension, weight gain, risk of developing type 2 diabetes, anticholinergic effects. No extrapyramidal side effects! Extrapyramidal Symptoms Movement disorders that resemble the symptoms of Parkinson’s. EPS due to blockade of D2 receptors. 1. Acute Dystonia: involuntary spasm of muscles in face, tongue, neck, back. 2. Parkinsonism – bradykinesia, mask like face, rigidity, stooped posture. Treat with anticholinergic drug to help relieve these symptoms. L-Dopa must be avoided!! L-Dopa can promote schizophrenic like symptoms. 3. Akathesia: pacing, squirming, desire to continually be in motion. First 3 occur early in treatment 4. Tardive Dyskinesia: in long term therapy with conventional antipsychotics, irreversible: involuntary twisting/writhing of face and tongue, lip smacking. Should be switched to atypical antipsychotic to prevent worsening of symptom MODULE 14B: EPILEPSY, DEPRESSION, ANXIETY • Epilepsy: neurological DISORDER that produces brief disturbances in the normal electrical activity in the brain. Sudden brief seizures, nature and intensity varies. Recurrent spontaneous epileptic seizures. • Seizure: sudden alteration of behaviour caused by CNS dysfunction in brain. Sudden and transient • Epileptic Seizure: caused by primary CNS dysfunction, due to excess depolarization and hyper synchronization of neurons in brain. Excess firing of APs due to depolarization • Non-epileptic Seizure: seizure like episode, not the result of abnormal electrical activity in the brain • Status Epilepticus: a single epileptic seizure of duration longer than 30min OR frequent seizures without recovery of awareness in between. An emergency. • Focal/Partial Seizures: arise in one area of the brain. Seizure activity is localized in 1 area of brain. 2 types. 1) Simple partial seizure: involves no loss of consciousness, sudden, brief, symptoms depend on where the seizure activity is arising from (where focus of seizure is). Contralateral side of body is affected. 2) Complex partial seizure: involves loss of consciousness, eyes open but not aware of surroundings. Symptoms depend on where seizure activity is. Contralateral effect on body. No memory of seizure. • Generalized Seizure: has bilateral diffuse onset, not a single area of focus, seems to arise from all areas of brain at once. 5 types 1) Absence Seizure: “petit-mal”, loss of consciousness, behavioural arrest and staring, eyes can be open. Usually brief, may occur in clusters and recur multiple times in a day. Rarely associated with automatisms (unusual purposeless movements), minor if any. Common in childhood, staring off into space. - Abnormal discharges as spikes on EEG (electrodes on brain to measure its activity) 2) Tonic/Clonic Seizure: “grand-mal seizure” abrupt loss of consciousness. Tonic period: muscles become rigid (1min) followed by clonic period: involuntary muscle contractions (lasts an additional 2-3min) - Tongue biting, post-ictal phase (after seizure): drowsy, confused, headache 3) Myoclonic Seizure: sudden, brief muscle contractions that can involve any muscle group, no loss of consciousness. Have myoclonic seizure → more susceptible to developing tonic/clonic seizure later on. 4) Tonic Seizure: sudden muscle stiffening (rigidity), impaired/lose consciousness 5) Atonic Seizure: sudden loss of muscle tone, brief (15sec), “drop seizure” b/c drop to the ground, falling injuries • Secondary Generalized Seizure: begins in one area of brain (focal seizure) and then activity spreads throughout brain (like generalized seizure). o Preliminary focal phase called “aura”, can predict they’re going to have a seizure before serious symptoms occur Location of a focal seizure can be determined by symptoms! Frontal Lobe: simple repetitive motor movements involving a localized muscle group associated with seizure activity in the contralateral primary motor cortex. → Tonic posturing affecting the entire side of body associated with seizure activity in the contralateral supplemental motor area (SMA) and other higher level motor structures. Complex behavioural automatisms that involve bilateral movement such as swimming, bike riding movements are associated with seizure activity in higher areas of the frontal cortex. These behaviours involve vocalizations, laughter, crying Temporal Lobe: emotions (anger, fear, euphoria), psychic symptoms (déjà vu, amnesia) associated with seizure activity in the temporal lobe. Auditory hallucinations (buzzing, voices), olfactory (smell) and gustatory (taste). → More complex sensory phenomena; visual distortions, paresthesias (numbness), autonomic disturbances Parietal Lobe: localized parasthesias (numbness, pins and needles) b/c of seizure activity in contralateral SS cortex. More complex and widespread parasthesias associated w/seizure activity in the SS association cortex. Seizure activity in higher order sensory association areas in the parietal lobe can be associated with complex multi-sensory hallucinations and illusions. Hard to distinguish from temporal lobe seizure (more common) Occipital Lobe: visual hallucinations (flashing) of things in the background (not organized objects, faces). Can produce temporary blindness or ↓vision after seizure. May have reflex nystagmus (involuntary eye movement) → Simple partial seizures in occipital lobe can be mistaken for migraine headaches, symptoms similar to common migraine auras. Epileptogenesis: causes/etiology of epilepsy: 1. Symptomatic epilepsy: arises from a known physical cause (brain tumor, stroke, infection to brain) 2. Idiopathic epilepsy: doesn’t have identifiable cause, family history of seizures, genetics play a role 3. Cryptogenic epilepsy: likely to have an underlying cause that hasn’t been identified. Seizures caused by spontaneous, uncontrollable discharges from hyper-excitable areas of the brain Seizure threshold is the balance b/w excitable and inhibitory forces in the brain The Seizure Threshold (everyone has one) affects how susceptible a patient is to having a seizure. Seizures are mediated by changes in electrical activity in brain, so the ability to reach threshold and fire an AP is imp in the generation of a seizure. Drugs target the generation of the APs. Factors that affect seizure threshold: stroke, head injury, drug, alcohol withdrawal, infection, tumor, severe fever, visual stimuli (flashing lights). Some cases of epilepsy, seizure threshold is lower, easier to reach it, AP fires more easily. Antiepileptic drugs (AEDs) prevent seizures 1. Blocking Sodium Channels; Na+ influx into cell is critical to generate AP. Excess firing of APs is a cause of an epileptic seizure. After Na+ enters the cell, the Na+ channel enters inactive state, further Na+ entry into cell is prevented. Sodium channel blocks prolong inactivation of Na+ channel, don’t allow neurons to fire at high freq Phenytoin: most widely used AED, blocks Na+ channels. Successful in treating all but absence seizures. - Metabolic capacity of liver to metabolize it is limited → phenytoin displays nonlinear kinetics (small ↑dose produces large ↑plasma []) - Narrow therapeutic range ∴therapeutic drug monitoring. Teratogen. - Adverse effects: sedation, gingival hyperplasia, skin rash 2. Blocking VG Ca+ channels; AP opens VG Ca+ channels, influx of Ca+ promotes NT release from presynaptic terminal. Blocking of Ca+ channels suppresses NT release; prevents uncontrollable firing of AP 3. Glutamate Antagonist; glutamate is an excitatory CNS NT that binds to NMDA or AMPA receptor. Blocking action of glutamate ↓CNS excitation. Glutamate antagonists block both the NMDA and AMPA receptors and prevent over-excitation in the CNS 4. Potentiating the actions of GABA; GABA is an inhibitory CNS NT. Binding of GABA to receptor causes Cl- to rush into cell, ↑-ve charge in cell, more difficult for threshold to be reached, more difficult to have an AP. - Drugs that potentiate the actions of GABA ↑inhibition in the CNS and suppress seizure activity. Can do it by enhancing the binding of GABA to receptor*, stimulating GABA release, inhibiting GABA reuptake or metabolism AEDs classified as traditional (phenytoin, valproic acid) or newer AEDs (lamotrigine). Similar effectiveness, newer AEDs have ↓side effects and doesn’t induce hepatic drug metabolizing enzymes as much, less susceptible to drug-drug interactions DEPRESSION • Depression requires 5 symptoms over more than 2 weeks. 9 types of depression • Exogenous depression→ triggered by external stimuli. o Pathological Grief: prolonged grieving coupled with excessive guilt. Psychotherapy > drug treatment o Adjustment Disorder: prolonged depression following failure or rejection (lose job). Symptoms: hypersomnia (excess sleep) and hyperphagia (over eating). Psychotherapy > drug therapy • Endogenous→ may/may not be related to external events o Major Depression: loss of interest, lack of response to +ve stimuli, insomnia, weight loss, symptoms worse in morning o Severe Depression: addition of severe suicidal ideation and psychoses o Atypical Depression: similar symptoms to major but atypical symptoms of hypersomnia and hyperphagia, often obese o Dysthymia: mood is regularly low but symptoms not as severe as major depression. More noticeable to family than patient. Psychotherapy > drugs o Seasonal affective disorder (SAD): mild symptoms of depression b/c of lack of sunlight, winter. o Postpartum Depression: moderate depression in women after delivery w/in 3 months. Drug therapy o Bipolar Disorder: alternating periods of elevated or irritable mood (manic) and depression Monoamine Hypothesis: exact cause of depression unknown. Altered monoamine release, receptor sensitivity or postsynaptic fxn leads to symptoms of depression - Jim takes ecstasy (depletes monoamine NT serotonin 5-HT), next week→ no motivation, depressed. Antidepressants act to increase the synaptic levels of monoamine NTs by inhibiting monoamine reuptake or metabolism (↑monoamine neurotransmission). Takes months to have effect. Some effects can be achieved with placebo - Classes of drugs used to treat depression: 1) Tricyclic Antidepressants: structure has 3 rings. Inhibit the reuptake of serotonin and NE (monoamine NTs) a. Blocks reuptake transport p- for serotonin or NE. ↑neurotransmission for serotonin and NE. NT stays in synaptic cleft for longer, mediate a greater effect. Effective in treating major depression b. Adverse effects: anticholinergic effects, sedation, orthostatic hypotension, ↓seizure threshold, cardiac toxicity (death!), weight gain, sexual dysfunction 2) Selective Serotonin Reuptake Inhibitors (SSRIs): most commonly used treatment of (major) depression a. Similar mechanism to TCA but only block serotonin reuptake. Similar efficacy to
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