John Diep Bimm118

Cholinergic System
Drug Names/Classes Parasympathomimetics Indirect ACh R Agonists Reversible Carbamates (Physostigmine) Quarternary Alcohol (edrophonium) Horny Goat Weed Insecticide (malathione) Nerve Gas (Sarin) Used for: Indicated for glaucoma. Antidote for atropine poisoning. Diagnose Myasthenia Gravis Indicated for erectile dysfunction Insects Lethal. Use atropine as antidote.

mACh R Blockers AgonistsDirect ACh R

Carbachol Bethanechol Pilocarpine

Phosphates)(Organo-Irreversible

Indicated for glaucoma Indicated for urinary retention. Indicated for Glaucoma

Parasympatholytics

Atropine

Causes pupil dilation, increases HR (indicated for bradycardia), reduces bronchosecretion (for surgery) Antidote for organophosphate poisoning. Indicated for motion sickness; antiemetic drug delivered transdermally Indicated for peptic ulcers; selectively blocks M1 Receptors, reduces gastric acid secretion Poison; respiratory paralysis. Muscle relaxant. Competitive antagonists Muscle relaxants; competitive antagonists

Scopolamine Pirenzipine
gDepolarizin DepolarizingNon-

nACh R Blocerks

Tubocuraraine Pancuronium Atracurium Succinylcholine/ Suxamethonium

Muscle relaxants nACh R agonists, but has parasympatholytic effect

Direct Parasympathomimetics drugs that mimic ACh and mostly binds mAChR Indirect Parasympathomimetics drugs that inhibit ACh-Esterase; raises [ACh] Muscarinic Parasympatholytics competitive antagonists Nicotinic Parasympatholytics neuromuscular junction blockers; muscle relaxants 1

John Diep Bimm118 Non-Depolarizing competitive antagonists; competes with ACh to prevent depolarization Depolarizing nACh R agonist; initially mimics ACh causing depolarization but it is not hydrolyzed by ACh-Esterase so the depolarization is prolonged, inhibiting other signals Nicotine Low Concentration acts as a direct nAChR agonist High Concentration has an antagonistic effect on nAChR due to channel inactivation; similar to succinylcholine. nAChR = nicotinic acetylcholine receptor mAChR = muscarinic acetylcholine receptor

John Diep Bimm118

Adrenergic System
Drug Name/Class Used For: Indicated for depression; inhibits metabolism of NE/E, DA, and 5HT; many side effects Found in diet pills; displaces NE from storage vesicles Displaces NE from storage, inhibits reuptake, inhibits MAO Indicated for anaphylactic shock and used as an adjuvant in local anesthetics. Dilates bronchii. Limited clinical use. Methoxamine treats hypotension Phenylephrine nasal decongestant Naphazoline nasal decongestant Indicated for hypertension. Presynaptic 2 receptors are inhibitory, reduces sympathetic tone on cardiovascular system. (+) inotropic & (+) chronotropic effect on heart Used in Dobutamine Stress Test Indicated for asthma (inhaler). Dilates bronchii Indicated for pheocromocytoma. Blocking 1 causes vasodilation; reducing BP Blocking 2 removes inhibition, increasing NE action on receptors increasing HR and cardiac output Indicated for hypertension and urinary retention. Side effects: Reflex tachycardia and postural hypotension. Increases sympathetic outpout. Used for male sexual dysfunction and as a weight loss drug. -1st gen. drug, cross reaction w/ 2 causes bronchoconstriction (side effect) -Labetalol also blocks 1 receptors (strong antihypertensive drug) -same indications as cardioselective blockers (below) Newer drugs are more 1 selective. Indicated for angina pectoris, hypertension, cardiac dysrhythmias, myocardial infarction, heart failure, and stage fright (anxiolytic).

Sympathomimetics

Indirect Agonists Direct Agonists

MAO Inhibitors (Tranylcypromine, Moclobemide) Ephedrine Amphetamines Ritalin ADD Fenfluramine diet pills Epinephrine(Adrenaline)
Non-selective

Norepinephrine (Noradrenaline) 1 Agonists (vasoconstrictor)

Sympatholytics

-receptor antagonists -receptor antagonists

2 Agonists (sympatholytic!) Clonidine Guanfacine 1 Agonists Dobutamine 2 Agonists Albuterol Non-selective Blockers Phentolamine

Selective 1 Blocker Prazosin, Terazosin, etc Selective 2 Blocker (sympathomimetic!) Yohimibine Noncardioselective blockers Propranolol

Cardioselective blockers Metoprolol, Atenolol

Selective

Drug/Class Direct Vasodilators (sympatholytics)Sympathetic Nervous System Suppressors 2 Receptor Agonists Clonidine Prazosin, Terazosin, etc -receptor antagonists Propranolol, Metoprolol, Atenolol, etc

Mechanism

Elicits 2 receptors inhibitory effect on the sympathetic Diep John nervous system. Less NE binding to 1 and 1 receptors. Bimm118 Promotes peripheral vasodilation, reducing resistance, thereby reducing BP. 1 receptor activation causes an increase in HR and contractility. Blocking this receptor will reduce the HR and contractility (reduces stroke volume) leading to a drop in blood pressure.

1 Receptor Antagonists Antihypertensive Drugs

Calcium channel blockers (Calcium antagonists) Dihydropyridines -Nifedipine, etc Potassium Channel Agonists Minoxidil

Nitroprusside sRenin-Angiotensin-Aldosterone System Targeting

ACE-Inhibitors Captopril Enalapril Benazepril Lisinopril

Targets L-Type channels (no cardiac effects), blocking Ca2+ entry into the smooth muscle cell arterial vasodilation; decreases afterload reducing BP Side effects: Reflex tachycardia, postural hypotension, and peripheral edema. Increases membrane permeability to K+, K+ efflux causes membrane hyperpolarization, inhibiting voltage gated Ca2+ channels relaxation of smooth muscles vasodilation reduces BP Side effect: hair growth, marketed as Rogaine Last resort for unresponsive hypertension. Delivered thru iv only and is metabolized into NO which directly activates cGMP production vasodilation Review phosphodiesterase inhibitors (Caffeine & Viagra). By inhibiting the ACE enzyme, angiotensin I cannot be converted into the active peptide (ATII) -no aldosterone & ADH release no fluid retention -no sympathomimetic effects -no vasoconstriction Side effect causes coughing

Angiotensin II (ATII) Receptor Blocker -Losartan -Candesartan -etc

Inhibits the effect of AT II by blocking the receptor -usually used if patient cannot tolerate the cough caused by ACE inhibitors

John Diep Bimm118

Other Cardiovascular Diseases

Angina Pectoris chest pain due to coronary heart disease; a symptom of myocardial ischemia (when heart doesnt get enough oxygen) Stable Angina Predictable episodes; usually during/after physical exertion or stress Treatment: Nitrates & -Blockers (Propranolol, etc.) Unstable Angina Chest pain unexpected and usually occurs at rest Treatment: Nitrates Variant Angina Chest pain almost always occurs at rest and does not follow physical exertion or stress. Due to coronary artery spasm. Treatment: Calcium channel blockers (Nifedipine, etc) Nitrates Converted to nitric oxide (NO) guanylate cyclase cGMP smooth muscle relaxation vasodilation Nitroglycerine Drug of choice for angina pectoris. Reduces cardiac workload (and its oxygen demand) by reducing venous return. Causes vasodilation primarily in veins. Many different forms of administration. Do NOT combine w/ other vasodilators (Viagra). Isosorbide-dinitrate Longer lasting effect when compared to nitroglycerine. (ISDN) Tolerance may occur, give lowest dose. Do NOT combine w/ other vasodilators. Nitrates Nitroprusside Promotes peripheral vasodilation. IV only; rapid onset and short duration allows for titration

Cardiac Arrhythmias abnormal rhythms of the heart that cause it to pump less effectively; abnormality in pacemaker cells, conduction pathway, or if other parts of the heart take over pacemaker. Class I: Slows depolarization phase of AP. Sodium Channel Procainamide used for atrial & ventricular arrhythmias Blockers Lidocaine used for acute ventricular arrhythmias Flecainide used for chronic treatment of ventricular arrhythmias Class II: Propranolol -Blockers -used for tachycardia Class III: Prolongs repolarization by blocking potassium efflux. Potassium Bretylium & Amiodarone Channel Blockers -used for intractable ventricular arrhythmias Class IV: Prolongs repolarization by blocking calcium influx Calcium Channel Verapamil blocks both L & T Type calcium channels! Blockers Blocking T Type channels slows conduction (Blocking L Type channels coronary + arterial vasodilation) Others Adenosine for paroxysmal supraventricular tachycardia Digoxin atrial fibrillation Epinephrine - bradycardia 5

John Diep Bimm118

Other Cardiovascular Diseases

Congestive Heart Failure inadequate contractility; ventricles unable to expel blood rise in venous blood pressure. Caused by blocked coronary arteries, viral infections, hypertension, leaky heart vavles, myocardial infarctions -Right sided failure lower limb edema -Left sided failure pulmonary edema & respiratory distress Cardiac Glycosides Slows heart rate and increases contractility. (Digoxin) Mechanism: Inhibits Na/K ATPase, leading to an increase intracellular Na+ Increased Na+ slows Na/Ca exchanger, leading to an increase intracellular Ca++ Low therapeutic index. Potassium competes with digoxin in binding to Na/K ATPase -antidote for cardiac glycoside poisoning -increased potassium will reduce potency of digoxin ACE inhibitors & Captopril & Losartan (review RAAS) ATII antagonists Effectively reducing cardiac workload (inhibits vasoconstriction, inhibits sodium/fluid retention, inhibits NE release) Vasodilators Nitrates: Nitroglycerine, etc. (review Nitrates notes) Diuretics Loop Diuretics: Furosemide Thiazides: Hydrocholorothiazide K+ Sparring: Spironolactone

John Diep Bimm118

Diuretics
Diuretics increases urine output; indicated for hypertension & edema (except CA inhibitors) Drugs Mechanism Carbonic Anhydrase Inhibitors Azetazolamide Dorzolamide Loop Diuretics (high ceiling) Furosemide Torasemide Inhibits conversion of CO2 (H+) + (HCO3-); effectively blocking reabsorption of Na+ -primarily indicated for Glaucoma! Causes metabolic acidosis (lower HCO3-). Inhibits Na+/K+/2Cl- symporter @ ascending limb in the Loop of Henle; effectively blocking Na, K, Cl reabsorption -most potent diuretic -for severe/moderate hypertension & edema Causes hypokalemia Inhibits Na+/Cl- symporter @ distal convoluted tube -for moderate hypertension & heart failure (edema) Causes hypokalemia

Thiazide Diuretics Hydrochlorothiazide Benzthiazide Potassium-Sparring Diuretics Spironolactone Amiloride

Acts as distal portion of distal tube; enhances Na excretion & reduces K excretion (K sparring) Spironolactone aldosterone receptor antagonist (slow) Amiloride directly blocks Na/K channel (fast) Used in combo w/ other diurectics Osmotic Diuretics Non-reabsorbable molecules that inhibit passive reabsorption Mannitol (iv only) of water (promoting water excretion w/ little Na excretion) -cannot cross blood-brain barrier; so water goes from brain to blood Used to reduce intracranial pressure Major side effects of diuretics (except K-sparing) -Mainly Hypokalemia (loss of potassium) & hyponatremia & hypochloremia as well (may give extra potassium orally/iv) -Hypotension & dehydration Interaction w/ Cardiac Glycosides (digoxin) -cardiac glycosides are Na/K ATPase inhibitors as a competitive K antagonist -Hypokalemia secondary to diuresis increases digoxin potency -digoxin has a narrow therapeutic index; this may cause it to become toxic

Uricosuric Agents
Indicated for kidney stones and gouts. @ therapeutic dose: promotes excretion and inhibits reabsorption of uric acid @ sub-therapeutic dose: inhibits both excretion and reabsorption -possibly increase uric acid concentration Probenecid -strongly inhibits penicillin excretion!! May be beneficial when trying to elevate antibiotic plasma concentration

John Diep Bimm118

Gastrointestinal Pharmacology
Antacids Weak Bases Tums, PeptoBismol, etc.. H2 Receptor Blockers Cimetidine Ranitidine Proton Pump Inhibitors Omeprazole Lansoprazole Neutralizes stomach acid. Magnesium Hydroxide causes diarrhea Aluminum hydroxide causes constipation These are often combined -competitively inhibits binding of histamine to H2 receptors on parietal cells; thus reducing histamine stimulated gastric acid production (there are other signals that may stimulate acid production) -irreversible inhibition of H+/K+ ATPase in parietal cells -only active at low pH (activity restricted to stomach) -inhibits acid production for 1-2days Note: prevents acid replenishment; does not neutralize acid already in the stomach (GERD is primarily treated w/ PPIs) Misoprostol PGE analog; stimulates mucus and HCO3 production; used w/ NSAIDS Sucralfate stabilizes mucus to inhibit H+ diffusion -not absorbed Diphenhydramine, Meclizine, etc Blocks H1 (histamine) receptors competitively. Scopolamine (anticholernergic) Lorazempam; potentiates effects of GABA in CNS Competitively blocks C2 receptors in the CTZ Also increases gastric emptying Contraindicated in patients w/ Parkinsons disease

Mucosal Protective Agents Misoprostol Sucralfate Antiemetic Drugs H1 Antagonists Muscarinic Receptor Antagonists Benzodiazepines D2 (dopamine) Antagonists Metoclopramide Domperidone

Cannabinoids Synthetic cannabinoids: Nabilone & Dronabinol (marijuana) -acts as an agonists at cannabinoid receptors in the CNS Peptic Ulcers ulcer formation in the stomach/duodenum due to insufficient mucus and/or bicarbonate and/or increased acid production (autodigestion of stomach/duodenal wall) Causes: H. pylori (majority) breaks down mucus and triggers inflammation NSAIDS inhibits PGE (needed for mucus/HCO3 production) Smoking stimulates gastric acid production Treatment of H. pylori infection and peptic ulcer: Use a combo of antibiotics and PPI (or other mucosal protectant/enhancers & antacids) Antibiotics: Bismuth/Amoxicillin disrupts cell wall Clarithromycin/Tetracyclin inhibits protein synthesis Metronidazole secondary agent, used when resistance develops or other agents are intolerated

John Diep Bimm118

Gastrointestinal Pharmacology
Laxatives Bulk Laxatives increases bowel content volume triggering stretch receptors causing reflex peristalsis Carbohydrate Based -insoluble/non-absorbable -Vegetable Fibers -expands with water -Bran (husk) May cause constipation if not enough water. Bulk Osmotically Active -Epsom salt -Glaubers salt -partially soluble/non-absrobable -potent and fast acting

Irritant Laxatives irritates enteric mucosa causing an increase secretion of water softening bowel content (stool); increased volume also triggers reflex peristalsis Ricinoleic acid (Castor Oil) -castor oil converted to ricinoleic acid -works in the small intestine Anthraquinones -works in the large intestine Diphenolmethanes Bisacodyl Sodium picosulfate Laxative Abuse: longer interval needed to refill colon, leads to constipation Loss of water/salts in gut leads to aldosterone release; causes excretion of K+ Hypokalemia reduces peristalsis Muscarinic receptor antagonists and opiates can cause constipation but are not useful for treating diarrhea because of its effect on other parts of the body. Loperamide (Imodium) -opiod derivative that selectively acts in the GI tract (w/ no CNS activity). -directly acts on the intestinal muscles reducing motility -this increases water and electrolyte reabsorption Dimethicone anti-gas agent that is often combined with antidiarrheal drugs Irritants

Anti-diarrheal

John Diep Bimm118

Metabolic Disorders (Diabetes Mellitus)

At low blood glucose levels (hypoglycemia); the body will increase blood glucose by: -Glucagon (secreted by pancreatic cells) promotes glycogenolysis & gluconeogenesis -epinephrine also released by adrenal medulla -blockers will mask symptoms of hypoglycemic shock -cortisol (anti-insulin effects) is also released by the hypothalamus extended use of steroidal drugs may induce diabetes At high blood glucose levels (hyperglycemia); the body will decrease blood glucose by: -Insulin (secreted by - pancreatic cells) promotes glucose uptake & glycolysis & glycogenesis Diabetes Mellitus Type 1 Diabetes autoimmune disease; destruction of pancreatic cells Treatment requires exogenous insulin replacement to control hyperglycemia Type 2 Diabetes hyperglycemia resulting from insulin resistance at target tissue or reduced insulin production by pancreatic cells Various levels of defect leading to resistance (receptor, signaling pathway, enzymes, glucose transporter) Treatment with exogenous insulin replacement or oral hypoglycemic agents Regular Insulin -unmodified; short acting -only insulin that can be administered thru iv Insulin Lispro (Humalog) -rapid onset (fastest) & short acting -used before a meal Insulin Lente -insulin + zinc micro-precipitates (delayed absorption) (sc injection only) -long lasting (UltraLente = longest lasting) NPH Insulin -insulin + protamine delayed absorption -long lasting Insulin Glargine (Lantus) -synthetic insulin that is soluble at low pH, but becomes insoluble and forms precipitates at neutral pH after sc administration -long lasting (similar to Lente) Sulfonylureas Stimulates insulin release; useful for diabetes caused by st -Tolbutamide (1 gen.) low insulin levels where - pancreatic cells are still present -Glimepiridide -Glipizide (For Type II only)Oral Hypoglycemic Agents Insulin Therapy Glitazones -Rosiglitazone -Pioglitazone Biguanides -Metformin -Increases insulin sensitivity at target cells -Acts as a nuclear hormone receptor (PPAR agonist) increasing transcription of insulin receptor signaling components and glucose transporters -unknown mechanism -increase glucose uptake & inhibits gluconeogenesis -lowers LDL + VLDL (bad cholesterol) -suppresses appetite -no hypoglycemic effects

Insulin and oral hypoglycemic agents may cause hypoglycemia (except Metformin) 10

John Diep Bimm118

Metabolic Disorders (Hyperlipidemia)

Statins Lovastatin Atorvastatin (Lipitor) -Reversible HMG-CoA Reductase inhibitors. HMG-CoA reductase is the rate-limiting enzyme in the production of cholesterol. Inhibition effectively reduces de novo synthesis of cholesterol precursors. -Lower cholesterol levels upregulates LDL receptors in liver removing LDL from the bloodstream. PPAR agonists stimulates -oxidation of fatty acids Promotes lipoprotein lipase activity Lowers VLDL (minor effect on LDL) Increases HDL levels Bile acid binding resins prevents reabsorption of bile acids in enterohepatic circulation. -The liver responds to this loss of bile acid by increasing cholesterol synthesis to make more bile acid (plasma cholesterol levels remain unchanged). -The liver will also upregulate LDL receptors to increase hepatic uptake of LDL (reducing plasma LDL). Resins are not absorbed into the blood.

Fibrates -Clofibrate -Benzafibrate Resins -Cholestyramine -Colestipol

11

John Diep Bimm118

Steroid Drugs
Corticosteriods (GC) inhibits all phases of inflammation -inhibits NFB (a transcription regulator of proinflammatory mediators -upregulates lipocortin (lipocortin inhibits PLA2 ; no PT or LT synthesis) -promotes fetal lung development by increasing surfactant Side Effects -immune suppression -anti-insulin effects -steroid diabetes -increased glucose promotes lipogenesis (fat) -increased catabolism (muscle atrophy) -salt/water retention due to cross reactivity with mineralcorticoid (aldosterone) receptors -osteoporosis Prolonged use of GC therapy causes adrenal cortex atrophy, so it is important to phase out slowly to avoid flare ups due to cortisol insufficiency. Addisons Disease Adrenal cortex failure low cortisol levels -hypotension -weight loss -fatigue -abnormal glucose levels -inability to cope with stress -blotchy colored skin; w/o cortisol, corticotropin is unregulated and it increases melatonin (skin pigmentation) Cushings Syndrome Adrenal cortex tumor high cortisol levels (symptoms similar to GC therapy) -hypertension -weight gain (upper body obesity, buffalo hump) -water retention -poor wound healing Hydrocortison -equivalent to endogenous cortisol -indicated for adrenal insufficiency (Addisons Disease) -mostly for topical application -cross-stimulation with mineralcorticoid receptors -have Na retaining effects Prednisone Pro-drug; converted to active form (prednisolone) Prednisolone Drug of choice for systemic administration -lower Na retaining effects Triamcinolone Stronger anti-inflammatory effect, 5x more potent than cortisol -no Na retaining effects Halogenated GC 30x more potent than cortisol (Betamethasone) -no Na or water retaining effects

12

John Diep Bimm118

Steroid Drugs
Female Sex Steriods Estrogens Estradiol Primary endogenous estrogen responsible for: -breast development -improving bone density -increase HDL -promotes uterus growth & supports endometrium development Rapidly metabolized by the liver and therefore not suitable as an oral drug Stable derivative of estradiol Usually found as the estrogen component of birth control pills Oral contraceptive Similar to ethinylestradiol with an extra methyl group; prodrug -cleavage of the methyl group yields ethinylestradiol Indicated for postmenopausal osteoporosis SERM = selective estrogen receptor modifier -anti-estrogenic effect on breast and endometrium -reduces stimulation in these tissues to avoid tumorgenesis -estrogenic effect on bone and lipid metabolism Indicated for breast cancer -anti-estrogenic effect on breast tissue -weak effect on bone and lipid metabolism Indicated for infertility -selectively inhibits estrogen binding in pituitary, effectively removing negative feedback -this causes an increase in LH ovulation Rapidly metabolized by the liver Stable derivatives: Hydroxy/medroxy progesterone Testosterone derivatives: norethindrone norgestrel Progesterone is important for the formation of secretory endometrium and the establishment of pregnancy. Induce medical abortions (<49days) Combine w/ PG analogue (Misoprostol) to increase uterine contraction

Ethinylestradiol Mestranol

Selective Estrogen Receptor Modifier

Raloxifene

Tamoxifene (antiestrogen) Clomiphene (antiestrogen)

Progesterone

Mifepristone (RU486) (anti-progesterone)

13

John Diep Bimm118

Steroid Drugs
Male Sex Steroids/Others Testosterone Responsible for both anabolic and androgenic effects Rapidly metabolized by the liver. -ester derivatives increases its half-life Nandrolone Strong anabolic effects. (banned) Injection only. Stanozolol Strong anabolic effects. (Not a blocker despite -olol ending) (banned) Oral. DHEA Dehydroepiandrosterone. Marketed as an anabolic steroid. This is misleading because its a precursor for both testosterone and estrogen. High levels of DHEA may lead to elevated levels of testosterone as well as estrogen. Flutamide Indicated for prostate cancer Competitive androgen receptor antagonist -blocks testosterones stimulating effects Finasteride Indicated for prostate gland enlargement and baldness -blocks the conversion of testosterone to DHT -DHT is a testosterone metabolite that is much more potent Note: bald men have elevated levels of DHT GnRH Modifiers/Analogus Anti-Androgens Androgens Danazol Indicated for endometriosis (growth of endometrium outside of the uterus) Inhibits GnRH release (no LH/FSH production) and consequently no steroid production Given in pulses (s.c.) induced ovulation (stimulates LH/FSH) Given continuously medical castration (desensitize GnRH receptors)

Synthetic GnRH -Gonadorelin -Buserelin

14

John Diep Bimm118

Steroid Drugs
Oral Contraceptives General Mechanism -Estrogen inhibits FSH; suppressing follicle development -Progesterone inhibits LH; inhibiting ovulation & increases mucus viscosity (prevents sperm penetration) -Both steroids alter endometrium, preventing implantation Combination Pills Highly effective Estrogen component: Ethinylestradiol Progesterone component: varies 29 day cycle (includes 7 day break to induce withdrawal bleeding) Biphasic preparation includes progesterone break after 7 day break Monophasic preparation no progesterone break (but [progesterone] varies through-out cycle) Less reliable than combination pills Contains only progesterone (used when estrogen is contraindicated) Contraception mechanism relies mainly on increased mucus viscosity. -mucolytic agents (usually found in cough medications) may cause contraception failure High dose of progesterone Must be taken within 72 hours.

Mini Pill

Morning After Pill -Levonorgestrel

Oral contraception failures: 1. Mucolytic agents 2. Barbituates. Barbituates or other P450 inducing drugs may cause failure because steroids are metabolized by P450 enzymes 3. Diarrhea or laxatives. Due to poor absorption of the drug.

15

John Diep Bimm118

Allergy Drugs
Allergy Mediators Allergen activates mast cells 1. Mast cell degranulation. Rapid release of histamine and other inflammatory agents 2. Activation of PLA2; producing leukotrienes and prostaglandins. Late stage response. 3. Stimulates cytokine transcription. Late stage inflammatory response. Review histamine and leukotriene actions (receptor specific) from lecture slides. Dephenhydramine Indicated for seasonal and skin allergies (Benadryl) Dimenhydrinate Used as an anti-emetic (for motion sickness) (Dramamine) Also blocks mAChRs. Doxyamine Most potent OTC sedative (better than barbiturates) (Nyquil) Same efficacy as diphenhydramine in terms of antiallergies. Chlorpheniramine Anti-allergy Anti-depressant (also blocks serotonin re-uptake) (Alklyamines) Meclizine Anti-emetic (but less drowsy) (Dramamine II) H1 Recptor Antagonists 1st Generation Drugs (Sedating) Piperazines Ethanolamines Hydroxyzine (Atarax) Pro-Drug, anti-allergy effect from metabolite Certirizine Hydroxyzine metabolite. (also a Piperazine) No drowsiness. Active metabolite = desloratadine Long half-life Highly selective for H1-receptor

2nd Gen. (Non-Sedating)

Certirizine (Zyrtec) Piperidines Loratadine (Claritin) Desloratadine (Clarinex) Fexofenadine (Allegra)

Mast Cell Stabilizers -Cromolyn -Nedcromil Leukotriene Receptor Blockers -Montelukast (Singulair) 5-Lipoxygenase Inhibitor -Zileuton (Zyflo)

Only preventative; acts by preventing mediator release from mast cells. Useless if histamine or other mediators are already released. Prophylactic agent for asthma and other allergy symptoms Prevents exercise and aspirin-induced asthma Antagonist of LTD4 at cysteinyl LT receptor Prevents production of all leukotrienes Not useful for treatment of attacks.

16

John Diep Bimm118

CNS Drugs
Hypnotics/Anxiolytics Barbiturates General inhibition of the CNS w/ sedative-hypnotic actions. -phenobarbital (long acting) -thiopental (short acting) Mechanism: Augments GABA responses (by potentiating GABA signal) and mimics GABA (by opening Cl-channels in the absence of GABA). Keeps Cl channels open longer, hyperpolarizing the cell preventing further excitation. Also blocks excitatory glutamate receptors. Indications: -epilepsy (phenobarbital) and anesthesia induction (thiopental) (not a first line drug due to many side effects) Side effects/Risks -high risk of dependence (severe/lethal withdrawal symptoms) -may lead to cardio-respiratory depression -potent inducers of P450 enzymes; drug interactions (contraceptives, etc.) Mechanism: Benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor (by selectively binding to benzodiazepine receptors which are coupled to the GABA receptors). While barbiturates increase the length of time Cl channels stay open, benzodiazepines increases the frequency of GABA binding (opening of Cl channels). Indications: Anxiolytic, anticonvulsant (anti-epilepsy), anesthesia induction, etc -all forms of anxieties -epilepsy (Clonazepam) -depression (Alprazolam) -anesthesia induction (Midazolam) Side effects/Risks: -anterogade amnesia (date rape drug) -much fewer side effects than barbiturates Both barbiturates and benzodiazepines have an inhibitory effect on the CNS by modulating GABA signals (hyperpolarizing cells to prevent further excitation). While both classes of drugs enhance GABA signals, barbiturates can also open Cl channels even in the absence of GABA.

Benzodiazepines -Diazepam (Valium) -Lorazepam - Alprazolam - Midazolam

17

John Diep Bimm118

CNS Drugs
Antidepressants Amine hypothesis of depression functional decrease in NE or serotonin causes depression (oversimplified) MAO Inhibitors Mechanism: Inhibits the metabolism of serotonin (as well as NE/E and dopamine); effectively increasing serotonin levels. -Tranylcypramine Side Effects: -may cause fatal hypertension (due to increase sympathetic input (NE)) -Food-Drug interaction: cheese-reaction Increased levels of tyramine which is usually metabolized by MAO may displace NE from storage vesicles, further increasing NE signals hypertensive crisis Only used if resistant to all other treatments. Tricyclic Mechanism: Prevents reuptake of NE and serotonin into pre-synaptic Antidepressants terminal thereby potentiating the effect of the (TCAs) neurotransmitters at the post-synaptic neurons. -Imipramine -Amitriptyline Selective Serotonin Reuptake Inhibitors (SSRIs) -Fluoxetine (Prozac) -Paroxetine (Paxil) -Sertraline (Zoloft) Side Effects -sedation (also binds H1 receptors) -strong interaction with alcohol Mechanism: Specifically prevents serotonin reuptake thereby potentiating its effect on post-synaptic neurons Same efficacy as TCAs but fewer side effects possibly due to its specificity for serotonin Side Effects -rare: may cause violence and aggression -inhibits sexual climax

These antidepressants produce a functional increase in serotonin levels in the CNS. Supports the amine hypothesis of depression.

18

John Diep Bimm118

CNS Drugs
Neuroleptics (anti-psychotics) Dopamine hypothesis of schizophrenia functional increase in CNS dopamine causes schizophrenia. Serotonin may also be involved in modulating dopamine responses. (over-simplified) Phenothiazines Mechanism: Blocks D2 receptors on post-synaptic neuron preventing -Chlorpromazine receptor activation by dopamine. Typical/Classical Neuroleptics Butyrophenones -haloperidol Side Effects Extrapyramidal Effects: Due to dopamine blockage in striatum -Acute dystonia: motor impairment (around face, neck); -immediate onset, reversible -Akatheisa: pseudo-Parkinsonism, tremor/rigidity -occurs days/months after treatment, reversible -Tardive Dyskinesia: involuntary movements of most body parts -occurs after extended treatment; irreversible -Sedation (blocks H1 receptor) -Dry mouth, constipation, and urinary retention -blocks mACh receptors and -adrenergic receptors -lactation (dopamine is needed to inhibit prolactin) -strong interaction with alcohol Mechanism: Blocks both dopamine and serotonin receptors preventing receptor activation by dopamine and serotonin. Acts more specifically in the limbic system (fewer extrapyramidal effects) Clozapine causes agranulocytosis (decrease in white blood cells)

Atypical Neruoleptics

Clozapine Olanzapine Risperidone

Note: Cocaine and amphetamines both causes an increase in dopamine levels in the CNS, which mimics schizophrenia symptoms.

19

John Diep Bimm118

CNS Drugs
Parkinsons Disease Pathology -Loss of dopaminergic suppression of excitatory cholinergic neurons in the striatum -Cholinergic neurons causes an increase in GABA output suppressing the thalamus which reduces signaling to the motor cortexcausing movement disorder Refer to lecture slide. L-Dopa & L-Dopa dopamine precursor that can cross the blood brain barrier Carbidopa (dopamine cannot cross the blood brain barrier) -L-Dopa can be converted to dopamine in the periphery leading to many side effects Dopamine Replacement Combine with Carbidopa! Carbidopa dopamine decarboxylase inhibitor -Since it cannot cross the blood brain barrier, it exerts its effect in the periphery by inhibiting the conversion of L-dopa to dopamine -this means more L-dopa will reach the CNS Actions similar to L-Dopa. Potent agonist of D2 receptor. (suppresses prolactin; was used to treat galactorrhoea) Indirect agonist. Specifically inhibits MAO-B in the CNS, extending dopamines half-life. MAO-B is responsible for the metabolism of dopamine.

Dopamine Agonist

Bromocriptine

Selegiline

Atropine

Muscarinic acetylcholine receptor antagonist. Reduces cholinergic signals in the CNS which is responsible for stimulating GABA output suppressing the thalamus.

No longer used for Parkinsons disease. Antipsychotics used to treat schizophrenia may induce symptoms similar to Parkinsons disease due to its dopamine lowering effect.

20

John Diep Bimm118

CNS Drugs
Epilepsy (seizures) Pathology Excessive excitability of neurons in the CNS, causing seizures Enhancement of GABA: Augment inhibitory effect of GABA to counter excessive excitation. Only useful for generalized and partial convulsive disorders (not for absence seizures) Carbamazepine Increases Cl- influx in response to GABA, counteracts (benzodiazepine) depolarization, (elevating seizure threshold.) Tiagabin Phenytoin Prevents GABA reuptake. Mechanism: Blocks voltage gated Na channels that are in the inactivated state, preferentially blocks high frequency discharges. use-dependent inhibition (does not elevate seizure threshold, but rather, limits the propagation and spread of seizure.) -eliminated by 0th order kinetics -Indicated for convulsive seizures, not absence seizures Ethosuximide Side Effect: hyperplasia (gum enlargement) Mechanism: Blocks T-type calcium channels; (elevates seizure threshold thru depression of nerve transmission) -good for absence seizures Mechanism: unknown; thought to be GABA-mediated -useful for both convulsive and absence seizures

Valproate

Side Effects -hepatotoxicity -teratogenic Strychnine a toxin that induces strong convulsions by blocking Glycine receptors -Glycine is an inhibitor NT that is similar to GABA -Glycine also binds NMDA receptor as a co-activator (with Glutamate) where it has excitatory functions (not strychnine sensitive) Antedotes: anticonvulsants (benzodiazepines) and muscle relaxants (nACh R blockers)

Alcoholism
Review lecture slides on effects of alcohol. Disulfuram inhibits aldehyde dehydrogenase; leading to acetylaldehyde accumulation causing hangover -also blocks the conversion of dopamine to NE, rise in dopamine levels causes schizophrenic symptoms Naltrexone opiod receptor antagonist; inhibiting the reward response that normally results for alcohol consumption

21

John Diep Bimm118

Pain Killers
General Anesthesia -unconciousness, analgesia, amnesia, and muscle relaxation -induced by intravenous anesthetics and maintained by inhalation anesthetics -inhalation anesthetics are generally removed simply by exhalation of unchanged gas Thiopental Rapid onset with high lipid solubility (accumulates in fat); slow recovery (barbiturate) Narrow therapeutic range No analgesic effect Propofol Rapidly metabolized for quick recovery. Used for same-day surgery Ketamine Phencyclidine (PCP) analogue; may cause hallucinations during recovery Have both anesthetic and analgesic properties -often used in veterinarian medicine and in tranqulizers Midazolam Benzodiazepine. Very short-acting. Have all benzodiazepine properties, often used for anesthesia induction Speed and Potency Solubility in blood speed of onset is inversely correlated w/ degree of solubility in blood -blood acts as a drug reservoir (need to saturate the blood first, to achieve effect) -more soluble = slower onset Inhalation Anesthetics Example Intravenous Anesthetics Solubility in lipid potency is directly correlated w/ lipid solubility -more lipophillic = more potent Ether Obsolete. Slow onset and recovery. Nitrous Oxide Low potency (must be combined with other agents to achieve anesthesia) Rapid induction and recovery Have both anesthetic and analgesic properties. Haloethanes High potency anesthetic; combined w/ N2O No analgesic properties. Some hepatic metabolism occurs; repeated use causes hepatoxicity Also causes hypotension (thru vasodilation and cardiac suppression) -Enfluran High potency anesthetic; similar to haloethanes -Isofluran Fewer side effects because less metabolized by liver. -Desfluran 1. Pre-medication 2. Anesthesia Induction 3. Anesthesia Maintenance 4. Recovery -Diazepam (anxiolytic, benzodiazepam) -Fantanyl (analgesis, opiod) -Atropine (autonomic stabilization, mACh R blocker) -Midazolam (benzodiazepine) or Thiopental (barbiturate) -Succinylcholine (muscle relaxant, nACh R blocker) -Haloethane (anesthesia) -Nitrous Oxide (analgesia & anesthesia) -Pancuronium (muscle relaxant, nACh R blocker) -Neostygmine (reversing neuromuscular block) ACh R agonist)

22

John Diep Bimm118

Pain Killers
Opioid Analgesics Analgesic Mechanisms 1. Spinal Analgesia Activation of pre-synaptic opioid receptors decreases Substance P release -Decreasing pain signal transmission from nocireceptors 2. Supraspinal Analgesia Activation of post-synaptic opioid receptors causes hyperpolarization -Inhibition of neurons in the pain pathway Morphine CNS sedation, nausea, and cough suppression Respiratory System reducing frequency and depth of breathing GI Tract increases segmentation and decreases peristalsis (constipation) Eyes papillary constriction (due to parasympathetic activation) Withdrawal symptoms -autonomic hyperactivity due to tolerance (elevated levels of cAMP in response to adenylyl cyclase upregulation) -diarrhea, vomiting, pain, etc Codeine Pro-drug, that is converted into morphine by CYP2D6. -CYP2D6 inhibitors (like Fluoxetine) may reduce codeine efficacy -Genetic polymorphism may also explain codeine resistance (lacking this enzyme) Little euphoric effect, so low risk for addiction. Used as an anti-tussive (cough suppressant) -may still cause constipation and respiratory suppression Dextromethrophan Synthetic morphine derivative that does not act thru opioid receptors. Same efficacy as codeine -no GI or analgesic effect Heroin Diamorphine; diacylated-morphine is more lipophilic than morphine so it crosses the blood-brain barrier more rapidly producing a greater rush. -2x more potent than morphine Hydrocodone Vicodin; often combined w/ NSAIDs for synergistic effect Oxycodone Indicated for chronic pain. -Addicts chew thru the slow release formulation to obtain immediate release to mimic heroin rush Meperidine Similar to morphine, but shorter duration. Used during labor. Methadone Similar to morphine, but much longer duration. Used to treat morphine/heroin addiction Fentanyl High potency. Can be used transdermally. Short-lasting. Used in anesthesia and patient controlled infusions. Naloxone Short-acting competitive antagonist used to rapidly reverse opioid induced analgesia and respiratory suppression. AntagonistsOpiate Naltrexone Long-acting competitive antagonist Used to protect detoxified addicts from relapsing.

23

John Diep Bimm118

Pain Killers
Local Anesthetics Mechanism Reversibly inhibits Na channels (cytoplasmic side) that are activated to block generation of action potentials. Use dependent Note: Phenytoin (antiepileptic) specifically blocks inactivated Na channels All are weak bases that exist mainly in its ionized form. Passes thru the plasma membrane in its unionized form, but exerts its effect in its ionized form intracellularly. Cocaine -contains ester bond; rapidly metabolized by non-specific esterases in the plasma -cocaines CNS effects are independent from its analgesic effect (blocks reuptake of DA, 5-HT, NE) Lidocaine -contains amide bond; longer acting compared to local anesthetics w/ ester bonds Local anesthetics often combined with vasoconstrictors (epinephrine) to extend duration of action and to minimize bleeding.

24

John Diep Bimm118

Pain Killers
NSAIDS (non-steroidal anti-inflammatory drugs) Mechanism: Inhibits cyclooxygenase (COX), preventing prostaglandin synthesis. Prostaglandins do not cause pain themselves, but sensitize nocireceptors to pain Note: COX1 constitutively expressed; house-keeping functions COX2 induced by pro-inflammatory factors (TNF & IL-1) Classical NSAIDs inhibits both COX1 and COX2 -inhibition of COX1 reduces overall house-keeping PGs side effects (gastric ulcers) Aspirin The only known irreversible COX inhibitor -have cardioprotective effects (low dose aspirin) PGIs anticoagulating effects; found in endothelial cells w/ nucleus. They can renew COX transcriptionally after aspirin is elminated TXa coagulating effect; found in thrombocytes w/o nucleus. They cannot renew COX even after aspirin is elminated. Low dose aspirin shifts PG synthesis to PGI. Side Effects -Reyes syndrome in children, do not use in children! -high doses may cause tinnitus and nausea Acetaminophen Indicated for analgesic and antipyretic property. (Tylenol) Easily crosses blood-brain barrier. Have little side effects but a very narrow therapeutic index. Overdose fatal hepatoxicity Acetaminophen can be converted into a toxic metabolite that requires glutathione conjugation. OD of acetaminophen will deplete glutathione and lead to accumulation of the toxic metabolite hepatic necrosis COX-2 Specific NSAIDs inhibits only COX 2 -supposedly fewer side effects -recent studies show that they increase the risk of cardiovascular diseases!!! -Reofecoxib (Vioxx) -Celecoxib (Celebrex)

Antibiotics (overview)
25

John Diep Bimm118 Cell Wall Synthesis Inhibitors General Mechanism: Inhibit transpeptidase required for cross-linking of peptidoglycan chains for bacterial cell wall synthesis. Also inactivates autolytic enzyme inhibitor. Penicillins Classifications: -Narrow Spectrum: active against gram (+) only -Broad or Extended Spectrum: active against gram (+) & gram (-) & some others -increased range is due to the addition of amino or carboxy group --Lactamase sensitive vs. -Lactamase resistant -antibiotics that are inactivated by -Lactamase are said to be -Lactamase sensitve -Lactamase Inhibitor -inhibits -Lactamase produced by the bacteria -Clavulanic Acid -allows -Lactamase sensitive antibiotics to become -sulbactam resistant Cephalosporins Same mechanism as penicillins There are 4 generations. The newer generations have: broader spectrum, increased resistance to -Lactamase, and increased ability to reach CSF. Vancomycin (polypeptides) Other cell wall inhibitors that operate thru a different Bacitracin (polypeptides) mechanism (different than - Lactam Antibiotics) General Mechanism Inhibit either 30s or 50s ribosomal subunit (which differ from mammalian cells). Since they operate intracellularly, they must be able to penetrate the cell wall and/or membrane. Entry inhibition would be a point of drug resistance. Aminoglycosides -O2 dependent transport to enter cells -Gentamycin -ineffective against anaerobes Tetracyclines -oral absorption impaired by Ca2+ and Mg2+ Macrolides -good alternative to penicillin -Azithromycin (long t1/2) -once daily dosing of Azithromycin increases compliance Chloramphenicol -very broad spectrum -reserved for resistant cases; severe side effects Clindamycin -used to treat penicillin-resistant cocci General Mechanism block folate synthesis (folate is required for nucleotide synthesis) Bacteria cannot take up folic acid and must make it from PABA. Folate Metabolism: PABA Folate Tetrathydrofolate DNA Sulfonamides -structurally similar to PABA; competes with PABA in the folate pathway (interferes with PABA folate) Trimethoprim -interferes with the folate tetrahydrofolate step -often combined with sulfonamides Ciprofloxain Mechanism inhibitor of bacterial DNA gyrase (enzyme Levofloxain that is involved in the winding/unwinding of DNA. This Etc results in inhibition of DNA synthesis/transcription -very broad spectrum -Focus on knowing the general mechanism and the classifications (cell wall synthesis inhibitors, protein synthesis inhibitors, folate antagonists, and quinolones).
Quinolones Folate Antagonists

Protein Synthesis Inhibitors

- Lactam Antibiotics

26