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Routes of Drug Administration Types of Orally Administered Drugs Percutaneous Drug Administration Other Topicals Parenteral Drug Administration Oral Topical (Percutaneous) Rectal or Vaginal Pulmonal Parenteral Pills (single dose) Tablets Coated Tablets (shell) Matrix Tablets (carrier meshwork) Capsules (gelatin shell) Troches/Lozenges Solutions Ointment + Lipophilic cream Paste Lotion Gels Can be single or multilayer, or contained in a reservoir Eye Drops Nose Drops Pulmonary Formulations Suppositories Ampules Vials Cartridge Ampules Infusions Advantage: 100% Absorption, enters circulation without hepatic elim, better bioavailability of hydrophilic drugs Types of Barriers for Drug Distribution/Absorption Drug Distribution Bioavailability Volume of Distribution Rate of Elimination External Absorption Barriers: (epithelial layer on skin, lung, intestine—Lipophilic barrier) Internal Blood-Tissue Barriers: Cardiac muscle, endocrine glands, gut, liver, CNS Passive Diffusion Active Transport Receptor-mediated Endocytosis [DRUG] IS A FUNCTION OF ABSORBTION AND ELIMINATION! The AUC of the administered drug divided by the AUC of the intraveneously administered drug IV>TD>IM=SC>Rectal>Oral=Inhal Vd=Amt of drug in the mody/[drug] R of E: Via kidney (filtration) or liver (metabolism) Usually first order kinetics 3 drugs have zero-order kinetics Rate of Elim/[Drug] Clearance Rate of Elim= k*Cp*Vd K= ln2/T ½ CL= K*Vd Phase I Reactions Phase II Reactions MFO Mixed Function Oxidases P450 Enzymes Conjugation Reactions Convert parent compound into more polar metabolite Add/unmask functional group: OH, SH, NH2, COOH, etc Oxidation, Reduction, hydrolytic cleavage, Alkylation, Dealkylation, etc… Conjugation with endogenous substrate (increase aq solubility) Conjugation with gucoronide, sulfate, acetate, amino acid Require reducing agent and molecular oxygen Two enzymes: 1) Flavoprotein, NADPH-cytochrome c reductase 2) Cytochrome P450 (electron acceptor); CYP PPAR ligands, CYP1, CYP2E, CYP2B Polymorphisms cause changes in drug metab: CYP2C19, CYP2B, CYP2D6 Induction of P450 enzymes=metabolize drug Glucoronidation Sulfation Acetylation Amino acid Conj Glutathione Conj Fatty acid Conj Condensation Reaction Monoamine Oxidases (MAO) Therapeutic Index Agonist Antagonist Four major drug targets Catalyze oxidative deamination of endogenous catecholamines (epinephrine) Lacated in never terminals and peripheral tissues Many drug/food interactions! (cheese, wine) Inhib by MAO inhib Maximum non-toxic dose/Min effective dose Doesn’t take into account variability btw indivs LD50/ED50 Can be drugs or endogenous ligands for the receptor Increasing [agonist] will produce increase in biological response Full:evokes 100% max possible effect Partial: not 100% Block or reverse effect of agonist No effect on their own Competitive, Non-competitive, inverse agonist (triggers neg response) Receptor Enzyme Ion Channel Transporter Ca++ as a Second Messenger Ca Channels G-Protein-coupled Receptors G-Proteins PKA Regulates many cellular and phys. Responses Gradient btw extracellular and intracellular (high:low) creates many opportunities for regulation Stored in ER and other Voltage mediated: L, N, T Ligand gated Store operated Sesnsors: Annexins, EF-hand proteins, Calmodulin, ProponinC Target of many drugs! GPCR: transmembrane Bind GTP and GDP GAPS, GEFS, RGSs important in this regulation Main Targets: Phospholipase C, Adenylate cyclase G-Proteins: Guanine nucleotide binding proteins 2 groups: Small GTP binding Heterotrimeric G proteins Target of cAMP Four subunits (2 reg, 2 catalytic) Phosphorylates transcription factors ex: CREB Regulation of Receptors Nuclear Receptors GC, Mineralcorticoids, Retinoids PPARs Phospholipids Phospholipases Heterologous desensitization (Incoming signal from different receptor) Homologous desensitization (only occurs on receptor which has already been stimulated) Lipid soluble ligands that penetrate cell membrane, Receptors contain DNA-binding domains (transcriptional activators/suppressors) Takes longer to act—requires penetration and protein synth first Common fatty acid chain+glycerol backbone+phosphor-residue PLA2 (reg through Ca++ and phos), PLC (Beta: Reg through GPCR, Gamma: EGFR or TCR, activated through tyrosine phosphorylation Phospholipases… DAG: membrane bound, acts as a substrate for PLA2 IP3: Ca++ regulated Arachidonic Acid Metabolism Eicosanoids: derivative of arachadonice acid Rapidly metab by COX into PG and LTs 1st reaction: cyclic ring structure (COX), 2nd reaction: oxidation (Peroxidase) Function of PGs Leukotrienes Nervous System Cholinergic Receptors Cholinomimetics= Parasympathomimetics Vascular tone (relaxation, constriction) Platelet agg (Inc and Dec) Uterus tone (Inc) Bronchial Muscle (Contriction, relaxation) Gastric secretion (Inib), temp/pain LTC4, D4 and E4 mediate allergic rxn (SRS-A) Mediate anaphylactic shock, 10,000 more postent than histamine Constricts bronchi, dilates bv LTB4 strong chemattractant for macrophage Divided into CNS and PNS PNS div into Somatic and Autonomous Auto: Sypmathetic and Parasympathetic Muscarinic Receptors: Heterotrimeric G protein coupled, CNS, gastric mucosa M1 Cardiac=M2, Glandular=M3 Nicotinic Receptors: Ion channel coupled Muscle type, Ganglion type, CNS type Direct Parasympathomimetics: Affinity for M or N receptors (mimic Ach) Inderect Parasympathometics: Inhibit activity of Achesterase (Ach increased) 1. Mimic Input 2. Block Input To affect Paraympathetic… To Treat associated diseases…. 3. Promote Parasymp 4. Block Symp Pilocarpine Muscarinic Parasymp, does not activate N rec, treates glaucoma (local! Eyedrops) Muscarine Muscarine has no therapeutic application! Carbamate Quaternary Alcohols Horny Goat Weed Ogranophosphates Nerve Gasses Achestease Inhibitors, raise Ach Physiostigmine (topical only) Neostigmine Edrophonium (diagnose Myasthenia Gravis) AcCh-ase inhib Acts as AcCh-ase inhib but active ingredient unkown Indirect stimulation of M3 receptor (vascular), triggers NO production=vasodilation Action similar to Viagra (dangerous) AcCh-ase inhibitors (irreversible) No medical application Atropine Hyoscine Nicotinic Parasympatholytics Succinocholine/Suxamethonium Transmitters in the Autonomic Nervous System Termination of (Nor)epinephrine action Muscarinic Parasympathomimetic Atropine (antagonist of cholinergic system): CNS stimulant, before anesth. Prevent hypersecretion of bronchial mucus, treats bradycardy.. Hyoscine=CNS depressant, antiemetic, Competitive Antagonists: Compete with AcCh for N rec, prevent depolarization, reversible Agonists: Depolarizing blockers, AcCh mimetics not hydrolyzed by AcCh-ase, trigger a sustained depolarization, irreversible Dimeric AcCh, Acts as agonist like AcCh, not hydrolyzed by AcCh-ase (only plasma esterase) Depolarization triggers muscle twitching initially, Used for brief procedures AcCh: Preganglionic, parasyathetic post ganglionic neurons Norepinephrine: Most symp. Post ganglionic neurons (except sweat glands and renal arteries) Epinephrine (adrenalin): Adrenal medulla--symp impulses (no gang) Reuptake into presynaptic nerve ending Catechol-O-methyltransferase MAO Presynaptic alpha 2 receptors Adrenergic Receptors Tranylcypromine Moclobemide Ephedrine Amphetamines Methylphenidate Fenfluramine Metamphetamine Epinephrine Norepinephrine Alpha1 (vasc smooth muscle) Alpha 2 (presynaptic) Beta 1 (Heart) Beta 2 (repiratory, uterine SM cells) Beta 3 (Adipocytes) MAO-Inhibitors Indirect Sympathicomimetics Inhib of MAO causes increase in free Nor-Ep, in CNS NAO metab dopamine and serotonin (inhib=increase in happy hormones) Indirect Sympathicomimetics Displace nor-E in storage vesicles=forced release of NorE Dietary Supplements Indirect Sympathomimetics Displace norE in storage vesicles, forced release, inhib NorE re-uptake and deg by MAO (TRIPPLE ACTION), Meth=ADD, Fen=Appetite suppressant, Meta=more lipophilic, depletes NorE Non-selective Agonists Sympathomimetics Ep: Activates alpha and beta rec Blood pressure increase, dilates bronchii, vasopressor, Treat anaphylactic shock NorE: alph receptors, increase BP, potent vasopressor Methoxamine Phenylephrine Naphazoline Oxymetazoline Xylometazoline Clonidine Guanfacine Alpha1 selective agonist Sympathomimetics Methoxamine: treatment of hypotensive state Phen: Local vasoconstrictor, nasal decongestant Zoline=alpha 1 Alpha 2 selective agonist Produce sympatholytic effect, but sympathomimetics! Actviate presynaptic a-2 rec in cardiovascular control in the CNS BP decrease Dobutamine B1-selective agonist, stimulate heart Strgon inotropic effect, little chronotropic effect, short term treatment of impaired cardiac function Metaproterenol Albuterol Formoterol B2 selective agonist Treat asthma, non-selective sympathomimetics Differ in speed and onset, duration of action Non-selective Blockers Phentolamine Indicated for pheocromocytoma. Blocking α1 causes vasodilation; reducing BP Blocking α2 removes inhibition, increasing NE action on β receptors increasing HR and cardiac output Prazosin, Terazosin, etc Yohimibine Propranolol Metoprolol, Atenolol… Selective α1 Blocker Indicated for hypertension and urinary retention. Side effects: Reflex tachycardia and postural hypotension Selective α2 Blocker (sympathomimetic!) Increases sympathetic outpout. Used for male sexual dysfunction and as a weight loss drug Noncardioselective β blockers 1st gen. drug, cross reaction w/ β2 causes bronchoconstriction Labetalol also blocks α1 receptors (strong antihypertensive drug) same indications as cardioselective blockers Cardioselective β blockers Newer drugs are more β1 selective. Indicated for angina pectoris, hypertension, cardiac dysrhythmias, myocardial infarction, heart failure, and stage fright (anxiolytic). CNS/ANS (decrease symp. tone) Potential targets of Antihypertensive Heart: decrease cardiac output drugs Veins: Dilate, decrease preload Arterioles: dilate, decrease afterload Kidneys: increase diuresis Dihydropyridines: Nifedipine, Nicardipine, Nimodipine… Minoxidil Nitroprusside Captopril Enalapril Benazepril Lisinopril Losartan Candesartan etc… Calcium channel blockers (antagonist) Inhibit Ca entry into cells of arteries Targets specifically L-type channels on VSMC, no cardiac effect Can cause peripheral edema Potassium Channel Agonists 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 (Rogaine) Vasodilator Delivered thru iv only and is metabolized into NO which directly activates cGMP production vasodilation, Rapid action! (Caffeine & Viagra) Hypertensive Emergencies! ACE-Inhibitors, angiotensin I not 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 Inhibits the effect of AT II by blocking the receptor usually used if patient cannot tolerate the cough caused by ACE inhibitors Stable Angina Predictable episodes; usually during/after physical exertion or stress. Treatment: Nitrates & β-Blockers (Propranolol, etc.) Unstable Angina Chest pain unexpected and usually occurs at rest Treatment: Nitrates Variant Angina Chest pain almost always occurs at rest. Due to coronary artery spasm. Treatment: Calcium channel blockers (Nifedipine, etc…) Nitroglycerine Isosorbide-dinitrate (ISDN) Nitroprusside Arrythmia Treatment Class I Arrythmia Treatment Class II Treats angina pectoris. Reduces cardiac workload (and its oxygen demand) by reducing venous return. Causes vasodilation primarily in veins. Oral, sublingual, IV, Buccal and Transdermal ROA Do not combine w/ other vasodilators (Viagra) More stable than nitroglycerine Tolerance can occur, give lowest dose Do NOT combine w/ other vasodilators Promotes peripheral vasodilation. IV only; rapid onset and short duration – allows for titration Sodium Channel Blockers Slows depolarization phase of AP. Procainamide – used for atrial & ventricular arrhythmias Lidocaine – used for acute ventricular arrhythmias Flecainide – used for chronic treatment of ventricular arrhythmias β-Blockers Propranolol used for tachycardia Arrythmia Treatment Class III: Potassium Channel Blockers Prolongs repolarization by blocking potassium efflux. Bretylium & Amiodarone used for intractable ventricular arrhythmias Class IV: Calcium Channel Blockers Prolongs repolarization by blocking calcium influx Verapamil – blocks both L & T Type calcium channels! Blocking T Type channels slows conduction (Blocking L Type channels coronary + arterial vasodilation) Other Cardiac Arrythmia Drugs Adenosine – for paroxysmal supraventricular tachycardia Digoxin – atrial fibrillation Epinephrine - bradycardia Congestive Heart Failure Cardiac Glycosides (Digoxin) ACE inhibitors & ATII antagonists Inadequate contractility; ventricles unable to expel blood rise in venous blood pressure. Caused by blocked coronary arteries, viral infections, hypertension, leaky heart vavles, myocardial infarction Right sided failure – lower limb edema, Left sided failure – pulmonary edema & respiratory distress Slows heart rate and increases contractility. 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 Reduces cardiac workload, inhibits vasoconstriction, inhibits sodium/fluid retention, inhibits NE release Captopril & Losartan Vasodilators Nitrates: Nitroglycerine, etc. (review Nitrates notes) Carbonic Anhydrase Inhibitors Azetazolamide Dorzolamide Inhibits conversion of CO2 (H+) + (HCO3-), blocking reabsorption of Na+ -Usually indicated for Glaucoma Causes metabolic acidosis (lower HCO3-) Loop Diuretics (high ceiling) Furosemide Torasemide Thiazide Diuretics Hydrochlorothiazide Benzthiazide Potassium-Sparring Diuretics Spironolactone Amiloride Osmotic Diuretics Mannitol Uricosuric Agents Probenecid Inhibits Na+/K+/2Cl- symporter at ascending limb in the Loop of Henle; blocking Na, K, Cl reabsorption most potent diuretic for severe/moderate hypertension & edema Causes hypokalemia Inhibits Na+/Cl- symporter at distal convoluted tube Used for moderate hypertension & heart failure (edema) Causes hypokalemia Acts as distal portion of distal tube; enhances Na excretion & reduces K excretion Spironolactone – aldosterone receptor antagonist (slow) Amiloride – directly blocks Na/K channel (fast) Used in combo w/ other diurectics Non-reabsorbable molecules that inhibit passive reabsorption of water (promoting water excretion w/ little Na excretion), does not cross blood-brain barrier, so water goes from brain to blood, Used to reduce intracranial pressure, IV only Indicated for kidney stones and gouts. Therapeutic dose: promotes excretion and inhibits reabsorption of uric acid Sub-therapeutic dose: inhibits both excretion and reabsorption Strongly inhibits penicillin excretion which is good if need long lasting penicillin performance Weak Bases: Aluminum Hydroxide Magnesium Hydroxide PeptoBismol, Tums H2 Receptor Blockers: Cimetidine Ranitidine Proton Pump Inhibitors: Omeprazole Lansoprazole Esomeprazole Rabeprazole Mucosal Protective Agents: Misoprostol Sucralfate Antiemetic Drugs: Potential Treatment Options Neutralizes stomach acid. Magnesium Hydroxide – causes diarrhea Aluminum hydroxide – causes constipation Often combined to reduce side effects of each Competitively inhibits binding of histamine to H2 receptors on parietal cells; reduces histamine stimulated gastric 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 Does not neutralize acid in stomach, only prevents production Misoprostol: PGE analog; stimulates mucus and HCO3 production Combined w/ NSAIDS Sucralfate: stabilizes mucus to inhibit H+ diffusion, not absorbed H1 Antagonists Muscarinic receptor antagonists Benzodiazepines D2 antagonists Cannabinoids H1 Antagonists Diphenhydramine, Meclizine, etc Blocks H1 (histamine) receptors competitively Muscarinic Receptor Antagonists Scopolamine (anticholernergic) Benzodiazepines Lorazempam; potentiates effects of GABA in CNS D2 (dopamine) Antagonists: Metoclopramide Domperidone Cannabinoids Competitively blocks C2 receptors in the CTZ Increases gastric emptying Contraindicated in patients w/ Parkinson’s disease Synthetic cannabinoids: Nabilone, Dronabinol Acts as agonist at cannabinoid receptors in the CNS Bulk Laxatives Increases bowel content volume triggering stretch receptors Carbohydrate Based Vegetable Fibers, Bran Insoluble, expands with water May cause constipation if not enough water Osmotically Active Epsom salt Glauber’s salt Irritants: Ricinoleic acid (Castor Oil) Anthraquinones Diphenolmethanes Bisacodyl Sodium picosulfate partially soluble/non-absrobable potent and fast acting Castor oil converted to ricinoleic acid works in the small intestine Works in the large intestine Laxative Abuse Longer interval needed to refill colon, most common cause of constipation Loss of water/salt in gut leads to aldosterone release Causes excretion of K+ Antidiarrheal: Loperamide (Imodium) Opiod derivative that selectively acts in the GI tract (w/no CNS activity) Acts on the intestinal muscles reducing motility=increase in water and electrolyte reabsorption Dimethicone: anti-gas agent that is often combined with anti-diarrheal drugs Insulin (unmodified) Insulin Lispro (Humalog) short acting only insulin that can be administered thru iv rapid onset and short acting Insulin Lente SC injection only, insulin + zinc microprecipitates delayed absorption long lasting, UltraLente = longest lasting Insulin Lente SC injection only, insulin + zinc microprecipitates delayed absorption 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 Tolbutamide (1st gen.) Glimepiridide Glipizide Stimulates insulin release; useful for diabetes caused by low insulin levels where β- pancreatic cells are still present Glitazones Rosiglitazone Pioglitazone Increases insulin sensitivity at target cells Acts as a nuclear hormone receptor (PPARγ agonist) increasing transcription of insulin receptor signaling components and glucose transporters Biguanides Metformin Statins Lovastatin Atorvastatin (Lipitor) Fibrates Clofibrate Benzafibrate Unknown mechanism Increases glucose uptake & inhibits gluconeogenesis Lowers LDL and VLDL Suppresses appetite No hypoglycemic effects 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 PPARα agonists – stimulates β-oxidation of fatty acids Promotes lipoprotein lipase activity Lowers VLDL (minor effect on LDL) Increases HDL levels Resins Cholestyramine Colestipol Glucorticoids (GCs) Bile acid binding resins prevent reabsorption of bile acids in enterohepatic circulation, Increases cholesterol synthesis to make more bile acid-plasma cholesterol levels remain unchanged. The liver also upregulates LDL receptors to increase hepatic uptake of LDL (reducing plasma LDL) Inhibit all phases of inflammation, inhibits NFκB, upregulates lipocortin (lipocortin inhibits PLA2, =no PT or LT synthesis, promotes fetal lung development by increasing surfactant Addison’s Disease Adrenal cortex failure, Lack of GC production Cushing Syndrome Adrenal cortex tumors, GC overproduction Hydrocortison Prednisone =Cortisol, main GC in humans Used for adrenal insufficiency (Addison’s Disease) mostly topical application Binds with mineralcorticoid receptors Have Na retaining effects Pro-drug; converted to active form (prednisolone) Prednisolone Drug of choice for systemic administration Lower Na retaining effects Triamcinoline Halogenated GC Estrogens: Stronger anti-inflammatory than cortisol No Na retaining effect Betamethasone, Dexamethasone: 30x more potent than cortisol, no water or Na retaining effects Estrone Produced from andgrogen precursors Estradiol=primary estrogen in human, breast devel, bone density, growth of uterus, increase HDL, etc., no oral admin (1st pass hepatic elim) Estriol Estriol only during pregnancy Ethinylestradiol Most widely used Induce expression of progesterone receptors, Progesterone inhib expression of estrogen receptors Diethyl-Stilbestrol Oral contraceptive Raloxifene Indicated for postmenopausal osteoporosis, Selective estrogen receptor modifier (SERM), Anti-estrogenic effect on breast and endometrium, Estrogenic effect on bone and lipid metabolism Mestranol Oral contraceptives, prodrug Estradiol Tamoxifene (antiestrogen) Indicated for breast cancer anti-estrogenic effect on breast tissue weak effect on bone and lipid metabolism Progesterones: Progesterone Inhibits rhythmic contractions of myometrium, not for oral admin (1st pass elim) Hydroxyprogesterone Stable derivatives Medroxyprogesterone Progesterone Norethindrone Norgestrel Desogestrel Anti-Progesterones Mifepristone Testosterone Nandrolone (banned) Testosterone derivatives with progesterone activity 1980s French company, found that it blocks progesterone receptors, induces abortion Addition of small doses of prostaglandin analogue few days later stimulates uterine contractions=very efficacious for termination of pregnancy Responsible for both anabolic and androgenic effects Rapidly metabolized by the liver. -ester derivatives increases its half-life Strong anabolic effects, Injection only Stanozolol (banned) Strong anabolic effects (Not a β blocker!) Oral admin DHEA Flutamide Finasteride Danazol Synthetic GnRH -Gonadorelin -Buserelin Dehydroepiandrosterone. Marketed as an anabolic steroid Misleading b/c it’s a precursor for both testosterone and estrogen. High levels of DHEA may lead to elevated levels of testosterone and estrogen. Used to treat prostate cancer Competitive androgen receptor antagonist Blocks testosterone stimulating effects Treats prostate gland enlargement and baldness, blocks the conversion of testosterone to DHT (testosterone metabolite that is much more potent) Bald men have elevated levels of DHT Treats endometriosis (growth of endometrium outside of the uterus) Inhibits GnRH release, no LH/FSH production=no steroid production Given in pulses (s.c.), induced ovulation (stimulates LH/FSH) Given continuously, medical castration (desensitize GnRH receptors) Resins Cholestyramine Colestipol Glucorticoids (GCs) Bile acid binding resins prevent reabsorption of bile acids in enterohepatic circulation, Increases cholesterol synthesis to make more bile acid-plasma cholesterol levels remain unchanged. The liver also upregulates LDL receptors to increase hepatic uptake of LDL (reducing plasma LDL) Inhibit all phases of inflammation, inhibits NFκB, upregulates lipocortin (lipocortin inhibits PLA2, =no PT or LT synthesis, promotes fetal lung development by increasing surfactant Addison’s Disease Adrenal cortex failure, Lack of GC production Cushing Syndrome Adrenal cortex tumors, GC overproduction Hydrocortison Prednisone =Cortisol, main GC in humans Used for adrenal insufficiency (Addison’s Disease) mostly topical application Binds with mineralcorticoid receptors Have Na retaining effects Pro-drug; converted to active form (prednisolone) Prednisolone Drug of choice for systemic administration Lower Na retaining effects Triamcinoline Halogenated GC Estrogens: Stronger anti-inflammatory than cortisol No Na retaining effect Betamethasone, Dexamethasone: 30x more potent than cortisol, no water or Na retaining effects Estrone Produced from andgrogen precursors Estradiol=primary estrogen in human, breast devel, bone density, growth of uterus, increase HDL, etc., no oral admin (1st pass hepatic elim) Estriol Estriol only during pregnancy Ethinylestradiol Most widely used Induce expression of progesterone receptors, Progesterone inhib expression of estrogen receptors Diethyl-Stilbestrol Oral contraceptive Raloxifene Indicated for postmenopausal osteoporosis, Selective estrogen receptor modifier (SERM), Anti-estrogenic effect on breast and endometrium, Estrogenic effect on bone and lipid metabolism Mestranol Oral contraceptives, prodrug Estradiol Tamoxifene (antiestrogen) Indicated for breast cancer anti-estrogenic effect on breast tissue weak effect on bone and lipid metabolism Progesterones: Progesterone Inhibits rhythmic contractions of myometrium, not for oral admin (1st pass elim) Hydroxyprogesterone Stable derivatives Medroxyprogesterone Progesterone Norethindrone Norgestrel Desogestrel Anti-Progesterones Mifepristone Testosterone Nandrolone (banned) Testosterone derivatives with progesterone activity 1980s French company, found that it blocks progesterone receptors, induces abortion Addition of small doses of prostaglandin analogue few days later stimulates uterine contractions=very efficacious for termination of pregnancy Responsible for both anabolic and androgenic effects Rapidly metabolized by the liver. -ester derivatives increases its half-life Strong anabolic effects, Injection only Stanozolol (banned) Strong anabolic effects (Not a β blocker!) Oral admin Combination Pills Mini Pill Highly effective, Estrogen component: Ethinylestradiol, Progesterone component varies Biphasic preparation – includes progesterone break after 7 day break Monophasic preparation – no progesterone break (but [progesterone] varies throughout cycle) Less reliable than combination pills Contains only progesterone, used when estrogen is contraindicated Contraception mechanism relies mainly on increased mucus viscosity. -mucolytic agents (cough medications) may cause contraception failure Morning After Pill Levonorgestrel High dose of progesterone Must be taken within 72 hours of sexual intercourse Dephenhydramine (Benadryl) H1 antagonists (antihistamine), 1st generation Indicated for seasonal and skin allergies Dimenhydrinate (Dramamine) Anti-emetic Also blocks mAChRs Doxyamine (Nyquil) H1 antagonist, 1st generation Most potent OTC sedative (better than barbiturates) Same efficacy as diphenhydramine in terms of anti-allergies Clemastine Chlorpheniramine 1st generation H1 antagonist Also anti-depressant (inhib serotonin uptake) Meclizine Antiemetic (less drowsiness) Hydroxyzine Antihistamine due to metabolite Cetrizine 2nd generation H1 antagonist Loratadine No entry to CNS, no drowsiness T ½=8 hr Desloratadine Longer T ½ Fexofenadine Highly selective for H1 receptor Cromolyn Nedocromil Montelukast (Singulair) Mast cell stabilizer Prevents asthma, does not stop attack Prevents mediator release from mast cells Inhalation or eye drops Leukotriene Receptor Blockers Prevents exercise and aspirin-induced asthma Antagonist of LTD4 at cysteinyl LT receptor Zileuton (Zyflo) 5-Lipoxygenase Inhibitor Prevents production of all leukotrienes Not useful for treatment of attacks Barbiturates General inhibition of the CNS w/ sedative-hypnotic actions 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. Alsoblocks excitatory glutamate receptors phenobarbital Barbituates epilepsy (phenobarbital) and anesthesia thiopental induction (thiopental) Side effects/Risks: Amobarbital high risk of dependence (severe/lethal Pentobarbital withdrawal symptoms) Secobarbital may lead to cardio-respiratory depression potent inducers of P450 enzymes; drug interactions (contraceptives, etc.) Benzodiazepines Seven-membered ring fused to aromatic ring, Selective activates GABA receptor Chlordiazepoxide, Diazepam, operated Cl channels, Increase affinity of Lorazepam, Flunitrazepam, Alprazolam, GABA for rec., Treat Anxieties, fewer Triazolam side effects than barb., anterograde amnesia MAO Inhibitors as Antidepressants Tranylcypromine Phenelzine Increase norepinephrine, serotonin, and dopamine (prevents metab) Side effects high Food-drug interaction: cheese SSRIs Fluoxetine Paroxetine Sertraline Clotalopram Increase serotonin levels by preventing neuronal reuptake Same efficacies as TCAs, fewer side effects Inhib sexual climax, can cause aggression Tricyclic Antidepressants Imipramine Desipramine Clomipramine… Increase norepinephrine and serotonin by preventing neuronal reuptake, strong interaction with alcohol. Sedation=side effect Phenothiazines Treat Schizophrenia 1st gen: neuroleptic Block dopamine receptor on post synaptic vesicle, Cause acute dystoni, akathesia, tardive dyskinesia, sedation, dry mouth, lactation, interaction with alcohol Butyrophenones Clozapine Olanzapine L-dopa (Levodopa) Carbidopa Atypical Neuroleptics (2nd gen) Inhibit 5-HT and D2 receptors, act mostly on limbic system, not in striatum (fewer side effects) Treat Parkinsons Disease Metabolic precursor of dopamine, often combined with Carbidopa (LDOPA decarboxylase inhib). Increases amt of LDopa that reaches the brain Bromcriptine Pergolide Dopamine Agonists Similar to L-dopa D2 agonists, treat Parkinsons Pramipexole Selegiline Atropine Inhib of MAOb, extends half-life of dopamine, Indirect dopamine agonists, Treats Parkinsons, also antidepressant Muscarinic acetylcholine receptor antagonist. Reduces cholinergic signals in the CNS (responsible for stimulating GABA output suppressing the thalamus) No longer used for Parkinson’s disease Phenytoin Ethosuximide Blocks voltage gated Na channels that are in the inactivated state, preferentially blocks high frequency discharges. (usedependent inhibition) (does not elevate seizure threshold, limits the propagation and spread of seizure), Zero order kinetics, Indicated for convulsive seizures, Side Effect: hyperplasia Treats Epilepsy, inhib of ca channels, Etho=blocks T-type channels, drug of choice for absence seizures Valproate Val=mech unclear, good for convulsive and absence seizures Hepatotoxic Disulfuram Naltrexone Thiopental (barbiturate) Propofol Ketamine Treats alcholoism inhibits aldehyde dehydrogenase; leading to acetylaldehyde accumulation causing “hang-over” -also blocks the conversion of dopamine to NE, rise in dopamine levels causes schizophrenic symptoms Treats Alcoholism opiod receptor antagonist; inhibiting the reward response that normally results for alcohol consumption IV anesthetic Rapid onset with high lipid solubility (accumulates in fat); slow recovery Narrow therapeutic range No analgesic effect IV anesthetic Rapidly metabolized for quick recovery. Used for same-day surgery IV anesthetic Phencyclidine (PCP) analogue; may cause hallucinations during recovery Have both anesthetic and analgesic properties -often used in veterinarian medicine and in tranqulizers Midazolam Ether Nitrous Oxide Haloethanes Enfluran Isofluran Desfluran IV anesthetic Benzodiazepine. Very short-acting. Have all benzodiazepine properties, often used for anesthesia induction Obsolete Slow onset and recovery Post operative nausea, vomiting Low potency (must be combined with other agents to achieve anesthesia) Rapid induction and recovery Both anesthetic and analgesic properties 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) High potency anesthetic; similar to haloethanes Fewer side effects because less metabolized by liver. Morphine Codeine Dextromethrophan Heroin 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) Pro-drug, that is converted into morphine by CYP2D6. CYP2D6 inhibitors may reduce codeine efficacy, Genetic polymorphism may also explain codeine resistance Little euphoric effect, so low risk for addiction.Used as an anti-tussive (cough suppressant) Synthetic morphine derivative that does not act thru opioid receptors. Same efficacy as codeine No GI or analgesic effect 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 Meperidine Indicated for chronic pain. Addicts chew thru the slow release formulation to obtain immediate release to mimic heroin rush Similar to morphine, but shorter duration. Used during labor. Similar to morphine, but much longer duration. Used to treat morphine/heroin addiction Methadone Fentanyl Naloxone High potency. Can be used transdermally. Short-lasting. Used in anesthesia and patient controlled infusions. Opiate Antagonist Short-acting competitive antagonist used to rapidly reverse opioid induced analgesia and respiratory suppression Naltrexone Opiate Antagonist Long-acting competitive antagonist Used to protect detoxified addicts from relapsing Cocaine -contains ester bond; rapidly metabolized by non-specific esterases in the plasma -cocaine’s 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 Classification of Antibiotics Cell wall synth inhib Protein synth inhib Folate antagonists Quinolones Penicillins Cephalosporins Carbapenems Monbactams Vancomycin, Bacitracin All Beta-Lactam Antibiotics Benzylpenicillin Phenoxymethylpenicillin Penicillins, cell wall synth inhib Inhibit transpeptidase, cant make cell wall Beta-lactamase sensitive Narrow spectrum Phenoxy has better oral avail G+ bacteria Methicillin Oxacillin Cloxacillin Dicloxacillin Narrow spectrum, b-lactamase resistant Cell wall synth inhib G+ bacteria Methicillin=poor oral avail Oxacillin=good oral avail Ampicillin Broad spectrum, penicillinase sensitive Cell wall synth inhib Amp=good oral avail, G+ and G-, entero Amox=excellent oral avail Amoxicillin Carbenicillin Ticarcillin Mezlocillin Pipercillin Cefazolin Cephalexin Extended spectrum, b=lactamase sensitive, cell wall synth inhib Carb=poor oral avail, G+ and G-, pseudomonas, Klebsiella B-lactamase sensitive Cell wall synth inhib st 1 generation cephalorsporins Cross allergies with pen. G+ bacteria Cefaclor Cefamandole 2nd generation Cephalosporins B-lactamase sensitive Cell wall synth inhib Some G-, mostly G+ Cefoxitin Clavulanic Acid Sulbactam Vancomycin Bacitracin Aminoglycosides Tetracyclins Macrolides Chloramphenicol Clindamycin Gentamicin Tobramycin Streptomycin Neomycin Kanamycin Amikacin B-lactamase inhib, cell wall synth inhib Irreversible inhib, good oral absorption Often combined with amoxicillin or ticarcillin Cell wall syth inhib Vanc=only effective against G+, poor oral absorption, used to treat GI infections Bacitracin=mixture of polypeptides, serious nephrotoxicity Protein synth inhib Inhibit either 30s or 50s ribosomal unit Drugs need to enter bacteria (point of resistance) Aminoglycosides (protein synth inhibitors) Tetracycline Oxytetracycline Minocycline Doxycycline Erythromycin Azithromycin Clarithromycin Chloramphenicol Clindamycin Tetracyclines, energy dependent transport, oral absorption impaired by food (antacids, Ca) Incorp into teeth and bones=staining, causes photosensitivity Broad spectrum antibiotics Macrolides Narrow spectrum, good alternative for patients with allergy to pen, few side effects Azi=long T ½ , convenient 6 pills regimen Clarith=used for H. pylori infection Protein synth inhib Chlor=broad spectrum, severe side effects, reserved for life threatening situations Clind=medium broad spectrum, treat pen resistant cocci Side effect=collitis Sulfonamides Sulfadiazine Sulfadimidine Sulfamethoxazole Trimethroprim Folate antagonist, blocks folate synth=blocked replication Structural analogues of PABA Competes with folates fro Dihydrofolatereductase (folate antag), Similar to sulfonamides, combined with Sulfomethoxazole Treat UTIs Quinolones Nalidixic acid Ciprofloxacin …floxacin Inhibit DNA-Gyrase (Topoisomerase II), very broad spectrum, bactericidal, usually fluorinated (Fluoroquinolones)