Cholinergic Pharmacology Receptors: Muscarinic: SA Node => HR SLUD/SCUD Renal/mesenteric beds => vasodilate (not enervated) GI => peristalsis and secretions. eye => miosis (papillary constriction), lacrimation bronchoconstriction, sweating (sympathetic) Nicotinic: skeletal muscle, Nm => contraction Autonomic ganglia, Nn => depends on dominant tone of organ
Direct-Acting Cholinomimetics Non-selective agonists Acetylcholine carbachol Muscarinic Agonists Bethanecol Nicotinic Agonists Nicotine
Polar, short t1/2. At lower doses, works primarily at M-Rs in SA node & renal/mesenteric beds. Not substrate for AChE, longer t1/2, polar. M-Rs primarily. No AChE, polar, negative chronotropy. Bronchoconstriction. glands. GI activity. SLUD/SCUD. Long exposure desens. & symp block. Acts at ganglionic Nn, action depends on predominant tone. Addictive due to dopamine from nucleus accumbens.
Indirect-Acting Cholinomimetics: Acetylcholinesterase Inhibitors At low doses, have effects only at M-Rs. Reversible Physostigmine CNS. Counter atropine toxicity. Neostigmine Polar. Some activity at NM-Rs. Used in Myasthenia Gravis & GI atony. Donepezil CNS. Alzheimer’s. Edrophonium Short t1/2, Dx of Myasthenia Gravis. Cholinergic Crisis: desensitization of N-Rs. Irreversible Isofluorphate Most are nerve gases or insecticides. Eye drops for glaucoma. Can cause cataracts and retinal detachment, see -antagonists. Cholinesterase Reactivator Pralidozime Reactivates P-ated AChE by competing for the P group. Cholinergic Receptor Blockers Muscarinic Antagonists Ganglionic Antagonists mydriasis, aggravate glaucoma. saliva, HR, block vagal baroreflex, GI tone, GI secretion. No effect on vessels. Hexamethonium Action depends on Rs at organ: BP in acute dissecting aorta. Atropine
NM blockers (comp) NM blockers (depol)
Tubocurarine Succinylcholine
Polar. Poison arrow frogs. Muscle relaxation. Synergistic w/ Ca channel blockers & general anesthetics. Surgery. Fasciculations followed by paralysis. Short t1/2. Relaxation before intubation. Anti-AChE synergize due to hydrolysis. Adrenergic Pharmacology
Receptors:
1: 2: 1: 2: DA:
peripheral blood vessels => vasoconstriction all adrenergic nerve terminals => inhibit NE release. SA node => HR myocytes => contractility bronchodilation skeletal muscle => vasodilate (triggered by hormonal epi, not enervated) renal/mesenteric => vasodilate side effects Arhythmias, stroke, anxiety, HA’s, palpitations. Not widely used. SE’s as above Arrhythmias, tachycardia, etc. Nausea, vomiting due to CTZ effects. Symp heart problems. Arrhythmias
Catecholamines Epinephrine Norepinephrine Isoproterenol Dopamine Dobutamine
Acts at 1 & 2, then 1. 1 & 1 only. 1 & 2 only. Low-dose: DA-Rs, some ’s. High-dose: All! Low-dose: 1 (contractility only) High-dose: 1, some 2 & 1
Non-catecholamine sympathomimetic amines -stimulators Phenylephrine Decongestant, dilate pupils, BP Phenylpropanolamine Diet pills, decongestant (PPA) Ephedrine Decongestant, pressor. Ephedrine ““ -stimulators Albuterol Bronchodilation (2), some 1 side effects. Terbutaline ““““““ CNS Amphetamine Releases NE from nerve terminals by displacement, diet. stimulants Methylphenidate Ritalin, ADHD. concentration. CV side effects
Xanthines
Caffeine, theophylline .
Inhibit breakdown of cAMP. CNS stimulation, HR, BP, cerebral vessels constricted, inh mast cell degranulation bronchodilation (tx asthma).
Anti-adrenergics -blockers Nonselective Selective BP (1). HR (2 in heart), pheochromocytoma (adrenal tumor), SE’s: postural hypotension, reflex tach. No ejaculation, nasal stuffiness. Prazosin Reversible, 1 selective. Tx HTN. SE: first-dose phenomenon: ortho hypoTN. Evoke Na & H20 retention. Phenoxybenzamine Irreversible, 1 specific, lasts 24 hrs, pheochromocytoma, BPH. SE’s as above, but less reflex tach. Phentolamine
-blockers (none are completely 1-selective, can see bronchospasm) NonPropranolol HR & CO (1), BP: net despite blocking 2 due to 1) Selective CO, 2) plasma renin, 3) sympathetic tone @ level of CNS Selective Atenolol Esmolol Relatively 1 selective As above w/ shorter t1/2.
SE: VLDL, HDL. airway resistance (2) erectile dysfunction, depression, insomnia. Don’t use in low renin populations (elderly, Africanamerican). Less danger of respiratory effects.
Presynaptic symp. inhibitory drugs Guanethidine Enters peripheral nerve terminal by NE reuptake pump, stabilizes membrane to exocytosis. SE: sex dysfxn, postural hypoTN. Reserpine Central & peripheral. Prevents uptake of amines into vesicles. Chewed up by MAO. SE: CNS, sedation, depression. 2-agonists: sympathetic outflow at level of CNS, inhibit NE release at peripheral presynapses. Clonidine Used in HTN. Opioid w/drawal symptoms , ADHD. SE: dizziness, libido, sedation, depression, poor adherence, w/drawal can ppt hypertensive crisis. MethylCentral. Metabolized to -methyl-NE, an 2 agonist. Low risk to SE: as above + Autoimmune response. DOPA fetus of hypertensive women.
Diuretics Osmotic Mannitol renal blood flow ( osmotic gradient), osmolality of filtrate.
Not absorbed orally Maintain flow in renal failure ICP or intraocular before surgery
Carbonic-Anhydrase Inhibitors Acetazolamide reabsorption of HCO3 in proximal tubule, H+ secretion. dorzolamide neg. ion in tubule inhibits Na & K reabsorption
Ind: Altitude sickness, urinary alkalinization for weak acid elimination. SE: HCO3 wasting, none for COPD, renal stones. Ind: topically in eye to IOP
Loop Diuretics: most efficacious. Inhibit NaK2Cl transporter of TAL. No K recycling means Mg & Ca reabsorption. osmotic gradient. Furosemide Also weak CA inhibitor Ethacrynic acid SE: ototoxicity Bumetanide Torsemide Active metabolite w/ longer t1/2 Ind: acute pulmonary edema, refractory edema of cardiac, hepatic, or renal origin. SE: Hypotension, electrolyte imbalance. Thiazides: act at DCT to block NaCl symporter, maintain osmotic gradient. Causes Ca reabs’n. Hydrochlorothiazide thiazide, tx HTN, CHF. First, SE: hypercalcemia, LDL, total chol, and triglycerides, arrhythmias, Impotence, volume, later resistence hypokalemia (use K sparer to minimize in heart conduction). Chlorthalidone Thiazide-like diuretics “ Metolazone “ “ Indapamide “ “
K sparing: Spironolactone
Metabolized to active drug, acts at
NaCl excretion, K secretion
CT, comp inh of aldosterone
Triamterene amiloride
Block CT Na channels “
Ind: given w/ thiazides or loops to prevent K loss, 20 hyperaldosteronism from CHF. SE: not for use w/ renal failure, gynecomastia, menstrual irregularities, hyperkalemia (w/ ACE inh’s). Ind: as above SE: in renal disease, hyperkalemia, acidosis & BUN, kidney stones “
Anti-Anginal Drugs Organic Nitrates Nitroglycerin cGMP to deP MLCK, vasodilates esp. venules. 1) systemic venules = preload which LV pressure 2) preload = tension in cardiac walls. 3) large epicardial vessels: small vessels autoregulate (no coronary steal) Isosorbide as above, longer t1/2 dinitrate
Tolerance, short t1/2, first pass SE: HA, dizzy, weak,
Ca-Channel blockers (good for HTN, angina, and arrhythmia in low-renin populations) Verapamil blocks L-type, relaxes arterioles, not veins. contractility, HR, AV conduction. diltiazem as above, non-specific inhibition of sympathetic NS. nifedipine Dihydropyridine, arteriodilates before contractility, reflex HR, contractility. nimodipine as above, high affinity for cerebral vessels,. Propranolol – see above Antihypertensives Vasodilators hydralazine
SE: cardiac depression, arrest, bradycardia, AV block, CHF. “ SE: as above, can risk of angina in pts w/ impaired heart fxn. “
relaxes arterial smooth mu,
SE: reflex HR, contr, renin, fluid retention. Often given w/ / blockers
minoxidil Nanitroprusside
causes hyperpolarizat’n, relaxat’n of arterioles. “Rogaine” topical hair growth metabolized to NO, see organic nitrates above.
as above SE: only modest HR, Ind: acute MI and HTN emergencies.
1 blockers, see prazosin above. Symp. inhibitors, see guanethidine & reserpine above. 2 agonists, see methyldopa & clonidine above. antagonists, see propranolol above. Ca channel blockers Amlodipine Dihydropyridine, verapamil, see above. diuretics, see hydrochlorothiazide (thiazide) & amiloride (K sparing) above. ACE inhibitors captopril angio II, aldosterone. No baro reflex. LV hypertrophy and MI. Slow progression of renal disease. Angiotensin II receptor antagonists losartan block Angio II effects aldo. No benefit in LV hypertrophy, HF, MI, or diabetics. SE: prolongs bradykinin dry cough. Contra: pregnancy, bilateral renal stenosis: GFR no bradykinin contra: pregnancy SE: reflex HR, contractility, etc.
Histamine/Antihistamines Histamine From L-His, degraded quickly by 1) imidazole-N-methyltransferase & mao 2) diamine oxidase. Stored heparin-bound in mast & basophils, need Na to release. ECL parietals acid. Bradykinin See above, and stimulates histamine release
R’s H1 H2 H3
site of action Vascular endothelium Sm muscle (lg vessels & bronchioles) Parietal cells Presynaptic
effect Ca Phospholipase A2 EDRF/NO & prostaglandins sm muscle relaxation BP Stim phospholipase C (DAG, IP3) Ca contraction. cAMP Ca H+ release into lumen transmitter (hist, NE, ACh, etc)
Non-receptor active antihistamines Cromolyn sodium Inhibits histamine release from mast cells
Ind: asthma
H1 blockers (best if given before allergic insult) Diphenhydramine Benadryl, Short t1/2, SE: anti-muscarinic dry mouth, GI SE’s, sedation, drowsiness, synergy w/ depressants. motion sick Dimenhydrinate Dramamine, “, “ SE: also anti-musc. Chlorpheniramine “ Slight sedation, OTC cold med’s. 1/2 Loratadine Claritin, longer t No anti-musc Fexofenadine Allegra, " “ H2 blockers Cimetidine (tagamet) Inh cyt P-450 & hepatic BF to drug clearance, rarely CNS & sexual SE’s Ranitidine (zantac) 4-10x more potent than above No drug metabolism inh’n. SE: suppress EtOH metabolism. Famotidine (pepcid) 20-160x more potent than cimet., None of above SE’s longer t1/2
Antimicrobial Agents Mex of resistance 1 Altered target sensitivity of target to drug, e.g. in PBP 2 Detox NZ’s inactivation of drug, e.g. -lactamase 3 uptake permeability or efflux of drug, e.g. tetracycline-R 4 conversion to active drug Loss of converting NZ 5 target Need more drug to inhibit, ED50 6 comp. substrate production of competitor, e.g. normal metabolite which drug action
Inh Nucleic Acid Synthesis Sulfonamides Analogues of pABA, inh dihydropteroate synthase inh folate synth in NZ, [pABA] Trimethoprim Analogue of DHF, inh DHFR, THF. Affinity for bacterial DHFR, not mammalian Inh DNA Synthesis Norfloxacin Blocks bacterial DNA gyrase subunit A (DNA breakage & resealing) Need high [drug] to inh mammalian topoisomerase Rifampin Has much higher affinity for bacterial RNA pol Binds -sub of RNA pol Flucytosine Metabolized by fungus to 5-FUFdUMP (inh DNA)& FUMP (RNA) in fungal converting NZ Inh Cell Wall Synthesis (mammals gots no cell walls) (cidal) cycloserine 1) blocks Ala racemaseno D-ala 2) blocks D-ala, D-ala synthetaseno dipeptide Vancomycin Inh peptidoglycan synthetase NZ adds disach units to growing cell wall Bacitracin Inh regeneration of lipid disach carrier Used topically only Penicillin Inh transpeptidase NZ crosslinks peptidoglycan chains via peptide bond formation, Rx activates murein hydrolase Cephalosporins “ “ , -lactam looks like D-ala-D-ala, binds irreversibly to transpeptidase, murein hydrolase Inh Protein Synthesis (different ribos) (all but strep are static) Streptomycin Binds to S12 in 70S complex, but cannot move along mRNA. Also disrupts membrane. Tetracycline Blocks charged tRNA from binding A-site Chloramphenicol Blocks charged tRNA from binding peptidyl transferase Erythromycin Blocks AP translocation, release of unfinished peptidyl tRNAs in Membrane Permeability Polymyxin Amphipathic, affects gram -, disrupts membrane Amphotericin B Binds fungal ergosterol to form pore. Nystatin Ketoconazole Inh fungal cyt P-450 lanosterol ergosterol, faulty cell membranes
Lethal due to irreversible blockade of protein synthesis. Rx-R if S12 is mutated. Only bugs have transporter CAT Rx-R: methylation, pumping out
SE: Somewhat toxic SE: mammals have cholesterol, selectivity not great