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MCMP 407 Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible MCMP 407 Receptor agonists activate signal transduction pathways HO NH3 HO CH CH2 NH2 OH Norepinephrine a1 adrenergic receptor (+) Phospho- Gq lipase C PIP2 COOH IP3 Diacylglycerol Increase Ca2+ Activate Protein Kinase C Response MCMP 407 Receptor antagonists block agonist binding to the receptor HO HO Antagonist CH CH2 NH2 OH NH3 Norepinephrine Gq What effect would an antagonist alone have on receptor activation? COOH Phospholipase C MCMP 407 Clinical pharmacology of a-adrenergic receptor antagonists Drug Phenoxybenzamine Phentolamine Route of Receptor admin. Clinical uses a1, a2 a1, a2 Prazosin a1 Terazosin a1 Doxazosin a1 Oral Pheochromocytoma, hypertensive crisis Parenteral Pheochromocytoma, hypertensive crisis, male impotence Oral Hypertension, benign prostatic hypertrophy Oral Hypertension, benign prostatic hypertrophy Oral Hypertension, benign prostatic hypertrophy Side effects of a1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia MCMP 407 Non-selective adrenergic receptor antagonists b-Haloalkylamines R N CH2 CH2 R R= aromatic, alkyl X= Cl-, Br-, etc. X MCMP 407 Non-selective adrenergic receptor antagonists b-Haloalkylamines Non-selective a receptor antagonist Also blocks acetylcholine, histamine, and serotonin receptors Irreversible antagonist resulting from covalent modification of receptor CH3 O N Cl Phenoxybenzamine (Dibenzyline) MCMP 407 Non-selective adrenergic receptor antagonists b-Haloalkylamines: Mechanism of receptor inactivation R R R Cl- R N N R R Cl- R N N Nu Cl Aziridinium ion R receptor Nu alkylated receptor MCMP 407 Non-selective adrenergic receptor antagonists Imidazolines HO N N CH2 N H H3 C Phentolamine (Regitine) Non-selective a receptor antagonist Competitive (reversible) blocker Potent vasodilator, but induces pronouced reflex tachycardia Block of presynaptic a2 receptors may promote release of NE Also blocks 5-HT receptors, and is a muscarinic and histamine receptor agonist MCMP 407 1 M Phent 100 50 10 M Phent a 1 Adrenergic receptor activation a 1 Adrenergic receptor activation Reversible vs. Irreversible receptor blockade 100 1 M Phenox 50 10 M Phenox 0 0 -10 -8 -6 -4 Log [Norepinephrine] + Phentolamine -10 -8 -6 -4 Log [Norepinephrine] + Phenoxybenzamine MCMP 407 a1-adrenergic receptor antagonists O Quinazoline ring N H3CO N N N Piperazine ring H3CO NH 2 Prazosin: R = (Minipres) Terazosin: R = (Hytrin) R Acyl moiety O O O Doxazosin: R = (Cardura) O “Quinazolines” Vary in half-life: Prazosin 3 hrs Terazosin 12 hrs Doxazosin 20 hrs Undergo extensive metabolism, excreted mainly in the bile Vasodilators Relaxation of smooth muscle in enlarged prostate and in bladder base “First-dose” effect MCMP 407 Other a adrenergic receptor antagonists Ergot alkaloids O R' N O N R O NH O NCH3 N H Derivatives of Lysergic Acid Product of the grain fungus Claviceps purpura 5 Major alkaloids based on R and R’; Ergotamine the most common Used in the treatment of migraine Ergots possess strong oxytocic action MCMP 407 a2-adrenergic receptor antagonists N N H H H H H3CO2C Yohimbine (Yocon) OH Indole alkaloid Found in Rubaceae and related trees. Also in Rauwolfia Serpentina. Blockade of a2 receptors increases sympathetic discharge Folklore suggests use in the treatment of male impotence MCMP 407 b-adrenergic receptor antagonists Aryloxypropanolamines Note: non-carbon atom in side chain O Ar NH R OH Ar = aromatic ring structure R = bulky alkyl group (isopropyl or tert-butyl) MCMP 407 b-adrenergic receptor antagonists CH3 CH O N H OH CH3 Propranolol (Inderal) Non-selective Lipophilic Local anesthetic properties Blockade is activitydependent MCMP 407 b-adrenergic receptor antagonists CH3 CH O N H OH Propranolol (Inderal) CH3 Pharmacological effects Decreased cardiac output and heart rate Reduced renin release Increase VLDL, Decrease HDL Inhibit lipolysis Inhibit compensatory glycogenolysis and glucose release in response to hypoglycemia Increase bronchial airway resistance Therapeutic uses for b-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III) MCMP 407 Non-selective b-adrenergic receptor antagonists CH3 CH O N H HO CH3 OH HO Nadolol (Corgard) CH3 C O N H O CH3 CH3 OH N N N S Timolol (Timoptic, Blocadren) Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine Thiadiazole nucleus with morpholine ring Administered: Oral, Ophthalmic Uses: Hypertension, angina, migraine, glaucoma How will b-blockers affect pupil size? MCMP 407 Non-selective b-adrenergic receptor antagonists CH3 CH O N H OH CH3 N H Pindolol (Visken) Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral Uses: Hypertension, angina, migraine What would a pindolol dose-response curve look like? MCMP 407 NE 100 100 % Inhibition of %NE Response b 1 Adrenergic receptor activation Dose-Response Curves and Partial Agonists Pindolol 50 0 -10 -8 -6 Log [Drug] -4 NE + Pindolol 50 0 NE + Propranolol -10 -8 -6 Log [Drug] -4 MCMP 407 Non-selective b-adrenergic receptor antagonists CH3 O OH O N C CH3 H CH3 N H Carteolol (Cartrol, Ocupress) Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma MCMP 407 Selective b1-adrenergic receptor antagonists O OH CH3 CH N CH3 H R Metoprolol (Lopressor, Toprol) R= CH2 O CH3 CH3 Bisoprolol (Zebeta) CH R= O CH2 CH2 O CH3 “Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic, congestive heart failure MCMP 407 Selective b1-adrenergic receptor antagonists CH3 CH O N H CH3 OH NH 2 O Atenolol (Tenormin) “Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina MCMP 407 Selective b1-adrenergic receptor antagonists CH3 CH O N H CH3 OH O O CH3 Esmolol (Brevibloc) Very short acting Half-life: 9 minutes Rapid hydrolysis by esterases found in red blood cells Administered: Parenteral Note: incompatible with sodium bicarbonate Uses: Supraventricular tachycardia, atrial fibrillation/flutter, perioperative hypertension MCMP 407 Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome MCMP 407 Effect of chronic b-receptor blockade Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine Action Potential H+ DA NE NE Uptake 1 NE NE NE Effector organ NE MCMP 407 Effect of chronic b-receptor blockade: Receptor up-regulation Tyrosine Na+ Dopamine Tyrosine Action Potential H+ DA NE NE Uptake 1 NE NE NE Effector organ NE MCMP 407 Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Contraindications: Asthma, COPD, congestive heart failure (Type IV) MCMP 407 Mixed adrenergic receptor antagonists OH 1 H N 1' CH3 HO CONH 2 Labetalol (Normodyne, Trandate) Non-selective b receptor antagonist a1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses bblocking activity (1S, 1’R)-isomer possesses greatest a1 receptor blocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral, parenteral Uses: Hypertension, hypertensive crisis MCMP 407 Mixed adrenergic receptor antagonists OCH3 O O N H OH N H Carvedilol (Coreg) Non-selective b receptor antagonist a1 receptor antagonist Both enantiomers antagonize a1 receptors Only (S)-enantiomer possesses bblocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure (Types II and III) MCMP 407 Pharmacologic manipulation of the adrenergic system Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2 Action Potential H+ DA NE NE Uptake 1 NE NE 3 NE Effector organ NE b MCMP 407 HO CH2 CH NH2 TYROSINE COOH Inhibition of norepinephrine synthesis HO X tyrosine hydroxylase Metyrosine HO CH2 CH NH2 DOPA COOH aromatic L-amino acid decarboxylase HO HO CH2 CH2 NH2 DOPAMINE dopamine b -hydroxylase HO HO CH CH2 NH2 NOREPINEPHRINE OH phenylethanolamineN-methyltransferase HO HO CH OH CH2 NH CH3 EPINEPHRINE MCMP 407 Drugs that reduce storage or release of NE Tyrosine Na+ Dopamine Reserpine Guanethidine Tyrosine Action Potential H+ NE NE NE Guanethidine, Bretylium Effector organ Guanethidine b MCMP 407 Catecholamine depleters N H3CO N H H H O OC H H3CO2C OCH3 Reserpine (Serpasil) Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE OCH3 OCH3 OCH3 Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension May precipitate depression MCMP 407 Drugs that reduce storage or release of NE H N N C NH 2 NH Guanethidine (Ismelin) Possess guanidino moiety (pKa > 12) Resonance stabilization of cation “spreads” positive charge over the entire four atom system Almost completely protonated at physiological pH “Pharmacologic sympathectomy” Effects can be blocked by transport blockers Uses: Hypertension MCMP 407 Drugs that reduce storage or release of NE Tyrosine Na+ Dopamine Tyrosine Guanethidine Action Potential H+ NE NE NE Guanethidine, Effector organ Guanethidine b MCMP 407 Drugs that reduce storage or release of NE CH3 CH N CH2CH3 O3S CH3 Br Bretylium tosylate (Bretylol) Aromatic quaternary ammonium Precise mechanism unknown Displace and release NE and prevent further release (depletion) Local anesthetic Administered: Parenteral Uses: Antiarrhythmic (ventricular fibrillation) CH3