Sympatholytic pharmacology Selective vs. Non-selective Antagonist vs. Partial Agonist Reversible vs. Irreversible

Receptor agonists activate signal transduction pathways 2 N Norepinephrine NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response a1 adrenergic receptor

Receptor antagonists block agonist binding to the receptor 2 N Norepinephrine Antagonist NH 3 Phospho - G lipase C q What effect would an antagonist alone have on receptor activation? COOH

Clinical pharmacology of a-adrenergic receptor antagonists Route of Drug Receptor admin. Clinical uses Phenoxybenzamine a , a Oral Pheochromocytoma, hypertensive crisis 1 2 Phentolamine a , a Parenteral Pheochromocytoma, hypertensive crisis, 1 2 male impotence Prazosin a Oral Hypertension, benign prostatic 1 hypertrophy Terazosin a Oral Hypertension, benign prostatic 1 hypertrophy Doxazosin a Oral Hypertension, benign prostatic 1 hypertrophy Side effects of a1 receptor antagonists: Orthostatic hypotension, inhibition of ejaculation, nasal stuffiness, tachycardia

Non-selective adrenergic receptor antagonists b-Haloalkylamines R= aromatic, alkyl X= Cl-, Br-, etc.

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 Phenoxybenzamine (Dibenzyline)

Non-selective adrenergic receptor antagonists b-Haloalkylamines: Mechanism of receptor inactivation receptor alkylated receptor

Non-selective adrenergic receptor antagonists Imidazolines 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 Phentolamine (Regitine)

Reversible vs. Irreversible receptor blockade 1 M Phent 1 M Phenox 10 M Phenox 10 M Phent + Phentolamine + Phenoxybenzamine

a1-adrenergic receptor antagonists “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

Other a adrenergic receptor antagonists Ergot alkaloids 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

a2-adrenergic receptor antagonists 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 Yohimbine (Yocon)

b-adrenergic receptor antagonists Aryloxypropanolamines Note: non-carbon atom in side chain

b-adrenergic receptor antagonists Non-selective Lipophilic Local anesthetic properties Blockade is activity-dependent P r o p r a n o l o l ( I n d e r a l )

b-adrenergic receptor antagonists 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 P r o p r a n o l o l ( I n d e r a l ) Therapeutic uses for b-adrenergic receptor antagonists: Hypertension, angina, cardiac arrhythmias, migraine, stage fright, thyrotoxicosis, glaucoma, congestive heart failure (types II and III)

Non-selective b-adrenergic receptor antagonists Less lipophilic than propranolol Long half-life: ~20 hours Mostly excreted unchanged in urine Administered: Oral Uses: Hypertension, angina, migraine Nadolol (Corgard) Thiadiazole nucleus with morpholine ring Administered: Oral, Ophthalmic Uses: Hypertension, angina, migraine, glaucoma Timolol (Timoptic, Blocadren) How will -blockers affect pupil size?

Non-selective b-adrenergic receptor antagonists Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral Uses: Hypertension, angina, migraine Pindolol (Visken) What would a pindolol dose-response curve look like?

Dose-Response Curves and Partial Agonists NE NE + Pindolol Pindolol % NE + Propranolol

Non-selective b-adrenergic receptor antagonists Possesses “Intrinsic sympathomimetic activity (ISA) Partial agonist Less likely to cause bradycardia and lipid abnormalities Administered: Oral, Opththalmic Uses: Hypertension, glaucoma

Selective b1-adrenergic receptor antagonists “Cardioselective” Less bronchconstriction Moderate lipophilicity Half-life: 3-4 hours Significant first-pass metabolism Administered: Oral, parenteral Uses: Hypertension, angina, antiarrhythmic, congestive heart failure

Selective b1-adrenergic receptor antagonists “Cardioselective” Less bronchconstriction Low lipophilicity Half-life: 6-9 hours Administered: Oral, parenteral Uses: Hypertension, angina Atenolol (Tenormin)

Selective b1-adrenergic receptor antagonists 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 Esmolol (Brevibloc)

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome

Effect of chronic b-receptor blockade Na+ Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine Action Potential H+ MAO DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

Effect of chronic b-receptor blockade: Receptor up-regulation Na+ Tyrosine Na+ Dopamine Tyrosine Action Potential H+ MAO DA NE NE Ca2+ Uptake 1 Na+, Cl- NE NE NE NE Effector organ

Side effects of b-blockers: Bradycardia, AV block, sedation, mask symptoms of hypoglycemia, withdrawal syndrome Contraindications: Asthma, COPD, congestive heart failure (Type IV)

Mixed adrenergic receptor antagonists Non-selective b receptor antagonist a1 receptor antagonist Two asymmetric carbons (1 and 1’) (1R, 1’R)-isomer possesses b-blocking 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 Labetalol (Normodyne, Trandate)

Mixed adrenergic receptor antagonists Carvedilol (Coreg) Non-selective b receptor antagonist a1 receptor antagonist Both enantiomers antagonize a1 receptors Only (S)-enantiomer possesses b-blocking activity b-blocking activity prevents reflex tachycardia normally associated with a1 receptor antagonists Administered: Oral Uses: Hypertension, congestive heart failure (Types II and III)

1 2 3 Pharmacologic manipulation of the adrenergic system Na+ Presynaptic neuron Tyrosine Na+ 1 Dopamine Tyrosine 2 Action Potential H+ MAO DA NE NE Ca2+ Uptake 1 3 Na+, Cl- NE NE NE NE b Effector organ

Inhibition of norepinephrine synthesis C H 2 C H N H T Y R O S I N E 2 C O O H Metyrosine X t y r o s i n e h y d r o x y l a s e Inhibition of norepinephrine synthesis H O H O C H C H N H 2 2 D O P A C O O H a r o m a t i c L - a m i n o a c i d d e c a r b o x y l a s e H O H O C H C H N H D O P A M I N E 2 2 2 d o p a m i n e b - h y d r o x y l a s e H O H O C H C H N H N O R E P I N E P H R I N E 2 2 O H p h e n y l e t h a n o l a m i n e - H O N - m e t h y l t r a n s f e r a s e H O C H C H 2 N H E P I N E P H R I N E O H C H 3

Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Tyrosine Reserpine Guanethidine Action Potential H+ MAO NE NE Ca2+ NE Guanethidine, Bretylium Guanethidine b Effector organ

Catecholamine depleters Reserpine (Serpasil) Indole alkaloid obtained from the root of Rauwolfia serpentina Block vesicular monoamine transporters Deplete vesicular pool of NE Slow onset of action Sustained effect (weeks) Used in the treatment of hypertension May precipitate depression

Drugs that reduce storage or release of NE 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 Guanethidine (Ismelin)

Drugs that reduce storage or release of NE Na+ Tyrosine Na+ Dopamine Guanethidine Tyrosine Action Potential H+ MAO NE NE Ca2+ NE Guanethidine, Guanethidine b Effector organ

Drugs that reduce storage or release of NE 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)