Adrenergic Antagonists

α-Adrenergic Blocking Agents Affect BP-------decreased PVR------- reflex tachycardia

Phenoxybenzamine Nonselective, irreversible, noncompetitive Decrease PVR ----- reflex tachycardia α2 block--------- increased CO ????? Pretreatment with phenoxybenzamine followed by Epi??? Used in Pheochromocytoma (before surgery or inoperable tumor) & in Raynaud disease SEs: postural hypotension, nasal stuffiness, NV, sexual disturbances, & reflex tachycardia

Phentolamine Competitive, nonselective α-blocker (4 hrs) Postural hypotension Reflex cardiac stimulation CI in patients with coronary artery disease Used locally to prevent T necrosis Used for short term treatment of Pheochromacytoma Useful in hypertensive crisis due to clonidine abrupt withdrawal & in (tyamine + MAOIs)

Prazocin, Terazocin, Doxazocin, Tamsulosin, Alfuzocin Selective, competitive α1-blockers useful in hypertension Tamsolosin & alfuzocin used in benign prostatic hyperplasia (BPH) Metabolized & excreted in urine except for doxazocin Doxazocin have long duration of action Decreases PVR, BP (venous & arterial effect) Minimum effect on CO, RBF, & glomer. Filtration rate Tamsulosin has the least vascular effect (α1B) & higher effect on prostate (α1A)

α-blockers cont. 1st dose effect Modest improvement in lipid profile & glucose metabolism in hypertension SEs: dizziness, lack of energy, headache, orthostatic hypotension, Floppy iris syndrome α-blockers + vasodilators (ex. Nitrates or PDEIs)??? Sexual dysfunction

Yohimbine Selective, copmetetive α2-blocker Treat erectile dysfunction Increases CNS sympathetic out flow CI in CVDs, psychiatric conditions & renal dysfunction

β-Adrenergic Blocking Agents Competetive, nonselective β1 & β2 Differ in intrinsic sympathomimetic activity, CNS effects, blockade of sympathetic Rs, vasodilation & kinetics Decrease BP No postural hypotension ??? Used in Hpertension, Angina, Arrhythmia, MI, HF, Hyperthyroidism, Glaucoma & prophylaxis of Migraine headache All cpds end with (– olol)

Propranolol (nonselective) CVS: Decrease CO, -ve inotropic, chronotropic, & AV & SA inhibition----- Decrease CO, workload, & oxygen consumption--------------- Useful in supravent. Arrhythmia but not in vent. arrhythmia Peripheral vasoconstriction(β2, reflex response Increase PVR ----- Reflex vasoconst.----- In Hypertensive patients, total PVR return to normal ore below Gradual decreasae in syst. & diast. BP

Propranolol (cont.) Bronchoconstriction (precipitate COPD) Glucose metabolism (glycogenolysis, Glucagon) Prop. + Isoproterenol Prop + Epi ??? Prop + NE ???

Therapeutic uses: Hypertension (normotensive ???) Decrease CO Inhibit renin release from kidney Decrease total PVR Decrease sympathetic outflow Angina, (chronic management of stable angina) Myocardial infarction Prophylactic Immediate administration, …..? Reduce incidence of sudden arrhythmic death after MI Migraine (prophylactic, lipid soluble) Hyperthyroidism

Propranolol (cont.) Kinetics (absorption, metabolism, BBB) Adverse effects: Bronchoconstriction Arrhythmia (upregulation, ppt arrhythmia) Sexual impairment Metabolic disturbances: Glycogenolysis, glucagon ppt symptoms of hypoglycemia -----? Mobilize energy molecules ex. FFA(lipase activation, β2, β3 , bad, good cholesterol, selective β1 ) CNS effects (CNS dep., fatigue, weakness,------, selective β1 antag.)

Drug interaction Inhibitors: cimetidine, fluoxetine, paroxetine, and ritonavir Inducers: barbiturates, phenytoin, and rifampin

Nadolol, Timolol: non-selective β agents More potent than prop. Nadolol: long duration Timolol, betaxolol, carteolol------glaucoma (open-angle glaucoma, piloarpine???)

Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metaprolol, & Nebivolol Selective β1 antagonists Β1 selective, no bronchoconstriction (β2) This occurs at doses 50 – 100 fold less than β1 This effect disappear at high doses So SEs are predictable Used for hypertension & to increase exercise tolerance in angina Esmolol given IV, short duration of action??? Fewer effects on pulmonary system, PVR, & CHO metabolism ??? nevibolol releases NO from endothelial SMs------? Uses ???

Therapeutic uses:  hypertensive patients with impaired pulmonary function first-line therapy for chronic stable angina Bisoprolol and the extended-release formulation of metoprolol are indicated for the management of chronic heart failure Raynaud phenomenon) is less frequent???

Acebutolol, Pindolol: antagonists with Partial Agonist Activity Acebutolol β1 selective antagonist Pindolol nonselective β blocker With Intrinsic Sympathomimetic Activity (ISA)??? Diminished effect on heart Β blockers with ISA minimize disturbances in lipid & CHO metabolism compared with other β blockers Effective in hypertensive patients with bradycardia

Labetalol & Carvedilol: antagonists of both α & β adrenoceptors Labetalol, carvedilol: nonselective β-blocker with α1 blocking effect------ Decrease BP Carvedilol decrease lipid peroxidation, vascular wall thickening, so useful in HF Labetalol replaced methyldopa in pregnancy hypertension & used in hypertensive crisis (IV) SEs include orthostatic hypot. & dizziness

Clinical Uses of β-blockers

Drugs Affecting Neurotransmitter Reuptake or Release EMT: extraneuronal MAO transporter, NET: neuronal noradrenal;ine transporter

Drugs Affecting Neurotransmitter Release or Uptake Reserpine (plant alkaloid): Blocks Mg/adenosine triphosphate (biogenic amine transporter) Slow onset of action, long duration of action Used in hypertension replaced with newer drugs