Alpha-Adrenergic Blockers Type of blockade Phenoxybenzamine – non-competitive; slow onset and long duration. 2-stage blockade. All the rest: competitive Selectivity Nonselective: Phenoxybenzamine and phentolamine alpha-1 selective: Prazosin, terazosin, others alpha-2 selective: Yohimbine alpha/beta blockers: Labetalol Others: phenothiazines, tricyclic antidepressants

Phenoxybenzamine Prazosin Yohimbine

% Maximal Increase [Agonist], mg/kg EPI Receptors no longer available EPI + Phenoxybenzamine Phenoxybenzamine alone % Maximal Increase Decrease in the maximal efficacy of Epi due to a decrease in the number of receptors [Agonist], mg/kg

Pharmacological Effects -Phenoxybenxamine Cardiovascular system Blood pressure Cardiac Effects Organ Blood Flow Capillaries Central nervous system Respiratory system

Pharmacological Effects – cont’d Eye - miosis GI tract – Increased motility Urinary bladder – decreased tone in sphincter Metabolic effects – increased insulin secretion

Adverse effects Postural hypotension Tachycardia Sedation Nasal stuffiness Miosis Impotence (inhibits ejaculation) Exercise care in hypovolemic patients

Imidazoline derivatives - phentolamine Many other effects including: Parasympathomimetic Increased gastric acid secretion Cardiac stimulation Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreatic Coronary artery disease and peptic ulcer relative contraindication to it.

Alpha-1 selective blockers Prazosin Less cardiac stimulation since it preserves alpha-2 mediated negative feedback + other mechanisms Used in congestive heart failure and in hypertension but tolerance develops with time, maybe due to fluid retention. Adverse effects: First dose phenomenon. Favorable effect on plasma lipids: increase HDL/LDL ratio

BP Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate Before and After Prazosin ADR (µg/Kg) HR 0.1 1 10 100 500 BP 1 10 100 500 +PRAZOSIN

Alpha-2 selective blockers Yohimbine Cardiovascular effects – peripheral and central effects Blocks other receptors also – serotonin, dopamine Increases ADH release Enhances sexual activity – aphrodisiac Potential uses: depression, obesity, NIDDM

Ergot alkaloids Interact with serotonin and dopamine receptors also Direct smooth muscle contraction Structure-activity relationships Coronary vasoconstriction Toxicity: GI, vascular insufficiency –ergotism Use in migraine and post-partum

Therapeutic Uses of Alpha-Adrenergic Blockers Hypertension - alpha-1 selective Conditions associated with increased sympathetic activity – e.g. pheochromocytoma Hemodynamic shock Peripheral vascular disease – Raynaud’s Congestive heart failure Benign prostatic hyperplasia Pulmonary hypertension – tolazoline Yohimbine or intracavernous phentolamine+papaverine for impotence