Adrenoceptor Blockers Dumrongsak Pekthong M.Sc.(Pharmacology)

Wording Adrenoceptor Blocker Adrenergic Antagonist Subgroups in Sympathoplegic drugs Alpha Blocker, Alpha Antagonist Beta Blocker, Beta Antagonist

Objectives 1. Describe the effects of E and NE in the presence and in the absence of Alpha Blocker. 2. Compare the effects among Beta Blockers 3. Compare the pharmacokinetics among Beta Blockers 4. Describe the clinical applications and toxicity of typical Alpha- and Beta Blockers.

Outline I. Concepts II. Alpha-Blocking Drugs A. Classification B. Pharmacokinetics C. Mechanism of Action D. Effects

Outline II. Alpha-Blocking Drugs (cont’d) III. Beta-Blocking Drugs E. Clinical Uses F. Adverse Effects III. Beta-Blocking Drugs A. Classification and Mechanisms B. Effects and Clinical Uses C. Adverse Effects

I. Concepts Classification is based on receptor selectivity. These drugs differ markedly in their effects and clinical applications.

II. Alpha-Blocking Drugs A. Classification based on: selective affinity for alpha receptors, reversibility 1. Irreversible, long-acting alpha blockers 2. Reversible, short-acting alpha blockers 3. Alpha1-selective blockers 4. Alpha2-selective blockers

A. Classification 1. Irreversible alpha blockers : Phenoxybenzamine slightly a 1 -selective, long-acting 2. Reversible alpha blockers: Phentolamine (nonselective), tolazoline (slightly a 2 -selective) 3. a 1 blockers: Prazosin, Doxazosin, Terazosin 4. a 2 blockers: Yohimbine, rauwolscine used primarily in researches

B. Pharmacokinetics All active orally as well as parenterally Phenoxybenzamine: short t1/2 but long duration-48 hr (covalent bond) Phentolamine, tolazoline: parenteral, duration 20-40 min by parenteral route Prazosin: oral, duration 8-10 hr

C. Mechanism of Action Phenoxybenzamine: binds covalently--irreversible (insurmountable) blockade (slightly a 1 -selective) Other agents: competitive antagonists--the effects can be overcome by increased concn of agonist

D. Effects of Alpha Blockers 1. Nonselective alpha blockers block alpha-mediated sympathetic responses and exogenous sympathomimetics Most important effects: CVS effects vasodilation --reduce arterial and venous pressure (a 1 ) no significant direct cardiac effects

D. Effects of Alpha Blockers 1. Nonselective alpha blockers (cont) Cause reflex tachycardia (due to decreased MAP) Tachycardia may be exaggerated because a 2 receptors are also blocked. e.g. phenoxybenzamine, phentolamine, tolazoline

D. Effects of Alpha Blockers 2. Selective a 1 blockers The same effects as nonselective alpha blockers But cause much less tachycardia than nonselective blocker e.g. Prazosin, Doxazosin, Terazosin

Epinephrine Reversal occur when alpha blockers are given before Epi ---> Epi produce the opposite effects : decreased BP resulting from b 2 effect (a 1 ,a 2, b 1 ,b 2 )

Antagonistic effect of alpha blocker on pretreatment with alpha agonist

E. Clinical Uses 1. Nonselective alpha-blockers Presurgery of pheochromocytoma: phenoxybenzamine During surgery: phentolamine (sometimes) Carcinoid tumor: phenoxybenzamine (5-HT blocking) Mastocytosis: phenoxybenzamine (H1 antihistamine) Accidental local infiltration of alpha agonist: phentolamine Overdose of sympathomimetics (amphetamine, cocaine, phenylpropranolamine) Raynaud’ s phenomenon, erectile dysfunction (phentolamine)

E. Clinical Uses 2. Selective a 1 -blockers Prazosin and others Essential Hypertension Urinary hesitancy Prevention of urinary retention in benign prostatic hyperplasia (BPH)

F. Adverse effects of Alpha blockers Orthostatic hypotension (venodilatation) Reflex tachycardia (nonselective > selective) First dose hypotension (take before going to bed) Nausea/vomiting Caution in patients with coronary artery disease (CAD or CHD): angina

III. Beta-Blocking Drugs A. Classification and Mechanisms All are competitive antagonists Propranolol is prototype Classification is based on Beta subtypes selectivity Partial agonist activity Lipid solubility Local anesthetic action

A. Classification and Mechanisms 1. Receptor selectivity b 1 -selective: metoprolol, atenolol b 2 -selective: butoxamine (research only) Nonselective: propranolol Combined beta- and alpha-blocking: labetalol

A. Classification and Mechanisms 2. Partial agonist activity Intrinsic sympathomimetic activity, ISA eg, pindolol, acebutolol may be useful in patients with asthma

A. Classification and Mechanisms 3. Local anesthetic activity (membrane-stabilizing activity): disadvantage when used topically in the eye timolol: no this activity 4. Lipid solubility responsible for CNS adverse effects: propranolol

Pharmacokinetics of Beta blockers For systemic effects, developed for chronic oral use Esmolol: short-acting--only used parenterally Nadolol: longest-acting Atenolol, acebutolol are less lipid-soluble

B. Effects and Clinical Uses Predict from beta blockade decreased HR, force of contraction decreased A-V conduction slow firing rate of SA node Cardiovascular and ophthalmic applications are extremly important

B. Clinical Uses CVS: hypertension, angina pectoris, arrhythmia prophylaxis after MI, supraventricular tachycardias, hypertrophic cardiomyopathy, congestive heart failure* Glaucoma: reduce aqueous humor secretion (timolol)

B. Clinical Uses Migraine: propranolol Thyroid storm, thyrotoxicosis: propranolol Famillial tremor, other types of tremor, “stage fright” : propranolol

C. Adverse effects CVS: bradycardia, A-V blockade, congestive heart failure Patients with airway disease: asthmatic attack Mask sign of hypoglycemia in diabetic patients: tachycardia, tremor, anxiety CNS effects: sedation, fatigue, sleep alterations

Drug List Alpha-blockers Nonselective: phenoxybenzamine*, phentolamine* a 1 -selective: prazosin*, terazosin, doxazosin a 2 -selective: yohimbine

Drug List Beta-blockers Nonselective: propranolol*, timolol, nadolol Combined a - and b - blocking: carvedilol, labetalol b 1 -selective: metoprolol, atenolol b 2 -selective: butoxamine

The End