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 (contd)
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 n can be overcome by increased conc 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 (membranestabilizing 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:
b 2 -selective:

metoprolol, atenolol
butoxamine

The End