Adrenocept or Blockers

Dumrongsak PekthongM.Sc.(Pharmacology)

Wording• Adrenoceptor Blocker• Adrenergic Antagonist• Subgroups in Sympath

oplegic 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.

OutlineI. ConceptsII. Alpha-Blocking DrugsA. ClassificationB. Pharmacokinetics

C. Mechanism of Action

D. Effects

OutlineII. Alpha-Blocking Drugs (cont’d)E. Clinical UsesF. Adverse Effects

III. Beta-Blocking DrugsA. Classification and Mechanisms

B. Effects and Clinical Uses

C. Adverse Effects

I. Concepts• Classification is based on

receptor selectivity.• These drugs differ marke

dly in their effects and cli nical applications.

-II. Alpha Block ing Drugs

A. Classification– based on: selective affinity f

or alpha receptors, reversibility

1. Irreversible, -long acting alphh hhhhhhhh 2.Reversible, -short acting alpha blockers 3. Alpha

1-hhhhhhhhh hhhhhhhh

4. Al pha2

- selective blockers

A. Classification 1. Irreversible alpha blockers : hhhh

hhhhhhhhhhhh– slightly - selective, -long acting

2. :Reversible alpha blockers Phentolhhhhh hhhh(), (

ghtly 2 -) 3. : Prazosin hhhhhhhhh, , 4. 2 : hhhhhhhhh hhhhhhhhhhh,• used primarily in researches

B. Pharmacokinetics

• All active orally as well as parenterally

•Phenoxybenzamine : short t12/ bu

- t long duration 48 hr (covalent bond)• Phentolamine, tolazoline : parente

- ral, duration 20 40 min by parente ral route

•Prazosin - : oral, duration 8 10 hr

C. Mechanism o f Action

•h hhhhhhhhhhhh hhh : binds cova-- lently irreversible (insurmount

hhhhhhhh ) (slightly -selective)

•hhhhh hhhhhh : competitive antag-- onists the effects can be overc

ome by increased concn of agonist

D. Effects of Alp ha Blockers

1. Nonselective alpha blockers– - block alpha mediated sympathetic

responses and exogenous sympathomimetics– Most important effects: CVS effects• -- vasodilation reduce arterial and

venous pressure ( )• no significant direct cardiac effects

• Cause reflex tachycardia (due to decrease d MAP)

• Tachycardia may be exaggerated because2 receptors are also blocked.

• e.g. phenoxybenzamine, phentolamine, tolazoline

D. Effects of Alp ha Blockers

1. Nonselective alpha blockers (cont)

2. Selective hhhhhhhh

• The same effects as nonselective al pha blockers

• But cause much less tachycardia th an nonselective blocker

• e.g. Prazosin, Doxazosin, Terazosin

D. Effects of Alp ha Blockers

Epinephrine Reversal

occur when alpha blockers are given before Epi

---> Epi produce the opposite effects : decreased BP resulting from 2 effect

( ,22 )

hhhhhhhhhhhh hhhhhh hh hhhhh hhhhhhh hh hhhhhhhhhhhh hhhh h

hhhh hhhhhhh

E. Clinical Uses1. 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 -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 > selectiv

e) 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 MechanismsAll 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– -selective: metoprolol, atenolol

– 2 -selective: butoxamine (research only)– Nonselective: propranolol–Combined beta- and alpha-blocking: labetalol

A. Classification and Mechanisms2. Partial agonist activity –Intrinsic sympathomimetic activity, ISA–eg, pindolol, acebutolol–may be useful in patients with asthma

A. Classification and Mechanisms3. Local anesthetic activity (membrane-stabilizing activity):– disadvantage when used topicall

y in the eye– timolol: no this activity

4. Lipid solubility– responsible for CNS adverse effe

cts: propranolol

Pharmacokinetics of Beta blockers• For systemic effects, deve loped for chronic oral use

•Esmolol - --: short acting onl y used parenterally

•Nadolol -: longest acting• Atenolol, acebutolol are l

-ess 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 impo

rtant

B. Clinical Uses•CVS : hypertension, angina pector

is, arrhythmia prophylaxis after MI, supraventricular tachycardias

, hypertrophic cardiomyopathy, c ongestive heart failure*

•Glaucoma : reduce aqueous humo r secretion

(timolol)

B. Clinical Uses

• Migraine: propranolol• Thyroid storm, thyrotox

icosis: propranolol• Famillial tremor, other t

ypes of tremor, “stage f right” : propranolol

C. Adverse effects

•CVS - : bradycardia, A V blocka de, congestive heart failure

• Patients with airway disease : asthmatic attack• Mask sign of hypoglycemia in

diabetic patients: tachycardi a, tremor, anxiety

• CNS effects : sedation, fatigu e, sleep alterations

Drug ListAlpha-blockers–Nonselective: phenoxybenzamine*, phentolamine*– -selective: prazosin*, terazosin, doxazosin– 2 -selective: yohimbine

Drug ListBeta-blockers–Nonselective: propranolol*, timolol, nadolol

–Combined - and - blocking: carvedilol, labetalol

– -selective: metoprolol, atenolol

– 2 -selective: butoxamine

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