Adrenal Antagonist By Dr. Sara Sami

Yuzuncu Yil University

2015

Adrenoceptor Antagonist Drugs

Classification

– Alpha Antagonists

• Non Selective

• α1 Selective

• α2 Selective

– Beta Antagonists

• Non Selective

• β1 Selective

• β2 Selective

• Toxicity

Classification of adrenergic receptor antagonist.

Wording

• Adrenoceptor Blocker

• Adrenergic Antagonist

• Subgroups in Sympathoplegic drugs

• Alpha Blocker, Alpha Antagonist

• Beta Blocker, Beta Antagonist

General effects of α blockers

Blood vessels

• α1-blockade reduces peripheral resistance

Fall in BP

Postural hypotension

• α2-blockade in brain se vasomotor tone.

• Block pressor action of adrenaline, fall in BP due

toβ2.

action- “vasomotor reversal of Dale”

• Actions of selective α-agonists supressed.

Heart

• Reflex tachycardia due to:-

fall in mean arterial pressure

Blockade of presynaptic α2 receptors- ↑ NA release.

Nose: nasal stuffiness

Eye: miosis

GIT: intestinal motility se

Kidney: Hypotension

se GFR

NA+ & H2O reabsorption

Urinary bladder

• α1A blockade- se tone of smooth muscle in trigone,

sphincter & prostrate.

• Improved urine flow, used in BPH.

Reproductive system

• Contraction of vas deferens result in ejaculation

through α receptors.

• Blockade results in impotence.

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. a1-selective blockers

4. a2-selective blockers

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

used primarily in researches

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

Irreversible non-selective α- blockers

Phenoxybenzamine

• Cyclizes spontaneously to highly reactive

ethyleniminium intermediate.

• Binds covalently to α-receptors- irreversible or non-

equilibrium competitive block.

• Blockade is slow onset & longer duration (3-4 days).

• Also inhibits reuptake of NE.

• Shifts blood from pulmonary to systemic circuit.

• Shift fluid from extravascular to vascular compartment-

relaxation of postcapillary vessels.

Reversible alpha blockers

Yohimbine

• Natural alkaloid from Pausinystalia yohimbe.

• No established clinical role.

Idazoxan

• Has membrane stabilizing action.

Ergot alkaloids

• Ergotamine & Dihydroergotamine

• Competitive α-receptor blockers.

• Principal use is migraine.

Reversible, selective α1- blockers

Prazosin

• Highly selective α1-blocker , α1: α2 selectivity 1000:1

• Fall in BP with only mild tachycardia.

• Dilates arterioles more than veins

• Postural hypotension occurs as 1st dose effect,

minimized by starting with low doses at bed time.

• Also inhibits PDE- se cAMP in smooth muscle.

PK

• Effective orally, BA- 60%.

• Highly bound to plasma proteins (α1 acid

glycoprotein).

• Metabolized in liver, 1o excreted in bile.

• t1/2 – 2-3hrs, effect lasts for 6-8hrs.

Uses

• Primarily as antihypertensive.

• LVF not controlled by diuretics & digitalis.

• Raynaud’s disease

• BPH

• Scorpion sting

PK

• Preferred ROA- i.v.

• Lipid soluble penetrates brain.

• Mainly excreted through urine in 24 hrs.

• Accumulates in adipose tissue on ch. Administration.

Dose

20-60 mg/d oral

1mg/kg/1hr slow i.v infusion.

Uses

Pheochromocytoma, occasionally 2oshock, PVD.

Reversible non-selective α-blockers

Tolazoline

• Block is modest & short lasting.

• Direct vasodilator & stimulates the heart.

• Also blocks 5-HT receptors, histamine like gastric secretagouge & Ach like motor action on intestine.

SE

• N, V, cramps, diarrhoea, nervousness, chills

• Tachycardia, Exacerbation of MI, peptic ulcer.

Use

• PVD

• Pulmonary HT of newborn.

• Cause reflex tachycardia (due to decreased MAP)

• Tachycardia may be exaggerated because a 2 receptors are also blocked.

• e.g. phenoxybenzamine, phentolamine, tolazoline

Effects of Alpha Blockers

1. Nonselective alpha blockers (cont)

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)

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

Effects of Alpha Blockers

Clinical Uses

2. Selective a 1 -blockers

Prazosin and others

Essential Hypertension

Urinary hesitancy

Prevention of urinary retention in

benign prostatic hyperplasia (BPH)

Terazosin &Doxazosin

• Long acting( t1/212 & 18hr) congener of prazosin.

• Used in HTN & BPH as single daily dose.

Tamsulosin & Silodosin

• Uroselective α1A blocker

• α1A –bladder base, prostrate. α1B- blood vessels.

• Don't cause significant changes in BP & HR.

• t1/2- 6-9hr, MR cap(0.2-0.4 mg) can be taken OD.

• Efficacious in Rx of BPH.

• SE: retrograde ejaculation, dizziness,, floppy iris syd.

• Silodosin weaker(4-8mg/d) but longer acting.

Phentolamine

• More potent α-blocker than tolazoline.

• Other actions are less marked.

• Duration of action is shorter (min).

• Equally blocks α1 & α2 receptors- NA release sed.

Uses

• ∆sis & intraop.management of pheochromocytoma. 5mg

i.v- B.P falls by 25(D)or35(S)mmHg.

• HTN due to clonidine withdrawl, cheese reaction.

• Dermal necrosis due to extravasated i.v NA/DA. Given

S.C as local infiltration.

Bunazosin & Alfuzosin

• Orally effective α1 blockers similar to prazosin.

• Alfuzosin t1/2 4hrs (2.5mgTDS or 10mg SR OD).

• CI in hepatic impairment, metabolized in liver.

• Bunazosin slightly longer t1/2.

• Primarily used in 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

Side effects of α-blockers

• Palpitation

• Postural hypotension

• Nasal blockade

• Diarrhea

• Fluid retention

• Inhibition of ejaculation & impotence.

Receptor Type a1 a

2

Selective Agonist Phenylephrine Oxymetazoline

Clonidine Clenbuterol

Selective Antagonist Doxazosin Prazosin

Yohimbine Idazoxan

Agonist Potency Order

A=NA>>ISO A=NA>>ISO

Second Messengers and Effectors

PLC activation via

Gp/q causes inc.

[Ca2+]i

dec. cAMP via Gi/o

causes dec. [Ca2+]i

Physiological Effect Smooth muscle contraction

Inhibition of

transmitter release Hypotension,

anaesthesia, Vasoconstriction

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

3. Propranolol is contraindicated in

one of the following diseases:

a) Hypertension

b) Tachycardia

c) Hyperthyroidism

d) Angina pectoris

e) Bronchial asthma

4. Propranolol produces its

antihypertensive action by:

a) Vasodilatation

b) Ganglionic blockade

c) Decreased cardiac output

d) A diuretic action

e) Blockade of 1 receptors

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

Partial agonist activity

–Intrinsic sympathomimetic

activity, ISA

–eg, pindolol, acebutolol

–may be useful in patients

with asthma

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

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

Clinical Uses

• CVS: hypertension, angina pectoris, arrhythmia prophylaxis after MI, supraventricular tachycardias, hypertrophic cardiomyopathy, congestive heart failure*

• Glaucoma: reduce aqueous humor secretion (timolol)

Clinical Uses

• Migraine: propranolol

• Thyroid storm, thyrotoxicosis: propranolol

• Famillial tremor, other types of

tremor, “stage fright” : propranolol

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

Receptor Type

b1 b

2 b

3 b

4

Selective Agonist

Dobutamine xamoterol

Salbutamol salmeterol

BRL 37344 none

Selective Antagonists

Atenolol metoprolol

Butoxamine SR59230A Bupranolol

Agonist

Potency Order

ISO>A=NA ISO>A>>NA ISO=NA>A

Second

Messengers and Effectors

Inc cAMP via Gs

Inc cAMP via Gs

Inc cAMP via Gs

Inc cAMP via Gs

Physiological Effect

Inc heart rate and force

Vasodilatation

and broncho-dilation

Lipolysis and thermogenesis

Inc heart rate and force

SUMMARY

Selectivity

Partial

Agonist

Activity

Local

Anesthetic

Action

Elimination Half-

Life

Approximate

Bioavailability

Acebutolol β1 Yes Yes 3-4 hours 50

Atenolol β1 No No 6-9 hours 40

Betaxolol β1 No Slight 14-22 hours 90

Bisoprolol β1 No No 9-12 hours 80

Carteolol None Yes No 6 hours 85

Carvedilol None No No 7-10 hours 25-35

Celiprolol β1 Yes No 4-5 hours 70

Esmolol β1 No No 10 minutes 0

Labetalol None Yes Yes 5 hours 30

Metoprolol β1 No Yes 3-4 hours 50

Nadolol None No No 14-24 hours 33

Penbutolol None Yes No 5 hours >90

Pindolol None Yes Yes 3-4 hours 90

Propranolol None No Yes 3.5-6 hours 30

Sotalol None No No 12 hours 90

Timolol None No No 4-5 hours 50