Joy B.

Johnson
Bsc (Hons) Pharmacy, Msc Pharmacology,
MPC Pharm.
Department of Pharmacology
COMAHS, USL.
Overview
Recap (new)
Introduction
Summary of alpha receptor responses
Classification of alpha blockers
Pharmacology of the different classes
Pharmacological actions
Mode of actions
Pharmacokinetics
Clinical Uses
Side effects & contraindications
Recap new
Introduction
Alpha blockers are agents which inhibit the actions of
NA or A or direct acting sympathomimetic agents or
SNS stimulation on alpha receptors
They block alpha receptors
Blockage is either reversible or irreversible competitive
new
Summary of Alpha receptor
responses
Alpha- 1 Responses

 VSMs Contraction
 Eye Mydriasis (contraction)
 Pilomotor SMs
 Vas deferens Erects hair
 Liver Contration
 Intestinal SMs
 Intestinal sphincters
Glycogenolysis
Relaxation
contraction
Summary of Alpha receptor
responses
Alpha- 2 Responses

 Some VSMs Contraction

 Nerve terminals (NA & Ach)

Inhibit transmitter release
 Platelets

 Fat cells
Aggregation

Inhibition of lipolysis
new
Classification (Receptor selectivity)
Non-selective
Phenylalkylamines e.g.phenoxybenzamine
Imidazoline derivatives: phentolamine,
tolazoline
Selective
-alpha-1: Quinazoline derivatives: prazosin,
doxazosin, terazosin, tamsulosin
-alpha-2: yohimbine
Others: phenothiazines, TCA, labetalol
Classification (Type of Blockage)

Irreversible competitive
Phenylalkylamines e.g.phenoxybenzamine
Reversible competivitive
-Imidazoline derivatives: phentolamine, tolazoline
-alpha-1: Quinazoline derivatives: prazosin,
doxazosin, terazosin, tamsulosin
-alpha-2: yohimbine
Others: phenothiazines, TCA, labetalol
 Phenoxybenzamine

Prazosin Yohimbine
Pharmacological actions
Phenoxybenzamine
Primarily due to alpha blockage
Mostly limited to the CVS
Relative little or no effect on the BP of normal
supine subjects
Attenuates catecholamine-induced vasoconstriction
Reduces BP when SNS tone is high such as upright
posture (postural hypotension) or reduced BP.
Pharmacological actions
Phenoxybenzamine
CVS: vasodilatation →↓TPR → ↓BP
 Baroreceptors stimulated → ↑SN input to the
myocardium → refex tachycardia and may be ↑CO
 Blockage of alpha-2 pre-synaptic may also contribute to

the ↑HR and CO.

Others: blocks Ach, histamine and serotonin
receptors (side effects)
Also blocks uptake 1 and 2
 EPI Receptors
EPI + Phenoxybenzamine no longer
% Maximal Increase

Phenoxybenzamine alone available

Decrease in the
maximal efficacy
of Epi due to a
decrease in the
number of receptors

mg/kg[, Agonist]
Pharmacological actions
Phenoxybenzamine
Eye - miosis
GI tract – Increased motility
Urinary bladder – decreased tone in sphincter
Metabolic effects – increased insulin secretion
Pharmacokinetics
Absorbed after oral
Bioavailability is low
Kinetic properties not well established
Half-life –life span of the cell
Adverse effects
Postural hypotension (drowsiness/headache)
Tachycardia (refex)→arrhythmias, MI
Palpitations
Nasal stuffiness
Reversible inhibition of ejaculation
Miosis
Impotence (inhibits ejaculation)
CNS: fatigue, sedation and nausea
Alkylating agent, may have S/Es that have not yet been
characterized; causes tumours in animals (clinical
importance- unknown)
Phentolamine & tolazoline
Pharmacological effects similar to phenoxybenzamine

In addition: minor inhibitory effect at serotonin

receptors, but agonistic effects at muscarinic and
histamine (H1&2) receptors.

Parasympathomimetic

Increased gastric acid secretion

Increased secretion from exocrine glands, such as

salivary, sweat, lacrimal, pancreatic
Pharmacokinetics
Limited absorption after oral

Pharmacokinetic properties not well known

Peak levels achieved in 1 hour after oral

Half-life is 5-7 hrs

Side effects
Similar but not identical to those of phenoxybenzamine

Principal S/Es are ↑HR, arrhythmias, MI (after IV)

Oral-nasal congestion, ↑HR, headache

Ach-like S/Es- abd. pain, nausea, PUD etc.

Contraindicated in patients with asthma, peptic disease

and coronary artery disease.
Clinical Uses
Pheochromocytoma

BPH

Hypertensive crisis secondary to clonidine withdrawal

Prazosin
 CVS
 Arteriolar and venodilatation →↓TPR →↓BP

 Suppresses baroreceptor refex mechanisms

 Has little or no alpha-2 blocking effect

 Suppresses baroreceptor function

 No cardiac stimulating effect

 Tolerance develops may be due fuid retention

 Little or no metabolic effect

 Favorable effect on plasma lipids: increase HDL/LDL ratio

 Relaxation of the SMs of the prostate

Effect of Adrenaline (ADR) on Blood Pressure and Heart Rate
Before and After Prazosin

ADR
(µg/Kg)
0.1 1 10 100 500 HR

BP

1 10 100 500

PRAZOSIN+
Pharmacokinetics
Bioavailability 50-70%

Peak effect 1-3hrs after oral adm.

Highly (95%) bound to plasma proteins (α-1 acid

glycoprotein)

T1/2 - 2-3 hrs (in CHF 6-8 hrs)

Duration of effect 7-10 hrs

Terazosin- less potent than prazosin, bioavailability
-90%, t1/2-12hrs, duration-18hrs

Doxazosin- t1/2- 20hrs, duration-36hrs

Alfuzosin- bioavailability-64%, t1/2-3-5hrs (BPH)

Tamsulosin- benzenesulfonamide, very efficacious in

the treatment of BPH with little or no effect on BP
Side effects
First-dose phenomenon (marked postural
hypotension and syncope)
-Limit initial dose at bedtime
-Increase dose slowly
-Introduce additional antihypertensives cautiously
Headache
 dizziness
Impaired ejaculation (tamsulosin)
Alpha-2 selective blockers
Yohimbine
Cardiovascular effects – peripheral and central effects
(↑BP)
Blocks other receptors also – serotonin, dopamine
Increases ADH release
Enhances sexual activity – aphrodisiac (in the past use
to treat male sexual dysfunction)
Potential uses: depression, obesity, NIDDM
Additional alpha blockers
Ergot alkaloids- ergotamine, ergonovine
Also Interact with serotonin and dopamine receptors
Direct smooth muscle contraction
Coronary vasoconstriction

Toxicity: GI, vascular insufficiency –ergotism

Use in migraine and post-partum hemorrhage

Additional alpha blockers
Indoramin

Selective alpha-1 blocker

Also histamine and serotonin receptors
Bioavailability – less than 30%
Undergoes extensive first-pass metabolism
Some of its metabolites are active
T1/2 – 5 hrs

Toxicity: sedation, dry mouth, and failure of ejaculation

Use in hypertension, decrease the incidence of Raynaud’s

phenomenon
Additional alpha blockers
Ketanserin
Is a typical 5-HT blocker
Blocks alpha-1 receptors

Urapidil
Alpha-1 blocker with structure distinct from
prazosin and its congeners
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 disease

 Congestive heart failure

 Benign prostatic hyperplasia

 Pulmonary hypertension – tolazoline

 Yohimbine or intracavernous phentolamine+papaverine for impotence

Summary contd
Thanks for your attention