Transcript Alpha and Neuron Blockers

SYMPATHOLYTIC
AGENTS..2
Alpha Adrenergic receptor
blockers
ALPHA BLOCKERS
•Several agents
•Chemically heterogeneous and with different
specificities
•According to nature of action : Two Groups,
Competitive & Irreversible
•According to selectivity : Three Groups,
 1 >  2;  1 =  2;  2 >  1
Classification
 - RECEPTOR antagonist
1- SELECTIVE
competetive
 1 > 2
Prazosin
Terazosin
Doxazosin
Tamsulosin
2- SELECTIVE
competetive
2 > 1
Yohimbine
Idazoxan
Mianserin
NONSELECTIVE
Competetive
1 = 2
Phentolamine
Tolazoline
NONSELECTIVE
Irreversible
1 = 2
Phenoxybenzamine
Dibenamine
Pharmacological actions
Major actions on Blood pressure
Other effects based on
- role of  receptors in different tissues
- selectivity of the agent (2 vs 1)
CVS
Vasodilatation – arteriolar and venous
 BP
 PVR
Magnitude dependent on symp. activity at that
time
More in erect that in supine position
– postural hypotension
More marked if hypovolaemia is present
Baroreflex activation
– reflex tachycardia
– tends to oppose the fall by  HR and CO
•Reflex tachycardia more marked with non
selective agents – WHY?
•Compensatory salt and water retention with
long term use
•Prevent pressor response to usual doses of 
agonists
•Convert pressor response of Adrenaline to
depressor – Dale’s reversal
•Vascular 2 receptors also vasoconstrictor
but activated by circulating and not synaptic
NA --no marked effects of 2 blockers
•2 blockers can  NA release (presynaptic
action) – CV effects
OTHER EFFECTS
 ↓contraction of trigone and sphincter in bladder
- urine flow
insulin secretion from islet cells (2 blockers)
Miosis
Nasal stuffiness
 adrenergic sweating
α1 – blockers : Clinical uses
Reduce blood pressure
Hypertensive emergencies
Long term treatment
Phaeochromocytoma
Vasodilatation
Peripheral vascular insufficiency
To reverse vasoconstrictor excess
Improve urine flow
Benign prostatic hyperplasia
α1 – blockers : Adverse effects
•Postural hypotension
( less with α1 selective - venodilatation is less)
•Reflex tachycardia ( less with α1 selective)
•Salt and water retention
•Nasal stuffiness
•Miosis
•Failure of ejaculation
Specific Agents
Ergot alkaloids (ergotamine):
Partial agonist & blocking property
Also affect other receptors (eg. 5-HT, )
Therapeutic effects (migraine, uterus) not
related to  blockade.
Uses:
Migraine (acute attack)
Uterotonic – (methylergonovine) in PPH
Phenoxybenzamine:
1 > 2 ;
Irreversible : Covalent binding with receptor
Long duration of action (14 - 48 hrs)
Also blocks 5-HT, ACh & H1 receptors
-- ? significance
Inhibits neuronal & extra-neuronal uptake of NA
Absorbed from GIT, low bioavailability
Phenoxybenzamine
Clinical use:
Phaeochromocytoma
Control of BP
Prior to surgery
Adverse effects:
Postural hypotension,
Tachycardia,
Nasal stuffiness,
 ejaculation
Phentolamine :
1 = 2
 PVR –  blockade + direct (non adrenergic)
 HR – Reflex + 2 presynaptic on cardiac
symp. terminals
Poorly absorbed orally
Clinical use:
Phaeochromocytoma
Local vasoconstrictor excess
Adverse effects:
Cardiac stimulation :
- tachycardia, arrhythmia, angina
GIT Stimulation :
- diarrhoea;  gastric acid secretion
Tolazoline:
Similar to phentolamine
Slightly less potent
Better absorption from GIT
Rapidly excreted in urine
Limited clinical application:
peripheral vasospastic disease
1 Selective Agents
Prazosin & Terazosin: 1 >>>> 2
Effective in management of hypertension
Low affinity for 2
Relative absence of tachycardia
↓ Triglycerides & LDL, ↑ HDL (favourable)
Both are extensively metabolized by liver
Prazosin shows high 1st Pass effect (50%)
Oral absorption - good
Terazosin :Bioavailability >90%; >18 h action
Uses: Hypertension and BPH
Adverse effects
First dose effect
Postural hypotension
Salt & water retention ( long term use)
Doxazosin:
Similar to Prazosin but longer t ½ (22 Hr)
Alfuzosin : similar to prazosin
Tamsulosin
Selective α1 anatgonist
Has greater selectivity for α1A subtype
Has greater efficacy for BPH
Relatively smaller effects on blood vessels
USE: BPH
Indoramin & Urapidil :
Newer 1-selective agents
Have some utility in hypertension
2 selective
Yohimbine
Hardly used clinically
Idazoxan
Mianserin :
Used as an antidepressant;
2 – blocking action within CNS contributes
to its effect.
Other receptor actions also (eg. 5-HT)
Labetalol : 1 + 
Clinical Uses Of  Blockers
•Pheochromocytoma
•Hypertensive emergencies
•Chronic hypertension – non selective blockers
are not used
•Peripheral vascular diaease
– spastic (Raynauds), not morphological
•Local vasoconstrictor excess
– phentolamine useful- local infiltration
•Urinary obstruction – BPH
– prazosin, terazosin, tamsulosin
•CHF
α2- selective antagonists do not have any
recognised clinical use
Some neuroleptic agents (eg.
chlorpromazine, haloperidol) used in
psychiatry
possess α receptor
blocking activity
(in addition to
Dopamine receptor antagonism)
which may lead to cardiovascular
adverse effects with these agents.
ADRENERGIC NEURON BLOCKERS
Inhibit the function of peripheral, post-ganglionic
adrenergic neurons
Guanethidine
Guanadrel
Reserpine
Bretylium
-
Antihypertensive
Antihypertensive
Antihypertensive
Anti-arrhythmic
Not used now
Guanethidine :
Sympathoplegic,
Taken up and concentrated by neurons
Blocks NE release (LA like action on terminal)
Displaces NE from granules
IV : initial release – initial mimetic actions
Does not cross BBB
Widespread sympatholytic effects
Leads to several adverse effects
Chronic use causes effector supersensitivity
Guanadrel: Similar to Guanethidine
Bretylium :
Inhibits release of NE from terminals
Also has direct anti-arrhythmic activity
Reserpine :
Blocks vesicular uptake of NE – depletes vesicles
Displaces NE from terminal – initial mimetic actions
Crosses BBB – CNS effects:
Depression ,suicidal tendency
Adverse effects due to non specific sympatholysis
These drugs rarely used now for Hypertension
Autonomic Drugs Used for Glaucoma:
Cholinomimetics
Muscarinic agonists
AChE inhibitors
Alpha agonists
Non – selective
Selective α2
Beta Blockers
Pilocarpine
Physostigmine,
Ecothiophate
Increased outflow
Epinephrine
Dipevefrine
Increased outflow
Apraclonidine
Brimonidine
Decreased aqueous
secretion
Timolol, betaxolol
Decreased aqueous
secretion
Other drugs
Carbonic anhydrase inhibitors – acetazolamide – ↓ formation
Prostaglandins
– lanatoprost
– ↑ outflow
Targets for Pharmacological Interference
Tyrosine hyhroxylase
 MPT
 NA
DOPA decarboxylase
 Methyldopa
Dopamine  hydroxylase
Disulfiram
Release of NA
Tyramine
Sympathomimetic
Amphetamine
Release of NA
Guanethidine
Bretylium
Sympatholytic
Reuptake
Cocaine,
Imipramine
 effect of NT
 indirect mimetics
Reuptake into granules
Reserpine
Release Depletion
Pseudotransmitter*
Targets for Pharmacological Interference
Presynaptic 2
Catecholamines
 release
Presynaptic 2
Catecholamines
 release
Presynaptic M
ACh
 release
 MAO
Several
 metabolism
 Extrasynaptic uptake
PBZ, Steroids
 Effect
 COMT
Pyrogallol
Talcapone
Entacapone
---
Mean arterial blood pressure
Dale’s Reversal Phenomenon
PBZ
Adr
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