1. Alpha Adrenergic receptor blockers
SYMPATHOLYTIC AGENTS..2
Alpha Adrenergic receptor blockers

2. 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

3. Classification  - RECEPTOR antagonist 1- SELECTIVE competetive
1 > 2
2- SELECTIVE
competetive
2 > 1
NON-SELECTIVE
Competetive
1 = 2
NON-SELECTIVE
Irreversible
1 = 2
Prazosin Yohimbine Phentolamine Phenoxy-
Terazosin Idazoxan Tolazoline benzamine
Doxazosin Mianserin Dibenamine
Tamsulosin

4. Pharmacological actions
Major actions on Blood pressure
Other effects based on role of  receptors in different tissues selectivity of the agent (2 vs 1)

5. 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

6. 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

7. OTHER EFFECTS
↓contraction of trigone and sphincter in bladder  urine flow
insulin secretion from islet cells (2 blockers)
Miosis
Nasal stuffiness
 adrenergic sweating

8. 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

9. 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

10. 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

11. Phenoxybenzamine: 1 > 2 ;
Irreversible : Covalent binding with receptor
Long duration of action ( hrs)
Also blocks 5-HT, ACh & H1 receptors
-- ? significance
Inhibits neuronal & extra-neuronal uptake of NA
Absorbed from GIT, low bioavailability

12. Phenoxybenzamine
Clinical use:
Phaeochromocytoma
Control of BP
Prior to surgery
Adverse effects:
Postural hypotension,
Tachycardia,
Nasal stuffiness,
 ejaculation

13.  PVR –  blockade + direct (non adrenergic)
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

14. Tolazoline:
Similar to phentolamine
Slightly less potent
Better absorption from GIT
Rapidly excreted in urine
Limited clinical application:
peripheral vasospastic disease

15. 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)

16. 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

17. Indoramin & Urapidil :
Newer 1-selective agents
Have some utility in hypertension

18. 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 + 

19. 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

20. Some neuroleptic agents (eg
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.

21. ADRENERGIC NEURON BLOCKERS
Inhibit the function of peripheral, post-ganglionic
adrenergic neurons
Guanethidine - Antihypertensive
Guanadrel Antihypertensive
Reserpine Antihypertensive
Bretylium Anti-arrhythmic
Not used now

22. 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

23. 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

24. Autonomic Drugs Used for Glaucoma:
Cholinomimetics
Muscarinic agonists Pilocarpine
AChE inhibitors Physostigmine, Increased outflow
Ecothiophate
Alpha agonists
Non – selective Epinephrine Increased outflow
Dipevefrine
Selective α Apraclonidine Decreased aqueous
Brimonidine secretion
Beta Blockers Timolol, betaxolol Decreased aqueous
secretion
Other drugs
Carbonic anhydrase inhibitors – acetazolamide – ↓ formation
Prostaglandins – lanatoprost – ↑ outflow

25. Targets for Pharmacological Interference
Tyrosine hyhroxylase  MPT  NA
DOPA decarboxylase  Methyldopa Pseudotransmitter*
Dopamine  hydroxylase Disulfiram
Release of NA Tyramine Sympathomimetic
Amphetamine
Release of NA Guanethidine Sympatholytic
Bretylium
Reuptake Cocaine,  effect of NT
Imipramine  indirect mimetics
Reuptake into granules Reserpine Release Depletion

26. 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

27. Dale’s Reversal Phenomenon
Mean arterial blood pressure
PBZ
Adr
Back