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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, - PowerPoint PPT Presentation
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SYMPATHOLYTIC SYMPATHOLYTIC AGENTS..2AGENTS..2
Alpha Adrenergic receptor Alpha Adrenergic receptor blockersblockers
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
1- SELECTIVEcompetetive
1 > 2
2- SELECTIVEcompetetive
2 > 1
NON-SELECTIVECompetetive
1 = 2
NON-SELECTIVEIrreversible
1 = 2
- RECEPTOR antagonist
Prazosin Yohimbine Phentolamine Phenoxy-Terazosin Idazoxan Tolazoline benzamineDoxazosin Mianserin DibenamineTamsulosin
Classification
Pharmacological actions
Major actions on Blood pressure
Other effects based on - role of receptors in different tissues - selectivity of the agent (2 vs 1)
CVSVasodilatation – arteriolar and venous
BP PVR
Magnitude dependent on symp. activity at that time More in erect that in supine position – postural hypotensionMore marked if hypovolaemia is presentBaroreflex 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 blockers2 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 pressureHypertensive emergenciesLong term treatmentPhaeochromocytoma
VasodilatationPeripheral vascular insufficiency
To reverse vasoconstrictor excess
Improve urine flowBenign 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
Clinical use:Phaeochromocytoma
Control of BPPrior to surgery
Adverse effects: Postural hypotension, Tachycardia, Nasal stuffiness, ejaculation
Phenoxybenzamine
Phentolamine : 1 = 2
PVR – blockade + direct (non adrenergic) HR – Reflex + 2 presynaptic on cardiac
symp. terminals
Poorly absorbed orally
Clinical use: PhaeochromocytomaLocal vasoconstrictor excess
Adverse effects: Cardiac stimulation : - tachycardia, arrhythmia, angina GIT Stimulation : - diarrhoea; gastric acid secretion
Tolazoline: Similar to phentolamineSlightly less potentBetter absorption from GITRapidly excreted in urine Limited clinical application: peripheral vasospastic disease
1 Selective AgentsPrazosin & 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 liverPrazosin shows high 1st Pass effect (50%)Oral absorption - goodTerazosin :Bioavailability >90%; >18 h actionUses: Hypertension and BPHAdverse effects First dose effect
Postural hypotensionSalt & water retention ( long term use)
Tamsulosin
Selective α1 anatgonist Has greater selectivity for α1A subtypeHas greater efficacy for BPH Relatively smaller effects on blood vessels
USE: BPH
Doxazosin: Similar to Prazosin but longer t ½ (22 Hr)
Alfuzosin : similar to prazosin
Indoramin & Urapidil : Newer 1-selective agents Have some utility in hypertension
2 selective
YohimbineHardly 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 - AntihypertensiveGuanadrel - AntihypertensiveReserpine - AntihypertensiveBretylium - 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 actionsDoes not cross BBB
Widespread sympatholytic effects Leads to several adverse effectsChronic 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 actionsCrosses BBB – CNS effects: Depression ,suicidal tendencyAdverse effects due to non specific sympatholysis
These drugs rarely used now for Hypertension
Autonomic Drugs Used for Glaucoma:
Cholinomimetics Muscarinic agonists Pilocarpine AChE inhibitors Physostigmine, Increased outflow Ecothiophate
Alpha agonists Non – selective Epinephrine Increased outflow Dipevefrine
Selective α2 Apraclonidine Decreased aqueous Brimonidine secretion
Beta Blockers 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 Pseudotransmitter*
Dopamine hydroxylase Disulfiram
Release of NA Tyramine Sympathomimetic
Amphetamine
Release of NA Guanethidine SympatholyticBretylium
Reuptake Cocaine, effect of NTImipramine indirect
mimetics
Reuptake into granules Reserpine Release Depletion
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 ---TalcaponeEntacapone
Dale’s Reversal Phenomenon
AdrPBZ
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