Dr Shahid Saache
JR1, Dept Of Pharmacology
B.J.G.M.C PUNE
INTRODUCTION
ANS also called visceral, vegetative or involuntary
nervous system
Distributed widely through out body
Regula...
End of postganglionic
sympathetic synapse-
adrenergic receptors
“Block or decrease the effects of sympathetic nerve
stimulation, endogenous catecholamines and adrenergic
drugs”
Adrenergi...
Neuron blocking drugs
Guanethidine
Act mainly by preventing release of NE at nerve endings
Pharmacological sympathectomy
U...
Guanadrel
False neurotransmitter- accumulated, stored & released
like NE but is inactive at adrenergic receptors
M/A- Repl...
Metyrosine
Inhibits tyrosine hydroxylase
Adjuvant to phenoxybenzamine & other α adrenergic
blockers for pheochromocytoma &...
Central sympatholytics
α Methyldopa
MOA: Converted to α methyl NE which acts on α2
receptors in brain & causes inhibition ...
Alpha Blockers
Prazosin
Well absorbed orally ; bioavailability is 50-70%
Peak concentrations within 1-3 hours after oral dose
Initial dos...
Terazosin
Less potent than prazosin but retains high specificity
for α1 receptors
Bioavailability -high (>90%), t1/2 ~12 h...
Doxazosin
Highly selective antagonist at α1 receptors
T1/2 is 20 hours, duration of action may extend to 36
hrs bioavailab...
Alfuzosin
Similar affinity at all of the α1 receptor subtypes
Bioavailability is ~64%, t1/2 3-5 hrs
Substrate of CYP3A4 an...
Tamsulosin
Selectivity for α1a (and α1d) subtypes
Efficacious in treatment of BPH & little effect on BP
Well absorbed, t1/...
Silodosin
Selectivity for the α1a, over the α1b adrenergic
receptor
Approved for the treatment of BPH and is reported,
as ...
Adverse effects
Marked postural hypotension & syncope seen 30-90
mins after an initial dose of prazosin & 2-6 hours after
...
Therapeutic Uses
Hypertension
Prazosin and its congeners -used successfully in the
treatment of essential HTN
These drugs ...
Congestive Heart Failure
α receptor antagonists have been used in the treatment
of CHF, as have other vasodilating drugs
D...
Benign Prostatic Hyperplasia (BPH)
Prazosin ↓ resistance in some patients with impaired
bladder emptying caused by prostat...
Other Disorders
Variant angina (prinzmetal's angina)
Vasospastic disorders
↓ Ventricular arrhythmias induced by coronary
a...
α2 Receptor Antagonists
Yohimbine
Competitive antagonist
May benefit some patients with psychogenic erectile
dysfunction
U...
Non-Selective α Adrenergic
Antagonists:
Phenoxybenzamine & Phentolamine
Referred to as "classical" α blockers
Postural hyp...
Therapeutic Uses
Pheochromocytoma
Phenoxybenzamine is often used in preparing the
patient for surgery
Controls episodes of...
Direct intracavernous injection of phentolamine (in
combination with papaverine) for male sexual
dysfunction but may cause...
Toxicity and Adverse Effects
Hypotension -major adverse effect
Alarming tachycardia, cardiac arrhythmias, and
ischemic car...
Additional α Adrenergic Receptor Antagonists
Ergot Alkaloids
Indoramin
selective, competitive α1 receptor antagonist that ...
Ketanserin
blocks α 1 receptors
Urapidil
a novel, selective α1 receptor antagonist
role in the treatment of hypertension r...
Beta blockers
β antagonists can be distinguished by the following
properties:
Relative affinity for β1 and β2 receptors
Intrinsic sympat...
MSA ISA Lipid
Solub.
Absorpn
(%)
BA (%) T1/2 Protein
binding
Therapeutic Uses
Cardiovascular Diseases
Hypertension, Angina, Acute Coronary Syndromes &
Congestive Heart Failure
Hyperte...
Myocardial Infarction
Many trials- β receptor antagonists administered
during the early phases of acute MI & continued lon...
Congestive Heart Failure
A number RCTs shows certain β receptor antagonists are
highly effective for pts with all grades o...
Use of β Antagonists in Other Cardiovascular
Diseases
Propranolol- in hypertrophic obstructive
cardiomyopathy and angina, ...
Glaucoma
Useful for open-angle glaucoma
e.g.Carteolol, betaxolol, levobunolol, metipranolol
timolol and levobetaxolol
Have...
Other Uses
Propranolol, timolol, and metoprolol are effective for
the prophylaxis of migraine
Propranolol- effective in co...
Propranolol also may be useful in the treatment of
essential tremor
Of some value in the treatment of patients
undergoing ...
Adverse Effects and Precautions
On Cardiovascular System
β receptor antagonists may induce congestive heart
failure in sus...
Pulmonary function
May cause a life-threatening increase in airway
resistance
CNS
Fatigue, sleep disturbances (including i...
Drug Interactions
Aluminum salts, cholestyramine, and colestipol may
decrease the absorption of β blockers
Phenytoin, rifa...
Overdosage
Hypotension, bradycardia, prolonged AV conduction
times, and widened QRS complexes are common
manifestations of...
Non-Selective β Adrenergic Receptor
Antagonists
Propranolol
For HTN & angina, initial oral dose 40-80 mg/day
Uses - suprav...
Nadolol
Long-acting antagonist with equal affinity for 1 and
2 receptors
Distinguishing characteristic of nadolol is its
r...
Pindolol
with intrinsic sympathomimetic activity
Used to treat angina and hypertension
Preferred as antihypertensive in in...
β1 selective adrenergic receptor antagonists
Metoprolol
Devoid of ISA and MSA
Significant first-pass metabolism
Uses: esse...
Esmolol
Rapid onset ,short duration
Also class 2 anti arrhythmic
Slow iv injection
Used during surgeries to prevent or tre...
Acebutalol
Have lipophilic properties
Used for HTN, arrhythmias, MI, Smith Magenis
syndrome
Bisoprolol
Higher β1 selectivi...
THIRD GENERATION β BLOCKERS
NITRIC OXIDE
PRODUCTION
ALPHA2
RECEPTOR
AGONISM
ALPHA1
RECEPTOR
ANTAGONISM
Ca2+ ENTRY
BLOCKADE...
Labetalol
Selective Alpha1 and Nonselective Beta Blocker
↓ BP by ↓ SVR (alpha1)
Vasodilation via α1 blockade & partial bet...
Carvidilol
Has antioxidant and anti inflammatory property
Produces vasodilation
FDA approved for HTN, CHF,LV dysfunction f...
Nebivolol
Highly selective
NO donorvasodialation, potential to improve
endothelial fuction, no deleterious effect on lipi...
Tissues or organs employed for the study of
Adrenoceptors
 α1 receptor system
1. Rat isolated vas deference (contraction)...
 β1 receptor system
1. Rabbit isolated perfuse heart (contraction)
2. Rabbit isolated jejunum (inhibition)
 β2 receptor ...
Conclusion
Thank you
ADRENERGIC BLOCKERS
ADRENERGIC BLOCKERS
ADRENERGIC BLOCKERS
ADRENERGIC BLOCKERS
ADRENERGIC BLOCKERS
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ADRENERGIC BLOCKERS

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This presentation contains drugs which blocks the adrenergic system e.g receptor blockers like alpha and beta receptor antagonists, adrenergic neuron blocking agents in details.various animated pictures are also included to make the presentation interesting as well as i have used various diagrams and tables to have better understanding of the topic. Thank you.

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ADRENERGIC BLOCKERS

  1. 1. Dr Shahid Saache JR1, Dept Of Pharmacology B.J.G.M.C PUNE
  2. 2. INTRODUCTION ANS also called visceral, vegetative or involuntary nervous system Distributed widely through out body Regulates autonomic function without conscious control In periphery nerves, ganglia & plexuses that innervates heart, BV, glands, other visceral organs & SM
  3. 3. End of postganglionic sympathetic synapse- adrenergic receptors
  4. 4. “Block or decrease the effects of sympathetic nerve stimulation, endogenous catecholamines and adrenergic drugs” Adrenergic receptor blockers antagonize receptor action of epinephrine & related drugs Adrenergic neurone blocking agents act by interfering with release of adrenergic transmitter Central sympatholytics Ganglion blockers Chemical sympathectomy
  5. 5. Neuron blocking drugs Guanethidine Act mainly by preventing release of NE at nerve endings Pharmacological sympathectomy Uses- HTN, glaucoma, neuropathic pain,& given IM for htnsive crises, severe pre eclampsia ADRs- severe postural hypotension, diarrheoa, renal impairment Bretylium Causes initial release of NE→ blocks adrenergic transmission by preventing NE release from adrenergic nerve endings Blocks K+ channels- class III antiarrhythmic activity
  6. 6. Guanadrel False neurotransmitter- accumulated, stored & released like NE but is inactive at adrenergic receptors M/A- Replacement of NE with inactive transmitter ADRs- hypotension, fatigue ,lassitude, Sexual dysfunction, Diarrhoea Reserpine Inhibit vesicular catecholamine transporter Sedation, inability to concentrate- MC ADRs occasionally psychotic depressionsuicide Recent interest -at low doses, in combination with diuretics, for hypertension
  7. 7. Metyrosine Inhibits tyrosine hydroxylase Adjuvant to phenoxybenzamine & other α adrenergic blockers for pheochromocytoma & in preoperative preparation for resection of pheochromocytoma ADR- crystalluria
  8. 8. Central sympatholytics α Methyldopa MOA: Converted to α methyl NE which acts on α2 receptors in brain & causes inhibition of adrenergic discharge in medulla – ↓PVR & ↓BP Various adverse effects – cognitive impairment, postural hypotension, positive coomb`s test etc – Not used therapeutically now except in Hypertension during pregnancy (category B drugs) Clonidine Imidazoline derivative, partial agonist of central α2 receptor Not frequently used now because of tolerance and withdrawal hypertension
  9. 9. Alpha Blockers
  10. 10. Prazosin Well absorbed orally ; bioavailability is 50-70% Peak concentrations within 1-3 hours after oral dose Initial dose 1 mg, usually given at bedtime A maximal effect generally is observed with a total daily dose of 20 mg in patients with hypertension Uses- HTN, BPH,nightmares a/w PTSD, scorpion bite S/E- orthostatic hypotension, syncope, nasal congestion "first dose response"
  11. 11. Terazosin Less potent than prazosin but retains high specificity for α1 receptors Bioavailability -high (>90%), t1/2 ~12 hours, duration of action extends beyond 18 hrs More effective than finasteride for BPH Interesting aspect of the action of terazosin and doxazosin for BPH is induction of apoptosis in prostate SM cells Initial first dose of 1 mg is recommended Doses of 10 mg/day may be required for maximal effect in BPH
  12. 12. Doxazosin Highly selective antagonist at α1 receptors T1/2 is 20 hours, duration of action may extend to 36 hrs bioavailability & extent of metabolism is similar to prazosin Given initially as a 1mg dose for HTN & BPH
  13. 13. Alfuzosin Similar affinity at all of the α1 receptor subtypes Bioavailability is ~64%, t1/2 3-5 hrs Substrate of CYP3A4 and concomitant administration of CYP3A4 inhibitors is contraindicated Avoided in patients at risk for prolonged QT syndrome One 10-mg extended release tablet daily to be taken after meal Used extensively in treating BPH; it is not approved for treatment of hypertension
  14. 14. Tamsulosin Selectivity for α1a (and α1d) subtypes Efficacious in treatment of BPH & little effect on BP Well absorbed, t1/2 of 5-10 hrs 0.4 mg starting dose, a dose of 0.8 mg will be more efficacious ADR- Abnormal ejaculation (experienced by 18%)
  15. 15. Silodosin Selectivity for the α1a, over the α1b adrenergic receptor Approved for the treatment of BPH and is reported, as is tamsulosin, to have lesser effects on BP than the non-α1 subtype selective antagonists Chief side effect- retrograde ejaculation (in 28%)
  16. 16. Adverse effects Marked postural hypotension & syncope seen 30-90 mins after an initial dose of prazosin & 2-6 hours after an initial dose of doxazosin Syncopal episodes also have occurred with a rapid ↑ in dosage or with the addition of a 2nd antihypertensive with prazosin Nonspecific ADRs- headache, dizziness & asthenia rarely limit treatment with prazosin
  17. 17. Therapeutic Uses Hypertension Prazosin and its congeners -used successfully in the treatment of essential HTN These drugs improve rather than worsen lipid profiles and glucose-insulin metabolism who are at risk for atherosclerotic disease
  18. 18. Congestive Heart Failure α receptor antagonists have been used in the treatment of CHF, as have other vasodilating drugs Due to dilation of both arteries & veins → reduction of preload & afterload, which ↑cardiac output & ↓pulmonary congestion
  19. 19. Benign Prostatic Hyperplasia (BPH) Prazosin ↓ resistance in some patients with impaired bladder emptying caused by prostatic obstruction or spinal injury Finasteride and dutasteride- inhibit conversion of testosterone to DHT & can ↓ prostate volume in some patients, approved as monotherapy & in combination with α receptor antagonists Tamsulosin ( 0.4 mg daily) & silodosin (0.8 mg) less likely to cause orthostatic hypotension than others Combination therapy with doxazosin and finasteride significantly better than either drug alone
  20. 20. Other Disorders Variant angina (prinzmetal's angina) Vasospastic disorders ↓ Ventricular arrhythmias induced by coronary artery ligation or after reperfusion in animals Mitral or aortic valvular insufficiency
  21. 21. α2 Receptor Antagonists Yohimbine Competitive antagonist May benefit some patients with psychogenic erectile dysfunction Useful for diabetic neuropathy and in the treatment of postural hypotension Approved in veterinary medicine for the reversal of xylazine anesthesia
  22. 22. Non-Selective α Adrenergic Antagonists: Phenoxybenzamine & Phentolamine Referred to as "classical" α blockers Postural hypotension is a prominent feature can precipitate cardiac arrhythmias
  23. 23. Therapeutic Uses Pheochromocytoma Phenoxybenzamine is often used in preparing the patient for surgery Controls episodes of severe HTN and minimizes other ADRs of catecholamines Dose 40-120 mg given in two or three divided portions Useful for the treatment of hypertensive crises that follow withdrawal of clonidine or ingestion of tyramine-containing foods during the use of non- selective MAO inhibitors
  24. 24. Direct intracavernous injection of phentolamine (in combination with papaverine) for male sexual dysfunction but may cause orthostatic hypotension & priapism FDA approved the use of phentolamine to reverse or shorten the duration of soft-tissue anesthesia Phenoxybenzamine has been used off-label to control the manifestations of autonomic hyperreflexia in patients with spinal cord transection
  25. 25. Toxicity and Adverse Effects Hypotension -major adverse effect Alarming tachycardia, cardiac arrhythmias, and ischemic cardiac events, including myocardial infarction Reversible inhibition of ejaculation Phentolamine should be used with caution in patients with a history of peptic ulcer
  26. 26. Additional α Adrenergic Receptor Antagonists Ergot Alkaloids Indoramin selective, competitive α1 receptor antagonist that is used for the treatment of hypertension, BPH, and in the prophylaxis of migraine ↓ BP with minimal tachycardia ↓ incidence of attacks of Raynaud's phenomenon. lacks a well-defined place in current therapy
  27. 27. Ketanserin blocks α 1 receptors Urapidil a novel, selective α1 receptor antagonist role in the treatment of hypertension remains to be determined Bunazosin 1-selective antagonist ,useful in hypertension Neuroleptic Agents
  28. 28. Beta blockers
  29. 29. β antagonists can be distinguished by the following properties: Relative affinity for β1 and β2 receptors Intrinsic sympathomimetic activity Differences in lipid solubility Capacity to induce vasodilation Pharmacokinetic parameters
  30. 30. MSA ISA Lipid Solub. Absorpn (%) BA (%) T1/2 Protein binding
  31. 31. Therapeutic Uses Cardiovascular Diseases Hypertension, Angina, Acute Coronary Syndromes & Congestive Heart Failure Hypertension One of the 1st choice drugs because of good pt acceptability & cardioprotective potential
  32. 32. Myocardial Infarction Many trials- β receptor antagonists administered during the early phases of acute MI & continued long- term may ↓ mortality by ~25% Angina pectoris Act by ↓ cardiac work & O2 consumption C/I in variant angina
  33. 33. Congestive Heart Failure A number RCTs shows certain β receptor antagonists are highly effective for pts with all grades of heart failure secondary to left ventricular systolic dysfunction
  34. 34. Use of β Antagonists in Other Cardiovascular Diseases Propranolol- in hypertrophic obstructive cardiomyopathy and angina, palpitations, and syncope in patients with this disorder Pheochromocytoma – should only used after administering α blockers Acute dissecting aortic aneurysm
  35. 35. Glaucoma Useful for open-angle glaucoma e.g.Carteolol, betaxolol, levobunolol, metipranolol timolol and levobetaxolol Have an onset in ~30 mins with a duration of 12-24 hrs systemic absorption can lead to adverse cardiovascular and pulmonary effects in susceptible patients Caution- pts at risk for adverse systemic effects of β receptor antagonists Betaxolol- most effective antiglaucoma drug at reducing Na+/Ca2+ influx
  36. 36. Other Uses Propranolol, timolol, and metoprolol are effective for the prophylaxis of migraine Propranolol- effective in controlling acute panic symptoms in individuals who are required to perform in public or in other anxiety-provoking situations
  37. 37. Propranolol also may be useful in the treatment of essential tremor Of some value in the treatment of patients undergoing withdrawal from alcohol or those with akathisia Propranolol and nadolol are efficacious in the primary prevention of variceal bleeding in patients with portal hypertension
  38. 38. Adverse Effects and Precautions On Cardiovascular System β receptor antagonists may induce congestive heart failure in susceptible patients Life-threatening bradyarrhythmias Symptoms of peripheral vascular disease may worsen Abrupt discontinuation of receptor antagonists after long-term treatment can exacerbate angina and may increase the risk of sudden death
  39. 39. Pulmonary function May cause a life-threatening increase in airway resistance CNS Fatigue, sleep disturbances (including insomnia and nightmares), & depression Metabolism Should be used with great caution in patients with diabetes who are prone to hypoglycemic reactions Miscellaneous Sexual dysfunction Pregnancy
  40. 40. Drug Interactions Aluminum salts, cholestyramine, and colestipol may decrease the absorption of β blockers Phenytoin, rifampin, and phenobarbital, smoking- induce hepatic biotransformation enzymes - decrease plasma concentrations of receptor antagonists (e.g., propranolol) Cimetidine and hydralazine may increase the bioavailability of agents such as propranolol and metoprolol by affecting hepatic blood flow
  41. 41. Overdosage Hypotension, bradycardia, prolonged AV conduction times, and widened QRS complexes are common manifestations of overdosage
  42. 42. Non-Selective β Adrenergic Receptor Antagonists Propranolol For HTN & angina, initial oral dose 40-80 mg/day Uses - supraventricular arrhythmias, ventricular arrhythmias, PVCs, digitalis-induced tachyarrhythmia's, MI, pheochromocytoma, essential tremor & prophylaxis of migraine
  43. 43. Nadolol Long-acting antagonist with equal affinity for 1 and 2 receptors Distinguishing characteristic of nadolol is its relatively long t1/2 Timolol A potent, non-selective β receptor antagonist Interestingly, the ocular formulation of timolol used for the treatment of glaucoma, may be extensively absorbed systemically Adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure
  44. 44. Pindolol with intrinsic sympathomimetic activity Used to treat angina and hypertension Preferred as antihypertensive in indivisual with diminished cardiac reserve or propensity to bradycardia
  45. 45. β1 selective adrenergic receptor antagonists Metoprolol Devoid of ISA and MSA Significant first-pass metabolism Uses: essential HTN, Angina, tachycardia, CHF, Adjunct to treat hyperthyroidism Atenolol Very hydrophilic Also used in graves disease Initial dose is 50 mg/day OD may be ↑100 mg Less CNS s/e than other β blockers and less bronchoconstriction
  46. 46. Esmolol Rapid onset ,short duration Also class 2 anti arrhythmic Slow iv injection Used during surgeries to prevent or treat tachycardia And SVT Useful in severe post op HTN AHA/ACC recommends against using esmolol in patients already on β blockers, bradycardiac pts and decompensated heart failure pts Betaxolol Mainly used in glaucoma to ↓IOP by↓ production of aqueous humor
  47. 47. Acebutalol Have lipophilic properties Used for HTN, arrhythmias, MI, Smith Magenis syndrome Bisoprolol Higher β1 selectivity than others except Nebivolol Used in HTN ,CHF Well tolerated a/w 34% mortality benefit in CIBIS2
  48. 48. THIRD GENERATION β BLOCKERS NITRIC OXIDE PRODUCTION ALPHA2 RECEPTOR AGONISM ALPHA1 RECEPTOR ANTAGONISM Ca2+ ENTRY BLOCKADE K+ CHANNEL OPENING ANTIOXIDANT ACTIVITY Celiprolola Celiprolola Carvedilol Carvedilol Tilisolola Carvedilol Nebivolol Carteolol Bucindolola Betaxolol Carteolol Bopindolola Bevantolola Bevantolola Bopindolola Nipradilola Nipradilola Labetalol
  49. 49. Labetalol Selective Alpha1 and Nonselective Beta Blocker ↓ BP by ↓ SVR (alpha1) Vasodilation via α1 blockade & partial beta2 agonist activity ↓ HR by attenuating reflex tachy via β Blockade Unchanged C.O. S/e – postural hypotension Bucindolol ↑ LV systolic EF, ↓PR hence ↓afterload ↑plasma HDL
  50. 50. Carvidilol Has antioxidant and anti inflammatory property Produces vasodilation FDA approved for HTN, CHF,LV dysfunction following MI Improves ventricular function and ↓ mortality and morbidity in mild to severe CHF Celiprolol Selective β1 receptor antagonist, but a β2 receptor partial agonist. It is also a weak α2 receptor antagonist Recent clinical trial – possible use – vascular complications of Ehler Danlos syndrome
  51. 51. Nebivolol Highly selective NO donorvasodialation, potential to improve endothelial fuction, no deleterious effect on lipid profile & carbohydrate metabolism Use: HTN, CHF
  52. 52. Tissues or organs employed for the study of Adrenoceptors  α1 receptor system 1. Rat isolated vas deference (contraction) 2. Rabbit and guinea pig isolated aorta (contraction) 3. Rabbit isolated jejunum (inhibition) 4. Guinea pig isolated ileum (inhibition)  α2 receptor system 1. Transmurally stimulated rat isolated vas deferens (inhibition) 2. Electrically stimulated guinea pig isolated ileum (inhibition)
  53. 53.  β1 receptor system 1. Rabbit isolated perfuse heart (contraction) 2. Rabbit isolated jejunum (inhibition)  β2 receptor system 1. Guinea pig perfused lungs (brochodilatation) 2. Rat isolated uterus (inhibition) 3. Anaesthetized dog B.P (depression)  Both α and β receptor system 1. Mouse isolated spleen (α- contraction, β-relaxation)
  54. 54. Conclusion Thank you
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