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.

1. Dr Shahid Saache
JR1, Dept Of Pharmacology
B.J.G.M.C PUNE

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

4. End of postganglionic
sympathetic synapse-
adrenergic receptors

5. “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

6. 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

7. 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

8. Metyrosine
Inhibits tyrosine hydroxylase
Adjuvant to phenoxybenzamine & other α adrenergic
blockers for pheochromocytoma & in preoperative
preparation for resection of pheochromocytoma
ADR- crystalluria

9. 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

12. Alpha Blockers

13. 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"

14. 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

15. 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

16. 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

17. 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%)

18. 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%)

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. Non-Selective α Adrenergic
Antagonists:
Phenoxybenzamine & Phentolamine
Referred to as "classical" α blockers
Postural hypotension is a prominent feature can
precipitate cardiac arrhythmias

26. 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

27. 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

28. 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

29. 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

30. 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

31. Beta blockers

32. 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

35. MSA ISA Lipid
Solub.
Absorpn
(%)
BA (%) T1/2 Protein
binding

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. Overdosage
Hypotension, bradycardia, prolonged AV conduction
times, and widened QRS complexes are common
manifestations of overdosage

47. 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

48. 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

49. Pindolol
with intrinsic sympathomimetic activity
Used to treat angina and hypertension
Preferred as antihypertensive in indivisual with
diminished cardiac reserve or propensity to
bradycardia

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. Nebivolol
Highly selective
NO donorvasodialation, potential to improve
endothelial fuction, no deleterious effect on lipid profile
& carbohydrate metabolism
Use: HTN, CHF

57. 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)

58.  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)

59. Conclusion
Thank you