An updated PowerPoint presentation on Adrenergic Drugs suitable for UG MBBS level Medical students

1. Antiadrenergic Drugs
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. Introduction
• Drugs which antagonize the receptor action of
Adrenaline and other related drugs at the receptor level
• They occupy adrenergic receptors (α and β ) but do not
produce signal transduction – affinity is there but without
IA - - competitive antagonists
• Antiadrenergics Vs Adrenergic Neurone Blockers !
• For pharmacologic research, adrenoceptor antagonist
drugs have been very useful in the experimental
exploration of autonomic nervous system function
• Effects vary according to the drug's selectivity for and
receptors - α and its subtype specific or β and its
subtype specific

3. Antiadrenergic Drugs -
Background
 Clinically – to modify the responses of endogenous catecholamines
(Adrenaline and Noradrenaline) - physiologic and pathophysiologic
 Nonselective α-antagonists: have been used in the treatment of
pheochromocytoma (tumors that secrete catecholamines), and α-1
selective antagonists are used in primary hypertension and
benign prostatic hyperplasia (BHP)
 β-receptor antagonist: hypertension, ischemic heart disease,
arrhythmias, endocrinologic and neurologic disorders, and
many other conditions
 Blockade of peripheral dopamine receptors is of no recognized
clinical importance at present
 In contrast, blockade of central nervous system dopamine receptors
is very important – antiemetic, antipsychotic and TCAs

4. α – receptor adrenergic
Blockers

5. Drugs –
Classification
 Nonequilibrium type:
 β-haloalkylamines: Phenoxybenzamine
 Equilibrium:
I. Nonselective:
1. Ergots: Ergotamine and Ergotoxine
2. Hydrogenated ergot alkaloids: DHE, Dihydroergotoxine
3. Imidazolines: Tolazoline, Phentolamine
4. Miscellaneous: Chlorpromazine, Histamine and Serotonin
II. Selective α-1: Prazosin, Terazosin, Doxazosin and
Tamsulosin
III. Selective α-2: Yohimbine

6. Ergot Images (Claviceps
purpurea)
Sclerotium – St Anthony`s Fire
Ergotism

7. Ergots
 Natural: considered derivatives of Lysergic acid
(LSD) – cognition enhancer
 Amine alkaloid: Ergometrine (ergonovine)
 Amino acid alkaloids: Ergotamine and ergotoxine –
vasoconstrictor, partial agonist and antagonist at α
receptors and 5-HT receptors (1 and 2)
 Semisynthetic derivatives: Dihydroergotamine
(DHE) and Dihydroergotoxine – more α-
receptor blocking property

8. General Effects of alpha Blockade
- CVS
 Arteriolar and venous tone are determined to a large
extent by receptors on vascular smooth muscle
 Reduction in Blood Pressure: Blockade of α-1 (also α-
2) receptor causes – pooling of blood in capacitance
vessels – reduced venous return and Cardiac output –
fall in mean BP
 Postural Reflex is interfered – dizziness and Syncope on
standing
 Reason: Normally 700 ml of blood is pooled to legs when a person
stands up, and therefore syncope should occur. But do not occur in
case of normal person because of Baroreceptor reflex which
stimulates VMC and sympathetic system is activated. Contraction of
veins occur via α-1 receptor. Blockade of such receptor may therefore
may lead to Postural hypotension
 Vasopressor effects of Adrenaline is not found - Vasomotor
reversal of Dale

9. Effects of alpha Blockade -
Others
 Reflex tachycardia due to fall in - BP and increased
NA release due to presynaptic alpha-2 blockade
 Nasal stuffiness and Miosis
 Increased Intestinal Motility - diarrhoea
 Reduced GFR: Sodium retention and increase in blood
volume – also reflex renin release
 Tone of the Bladder trigone, sphincter and prostate is
maintained by α1A sympathetic
 Blockade produces increased urine flow
 Inhibition of Ejaculation – due to inhibition of contraction
of vas deferens and others

10. Individual Agents -
Phenoxybenzamine
 Non specific, long acting irreversible alpha antagonist
 MOA: Spontaneously cyclizes in the body to give ethyleniminium
intermediate – forms a strong covalent bond with α receptors –
blockade of alpha receptor (lasts for 3 – 4 days)
 Also blockade of 5-HT, histaminergic and cholinergic receptors
 Clinically:
 Postural hypotension: Venodilatation>arteriolar
 In recumbent position, however:
 Blood flow to many organ increased due to reduction in peripheral
resistance and increased venous return
 Shifts blood from pulmonary to systemic circulation
 Shifts blood from extravascular to vascular compartment
 CNS stimulation – nausea, vomiting on IV injection but oral
doses cause depression, tiredness and lethargy

11. DRC
100% _
50% _
0.1 1 10 100
Log dose
A
A+1XC
A+10XC
A = Agonist
C = antagonist

12. Phenoxybenzamine
 Pharmacokinetics:
 Erratic oral absorption and painful on IM or SC injections
 Most of the administered drug Excretes in urine in 24 Hrs
 Small amount may remain in tissue bound covalently – leading to
accumulation in adipose tissue
 ADRs: Postural hypotension, nasal stuffiness, miosis
and inhibition of ejaculation
 Uses:
 Phechromocytoma, Secondary shock and Peripheral vascular
disease (Raynaud`s disease)
 Preparation and dosage:
 20-60 mg orally
 1 mg/kg IV infusion for 1 Hr.

13. Phentolamine
 Non specific, short acting reversible alpha antagonist
 Potent competitive antagonist at both 1 and 2 receptors
 Quick acting (in minutes)
 Reduction in Peripheral Resistance - blocking both α-1 and α-2
receptors - causes NA release and venodilatation more than
arteriolar
 Cardiac stimulation:
 Enhanced NA release due to alpha-2 blockade
 Inhibits serotonin release – muscarinic agonist (?)
 Uses: Pheochromocytoma, clonidine withdrawal, cheese
reaction and in extravasations of NA and Adr injection
 Dose: 5 mg IV injection as and when needed

14. Prazosin
 Highly selective alpha-1 blocker (1:1000)
 Non-specific blockade of all subtypes - α1A, α1B and α1D
 Blockade of sympathetic vasoconstriction - fall in BP
 NA is not released as α-2 is not blocked (only mild tachycardia)
 Dilates arterioles more than veins – Postural hypotension is less –
only 1st
dose effect (dizziness and fainting)
 Also inhibits PDE – rise in smooth muscle cAMP - vasodilatation
 Kinetics: effective orally (70%), metabolized in liver and half life is
6-8 Hrs
 Uses:
 Hypertension
 Raynaud`s disease
 BHP
 Dose: start with 0.5 mg bed time and then 1- 4 mg tds.

15. Other alpha Blockers
 Terazosin:
 Similar to Prazosin but better bioavailability (90%)
 Duration of action is longer – 24 Hrs
 Use: Preferred in BHP – single dose and apoptosis, also in
hypertension
 Similar is Doxazosin
 Tamsulosin:
 Uroselective (vasicoselective) - α1A and α1D but not α1B
 No change in BP and HR at therapeutic doses and
Postural hypotension
 Preferred drug in BHP
 Only once dosing regime (MR caps)
 ADRs: Retrograde ejaculation and dizziness

16. Comparison of alpha blockers
Receptor affinity

17. Uses of α-blockers
Pheochromocytoma:
 Tumor of medullary cells of Adrenals
 VMA and normetanephrine estimation is diagnostic
 Phentolamine test: Injection of 5 mg IV over 1 minute
(recumbent)
 35 mm (Systolic) and 25 mm (Diastolic) of Hg
 Treatment:
 Surgery
 Phenoxybenzamine in preoperatively and intra-operative because:
 To Normalize blood volume: Excess CA shifts blood from vascular to extra
vascular
 To prevent outpouring of CA during surgery
 To prevent unwanted hypotension due to dilatation of blood vessels
following removal of tumor
(Previously - Clonidine suppression test – Measurement of plasma
CA levels)

18. Uses of α-blockers
– contd.
Hypertension:
 Not useful except Prazosin due to
 Compensated cardiac stimulation
 Postural hypotension, Impotence, nasal blockage etc.
 Phentolamine and Phenoxybenzamine – in clonidine withdrawal and cheese
reaction
BHP:
 Static component: Size of prostate (5-alpha reductase)
 Dynamic component: Tone of Prostate and bladder neck (alpha-1
mediated)
 Converts testosterone to active dihydrotestosterone)
 Effects of α blocking – relaxation of neck and prostate structures –
reduction in obstruction
 5-α reductase inhibitors like Finesteride decreases size of the prostate –
better voiding
 α blockers – 2 weeks and 5-alpha reductase inhibitors – 6 months
 Remember – BHP is a progressive disease

19. Other uses of α-blockers
 Secondary Shock – Phenoxybenzamine
 Peripheral vascular disease – beneficial in
Raynaud`s disease
 Congestive Heart Failure – short term
 Papaverine/Phentolamine induced penile
erection (PIPE) for impotence

20. Postural Hypotension and 1st
dose effect
Remember !

21. Next Class
β-adrenergic Receptor
Blockers

22. β - adrenergic Blockers
 Cardioselective:
 Metoprolol, atenolol, acebutalol, bisoprolol,
esmolol, betaxolol, celiprolol, nebivolol
 Nonselective (β1 and β2):
 Without intrinsic sympathomimetic activity:
Propranolol (membrane stabilizing action), Sotalol
and Timolol
 With intrinsic sympathomimetic activity (ISA):
Pindolol and Oxprenolol
 Additional alpha blocking property: Labetolol and
Carvedilol

23. Actions –
Propranolol
 Heart:
 Decrease in Heart rate, decrease in cardiac output, decrease in
force of contraction
 Prolongs systole - synergy of contraction disturbed in ventricles
 Not prominent in Normal persons, but in presence of sympathetic
over activity (exercise, emotion)
 Decreased ventricular size in normal subject – dilatation in low
cardiac reserve patients
 Cardiac work and oxygen consumption - reduced
 Total coronary flow reduction (aortic pressure) – subepicardial
region but not subendocardial region – benefit in angina
 Delayed AV conduction
 At high doses membrane stabilizing and direct depressant action

24. Propranolol –
Blood Pressure
 No direct and acute action on Blood Pressure
 In fact blocks vasodilatation fall in BP by Isoprenaline and enhances
rise in BP by adrenaline – re-reversal of vasomotor reversal
 But beneficial in hypertensives on prolonged administration
 Normally, propranolol would block CA induced vasodilatation and
cause increase in TPR and decrease in cardiac output – but
negligible change in BP
 ADAPTATION: But chronic exposure will lead the resistance
vessels to adapt to chronically low CO – TPR falls (Most possible
explanation of antihypertensive effect)
 Other explanations may be:
 Decreased Renin release (β1)
 Central reduction of sympathetic outflow
 Blockade of NA release – blockade of beta recptors

25. Re-reversal of Vasomotor
reversal

26. Actions - Propranolol
 Respiratory:
 Bronchoconstriction due to blockade of dilator beta-2 receptors
 Not considerable in normal individual - May be dangerous in
presence of asthma (avoid)
 Beta-1 selective drugs are preferred
 Contrary: COPD patients tolerate
 Eye: Decreases IOP by reducing production of aqueous humor –
glaucoma
 CNS: No considerable CNS effect except – behavioural,
forgetfulness and nightmare etc. Suppresses anxiety
 Skeletal Muscle:
 Reduction of Tremor
 Reduction of exercise capacity: reduction in blood flow,
glycogenolysis and lipolysis

27. Propranolol Actions –
Metabolic
 Lipid: Inhibits sympathetic stimulation of lipolysis and
consequent increase in free fatty acid level – triglyceride level
increased. LDL/HDL ratio increases
 Carbohydrate: Inhibition of glycogenolysis in heart, muscle and
liver – β2 mediated
 Recovery from insulin action delayed
 Warning signs are masked
 But, Glucagon is the main hormone that responses to
hypoglycaemia
 Still, beta blockers should be used in caution in patients with
diabetes and low glucagon reserve patients and in
pancreatectomized patients
 β1 selective are much safer

28. Pharmacokinetics (Propranolol
as prototype) - absorption
 Most of the drugs are well absorbed after oral administration;
peak concentrations occur 1–3 hours after ingestion including
propranolol
 Propranolol undergoes extensive hepatic (first-pass) metabolism
 High oral:parenteral ratio – 40:1
 Interindividiual and equieffective dose bioavailability variation
 Metabolism dependent on hepatic blood flow – itself decreases
hepatic blood flow – higher bioavailability on chronic
administration – saturation of hepatic extraction mechanism
 Higher bioavailability if taken with food
 Dose available as 10-80 mg tabs. (40 – 160 mg /day)
 Sustained-release preparations of propranolol and metoprolol are
available

29. Propranolol – ADRs and CI
1. Precipitation of CCF/Oedema –
loss of sympathetic support –
careful addition of beta-1 selective
2. Bradycardia
3. Respiratory: COAD and Bronchial
asthma (life threatening asthma)
4. Risk of Coronary Heart Disease
(triglyceride and LDL increase and
fall in HDL)
5. Tiredness and reduced exercise
capacity – beta-2 muscle
6. Variant angina exacerbation –
unopposed coronary constriction
by alpha receptor
7. Cold hands and feet – worsening
of Peripheral vascular disease
8. Withdrawal
9. Others: GIT upset, nightmare,
forgetfulness and sexual distress

30. Drug Interactions
 Propranolol and insulin:
 Delayed recovery of hypoglycemia by insulin
 Warning signs are suppressed
 Propranolol + alpha agonists: Rise in BP
 NSAIDs + Propranolol: Attenuation of
antihypertensive action of beta-blockers

31. Other Drugs – beta blockers
 Cardioselectivity: More selective in blocking β1 receptors than β2
 Advantages:
 Lower propensity to cause Bronchoconstriction
 Lesser interference with carbohydrate metabolism – safer in diabetics
 Lower incidence of cold hand and feet – no/less β2 block
 Lesser suppression of essential tremor
 Lesser impairment of exercise capacity
 Intrinsic sympathomimetic activity: Pindolol, celiprolol
 Advantages: Partial agonist action
 Lesser bradycardia and depression of contractility – preferred in elderly, sick
sinus syndrome etc.
 Favourable withdrawal
 Less/no interference with lipid profile not effective in migraine prolhylaxis

32. Other beta blockers – contd.
 Membrane stabilizing effect: like lidocaine
 Local anaesthetic action
 Typically blocks Na+ channel – antiarrhythmic
action
 Lipid insolubility: Atenolol, celiprolol,
bisoprolol etc.
 Less likely to produce sleep disturbances
 Longer acting – incompletely absorbed, no first
pass metabolism, excreted unchanged in urine –
t1/2 – 6-2 Hrs Vs 2-6 Hrs

33. Other Beta Blockers
 Metoprolol:
 Prototype of cardioselective blockers - β1 selective (also inverse
agonist)
 Safer in patients with bronchoconstriction and preferred in
patients with insulin
 Less first pass metabolism
 Slow and fast hydroxylators (CYP2D6 substrate)
 Used:
 In Diabetics and patients in OHs
 Cold hands and feet with Propranolol
 Available as tab – 25/50/100/ mg and IV injection
 Atenolol:
 Selective β1 and low lipid solubility, less 1st
pass metabolism
 Longer duration of action – once daily dosing
 No lipid profile adverse effects - Hypertension and angina

34. Other Beta Blockers
 Partial beta-agonist: Pindolol and celiprolol,
carteolol, bopindolol, oxprenolol, and penbutolol:
 Major CVS applications – less plasma lipid action and
bradycardia
 Intrinsic sympathomimetic activity
 However, doubtful clinical benefit
 Esmolol: partial agonist and MSA
 Ultra short acting (less than 10 minutes) - inactivated by
esterases in blood
 Degree of blockade can be titrated - Steady dose can be
maintained
 Given as IV infusion in SVT, AF, Atrial flutter, arrhythmia
during anaesthesia and cardiac surgery etc.
 Available as injections IV: 100 – 500 mg/10 ml inj.

35. Other Beta Blockers
 Celiprolol:
 Selective beta-1 with additional beta-2 agonistic activity
 Safe in asthmatics
 Causes vasodilatation by NO production (NA receptor mediated)
– additional benefit as antihypertensive. Dose: 200-600 mg
 Nebivolol:
 Highly selective beta-1 blocker
 Acts as NO donor - Improves endothelial function and delay of
atherosclerosis
 No deleterious effects on carbohydrate, lipid metabolism
 In CHF and hypertension
 Dose: 2.5/5 mg

36. Uses of Beta Blockers
1. Hypertension: 1st
line of agent (JNC 7)
2. Angina pectoris – not in vasospastic
3. Myocardia infarction:
 Prophylaxis: Prevent reinfarction and Prevent ventricular fibrillation
 Myocardial salvage: reduction in infarct size
1. Cardiac arrhythmias: Class II type of agent – Propranolol IV
(digitalis and anaesthesia induced)
2. Congestive Heart failure
3. Phaeochromocytoma
4. Hyperthyroidism: T4 - T3 + sympathetic symptoms
5. Migraine
6. Anxiety: social phobia
7. Essential Tremor
8. Glaucoma

37. α + β blockers
 Labetolol: Alpha + beta blocker (4 diastereomers)
 Commercially – α1 + β1 + β2 block + β2 agonistic
 Beta blockade – 1/3rd
of Propranolol and alpha – 1/10th
of Phentolamine
 Beta: alpha = 1: 5
 Clinically: Low dose – like propranolol and high dose like Propranolol +
Prazosin
 Fall in BP (Syst + diast) + vasodilatation (beta-2)
 Limb blood flow increases - propranolol does not
 Also inhbition of NA uptake
 Moderately potent and Used in Phaechromocytoma, clonidine withdrawal
 ADRs: Postural hypotension, failure of ejaculation and others but no
change in lipid profile
 Carvedilol: β1 + β2 and α1 blocker and also Ca+ channel block
 Vasodilatation – α + Ca++ channel block + antioxidant
 Uses: Hypertension and especially preferred in CHF as cardioprotective

38. Summary
 Usefulness and actions of β blockers shall be discussed
later - in relation to their use in the particular CVS
disease conditions
 Remember:
 Effects of alpha blockade - Phenoxybenzamine, Phentolamine
Test (Phaechromocytoma)
 Selective alpha-1 blockers and uses - Prazosin, Terazosin and
Tamsulosine
 Name with selectivity of β blockers as per classification given
 Pharmacological actions and ADRs of Propranolol as discussed
 Overall therapeutic uses of beta-blockers – general Idea
 Individual drugs - Metoprolol, atenolol, esmolol, Labetolol and
carvedilol etc.

39. THANK YOU