Adrenergic agonists and antagonists act on alpha and beta adrenoreceptors. Direct-acting sympathomimetic drugs act directly on adrenergic receptors, while indirect drugs increase norepinephrine availability. Alpha-1 selective agonists constrict blood vessels and increase blood pressure. Alpha-2 agonists lower blood pressure by suppressing sympathetic outflow. Beta agonists stimulate cardiac contraction and bronchodilation. Alpha antagonists lower blood pressure by reducing peripheral resistance and are used to treat hypertension and benign prostatic hyperplasia.

1. Adrenergic agonists and antagonists
(PC-630)
Dr Bidya Dhar Sahu

2. ADRENOCEPTORS:
α: noradrenaline > adrenaline > isoprenaline
β: isoprenaline > adrenaline > noradrenaline
ADRENERECEPTORS
β
𝞪
𝞪1A
𝞪2
𝞪1B 𝞪1D
𝞪1
𝞪2A 𝞪2B
𝞪2C
β1 β2 β3

3. Mechanism of 𝞪1 receptor:
(Gq mediated GPCR)

4. Mechanism of β
receptor (Gs
mediated) and 𝞪2
receptor (Gi
mediated GPCR):

5. Characteristics of 𝞪
adrenoreceptors:

6. Difference between 𝞪1 and 𝞪2 adrenoreceptors:

7. Characteristics of β adrenoreceptors:

8. Difference between β adrenoreceptors:

10. Direct-acting sympathomimetic drugs:
o These drugs act directly on one or more of the adrenergic receptors.
o These drugs
o may act selectivity for a specific receptor subtype (e.g.,
phenylephrine for α1, terbutaline for β2) or
o may have no or minimal selectivity and act on several receptor types
(e.g., Epinephrine for α1, α2, β1, β2, and β3 receptors;
Norepinephrine for α1, α2, and β1 receptors).

11. Indirect-acting sympathomimetic drugs:
These drugs increase the availability of Norepinephrine or Epinephrine to
stimulate adrenergic receptors by several mechanisms:
o By releasing or displacing NE from sympathetic nerve varicosities
o By inhibiting the transport of NE into sympathetic neurons (e.g., cocaine),
thereby increasing the dwell time of the transmitter at the receptor
o By blocking the metabolizing enzymes, MAO (e.g., pargyline) or COMT
(e.g., entacapone), effectively increasing transmitter supply

12. α1-Selective Adrenergic Receptor Agonists
o The major effects due to activation of α adrenergic receptors in vascular
smooth muscle.
o As a result, peripheral vascular resistance is increased, and blood
pressure is maintained or elevated.
o The clinical utility of these drugs is limited to the treatment of some
patients with hypotension, including orthostatic hypotension, or shock.
𝞪1 agonist: Ex. Phenylephrine, Methoxamine, Midodrine (desglymidodrine), Metaraminol,
Oxymetazocine

13. α2-Selective Adrenergic Receptor Agonists
o Used primarily for the treatment of systemic hypertension.
o Clonidine, an α2-agonist, was developed as a vasoconstricting nasal decongestant;
its lowers blood pressure by activating α2 receptors in the CNS, thereby suppressing
sympathetic outflow from the brain.
o Clonidine decreases discharges in sympathetic preganglionic fibers in the splanchnic
nerve and in postganglionic fibers of cardiac nerves.
o The α2 agonists also reduce intraocular pressure by decreasing the production of
aqueous humor (Ex. clonidine, apraclonidine and brimonidine, applied topically to the
eye, decrease intraocular pressure with little or no effect on systemic blood
pressure).
𝞪2 agonist: Ex. Clonidine, methyldopa (α-methylnoradrenaline), Apraclonidine, Brimonidine,
guanfacine, guanabenz, moxonidine, rilmenidine.
Non-specific 𝞪 agonist: Adrenaline, Noradrenaline

14. β Adrenergic Receptor Agonists
o Major role only in the treatment of bronchoconstriction in patients with asthma or
COPD.
o Minor uses include management of preterm labor, treatment of complete heart block in
shock, and short-term treatment of cardiac decompensation after surgery or in
patients with congestive heart failure or myocardial infarction.
o β Receptor agonists may be used to stimulate the rate and force of cardiac
contraction.
Isoproterenol: (isopropyl norepinephrine, isoprenaline) is a potent, nonselective β
receptor agonist with very low affinity for α receptors.
Adverse Effects
Palpitations, tachycardia, headache, and flushing are common. Cardiac ischemia and
arrhythmias may occur, particularly in patients with underlying coronary artery disease.

15. Dobutamine
o Dobutamine possesses a center of asymmetry; both enantiomeric forms are present in
the racemate used clinically.
o The (–) isomer of dobutamine is a potent α1 agonist and can cause marked pressor
responses. In contrast, (+)-dobutamine is a potent α1 receptor antagonist, which can
block the effects of (–)-dobutamine.
o Both isomers are full agonists at β receptors; the (+) isomer is a more potent β agonist
than the (–) isomer by about 10-fold.
Therapeutic Uses:
Dobutamine has a t1/2 of about 2 min;
Dobutamine is indicated for the short-term treatment of cardiac decompensation that may
occur after cardiac surgery or in patients with congestive heart failure or acute myocardial
infarction.
β1 Adrenergic Receptor Agonists:

16. o Short-Acting β2 Adrenergic Agonists (3-4h)
Metaproterenol (called orciprenaline in Europe), Albuterol, Levalbuterol (R-enantiomer of
albuterol), Pirbuterol, Terbutaline, Isoetharine, Fenoterol, Procaterol.
o Long-Acting β2 Adrenergic Agonists (LABAs) (>12h)
Salmeterol, Formoterol, Arformoterol (an enantiomer of formoterol)
o Very Long-Acting β2 Adrenergic Agonists (VLABAs)
Developed primarily for treating COPD. These drugs are not recommended for treating
asthma. Indacaterol, Olodaterol, Vilanterol
o Other β2-Selective Agonists
Ritodrine: Ritodrine is a β2-selective agonist that was developed specifically for use as a
uterine relaxant.

17. β3 Adrenergic Receptor Agonists:
o In humans, the β3 receptor is expressed in brown adipose tissue, gallbladder, and
ileum and to a lesser extent in white adipose tissue and the detrusor muscle of the
bladder;
o To date, the major therapeutic target that has emerged from this field has been the
development of β3 receptor agonists for use in urinary incontinence
Mirabegron is a β3 adrenergic receptor agonist approved for use against incontinence.
Activation of this receptor in the bladder leads to detrusor muscle relaxation and
increased bladder capacity. This action prevents voiding and provides relief for those
with an overactive bladder and urinary incontinence.
Side effects include increased blood pressure, increased incidence of urinary tract
infection, and headache.

20. ADRENORECEPTOR AGONIST:

21. Clenbuterol, an ‘anabolic’ drug used illicitly by athletes to improve performance is a β2 agonist that acts in this way.
ADRENORECEPTOR AGONIST:

22. TYR—tyrosine;
α M-p-Tyr—α methyl-p-tyrosine;
α M-Dopa—α methyl dopa;
MAO—monoamine oxidase;
MAOI—monoamine oxidase inhibitor;
COMT—catechol-o-methyl
transferase;
NMN—nor-metanephrine;
VMA—vanillyl mandelic acid;
NET—Norepinephrine transporter;
VMAT-2—Vesicular
Figure: Adrenergic neurotransmission and its modification by drugs:

26. False-Transmitter Concept:
o Indirectly acting amines are taken up into sympathetic nerve terminals and
storage vesicles, where they replace NE in the storage complex.
o Phenylethylamines is synthesized in the GI tract by bacterial tyrosine
decarboxylase. The tyramine formed are oxidatively deaminated (MAO) in the
GI tract and the liver, have not reach the systemic circulation in significant
concentrations.
o However, when a MAO inhibitor is administered, tyramine may be absorbed
systemically and transported into sympathetic nerve terminals, the tyramine
then is β-hydroxylated to octopamine and stored in the vesicles in this form.
o As a consequence, NE gradually is displaced, and stimulation of the nerve
terminal results in the release of a relatively small amount of NE along with a
fraction of octopamine.

27. False-Transmitter Concept: (Continue)
o Patients who have received MAO inhibitors may experience severe
hypertensive crises if they ingest cheese, beer, or red wine. These and
related foods, which are produced by fermentation, contain a large quantity of
tyramine and, to a lesser degree, other phenylethylamines.
o When GI and hepatic MAO are inhibited, the large quantity of tyramine that is
ingested is absorbed rapidly and reaches the systemic circulation in high
concentration. A massive and precipitous release of NE can result, causing
hypertension severe enough to precipitate a myocardial infarction or a stroke.
o Methylnoradrenaline is formed as a false transmitter from methyldopa,
developed as a hypotensive drug (now largely obsolete, except during
pregnancy).

28. Pharmacological actions:

29. Pharmacological actions:

30. THERAPEUTIC USES OF ADRENERGIC DRUGS
1. Vascular uses
(i) Hypotensive states (shock, spinal anaesthesia, hypotensive drugs). Shock is a
clinical syndrome characterized by inadequate perfusion of tissues; it usually is
associated with hypotension and ultimately with the failure of organ systems.
(ii) Along with local anaesthetics Adr 1 in 200,000 to 1 in 100,000 for infiltration, nerve
block and spinal anaesthesia.
(iii) Control of local bleeding Ex. Adrenaline
(iv) Nasal decongestant (In colds, rhinitis, sinusitis, blocked nose or eustachian tube)
(v) Peripheral vascular diseases like Buerger’s disease, Raynaud’s phenomena,
diabetic vascular insufficiency, gangrene, frost bite, ischaemic ulcers, night leg
cramps, cerebral vascular inadequacy

31. 2. Cardiac uses
(i) Hypotensive states Cardiac arrest (drowning, electrocution, Stokes-Adams
syndrome and other causes) Adr may be used
(ii) Partial or complete A-V block: Isoprenaline may be used as temporary
measure to maintain sufficient ventricular rate.
(iii) Congestive heart failure (CHF): Controlled short term i.v. infusion of
DA/dobutamine used
3. Bronchial asthma and COPD Adrenergic drugs, especially β2 stimulants
4. Allergic disorders, Adr is a physiological antagonist of histamine
5. Mydriatic Phenylephrine is used to facilitate fundus examination. It tends to
reduce intraocular tension in wide angle glaucoma.

32. 6. Central uses:
(i) Attention deficit hyperkinetic disorder (ADHD): also called minimal brain
dysfunction, is usually detected in childhood and the sufferer is considered a
‘hyperkinetic child’, Ex. Amphetamines
(ii) Narcolepsy Narcolepsy is sleep occurring in fits and is adequately controlled by
amphetamines. Ex. Modafinil
(iii) Epilepsy Amphetamines are occasionally used as adjuvants and to counteract
sedation caused by antiepileptics.
(iv) Parkinsonism Amphetamines improve mood and reduce rigidity (slightly) but do
not benefit tremor. They are occasionally used as adjuvants in parkinsonism.
(v) Weight reduction, currently no approved sympathomimetic anorectic drugs
used.
Ex. Amphetamine, promotes weight loss by suppressing appetite Mirabegron, B3 agonist

33. 7. Nocturnal enuresis in children and urinary incontinence, Amphetamine
affords benefit both by its central action as well as by increasing tone of vesical
sphincter.
8. Uterine relaxant, Isoxsuprine has been used in threatened abortion and
dysmenorrhoea,

34. Adrenergic antagonists

37. ADRENORECEPTOR ANTAGONIST:

39. Pharmacological effects of 𝞪-adrenergic blockers:
1. Effect on Blood Pressure:
o Blockade of vasoconstrictor α1 (also α2) receptors reduces peripheral
resistance and causes pooling of blood in capacitance vessels → venous return
and cardiac output are reduced → fall in BP.
o Postural reflex is interfered with → marked hypotension occurs on standing →
dizziness and syncope.
o The α blockers abolish the pressor action of Adr (injected i.v. in animals), which
then produces only fall in BP due to β2 mediated vasodilatation. This was first
demonstrated by Sir HH Dale (1913) and is called vasomotor reversal of Dale.

40. Pharmacological effects of 𝞪-adrenergic blockers:
2. Reflex tachycardia occurs due to fall in mean arterial pressure and increased
release of NA due to blockade of presynaptic α2 receptors.
3. Nasal stuffiness and miosis result from blockade of α receptors in nasal
blood vessels and in radial muscles of iris respectively.
4. Intestinal motility is increased due to partial inhibition of relaxant
sympathetic influences— loose motion may occur.
5. Hypotension produced by α blockers can reduce renal blood flow → g.f.r. is
reduced and more complete reabsorption of Na+ and water occurs in the tubules
→ Na+ retention and expansion of blood volume.

41. 6. Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by
blockade of α1 receptors (mostly of the α1A subtype) → urine flow in patients with
benign hypertrophy of prostate (BHP) is improved.
7. Contractions of vas deferens and related organs which result in ejaculation are
coordinated through α receptors—α blockers can inhibit ejaculation; this may
manifest as impotence.
8. The α blockers have no effect on adrenergic cardiac stimulation,
bronchodilatation, vasodilatation and most of the metabolic changes, because
these are mediated predominantly through β receptors.
Pharmacological effects of 𝞪-adrenergic blockers:

42. α1-selective antagonist:
o Prazosin is the prototypical α1-selective antagonist.
o The affinity of prazosin for α1 adrenergic receptors is about 1000-fold greater
than that for α2 adrenergic receptors.
o Prazosin has similar potencies at α1A, α1B, and α1D subtypes.
o Interestingly, the drug also is a relatively potent inhibitor of cyclic nucleotide
PDEs, and it originally was synthesized for this purpose.
o Prazosin and the related α receptor antagonists doxazosin and tamsulosin
frequently are used for the treatment of hypertension

43. Terazocin:
o The drug may be taken once daily to treat hypertension and BPH in most
patients.
o It is more effective than finasteride in treatment of BPH.
o Terazosin and doxazosin induce apoptosis in prostate smooth muscle cells.
Alfuzosin:
o Alfuzosin is a quinazoline-based α1 receptor antagonist used extensively in
treating BPH; it is not approved for treatment of hypertension.
o Alfuzosin has a t1/2 of 3–5 h.
o Alfuzosin is a substrate of CYP3A4, and the concomitant administration of
CPY3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir)
is contraindicated. Alfuzosin should be avoided in patients at risk for prolonged
QT syndrome.
o Side effects: postural hypotension and syncope, Nonspecific adverse effects
such as headache, dizziness, and asthenia

44. Therapeutic Uses
o Treatment of hypertension
o Used to treat Pheochromocytoma, It is a tumour of adrenal medullary cells.
Excess CAs are secreted which can cause intermittent or persistent hypertension.
o Congestive Heart Failure
o Benign Prostatic Hyperplasia
o α1-Selective antagonists have efficacy in BPH owing to relaxation of smooth muscle in the bladder
neck, prostate capsule, and prostatic urethra.
o Finasteride and dutasteride, two drugs that inhibit conversion of testosterone to
dihydrotestosterone and can reduce prostate volume in some patients, are approved as
monotherapy and in combination with α receptor antagonists.
o Combination therapy with doxazosin and finasteride reduces the risk of overall clinical progression
of BPH significantly more than treatment with either drug alone.

45. α2 Adrenergic Receptor Antagonists:
o Activation of presynaptic α2 receptors inhibits the release of NE and other
cotransmitters from peripheral sympathetic nerve endings.
o Activation of α2 receptors in the pontomedullary region of the CNS inhibits
sympathetic nervous system activity and leads to a fall in blood pressure.
o Blockade of α2 receptors with selective antagonists such as yohimbine thus
can increase sympathetic outflow and potentiate the release of NE from nerve
endings, leading to activation of α1 and β1 receptors in the heart and
peripheral vasculature with a consequent rise in blood pressure.

46. Yohimbine
o Yohimbine is a competitive antagonist that is selective for α2 receptors.
o The compound is an indole alkylamine alkaloid and is found in the bark of the tree
Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of
reserpine.
o Yohimbine readily enters the CNS, where it acts to increase blood pressure and
heart rate; it also enhances motor activity and produces tremors.
o These actions are opposite to those of clonidine, an α2 agonist.
o Yohimbine also antagonizes effects of 5HT.
o In the past, it was used extensively to treat male sexual dysfunction. However, the
efficacies of PDE5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) and
apomorphine (off-label) have been much more conclusively demonstrated in oral
treatment of erectile dysfunction.

47. Pharmacological action Beta blockers:
Propranolol is considered as prototype of Beta blocker.
1. Cardiovascular System:
Heart:
o Decreases heart rate, force of contraction (at relatively higher doses) and cardiac
output (c.o.).
o Cardiac work and oxygen consumption are reduced as the product of heart rate
and aortic pressure decreases.
o The overall effect in angina patients is improvement of O2 supply/demand status;
exercise tolerance is increased.
o Abbreviates refractory period of myocardial fibres, decreases automaticity and A-V
conduction is delayed.

48. Pharmacological action Beta blockers:
Blood vessels:
o Propranolol has no direct effect on blood vessels and there is little acute change in BP.
o On prolonged administration BP gradually falls in hypertensive subjects but not in
normotensives. Total peripheral resistance (t.p.r.) is increased initially (due to blockade of β
mediated vasodilatation) and c.o. is reduced, so that there is little change in BP. With continued
treatment, resistance vessels gradually adapt to chronically reduced c.o. and t.p.r. decreases—
both systolic and diastolic BP fall. This is considered to be the most likely explanation of the
antihypertensive action.
Other mechanisms that may contribute are:
o Reduced NA release from sympathetic terminals due to blockade of β receptor mediated
facilitation of the release process.
o Decreased renin release from kidney (β1 mediated)
o Central action reducing sympathetic outflow. However, β blockers which penetrate brain poorly
are also effective antihypertensives.

49. Pharmacological action Beta blockers:
2. Respiratory tract
o Increases bronchial resistance by blocking dilator β2 receptors. In asthmatics,
condition is consistently worsened and a severe attack may be precipitated.
3. CNS
o No overt central effects are produced by propranolol.
o However, subtle behavioural changes, forgetfulness, increased dreaming and
nightmares have been reported with long-term use of relatively high doses.
o Propranolol suppresses anxiety in short-term stressful situations.
4. Local anaesthetic
o Propranolol is as potent a local anaesthetic as lidocaine, but is not clinically
used for this purpose because it causes irritation at the injected site.

50. Pharmacological action Beta blockers:
5. Metabolic effect
o Propranolol blocks adrenergically induced lipolysis and consequent increase
in plasma free fatty acid levels.
o Plasma triglyceride level and LDL/HDL ratio is increased during propranolol
therapy.
o It also inhibits glycogenolysis in heart, skeletal muscles and in liver.
6. Skeletal muscle
o Propranolol inhibits adrenergically provoked tremor. This is a peripheral action
exerted directly on the muscle fibres (through β2 receptors).

51. DRUG INTERACTIONS
1. Additive depression of sinus node and A-V conduction with digitalis and verapamil
— cardiac arrest can occur.
2. Propranolol delays recovery from hypoglycaemia due to insulin and oral
antidiabetics. Warning signs of hypoglycaemia mediated through sympathetic
stimulation (tachycardia, tremor) are suppressed. In some cases BP rises due to
unopposed α action of released Adr.
3. Phenylephrine, ephedrine and other α agonists present in cold remedies can cause
marked rise in BP due to blockade of sympathetic vasodilatation.
4. Indomethacin and other NSAIDs attenuate the antihypertensive action of β
blockers.
5. Cimetidine inhibits propranolol metabolism. However, the dose range of propranolol
is wide, and this may not be clinically significant.
6. Propranolol retards lidocaine metabolism by reducing hepatic blood flow.
7. Propranolol increases bioavailability of chlorpromazine by decreasing its first pass
metabolism.

52. ADVERSE EFFECTS AND CONTRAINDICATIONS
o Propranolol can accentuate myocardial insufficiency and can precipitate CHF/edema by
blocking sympathetic support to the heart, especially during cardiovascular stress.
o Propranolol worsens chronic obstructive lung disease, can precipitate life-threatening attack of
bronchial asthma: contraindicated in asthmatics.
o Propranolol exacerbates variant (vasospastic) angina due to unopposed α mediated coronary
constriction.
o Carbohydrate tolerance may be impaired in prediabetics. Plasma lipid profile is altered on long
term use: total triglycerides and LDL-cholesterol tend to increase while HDL- cholesterol falls.
o Withdrawal of propranolol after chronic use should be gradual, otherwise rebound
hypertension, worsening of angina and even sudden death can occur. This is due to
supersensitivity of β receptors occurring as a result of long-term reduction in agonist
stimulation.
o Propranolol is contraindicated in partial and complete heart block: arrest may occur.
o Tiredness and reduced exercise capacity: due to blunting of β2 mediated increase in blood
flow to the exercising muscles as well as attenuation of glycogenolysis and lipolysis.
o Cold hands and feet, worsening of peripheral vascular disease are noticed due to blockade of
vasodilator β2 receptors.

53. THERAPEUTIC USES OF β BLOCKERS:
o Hypertension β blockers are relatively mild antihypertensives.
o Angina pectoris All β blockers benefit angina of effort.
o Cardiac arrhythmias β blockers (mainly propranolol) suppress extrasystoles and tachycardias,
especially those mediated adrenergically (during anaesthesia, digitalis induced)—may be used
i.v. for this purpose.
o Myocardial infarction (MI) In relation to MI, β blockers have been used for two purposes: (i)
Preventing reinfarction, (ii) Preventing sudden ventricular fibrillation at the subsequent attack of
MI.
o Congestive heart failure Although β blockers can acutely worsen heart failure, several studies
have reported beneficial haemodynamic effects of certain β blockers including metoprolol,
bisoprolol, nebivolol, carvedilol over long-term in selected patients with dilated cardiomyopathy.
o Dissecting aortic aneurysm β blockers help by reducing cardiac contractile force and aortic
pulsation. Nitroprusside infusion is often added.

54. THERAPEUTIC USES OF β BLOCKERS:
o Pheochromocytoma β blockers may be used to control tachycardia and arrhythmia,
o Thyrotoxicosis Propranolol rapidly controls the sympathetic symptoms (palpitation, nervousness,
tremor, fixed stare, severe myopathy and sweating) without significantly affecting thyroid status. It
also inhibits peripheral conversion of T4 to T3 and is highly valuable during thyroid storm.
o Migraine Propranolol is the most effective drug for chronic prophylaxis of migraine
o Anxiety Propranolol exerts an apparent antianxiety effect, especially under conditions which
provoke nervousness and panic, e.g. examination, unaccustomed public appearance, etc. This is
probably due to blockade of peripheral manifestations of anxiety
o Glaucoma Ocular β blockers are widely used for chronic simple (wide angle) glaucoma; also used
as adjuvant in angle closure glaucoma
o Hypertrophic obstructive cardiomyopathy: Forceful contraction of this region under
sympathetic stimulation (exercise, emotion) increases outflow resistance which has incapacitating
haemodynamic consequence. β blockers improve c.o. in these patients during exercise by
reducing left ventricular outflow obstruction, though they have little effect while at rest.

55. α + β ADRENERGIC BLOCKERS
Labetalol
o It is the first adrenergic antagonist capable of blocking both α and β receptors.
o The commercial preparation has equal parts of each diastereomer and displays
β1 + β2 + α1 blocking as well as weak β2 agonistic activity.
o The β blocking potency is about 1/3 that of propranolol, while α blocking potency
is about 1/10 of phentolamine.
o Labetalol is 5 times more potent in blocking β than α receptors.
Carvedilol
o It is a β1 + β2 + α1 adrenoceptor blocker; produces vasodilatation due to α1
blockade as well as calcium channel blockade, and has antioxidant property.
o It has been used in hypertension and is the β blocker especially employed as
cardioprotective in CHF. Oral bioavailability of carvedilol is 30%. It is primarily
metabolized and has a to of 6–8 hrs.

58. THANK YOU