adrenoreceptor

1. PHARMOCOLOGY
Adrenoreceptor antagonist
Amrit Pandey(05) and Anil Regmi(06)
B.V.Sc. And A.H.
4th semester

2. Introduction
 adrenoreceptor are G-protein coupled receptor
which are activated by catecolamines,
norepinephrine and epinephrine.
 They are of two types i.e. Alpha(α) and
beta(β).

3. Adrenoreceptor
antagonist(Sympatholytic)
 Are group of drug which interfere with the post
ganglionic functioning of the sympathetic nervous
system.
 Mostly used for the treatment of cardiovascular
disease.
 Act by either blocking the adrenergic receptor(α
and/or β) or affecting the synthesis, storage or release
of norepinephrine from its storage site.

4. Contn………
 They are divided into two groups i.e.
1.adrenergic receptor blocking drugs
2.adrenergic neuron acting drugs

5. Adrenergic receptor antagonist
 They interact with adrenergic receptor (α and/or β)
on effecter cells and do not allow endogenous
catecolamines or exogenous sympathomimetic drug
to act on them.
 Depending on the adrenergic receptors acting upon
by ; they are divided into three main groups i.e.
1.alpha-adrenergic receptor antagonist
2.beta-adrenergic receptor antagonist
3.alpha and beta adrenergic receptor antagonist

6. Alpha-adrenergic receptor
antagonist
 These inhibit responses mediated through α-
adrenergic receptor without affecting those mediated
through β-adrenergic receptor.
 Have wide spectrum of pharmacological activities.
 Also have some other unrelated action with
adrenergic receptor blockade.

7. Classification
A. Non-selective alpha adrenergic receptor
antagonist
e.g. phenoxybenzamine, tolazolin, phentolamine etc
B. Selective alpha adrenergic receptor
antagonist
e.g. prazosin, yohimbine, antipemazol, indoramine,
urapidil etc

8. Non-selective alpha adrenergic receptor
antagonist
 Bind to all types of alpha adrenoreceptor (α1 and α2)
and prevent their activation by endogenous
catecolamines and exogenously administrated
sympathomimetics.
 Important effect of these are seen in cardiovascular
system, CNS and PNS.
 Some of these drugs are as follow;

9. 1.Phenoxybenzamine:
 is haloalkaylamine agents that blocks both α1 and
α2 adrenergic receptors .
 Reversible action and used for the treatment of
hypertension especially caused by phaeochrocytoma
(vascular tumor of adrenal gland ; hypersecreation
of epinephrine)

10. a. Mode of action:
 Phenoxybenzamine effect develops gradually ; in
initial stage it may be reversible subsequently the
receptor blockade become irreversible or non-
equilibrium with time.
b. Pharmacological effect :
 Major effect seen by the blockade of alpha adrenergic
receptor of vascular and other smooth muscle.

11. Contn….
 decreases total peripheral resistance, causing
hypotension.
 Heart rate may be increased via de-activation of
the baroreceptor reflex.
 Phenoxybenzamine can block pupillary dilation,
lid retraction, and contraction of the nictitating
membrane.

12. Contn…
c. Therapeutic uses.
 It is administered orally.
 In dogs and cats, phenoxybenzamine reduces
hypertonus at the urethral sphincter.
 In horses, phenoxybenzamine has been used to treat
laminitis and secretary diarrhea.

13. d. Pharmacokinetics.
 No information is available for animals.
 In humans, it is poorly absorbed from the GI tract
with a bioavailability of 20–30%.
 Onset of action of the drug is slow (several hours)
and increases over several days after regular dosing.
 Effects persist for 3–4 days
 Phenoxybenzamine is highly lipid soluble and may
store in adipose tissue. It is metabolized and excreted
in both the urine and bile.
 The plasma t 1/2 is ∼24 hours in humans.

14. e. Adverse effects:
 Hypotension may be enhanced in hypovolemic
animals.
 It should not be used in horses with colic.
2. Dibenamine :
 Dibenamine is structurally related to
phenoxybenzamine.
 It also a long acting non selective α-adrenoreceptor
blockers

15. 3. tolazolin
 Is the imidazoline compound with complex
pharmacological porperties.
 It is weak to modest α1 and α2 adrenergic receptor
blocking drug.
 It also act as direct vasodilation and cardic
stimulants.

16. Contn….
a. PHARMACOLOGICAL EFFECT:
 Causes peripheral vasodilatation and decrease total
peripheral resistance due to direct smooth muscle
relaxant.
 Heart rate increases due to direct cardiac stimulants
effects .
 Blood pressure remains unchanged or often slightly
increase.
 Also stimulates GI smooth muscle and secreation
by salivary, lachrymal and sweat glands.

17. b. Therapeutic uses.
 It is administered IV (slowly) to reverse the
pharmacologic effects of α2-agonists, for example,
xylazine, particularly in ruminants.
c. Pharmacokinetic :
 Well absorbed after oral and prenatal administration.
 But less effective orally due to slow absorption and
fast excretion from kidney.

18.  After IV administration in horses, its action is seen in
5 mins, but have short duration of time due to short
half life i.e. 60mins.
 After IV dose of 4mg/kg in cattle the concentration
of tolazolin is <10 µmg/kg by 96 hrs in tissue and 48
hrs in milk.
 The preslaughter withdrawal time is 8 days and milk
withdrawal time is 48 hrs in cattle.

19. c. Adverse effect:
 Adverse effect in horses include transient
tachycardia, sweating, lachrymation, muscle
fasciculation and nasal discharge.
 Over dose can produce GI hyper motility with mild
colic and transient diarrhea.

20. d. Therapeutic uses:
 In veterinary medicine, tolazoline is used for the
antidote to xylazine overdose.
 In human medicine, tolazoline is used for the
treatment of frost bite and also in the persistent
pulmonary hypertension.

21. 4. Phentolamine:
 More potent α-adrenoreceptor than the tolazoline.
 Its action in cardiovascular system is more similar to
that of phenoxybenzamine.
a. MOA:
 Phentolamine is a competitive α1- and α2-receptor
antagonist.

22. b. Pharmacologic effects
 Heart rate may be increased by de-activation of the
baroreceptor reflex or by blocking the presynaptic
α2-receptors of the heart.
 Blood pressure is lowered by inhibition of α1- and
α2-receptors in vascular smooth muscle.
c. Therapeutic uses.
 is administered IV or IM to treat hypertension and to
control high blood pressure resulting from
sympathomimetic amine overdose.

23. d. Pharmacokinetics.
 No information is available for animals.
 In humans, it is metabolized in the liver and is
excreted into the urine mostly as metabolites. The
elimination t 1/2 is ∼20 minutes.
e. Adverse effects.
 Tachycardia is frequently observed.

24. SELECTIVE α-ADRENERGIC
RECEPTOR BLOCKERS
A. Selective α1-adrenergic receptor antagonist:
 These are the new class of anti-adrenergic drug
primarily to inhabit α1-adrenergic receptors in
blood vessels without an appreciable effect on α2-
receptors.
 They are mainly used for the treatment of the
hypertension and have largely replaced the non-
selective haloalkylmine and imidazole α-receptor
antagonist.

25. 1. Prazosin
a. Mechanisms of action:
 Are extremely potent and highly selective α1-
adrenergic receptor blocking drug with no effect on
the α2-adrenergic receptors.
 Its affinity for α1-adrenergic receptor is 1000 times
greater than α2-adrenergic receptor.
 It has equal potencies for its all subtypes.

26. b. Pharmacological effect:
 Are result of its blockade of α1-adrenergic receptors in
arterioles and veins.
 Prazosin relaxes arterial and venous smooth muscle.
 There is a decrease in total peripheral resistance. High
doses may cause hypotension.
c. Pharmocokinetics :
 The pharmacokinetics studies on prazosin in animals are
limited.

27.  In human, prazosin is well absorbed after oral
administration with bioavailability of 50-70%.
 Its peak level reach in 2-3 hours and highly bound
to plasma proteins (95%).
 Prazosin is extensively metabolized in liver and
excreated mainly in inactive products in faces via
bile.
 Its duration of time is about 6-8 hrs.

28. d. Adverse and side effects:
 Adverse effects include diarrhea, tachycardia,
hypotension, and fluid retention.
e. Clinical uses:
 Primarily used in human beings and less in animals
for the management of hypertension.
 Occasionally could be used for the adjunctive therapy
of congestive heart failure.

29. 2. Terazosin :
 Structural analogue of prazosin however, it is less
potent, but longer acting (>12 hrs) .
 Its bioavailability after oral administration is also
better (>90%).
Other quinazoline derivatives are Doxazosin,
trimazosin ; which are primarily used for the
human medicine.

30. Selective alpha2-adrenergic
receptor antagonist
Selective α2-adrenergic receptor antagonist are a
special class of anti-adrenergic drug which are used
mainly to reverse the adverse effect of α2-
adrenoreceptor agonist such as xylazin and
meditomidine.
1. Yohimbine:
 indolealkylamine alkaloid with selective α2-
adrenoreceptor antagonist.
 obtained naturally from the bark of West African
evergreen tree pausinystalia yohimbi.

31. a. Mechanisms of action:
 is a competitive α2-receptor antagonist that promotes
the formation of cAMP by blocking α2-receptor
activation.
b. Pharmacologic effects:
 cause CNS stimulation, increased heart rate, and
increased blood pressure by increasing NE release
from the adrenergic nerve endings.
 can increase GI motility by increasing
parasympathetic tone.
 it may increase plasma insulin levels, because α2-
receptors inhibit insulin release.

32. d. Pharmacokinetics
 it is distributed evenly after IV administration. The
total body clearance is 35 ml/min/kg in horses and 30
ml/min/kg in dogs.
 The t 1/2 of the drug is 0.5–1.5 hours in horses and
1.5–2 hours in dogs.
e. Adverse effects :
 are primarily CNS stimulation, tachycardia,
hypertension, and increase in GI motility.

33. f. Therapeutic uses:
 Yohimbine is used IV and IM in monogastric
animals to reverse the effects of α2-receptor agonists
(i.e., xylazine, detomidine, medetomidine, and
romifedine)
 Yohimbine is marginally effective in ruminant.

34. 2. ANTIPAMEZOLE:
They are synthetic selective α2-adrenoreceptor
blocking drug primarily used as a reversal drug for
medetomidine and xylazine.
a. Pharmacological effects :
 Competitively blocks α2-adrenoreceptors in the
CNS and periphery, reverse the sedative, anesthetic
and cardiovascular effects.
 It cannot reverse the sedative effect of sedative and
analgesic class of drug.

35.  Transient decrease in systolic blood pressure,
followed by an increase in blood pressure.
b. Pharmacokinetics:
 It is administered IM, IV, or SC, but IM route is
preferred.
 After IM administration in the dog, peak plasma
levels occur in 10 minutes.
 It is metabolized in the liver to compounds that are
eliminated in the urine.
 Plasma half life of antipamezole is about 2-3 hours.

36. c. Adverse effects:
 Includes transient excitation, hypotension,
hypothermia, vomiting, panting, diarrhea and
salivation.
d. Clinical uses:
 It is used for the reversal of adverse effects of
medetomidine and dexmedetomidine.
 After 10 min of administration atipamezole shows
the effect in case of dog.

37. Beta-adrenergic receptor
anatagonist
 All drugs are the synthetic compound and
competitively inhabit the action of adrenergic agonist
on beta receptors.
 Used for the treatment of various cardiovascular
disorder such as hypertension, ischemic heart
disease, congestive heart failure and certain
arrhythmias.

38. Classification of beta-adrenergic
receptor antagonist
1. Non-selective beta-adrenergic receptor antagonist
e.g. :-propranolol, nadolol, pindolol, timolol, satolol
etc
2. Selective beta-adrenergic receptor antagonist :
a. selective beta1-adrenergic receptor antagonist
e.g. : metoprolol, atenolol, esmolol,betaxolol etc
b. selective beta2-adrenergic receptor antagonist
e.g. :butaxamine

39. Non-selective beta adrenergic
receptor antagonist
1. Propranolol :
a. Mechanisms of action:
 Propranolol is a nonselective β-receptor antagonist
that competitively blocks both β1- and β2-receptors.
 Also the type II antiarrhythemic drugs and acts as
powerful anesthetic drug.
 propranolol have inhibitory effect on transport and
storage of NE.

40. b. Pharmacologic effects:
 Propranolol decreases the sinus heart rate and
depresses AV conduction.
 decreases cardiac output.
 decreases myocardial oxygen demand.
 decreases the automaticity of cardiac tissue.
 increases airway resistance.

41. c. Therapeutic uses.
 It is administered IV, IM, SC, or orally for following
conditions:
 used to treat cardiac arrhythmia and hypertension
associated with thyrotoxicosis and pheochromocytoma,
respectively.
 It is used to treat arrhythmias (e.g., atrial and ventricular
premature complexes and supraventricular and
ventricular tachycardia).

42. d. Pharmacokinetics
 Propranolol is well absorbed following oral
administration.
 Propranolol is highly lipid soluble and readily crosses
the blood–brain barrier.
 The t 1/2 in dogs is 1–2 hours and <2 hours in
horses.
 There is a significant first-pass effect, which reduces
the systemic bioavailability. In dogs, only 2–27% of
an oral dose reaches the blood. Rapid metabolism
occurs in the liver. More than 99% of propranolol is
excreted as metabolites.

43. e. side/adverse effect :
 Result of beta-adrenoreceptor blockade and include
bradycardia, depression, impaired AV conduction,
congestive heart failure, hypotension, hypoglycemia
and bronchoconstriction.
 In case of dog nausea, vomiting and diarrhoea.

44. f. Contraindications :
 may cause bronchospasm and is contraindicated in
asthmatic animals.
 is contraindicated in animals with heart failure or
sinus bradycardia.
 is contraindicated in animals with hepatic disease.

45. Selective beta1-adrenergic
receptor antagonist
1. Metoprolol:-
a. Mechanism of action:
 is a selective β1-receptor antagonist. However, at
high doses it blocks β2-receptors as well.
b. Pharmacologic effects:
 Cardiovascular effects secondary to metoprolol’s
negative inotropic and chronotropic actions include
decreased sinus heart rate, slowed AV conduction,
diminished cardiac output, decreased myocardial
oxygen demand, reduced blood pressure, and
inhibition of the β-agonist-induced tachycardia.
.

46. c. Pharmocokinetics:
 is moderately lipophilic, so rapidly absorbed from the
GI tract .
 First pass metabolites are less marked (<50%) then
propranolol.
 Low plasma protein binding and is distributed well
into most tissue including the brain.

47. d. Therapeutic uses.
 Metoprolol can be used to treat supraventricular
tachyarrhythmias, premature ventricular contractions,
systemic hypertension, hypertrophic cardiomyopathy,
and thyrotoxicosis in cats.
 It is administered orally at every 12 hours. Because
metoprolol is relatively safe to use in animals with
bronchospastic disease, it is often chosen over
propranolol.

48. e. Adverse effects.
 They are similar to the adverse effects of propranolol.
2. Atenolol :
a. Mechanism of action.
 Atenolol is a competitive β1-receptor antagonist.
b. Pharmacologic effects.
 decreases heart rate, cardiac output, and systolic and
diastolic pressures.

49. c. Therapeutic uses:
 administered orally to treat supraventricular
arrhythmias, hypertrophic cardiomyopathy in cats,
and hypertension.
d. Pharmacokinetics:
 Atenolol has low lipid solubility and unlike
propranolol, only small amounts of atenolol are
distributed into the CNS.
 The plasma t 1/2 in dogs is 3.2 hours and in cats, it is
3.7 hours. Duration of β-adrenergic blockade in cats
is ∼12 hours.

50. e. Adverse effects:
 Excessive β1-blockade can greatly reduce cardiac
output.
 It is a negative inotrope, so it must be used with
caution in patients with congestive heart failure, in
renal failure patients, and in patients with sinus node
dysfunction.
 can cause hypotension and diarrhea.

51. Selective beta2-adrenergic
receptor antagonist
Butaxamine :
 Is selective beta2-adrenergic receptor antagonist.
 It is not used as blockade of beta 2 adrenergic
receptors has no therapeutic applications and on the
other hand causes bronchoconstriction.

52. Alpha and beta adrenergic
receptor antagonist
Labetolol :
 At low doses blocks only beta receptors but at higher
doses blocks both α and β receptor.
 It blocks both β-receptor but blocks only α1-
receptor.
 Causes fall in blood pressure without causing the
vasoconstriction.
 Used for treating hypertension.

53. a.Pharmacological effect :
 Cause fall in both systolic and diastolic blood
pressure due to alpha and beta blockade.
 At high dose cardiac output is decreased .
b. Pharmocokinetics:
 Effective after oral but undergoes first pass
metabolisms .
 Rapidly metabolized in liver and rate of
biotransformation is sensitive to hepatic blood flow.

54. c. Therapeutic uses :
 Used for treating hypertension and is particularly
useful in phaeochromocytoma.
 Also used in the treatment of pregnancy-induced
hypertension.
d. Side effect:
 Causes weakness, fatigue, sexual dysfunction,
depression, bronchoconstriction and edema.

55. Thanks for your attention……