Pharmacology Lecture Slides on Adrenergic Drugs- Catecholamines by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Adrenergic Drugs-
Catecholamines
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Role of the Sympathetic Division
• The sympathetic division is the “fight-or-flight” system
• Involves E activities –
– exercise,
– excitement,
– emergency, and
– embarrassment
• Promotes adjustments during exercise – blood flow to organs
is reduced, flow to muscles and heart is increased
• Its activity is illustrated by a person who is threatened
– Heart rate increases, and breathing is rapid and deep
– The skin is cold and sweaty, and the pupils dilated

4. NEUROTRANSMITTER
SYNTHESIS
Transmitter synthesis involves the following.
L-tyrosine is converted to
dihydroxyphenylalanine (DOPA) by
tyrosine hydroxylase (rate-limiting step).
Tyrosine hydroxylase occurs only in
catecholaminergic neurons.
DOPA is converted to dopamine by DOPA
decarboxylase.
Dopamine is converted to noradrenaline
by dopamine β-hydroxylase (DBH),
located in synaptic vesicles.
In the adrenal medulla, noradrenaline is
converted to adrenaline by
phenylethanolamine N-methyl
transferase.

5. sympathomimetic drugs
Catecholamines and
sympathomimetic drugs are
classified as:
 Direct acting
 Indirect acting
 Mixed acting
sympathomimetics.

7. sympathomimetic drugs
Direct-acting sympathomimetic drugs act
directly on one or more of the adrenergic receptors.
These agents may exhibit considerable
selectivity for a specific receptor subtype, e.g.,
 Phenylephrine for a1,
 Terbutaline for b2
or may have no or minimal selectivity and act
on several receptor types:
Epinephrine for a1, a2, b1, b2, b3 receptors;
[Epinephrine may be considered a single
prototype agent to affect all the receptor types.]
Nor-epinephrine for a1, a2, b1 receptors

8. sympathomimetic drugs
Indirect-acting drugs increase the
availability of nor-epinephrine or
epinephrine, in several ways:
(1) By releasing or displacing nor-
epinephrine from sympathetic nerve
varicosities (Ephedrine, Bretylium);
(2) By blocking the transport of nor-
epinephrine into sympathetic neurons (e.g.,
cocaine); or
(3) By blocking the metabolizing
enzymes, -(MAO) (e.g., pargyline) or
(COMT) (e.g., entacapone).

9. sympathomimetic drugs
Drugs that indirectly
release nor-epinephrine
and also directly activate
receptors are referred to as
mixed-acting
sympathomimetic drugs
(e.g., ephedrine,
dopamine).

10. CATECHOLAMINES &
SYMPATHOMIMETICS
Dopamine, norepinephrine, and epinephrine are
physiologically active molecules known as catecholamines.
Catecholamines act both as neurotransmitters and
hormones vital to the maintenance of homeostasis
through the autonomic nervous system.

11. CATECHOLAMINES &
SYMPATHOMIMETICS
Most of the actions of sympathomimetic agents can
be classified into seven broad types:
1)A peripheral excitatory action on certain
types of smooth muscle, such as those in blood
vessels supplying skin, kidney, and mucous
membranes, and on gland cells, such as those in
salivary and sweat glands;
(2) A peripheral inhibitory action on certain
other types of smooth muscle, such as those in
the wall of the gut and in blood vessels supplying
skeletal muscle;

12. CATECHOLAMINES &
SYMPATHOMIMETICS
(3) A cardiac excitatory action (Beta-1&2)
Increases heart rate, conduction and force of
contraction;
(4) Metabolic actions
Increase in the rate of glycogenolysis in liver and
muscle and liberation of free fatty acids from adipose
tissue;
(5) Endocrine actions
Modulation (increasing or decreasing) of the
secretion of insulin, renin, & pituitary hormones;

13. CATECHOLAMINES &
SYMPATHOMIMETICS
(6) Actions in CNS
Respiratory stimulation, an increase in
wakefulness and psychomotor activity, and a
reduction in appetite; and
(7) Pre-junctional actions
Inhibit or facilitate release of neurotransmitters,
the inhibitory action being physiologically more
important.
(8) Gastrointestinal system:
Both Alpha & beta receptors are located in smooth
muscle and ENS
Relaxation of smooth muscle (both)
Decrease in salt & water secretion (Alpha)

14. CATECHOLAMINES &
SYMPATHOMIMETICS
(9) Respiratory system:
Bronchial muscle is relaxed markedly in response to
beta2 agonists (salbutamol)
(10) Eyes:
The smooth muscle of pupillary dilator responds
to topical phenyephrine and similar alfa agonist with
mydriasis
Not all sympathomimetic drugs show each types of
action to the same degree.

15. Catecholamines- properties
High potency:
Drugs that are catechol derivatives show the highest
potency in directly activating a & b receptors.
Rapid inactivation:
They are metabolized by COMT post-synaptically
and by MAO intraneuronally. Thus, catecholamines
have only a brief period of action when given
parenterally, and they are ineffective when
administered orally.
Poor penetration into the CNS:
Catecholamines are polar and, therefore, do not
readily penetrate into the CNS. Nevertheless, most of
these drugs have some clinical effects (anxiety,
tremor, and headaches) that are attributable to action
on the CNS.

16. NOTES
Catecholamines are all rapidly inactivated by
COMT/ MAO, and hence inactive orally.
When given parenterally, they do not enter the
CNS in significant amounts.
Isoproterenol, a synthetic catecholamine is
not readily re-uptaken by the nerve endings.
Amphetamine and similar drugs are resistant
to MAO action and since are not catecholamines
are also resistant to COMT metabolism. Hence are
orally active and enter CNS, provide long
lasting effect.


17. b
ENDOGENOUS
CATECHOLAMINES
Noradrenaline (NA)
It acts as transmitter at post-ganglionic
sympathetic sites (except sweat glands, hair
follicles and some vasodilator fibres) and in
certain areas of brain.
Adrenaline (Adr)
It is secreted by adrenal medulla and may
have a transmitter role in the brain.
Dopamine (DA)
It is a major transmitter in basal ganglia,
limbic system, CTZ, anterior pituitary, etc.
and in a limited manner in the periphery.

19. Epinephrine
Epinephrine (adrenaline) is a very potent stimulant
of both a and b adrenergic receptors, and a well
known vasoconstrictor and cardiac stimulant.
It has positive inotropic and chronotropic actions
on the heart (b1 receptors) and the vasoconstriction
induced in many vascular beds ( a receptors), causing a
rise in BP.
Epinephrine also activates b2 receptors in some
vessels (eg, skeletal muscle blood vessels), leading to
their dilation. Consequently, total peripheral
resistance may actually fall, explaining the fall in
diastolic pressure that is sometimes seen with
epinephrine injection.
Activation of these b2 receptors in skeletal muscle
contributes to increased blood flow during exercise.

20. Epinephrine
BP--Epinephrine is one of the most
potent vasopressor drugs.
Rapid IV route, BP rises rapidly to
a peak proportional to the dose.
At small dose: fall in BP (Beta-2):
vasodilatation
At moderate dose: biphasic
response, ie increase in BP (beta-1);
increase in systolic > diastolic (beta-2),
subsequently the mean BP falls below
normal before returning to control value

21. Epinephrine
Vascular Effects
Both vasoconstriction (a) and vasodilatation
(b2) can occur depending on the drug, its dose and
vascular bed.
Vasoconstriction (a 1) is seen on the smaller
arterioles and pre-capillary sphincters,
although veins and large arteries also respond to
high dose.
Injected epinephrine markedly decreases cutaneous
blood flow, constricting pre-capillary vessels and
small veinules.
Dilatation predominates in skeletal muscles,
liver and coronary arteries.

22. Epinephrine
Respiration
Adr and isoprenaline, but not NA are potent
bronchodilators (b2).
Adr given by aerosol additionally decongests
bronchial mucosa by a action.
 Adr can directly stimulate respiratory centre
(RC) in high doses.
Toxic doses of Adr cause pulmonary edema
by shifting blood from systemic to pulmonary
circuit.

23. Epinephrine
Eyes
Mydriasis (a1)
Adrenaline penetrates poorly into cornea, minimal
effect following topical use.
IOP falls in wide angle glaucoma.
ADR has complex effects on
aqueous humour dynamics.
Overall, aqueous humour
formation is reduced and the
outflow is facilitated.

24. Epinephrine
GIT
Relaxation through activation of both a & b receptors
In intact animals peristalsis is reduced & sphincters are
constricted for short time & hence no clinical impact.
Bladder- hinder micturation
Detrusor relaxed (b)
Trigone constricted (a)
Uterus
Contraction (a) – Human non pregnant
Relaxation (b2)--- Human pregnant at term only
Spleen
Contracts (a)- more RBCs enter circulation
Action not seen in man.

25. Epinephrine
Skeletal muscle
Neuromuscular transmission is facilitated.
Alpha receptor activation on motor nerve endings
augments ACh release, probably because it is of the
alpha1 subtype.
CNS
Owing to poor penetration in the brain, does not produce
marked effects.
But restlessness, apprehension and tremor may occur.
Activation of alpha2 receptors in brainstem decreases
the sympathetic outflow, fall in BP and bradycardia.

26. Epinephrine
Metabolic effects
Glycogenolysis, hyperglycaemia,
hyperlactacidaemia (b2); lipolysis ---rise in
plasma free fatty acid (FFA).
Transient hyperkalemia followed by
hypokalaemia due to direct action on liver,
muscle and adipose tissues.
Reduction in Insulin secretion (alpha2)
Augmentation of glucagon secretion (b2)
Increase in O2 consumption

27. Routes
Subcutaneous: 0.1-0.5 mg of 1: 1000 aqueous
solution of epinephrine HCl
Intra-cardiac injection administered only in
cardiac arrest
Ophthalmic solution: epinephrine bitartate,
epinephrine hcl
Spray (aerosol): in ENT surgery.
IM- preferred in anaphylaxis

28. Epinephrine--THERAPEUTIC USES
Acute hypersensitivity reactions, including
anaphylaxis, to drugs (penicillin)and other
allergens.
To prolong the action of (LAs) local anesthetics,
presumably by vasoconstriction and a consequent
reduction in absorption.
It may restore cardiac rhythm in patients with
cardiac arrest.
A topical hemostatic agent on bleeding surfaces
such as in the mouth or in bleeding peptic ulcers
during endoscopy of the stomach and duodenum.
Inhalation may be useful in the treatment of
post-intubation.

29. Epinephrine—A/E
Restlessness, throbbing headache, tremor,
and palpitations; these effects rapidly subside with
rest, quiet, recumbency, and reassurance.
Serious A/E
Cerebral hemorrhage (sharp BP rise) [accidental
overdose or rapid IV injection]
Ventricular arrhythmias with Digitalis
Angina in patients with CAD
C/I
Patients taking non-selective Beta blocker drugs.
Unopposed vascular a1 –severe HTN and cerebral
hemorrhage.

30. Norepinephrine
Norepinephrine is released by mammalian
postganglionic sympathetic nerves.
NE constitutes 10% to 20% of the catecholamine
content of human adrenal medulla and as much as
97% in some pheochromocytomas, which may lack
the enzyme phenylethanolamine-N-
methyltransferase.
Pharmacological Properties
Norepinephrine & epinephrine have similar effects
on b1 receptors in the heart and differ mainly in
their effects on a and b2 receptors.

31. Norepinephrine
Norepinephrine has little effect
on b2 receptors. Consequently,
increases peripheral
resistance and both diastolic
and systolic blood pressure.
Compensatory vagal reflexes
cancel positive chronotropic
effects; however, the positive
inotropic effects on the heart
are maintained.

32. Norepinephrine
Therapeutic Uses
Limited
therapeutic value.
In shock
In the treatment
of low blood
pressure, the dose is
titrated to the desired
presser response.

33. Norepinephrine- A/E
Resembles that of Adrenaline
Typically greater elevation of BP with NE
Severe HTN with excessive doses
Necrosis and sloughing- IV extravasation
Impaired circulation at injection sites, with
or without extravasation of NE, may be relieved
by infiltrating the area with phentolamine, a
receptor antagonist.
Reduced blood flow to organs such as kidney
and intestines is a constant danger with the use
of NE.

34. Dopamine

It is agonist @ dopamine (D1 and D2) as well
as adrenergic Alpha and Beta1 (But not Beta
2) receptors.

The D1 receptors in renal and mesenteric
blood vessels are the most sensitive: IV
infusion of low dose of DA dilates these
vessels (by raising intracellular cAMP).

Thereby increasing GFR and Na+ excretion.

35. Dopamine Effects

Moderately high doses produce a positive inotropic
(direct B1 and D1 action + that due to NA release),
but little chronotropic effect on heart.

Vasoconstriction (alpha 1 action) occurs only when
large doses are infused.

At doses normally employed, it raises cardiac
output and systolic BP with little effect on diastolic
BP.

It has practically no effect on non-vascular alpha
and beta receptors; does not penetrate blood-brain
barrier-no CNS effects.

36. Dopamine- Uses

Cardiogenic or septic shock

Severe CHF

It increases BP and urine outflow.

It is administered by i.v. infusion (0.2-1
mg/min) which is regulated by monitoring BP
and rate of urine formation.

37. Non-Catecholamines:
Important General Properties :
 Do not contain catechol (Dihydroxybenzene)
 Effective orally.
 Given in large doses.
 Long duration of action.
 Resistant to inactivating enzymes (COMT&
MAO) of liver and other tissues .
 Substantial fraction is excreted unchanged.
 Cross BBB & are powerful CNS stimulants.
 Not all are directly acting ,some are indirectly
acting, some are mixed.

38. ISOPROTERENOL
Adrenergic agonist @Beta >>> alpha.
The drug has positive chronotropic and inotropic
actions; it is a potent vasodilator (B).
These actions lead to
 a marked increase in CO associated with
 a fall in diastolic and mean arterial pressure and
 a lesser decrease or a slight increase in systolic
pressure

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