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Drugs of Adrenergic system

Agonists
Antagonists
The adrenergic neuron
Adrenergic neurons release Norepinephrine (NE) as the
neurotransmitter.
These neurons are found in the CNS, and also in the SNS
Neurotransmission at adrenergic neurons
The process involves five steps:
synthesis,
storage,
release, and
receptor binding of NE, followed by removal of the
neurotransmitter from the synaptic gap
The adrenergic receptors are located either
presynaptically on the neuron or
post-synaptically on the effector organs
Biosynthesis of catecholamines
Drug intervention -- Adrenergic transmission

: Stimulatory Tyrosine
: Inhibitory
Solid: Agonistic (Rate-limiting) TH Metyrosine
Dotted: Antagonistic
DopaDA
Reserpine
Adrenergic antagonists
Vesicle (DANE)
Phentolamine (a-blocker)
Propranolol (b-blocker) Amphetamine, tyramine,
ephedrine
Release
Adrenergic agonists Bretylium, guanethidine
(direct acting)
Cocaine
Isoproterenol Tricyclic antidepressants
Albuterol
NE (e.g. imipramine)

Receptor Recapture
+ action by Uptake-1
Adrenergic receptors (adrenoceptors)
Two families of receptors, designated and
were identified on the basis of their response to the
adrenergic agonist epinephrine, norepinephrine, &
isoproterenol (synthetic agonist)
for receptor the rank order of potency
epinephrine nor epinephrine > isoproterenol
-receptors:- isoproterenol > epinephrine >
norepinephrine
CH3
OH CH3
CH3 OH H
OH C OH N OH N
N H H
OH OH H H
OH H
H H
(-) Epinephrine
OH
(Adrenalin)
(-) Norepinephrine
(-) Isoproterenol Binds and activates both (Arterenol)
Binds and activates a- and b-adrenoceptors
b-adrenoceptors selectively
Cont...
The -adrenoceptors are subdivided into two groups
1 and 2 based on their affinity for agonists
phenylephrine (agonist) => 1 has greater affinity than 2
Clonidine (agonist) => 2 has greater affinity than 1
1 Receptors: present post synaptically on the
membrane of effector organs
2 receptors: located primarily on pre-synaptic nerve
endings and on other cells, such as -cell of the
pancreas
Stimulation of 2-receptor causes feedback inhibition
of the ongoing release of NE when there is high
sympathetic activity.
Cont...

-receptors:- isoproterenol > epinephrine >


norepinephrine
The -receptorsubdivided into three groups.
1 receptors have approximately equal affinity for
epinephrine and nor-epinephrine.
2 receptors have higher affinity for epinephrine
than norepinephrine.
3involve in lipolysis
Distribution of receptors
Characteristic responses mediated by adrenoceptors
1
Vasoconstriction (skin & abdomen)
Increases peripheral resistance
Mydriasis (eye)
Increase closure of internal sphincter of bladder
2
Inhibition of nor-epinephrine release
Inhibition of insulin release ( -cells of pancreases)
1
Tachycardia
Increases myocardial contraction
2
Vasodilation (Skeletal. Muscle)
Increases muscle & liver glycogenolysis
Increases release of glucagon
Relax uterine smooth muscle
Characterstics of Adrenergic Agonists
Chemically classified as
1. Cathecolamines
2. Noncathecolamines
Most of the adrenergic drugs are derivatives of
phenylethylamine
Substitution on the benzene ring or on the
ethylamine side chain produce a great variety of
compounds with varying abilities to differentiate b/n
and receptors & to penetrate CNS
Phenylethylamine and some important catecholamines
12
A.Cathecolamines
Sympathommetic amines that contain the 3,4 di hydroxy benzene
group (cathecol) such as E, NE, isopreternol & dopamine are called
cathecolamines
These compounds share the following properties:
1. High potency:- in activating or receptors show the highest
potency
2. Rapid inactivation:-metabolized by COMT post synaptically and
MAO intra neuronally
Also metabolized in other tissues
E.g. By COMT: in the gut wall
By MAO: in gut wall & liver
Only have a brief of action when given parentrally, and are ineffective
when administered orally because of inactivation
3. Poor penetration into the CNS: -
Cathecolamines are polar & therefore do not penetrate into the CNS
B.Noncathecolamines
Compounds lacking the cathecol hydroxyl groups
have longer half lives because:
they are not inactivated by COMT
they are poor substrate for MAO
Permits greater access to CNS
These include phenylephrine, ephedrine &
amphetamine
Some noncatecholamine sympathomimetic drugs
15
Mechanism of action of adrenergic agonists
Direct-acting agonists:- these drugs act directly on
or receptors, producing effect similar to E or NE
e.g. Epinephrine, norepinephrine, isoproterenol &
phenylephrine
Indirect-acting agonists:- these agents are taken up
into the presynaptic neuron and cause the release of
NE from the vesicles of the adrenergic neurons e.g.
Amphetamine, tyramine, cocaine
Mixed action agonists:- these agents have the
capacity both to directly stimulate adrenoceptors
and to release NE from the adrenergic neuron e.g.
Ephedrine & metaraminol
Direct acting adrenergic agonists
A.Epinepherine:- is one of the catecholamines
Commonly used in therapy
Interacts with both and receptors
Actions
Cardiovascular
the major action of epinephrine is on CV
Strengthens the contractility of the myocardium
(positive inotropic: 1 action) & increase rate of
contraction (positive chronotropic 1 action)
Cardiac out put is increased
Constricts arterioles in the skin mucous membranes
& viscera ( effects) and dilates vessels going to the
liver and skeletal muscle (2 effects)
Cont...
Respiratory system
cause powerful bronchodilation by acting directly
on bronchial smooth muscle 2 action)
Hyperglycemia
a significant hyperglycemic effect b/c of increased
glycogenolysis in liver( 2 effect) increased release
of glucagons( 2effect) and a decreased release of
insulin (2 effect)
Lipolysis
Initiates lipolysis through its agonistic action on
the -receptors of adipose tissue.
Therapeutic uses
Bronchospasm
it is the primary drug used in emergency treatment of any
condition of bronchoconstriction
Therefore used in treatment of acute asthma
However, selective 2 agonists, such as terbutaline, are
favored in chronic treatment of asthma because of longer
duration of action and minimal cardiac stimulatory effect
Glaucoma:- it reduces the production of aqueous humor by
vasoconstriction of the cilliary body blood vessels
Anaphylactic shock:- it is the drug of choice for the
treatment of type1 hypersensitive reaction in response to
allergens
In anesthetics:- it increase the duration of local anesthetics
by producing vasoconstriction at the site of injection, there
by allowing the local anesthetic to persist at the site before
being absorbed in the circulation and metabolized
Pharmacokinetics
Rapid onset but short duration
It is given iv, sc or by endothracheal tube, by
inhalation, or topically to the eye
Oral administration is ineffective b/c its
inactivated by intestinal enzymes
Biotransformation
Metabolized by COMT and MAO
Adverse effects
i. CNS disturbances :anxiety, fear, tension,
headache and tremor
ii. Hemorrhage: may induce cerebral
hemorrhage as a result of a marked elevation
of blood pressure
iii. Cardiac arrhythmias
epinephrine is contraindicated in
hypersensitive, hyperthyroid and angina
patients
Presentation: adrenaline 1mg/1ml inj.
B. Norepinephrine
the -adrenergic receptor is most affected
Therapeutic uses: is used to treat shock
because it increases blood pressure
It is never used in asthma. Why?
C. Isoproterenol
Its direct acting synthetic catecholamine
Predominantly stimulates both 1 and 2 adrenergic
receptor (it is not selective on the -receptors)
Its action on -receptor is insignificant
Actions
Cardiovascular
Produce intense stimulation of the heart (increase rate &
force of contraction) 1 effect.
Dilates the arterioles of skeletal muscle, resulting in
decreased peripheral resistance
Its useful for the treatment of cardiac arrest
Pulmonary
a profound and rapid bronchodilation is produced by the
drug (2action)
Other effects: increase in blood sugar and increased
lipolysis
Cont...
Therapeutic uses:-
Rarely used as a bronchodilator in asthma
Can be employed to stimulate the heart in
emergency situation
PK: it is a marginal substrate for COMT and is
stable to MAO action
it can be administered sub-lingually or
parenterally
D.Dopamine:-
Activate and adrenergic receptors
In addition, D1 & D2 dopaminergic receptors occur in the
peripheral mesenteric & renal vascular beds, where binding of
dopamine produce vasodilation
Therapeutic uses:-
Shock: dopamine is the drug of choice for shock and is
given by continuous infusion
It raises the blood pressure by stimulating the heart
(1 action); in addition it enhances perfusion to the
kidney and splanchnic areas
Dopamine is superior to norepinephrine, which
diminishes the blood supply to the kidney & may
cause kidney shut down.
E.Dobutamine
Its a synthetic, direct acting catecholamine that is a 1
receptor agonist.
Therapeutic uses:- used to increase cardiac out put in
congestive heart faiture
F.Phenylephrine
Its synthetic, direct acting adrenergic drug.
binds primarily to -receptors; favors 1 receptors over 2
Therapeutic use:- act as nasal decongestant and produces
prolonged vasoconstriction

G.Albuterol (Salbutamol)
Is a selective 2 agonist with properties similar to those of
terbutaline.
The drug widely used as an inhalant to relieve
bronchospasm
Onset and duration of bronchodilation effects of inhaled adrenergic agonists
2. Indirect acting adrenergic agonists
Cause NE release from presynpatic terminals
Amphetamine
Marked central stimulatory action is often mistaken
by drug abusers as its only action.
However, the drug can increase blood pressure
Its actions are mediated primary through the cellular
release of stored catecholamines
Effects include-euphoria (feeling of happiness),
postponement of sleep, suppress apetite, decrease
the feeling of fatigue.
Uses- Narcolepsy, obesity reduction
3. Mixed-action adrenergic agonists
Induce the release of nor-epinephrine from presynaptic terminals
and activate adrenergic receptors on post synaptic memberane
Ephedrine
A plant alkaloid, is now made synthetically
It releases stored norepinephrine from nerve endings and directly
stimulate both and receptors (direct + indirect)
Ephedrine is not a catechol and is poor substrate for COMT and
MAO; thus, the drug has a long duration of action but less potent
Has excellent absorption orally and penetrates in to the CNS
It raises blood pressure by vasoconstriction and cardiac stimulation
It produces bronchodilation, but it is less potent than epinephrine
or isoproternol & produce its action more slowly
Ephedrine has been used to treat asthma, as nasal decongestant,
and to raise blood pressure
The clinical use of ephedrine is declining due to availability of
better, more potent agents which cause fewer site effects
Adrenergic Antagonists
Adrenergic Antagonists
The adrenergic antagonists
(also called blockers) bind to
adrenoceptors
but donot trigger the
usual receptor mediated
intracellular effect
They are classified according
to their relative affinity for
or receptors
-adrenergic blocking agents
adrenoceptor blockers profoundly affect BP
They decrease peripheral vascular resistance
induces a reflex tachycardia resulting from the lowered BP.
A.Phenoxybenzamineboth 1 and 2 ;
noncompetitive
Not successful for hypertension. Why?
Block 1 , reflex tachycaria plus 2 blockade means increased SNS
outflow => increased CO
B.Phentolaminecompetitive block of both 1 and
2
C. Prazosin, terazosin & doxazosin
1 selective blockers
decrease peripheral vascular resistance
These drugs, unlike phenoxybenzamine and
phentolamine, cause minimal changes in CO? Why?

Therapeutic uses: - hypertension

Yohimbine
selective competitive 2 blocker.
component of the bark of the yohimbe tree
-adrenergic Blocking Agents
All the clinically available -blockers are competitive
antagonists
Non-selective -blockers act on both 1 and 2
receptors;
whereas cardioselective antagonists primarily block 1 -
receptors
The names of all -blockers end in olol
except for labetalol and carvedilol
they do not induce postural hypotension,
because the -adrenoceptors remain functional
-blockers are effective in treating:
hypertension, angina, cardiac arrhythmias, myocardial
infarction, congestive heart failure, hyperthyroidism,
and glaucoma
-blockers
Propranolol: a prototype
non-selective -antagonist
(blocks both 1 and 2
receptors)

Elimination half-lives for some -blockers


Actions of propranolol
Cardiovascular:- diminishes CO, having both negative
inotropic and chronotropic effects by blockage of 1 -
receptors
Peripheral vasoconstriction:- prevents 2 -mediated
vasodilatation
The reduction in cardiac output leads to decreased
blood pressure triggers a reflex peripheral
vasoconstriction.. On balance BP will reduce
Bronchoconstiction:-blocking 2 receptors in the lungs
causes contraction of the bronchiolar smooth muscles
Therefore --blockers are thus contraindicated in
patients with asthma (especially nonselective ones)
Increased Na+ retention:
Reduced BP causes a decrease in renal perfusion, resulting
in an increase in Na+ retention and plasma volume
In some cases, this compensatory response tends to
elevate the blood pressure.
For these patients, -blockers are often combined with a
diuretic to prevent Na+ retention.
By inhibiting -receptors, renin production is also
prevented
Disturbances in glucose metabolism:
-blockade leads to decreased glycogenolysis and
decreased glucagons secretion
therefore if an insulin dependent diabetic is to be
given propranolol, pronounced hypoglycemia may
occur after insulin injection
Actions of propranolol and other -blockers
Therapeutic uses
1. Hypertension: - lower blood pressure in
hypertneison by decreasing cardiac output,
inhibition of renin release from the kidney and
decreased sympathetic outflow from the CNS also
contribute to propranolol's antihypertensive
effects
2. Angina pectoris: -decrease the work and oxygen
requirements of heart muscle
3. Glaucoma:- by decreasing the secretion of
aqueous humor by the ciliary body; timolol is
commonly used; for acute attack pilocrpine is better
4. Hyperthyroidism: Propranolol and other -blockers
are effective in blunting the widespread sympathetic
stimulation that occurs in hyperthyroidism
5. Myocardial infarction: Propranolol and other -
blockers have a protective effect on the myocardium.
The mechanism for these effects may be a blocking
of the actions of circulating catecholamines, which
would increase the oxygen demand in an already
ischemic heart muscle.
Propranolol also reduces the incidence of sudden
arrhythmic death after myocardial infarction.
Adverse effects:-
Bronchoconstriction:-
Arrhythmias:-
Disturbances in metabolism:-leads to decreased
glycogenolysis & decreased glucagon secretion.
Drug interactions:-Cimetidine, furosemide &
chloropromazine inhibit metabolism of
propranolol which may potentiate its anti
hypertensive effect.
Barbiturates, phenytoin & rifampicin stimulate
metabolism of propranolol and thus can mitigate
its effects.
B) Timolol & nadolol
Non selective -antagonists
Are more potent than propranolol
Nadolol has very long duration of action
Timolol reduces the production of aqueous
humor in the eye and is use topically in the
treatment of chronic glaucoma
C) Atenolol, acebutolol, metoprolol and esmolol
Selective 1 antagonists
Elminate the unwanted bronchoconstrictor effect
(2) of propranolol seen among asthmatic patients
Therapeutic use:-
useful for hypertensive patients with impaired
pulmonary function
useful in diabetic hypertensive patients who are
receiving insulin or oral hypoglycemic agents

Drugs Affecting Neurotranstter Release or Uptake


Reserpine
Guanethidine