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PHARMACOLOGY-1
PHL 313
1
❑ These are drugs which act on the adrenergic receptors (α & β).
❑ Adrenergic drugs may be:
1- Stimulants “Sympathomimetics”
2- Depressants “Sympatholytics”.
A) Sympathomimetics (Adrenergic Stimulants)
These are drugs which stimulate the adrenergic receptors (α & β).
➔ i.e stimulate the sympathetic nervous system.
❑ NOTE:
➢ The effect on α receptors is mainly excitatory (stimulatory) except on the
intestinal smooth M.
➢ The effect on β receptors is mainly inhibitory except on the heart.
2
Sympathomimetics act by 3 mechanisms:
1- Direct acting sympathomimetics:
They binds directly with the adrenergic receptors and stimulate them.
➔ Epinephrine.
2- Indirect acting sympathomimetics:
They don’t binds directly to receptors but stimulates the release of NE and EP
from the adrenergic nerve endings. NE and EP then binds to the receptors and
stimulate them.
➔ Tyramine
3- Mixed acting sympathomimetics:
Include direct and indirect mechanisms.
➔Amphetamine and Ephedrine.
3
1- Catecholamines 2- Non Catecholamines
1- Catecholamines
❑ These are drugs which contain a Catechol nucleus and stimulate the sympathetic
nervous system.
❑ Catecholamines : 2 types
➢ Endogenous: Epinephrine, Norepinephrine, Dopamine
➢ Synthetic: Isoproterenol (Isoprenaline), Dobutamine.
4
❑ EP is one of the neurotransmitters of the adrenergic nerves.
❑ Also it is one of the hormones of the adrenal medulla (Stress hormone).
❑ In the body, it is formed from the amino acid tyrosine.
❑ EP is one of the endogenous sympathomimetic catecholamines.
❑ It acts on α and β adrenergic receptors.
➔ Its actions are rapid in onset and short in duration.
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❑ Oral: Ineffective due to:
➔ Rapidly metabolized in the GIT mucosa and liver (COMT & MAO).
❑ IV: May be fatal, due to ventricular fibrillation.
❑ SC: Absorption occurs slowly, due to local vasoconstriction of cutaneous blood
vessels (α).
➔ Leading to long duration.
❑ IM: Absorption occurs rapidly, due to Vasodilatation of skeletal blood vessels
(β2).
➔ Leading to short duration.
❑ Intracardiac: In emergency.
❑ Inhalation: In bronchial asthma.
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❑ Eye:
1- EP binds to α receptors in the radial muscle of the iris
(dilator pupillae).
➔ Produces pupillary dilatation (myderiasis).
2- EP binds to α receptors in the conjunctival blood vessels.
➔ Produces vasoconstriction (decongestion).
❑ Respiratory system:
1- EP binds to β2 receptors in the smooth muscle of the
bronchioles.
➔ Produces dilatation of bronchioles.
2- EP binds to α receptors in the pulmonary blood vessels.
➔ Produces vasoconstriction of pulmonary blood vessels
(decongestion).
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❑ GIT:
1- EP binds to α and β2 receptors in the smooth muscle of
GI wall.
➔ So reduces the contractions of the GI wall leading to
decreased peristalsis.
2- EP binds to α receptors in the GI sphincters.
➔ Leading to contraction of sphincters
❑ CVS:
❖ Heart:
➢ Epinephrine binds to β1 receptors in:
▪ SA node: So increase the heart rate (+ve chronotropic).
▪ AV node: So increase the conduction.
▪ Atria & Ventricles: So increase the force of heart
contractility (+ve inotropic).
➔ The increase in the rate and force of heart contractility
increases the cardiac output (COP).
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❖ Blood vessels:
1- EP binds to α receptors in smooth M of cutaneous and mm blood vessels
➔ Leading to peripheral vasoconstriction
2- EP binds to β2 receptors in smooth M of coronary & skeletal blood vessels
➔ Leading to vasodilatation
❖ Blood pressure:
➢ EP increases BP due to:
▪ +ve chronotropic effect (increased heart rate).
▪ +ve inotropic effect (increased force of contractions).
▪ Peripheral vasoconstriction.
❑ Urinary bladder:
1- EP binds to β2 receptors in the smooth muscle of urinary bladder.
➔ Leading to relaxation of bladder smooth M.
2- EP binds to α receptors in the bladder sphincter.
➔ Leading to contraction of sphincter
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❑ Kidney:
➢ EP binds to β1 receptors in the kidney.
➔ So increase renin release which increase BP.
❑ Metabolic effects:
1- Stimulate the process of glycogenolysis in liver and skeletal muscles (α1 & β2).
➔ So increase the blood glucose level (hyperglycemia).
2- Decrease insulin secretion (α2).
➔ So increase the blood glucose level (hyperglycemia).
3- Stimulate the process of lipolysis (β3)
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1- Used locally to control epistaxis & bleeding after tooth extraction.
2- Congestion of mm of eye and nose.
3- During surgery: EP is added to the local anesthetic to cause vasoconstriction in the
surgery area in order to:
▪ Decrease bleeding
▪ Decrease the rate of absorption of the local anesthetic SO:
➔ Localizing anesthesia
➔ Decrease the risk of systemic toxicity of the local anesthetic.
➔ Prolonging the duration of anesthesia.
4- Sudden cardiac arrest (injected intracardial).
5- Acute bronchial asthma (by inhalation).
➔ however, now EP is replaced by β2 selective agonist.
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❑ Norepinephrine is one of the neurotransmitters of the adrenergic nerves.
❑ Also it is one of the hormones of the adrenal medulla (Stress hormone).
❑ In the body, it is formed from the amino acid tyrosine.
❑ Norepinephrine is one of the endogenous sympathomimetic catecholamines.
❑ Norepinephrine acts on α and β1 adrenergic receptors.
➔ Its actions are rapid in onset and short in duration.
12
❑ Oral: Ineffective due to:
➔ Rapidly metabolized in the GIT mucosa and liver
(COMT & MAO).
❑ SC: Not used due to its strong vasoconstrictor
effect of cutaneous blood vessels (α) which may
induce necrosis.
➔ May used in very diluted concentrations.
❑ IV: It is the ONLY ROUTE of administration
➔ IV infusion or drip.
13
❑ Eye:
1- NE binds to α receptors in the radial muscle of the iris (dilator pupillae).
➔ Produces pupillary dilatation (myderiasis).
2- NE binds to α receptors in the conjunctival blood vessels.
➔ Produces vasoconstriction (decongestion).
❑ Respiratory system:
➢ NE binds to α receptors in the pulmonary blood vessels.
➔ Produces vasoconstriction of pulmonary blood vessels (decongestion).
❑ GIT:
1- NE binds to α receptors in the smooth muscle of GI wall.
➔ So reduces the contractions of the GI wall leading to decreased peristalsis.
2- NE binds to α receptors in the GI sphincters.
➔ Leading to contraction of sphincters
14
❑ CVS:
❖ Heart:
➢ NE binds to β1 receptors in:
▪ SA node: So increase the heart rate (+ve chronotropic).
▪ AV node: So increase the conduction.
▪ Atria & Ventricles: So increase the force of heart contractility (+ve inotropic).
➔ The increase in the rate and force of heart contractility increases the cardiac
output (COP).
❖ Blood vessels:
NE binds to α receptors in smooth M of cutaneous and mm blood vessels
➔ Leading to peripheral vasoconstriction
❖ Blood pressure:
➢ NE increases BP due to:
▪ +ve chronotropic effect - increased heart rate.
▪ +ve inotropic effect – increased force of contractions.
▪ Peripheral vasoconstriction.
15
❑ Urinary bladder:
➢ NE binds to α receptors in the bladder sphincter.
➔ Leading to contraction of sphincter
Uses:
1- Used locally to control epistaxis & bleeding after tooth extraction.
2- Congestion of mm of eye and nose.
3- During surgery: Norepinephrine is added to the local anesthetic to cause
vasoconstriction in the surgery area in order to
Decrease bleeding
Decrease the rate of absorption of the local anesthetic SO:
➔ Localizing anesthesia
➔ Decrease the risk of systemic toxicity of the local anesthetic.
➔ Prolonging the duration of anesthesia.
NOTE: EP is more commonly used for this purpose.
4- Acute hypotension.
16
❑ Dopamine is one of the neurotransmitters of :
1- The adrenergic nerves
2- CNS: influences motor and thinking regions in the brain.
➔ When dopamine level decreases, motor functions and thinking process can be
impaired.
❑ In the body, it is formed from the amino acid tyrosine.
❑ It is one of the endogenous sympathomimetic catecholamines.
➔ Its actions are rapid in onset and short in duration.
Routes:
❑ Oral: Ineffective because it is rapidly metabolized in the GIT mucosa and liver
by COMT & MAO enzymes.
❑ IV: this is the ONLY ROUTE of administration (slow IV infusion).
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❑ The effects of dopamine are dose dependent.
❑ Small dose
➢ It stimulates D1 -receptors in renal and coronary vessels leading to:
1- Vasodilatation of renal and coronary vessels So, increases blood flow to kidney and
heart.
2- Increase the glomerular filtration, therefore Dopamine has a diuretic effect.
➔ it increases urine output from 5 mL/kg/hr to 10 mL/kg/hr.
❑ Moderate dose
➢ It stimulates D1 and β1 -receptors in heart producing +ve inotropic and +ve
chronotropic actions.
❑ High dose
➢ It stimulates α1 -receptors producing vasoconstriction and hypertension
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Clinical Uses
1- Small dose: ➔ used in Oliguria
NOTE:
▪ Oliguria is a low output of urine. It is defined as an output less than 500 mL/day
▪ Anuria is defined as an output less than 50 mL/day
2- Moderate dose: ➔ used to increase Cardiac Output in case of cardiogenic shock
NOTE:
▪ Cardiogenic shock is the failure of the heart to pump adequate amount of blood to
meet the body's needs.
3- High dose: ➔ used in treatment of profound hypotension following removal of
pheochromocytoma.
NOTE:
▪ Pheochromocytoma is a tumor of the adrenal medulla (originating in the
chromaffin cells) that produce excess adrenaline.
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Isoproterenol is one of the synthetic sympathomimetic catecholamines.
It acts on β adrenergic receptors.
➔ Its actions are slow in onset and long in duration.
Routes:
Not given orally (due to Significant 1st pass effect) So used by:
➔ Sublingual route
➔ Inhalation.
➔ IV drip (only for emergency).
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❑ Respiratory system:
Isoproterenol binds to β2 receptors in the smooth muscle of the bronchioles.
➔ Produces dilatation of bronchioles.
❑ GIT:
Isoproterenol binds to α and β2 receptors in the smooth muscle of GI wall.
➔ So reduces the contractions of the GI wall leading to decreased peristalsis.
❑ CVS:
❖ Heart:
➢ Isoproterenol binds to β1 receptors in:
▪ SA node: So increase the heart rate (+ve chronotropic).
▪ AV node: So increase the conduction.
▪ Atria & Ventricles: So increase the force of heart contractility (+ve inotropic).
➔ The increase in the rate and force of heart contractility increases the cardiac
output (COP).
21
❖ Blood vessels:
Isoproterenol binds to β2 receptors in smooth M of coronary & skeletal blood
vessels
➔ Leading to vasodilatation
❖ Blood pressure:
➢ Isoproterenol decreases BP due to:
▪ Vasodilatation of skeletal blood vessels.
❑ Urinary bladder:
Isoproterenol binds to β2 receptors in the smooth muscle of urinary bladder.
➔ Leading to relaxation of bladder smooth M.
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❑ Metabolic effects:
Stimulate the process of glycogenolysis in liver and skeletal muscles (β2).
➔ So increase the blood glucose level (hyperglycemia).
Uses:
1- Bronchial asthma (sublingual or inhalation).
➔ It is no longer used to treat the bronchial asthma because of it’s side effects on
the heart
2- Cardiac arrest (IV drip).
23
Dobutamine is one of the synthetic sympathomimetic catecholamines.
Related to Isoprenaline.
It acts as β1 selective agonist
➔ so its cardiac effect is more prominent than its bronchodilator effect.
It can resist COMT & MAO
➔ so produce a longer duration of action.
Uses:
1- To stimulates the heart:
a- during surgery.
b- after a heart attack.
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These are drugs which do not contain a Catechol nucleus but still activate the
sympathetic nervous system.
❑ Non catacholamines are not metabolized by COMT and MAO.
➔ So their duration is more longer than epinephrine and norepinephrine.
Ex:
➢ Aamphetamine
➢ Ephedrine
➢ Phenylephrine
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❑ Amphetamine is a synthetic sympathomimetic non catecholamine.
❑ It has both direct- and indirect sympathomimetic effects.
➔ Direct: It stimulates both α- and β1 -receptors.
➔ Indirect: It stimulates the release of norepinephrine from the adrenergic
nerves.
❑ Its actions are slow in onset and longer in duration.
❑ It is effective orally.
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1- It acts as Norepinephrine …………..
❖ The contractile effect on the sphincter of the urinary bladder is powerful
➔ So used for the treatment of incontinence.
2- In addition, it has powerful CNS stimulant effects:
➔ CNS effects include increased wakefulness, elevation of mood, euphoria,
decrease sense of fatigue and depressed appetite.
❖ Amphetamine stimulates the respiratory center in the medulla.
❑ Side effects:
❖ The side effects are due to chronic use.
◦ Tolerance
◦ Addiction
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❑ Uses:
NOTE: Amphetamine is a drug of abuse, that should not be prescribed.
However, amphetamine-like drugs can be prescribed for the following conditions:
1- Incontinence
NOTE:
▪ Incontinence is the inability to control urination.
2- Obesity: To suppress appetite
➔ In very obese persons Amphetamine can act centrally on the hunger center in the
hypothalamus to suppress appetite
3- In narcolepsy: Amphetamine stimulates the CNS & make the patient awake
NOTE:
Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night
4- Used illegally to improve athletic performance (doping).
NOTE:
▪ Doping is the use of a substance (as an anabolic steroid) to illegally improve athleticperformance
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❑ Ephedrine is a sympathomimetic non catecholamine.
❑ It is an alkaloid isolated from Ephedra plant.
❑ Ephedrine has both direct- and indirect sympathomimetic effects.
➔ Direct: It stimulates both α- and β-receptors.
➔ Indirect: It stimulates the release of norepinephrine from the adrenergic nerves.
❑ Its actions are slow in onset and longer in duration.
❑ It is effective orally.
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1- It acts as Epinephrine………………….
2- In addition, it has CNS and respiratory stimulant effects similar to
amphetamine, but less potent.
◦ It does not suppress the appetite Why?
Uses:
1- Nasal congestion (in the form of nasal drops).
➔ causes constriction of dilated arterioles and reduction of nasal blood flow, thus
decreasing congestion.
2- Bronchial asthma (bronchodilator).
3- To prevent hypotension during anaesthesia.
30
❑ Phenylephrine is a synthetic sympathomimetic non catecholamine.
❑ It has direct sympathomimetic effect by stimulating α- receptors.
➔ α1 selective agonist
Uses:
1- As a vasopressor agent in case of hypotension ◦ α1 stimulation causes VC leading to increase BP
2- As a decongestant ◦ Used as nasal drops to cause VC in the nasal blood vessels & relief
congestion
3- In combination with local anesthetics.
➔ retard the absorption of local anesthetics.
4- As a myderiatic agent to examine the eye◦ It acts on α1 – receptors in the radial dilator pupillary muscle
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❑ These are drugs which produce actions opposite to sympathetic nerve
stimulation
❑ Classifications:
I- Adrenergic receptors blockers:
➢ α- blockers.
➢ β - blockers.
II- Anti-adrenergic drugs:
➢ Drugs inhibit release of catecholamine e.g. Guanethidine.
➢ Drugs inhibit storage of catecholamine e.g. Reserpine.
➢ Drugs inhibit synthesis of catecholamine e.g. α-methyl dopa.
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α- blockers:
1- Non-selective α- blockers : (blocks α1 and α2)
➢ Phenoxybenzamine - Phentolamine - Tolazoline
2- Selective α- blockers :
a- Selective α1- blockers : (blocks α1 only)
➢ Alfuzosin - Prazosin - Terazosin
b- Selective α2- blockers : (blocks α2 only)
➢ Atipamezole - Yohimbine
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1- Non-selective α- blockers :
These are drugs which block α1 and α2-receptors so prevent the binding of
catecholamines to these receptors.
❑ Ex:
Phenoxybenzamine - Phentolamine - Tolazoline
MOA:
They act by blocking of :
➢ α1- receptors, so inhibit the vasoconstrictor effect of catecholamines leading to
vasodilatation and hypotension.
➢ α2- receptors, so increase insulin secretion.
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(Phenoxybenzamine - Phentolamine - Tolazoline)
❑ Eye:
➢ They blocks α1 receptors in the radial muscle of the iris (dilator pupillae).
➔ Produces pupillary constriction (miosis).
They blocks α1 receptors in the conjunctival blood vessels.
➔ Produces vasodilatation.
❑ Respiratory system:
➢ They blocks α1 receptors in the pulmonary blood vessels.
➔ Produces vasodilatation of pulmonary b.Vs.
➔ Nasal stuffiness due to vasodilatation of nasal b.Vs.
Nasal stuffiness = sensation of difficulty in nasal breathing.
35
❑ GIT:
➢ They blocks α1 receptors in the smooth muscle of GI wall.
➔ Increase the contractions of the GI wall leading to increased peristalsis, diarrhea.
➢ They blocks α1 receptors in the GI sphincters.
➔ Relaxation of GI sphincters
❑ CVS:
❖ Blood vessels:
➢ They blocks α1 receptors in smooth M of blood vessels.
➔ Vasodilatation of cutaneous and m.m. blood vessels.
❖ Blood pressure:
➢ They decreases BP due to vasodilation
❑ Urinary bladder:
➢ They blocks α1 receptors in the bladder sphincter.
➔ Relaxation of urinary bladder sphincter.
36
❑ Metabolic effects:
They blocks α1 receptors in the liver.
➔ Decrease hepatic glycogenolysis.
They blocks α2 receptors in the pancreatic islets.
➔ increase insulin secretion, SO decrease the blood glucose
level (hypoglycemia).
Therapeutic Uses
1- Hypertension
2- Pheochromocytoma (Plus β - blockers)
3- Peripheral vascular diseases such as Raynaud's disease.
NOTE:
▪ Raynaud's disease is the skin discolorations of the fingers
or the toes after exposure to cold temperature
➔ due to severe vasoconstriction producing cessation of blood flow to fingers, toes, earlobes, or tip of nose
37
2- Selective blockers :
A- Selective α1- blockers :
These are drugs which block α1-receptors so prevent the access of catecholamines to
these receptors.
Ex:
➢ Alfuzosin - Prazosin - Terazosin
MOA:
They act by blocking of α1- receptors, so inhibit the vasoconstrictor effect of
catecholamines leading to vasodilatation and hypotension.
Actions:
As Non-selective α-adrenergic blockers except:
The effect on the pancreatic islets.
38
Therapeutic Uses
1- Hypertension
2- Pheochromocytoma (Plus β –blockers).
3- Peripheral vascular diseases.
➔ such as Raynaud's disease.
39
B- Selective α2 - blockers :
Atipamezole – Yohimbine
These are drugs which block α2-receptors so prevent the access of catecholamines to
these receptors.
Actions:
They blocks α2 receptors in the pancreatic islets.
➔ increase insulin secretion, SO decrease the blood glucose level (hypoglycemia).
Uses:
❑ Not used clinically but used mainly in research.
❑ Yohimbine was previously used as an aphrodisiac.
40
β- blockers:
1- Non-selective β-adrenergic blockers : (blocks β1 and β2-receptors)
Propranolol (Inderal) - Pindolol - Timolol
2- Selective β-adrenergic blockers :
A- Selective β1-adrenergic blockers : (blocks β1-receptors only)
Atenolol – metoprolol – Esmolol
B- Selective β2-adrenergic blockers : (blocks β2-receptors only)
Butoxamine
41
β- blockers:
1- Non-selective β- blockers :
These are drugs which block β1 and β2-receptors so prevent the binding of
catecholamines to these receptors.
❑ Ex: Propranolol (Inderal) - Pindolol - Timolol
MOA:
They act by blocking of β1 and β2-receptors , so affect the heart and bronchioles.
Actions:
❑ Respiratory system:
➢ They blocks β2 receptors in the smooth muscle of the bronchioles.
➔ Produces constriction of bronchioles (bronchial asthma).
42
❑ GIT:
➢ They blocks β2 receptors in the smooth muscle of stomach and intestine.
➔ Increase the contractions of stomach and the intestinal motility.
❑ CVS:
❖ Heart:
They blocks β1 receptors in the cardiac muscle so inhibits all properties of the
heart.
➔ Decreases the force of contractions (-ve inotropic).
➔ Decreases the rate of contractions (-ve chronotropic).
➔ So it decreases the cardiac output (CO).
❖ Blood vessels:
They blocks β2 receptors in smooth M of blood vessels.
➔ Little vasoconstriction of coronary & skeletal blood vessels. !!!!!!!!!!
43
❖ Blood pressure:
Non-selective β- blockers decreases BP due to:
1- Reduction in cardiac output (due to –ve chronotropic and –ve inotropic effects).
2- Reduction in renin release from the kidneys.
❑ Urinary bladder:
➢ They blocks β2 receptors in the smooth muscle of urinary bladder.
➔ Contraction of bladder smooth M.
❑ Kidney:
They blocks β1 receptors in the kidney so inhibits renin secretion.
❑ Metabolic effects:
➢ They blocks β2 receptors so reduce the process of glycogenolysis in liver and
skeletal muscles.
➔ Decrease the blood glucose level (hypoglycemia)
44
Uses:
1- Hypertension especially in mild cases.
2- Angina pectoris
➔ due to -ve chronotropic and –ve inotropic effects SO reduce cardiac workload
3- Cardiac arrhythmias.
➔ due to depression of SA node function
4- Pheochromocytoma, in combination with α-blockers
5- Glaucoma: Timolol reduce the production of aqueous humor (Reduces IOP) so
used for glaucoma.
45
2- Selective β- blockers :
A- Selective β1 - blockers :
These are drugs which block β1 -receptors so prevent the access of catecholamines to
these receptors.
Ex:
Atenolol - Metoprolol - Esmolol
MOA:
They act by blocking of β1 - receptors so, mostly affect the heart and do not affect
the bronchioles.
46
Actions:
❑ CVS:
❖ Heart:
They blocks β1 receptors in the cardiac muscle.
➔ Decreases the force of contractions (-ve inotropic).
➔ Decreases the rate of contractions (-ve chronotropic).
➔ So they decreases the cardiac output (CO).
❖ Blood pressure: Hypotension.
❑ Kidney:
They blocks β1 receptors in the kidney so inhibits renin secretion.
Uses:
➢ Hypertension - Angina pectoris - Cardiac arrhythmias
47
B- Selective β2- blockers :
These are drugs which block β2-receptors so, prevent the access of catecholamines
to these receptors.
Ex: Butoxamine
MOA:
They act by blocking of β2- receptors, so mostly affect the bronchioles and do
not affect the heart .
No common clinical applications, but used in experiments.
48
❑ These are drugs which interfere with the actions of catecholamines by prevention
of its release, depletion of its stores or prevention of its synthesis.
❑ Ex: Guanithidine , Reserpine , -methyl dopa (Aldomet).
Actions: Sum of - blockers + - blockers.
49
MOA:
❑ Guanithidine:
It substitute NE in chromaffin granules and released from the adrenergic nerves
by nerve stimulation (false transmitter).
❑ Reserpine
It depletes the stores of catecholamines in many organs by inhibiting the ATP-
Mg2+ uptake mechanism.
❑ -methyl dopa (Aldomet):
It prevent the synthesis of catecholamines by inhibiting the decarboxylation of
dopa into dopamine.
Uses of Anti-adrenergic drugs:
Hypertention.
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