PHARMACOLOGY-1 PHL 313 - Cairo UniversityPHARMACOLOGY-1 PHL 313 1 These are drugs which act on the...

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.

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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.

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❑ 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).


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).


❑ Norepinephrine is one of the endogenous sympathomimetic catecholamines.

❑ Norepinephrine acts on α and β1 adrenergic receptors.


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❑ 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.

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❑ 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).


➢ 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

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❑ CVS:

❖ Heart:

➢ NE binds to β1 receptors in:



▪ 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.

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➢ 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.

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❑ 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.


❑ It is one of the endogenous sympathomimetic catecholamines.


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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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:



▪ 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:

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.


Isoproterenol binds to β2 receptors in the smooth muscle of urinary bladder.

➔ Leading to relaxation of bladder smooth M.

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Stimulate the process of glycogenolysis in liver and skeletal muscles (β2).


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).

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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.

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❑ 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.


➢ 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.

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❑ 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


➢ They blocks α1 receptors in the bladder sphincter.

➔ Relaxation of urinary bladder sphincter.

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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

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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.

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Therapeutic Uses

1- Hypertension

2- Pheochromocytoma (Plus β –blockers).

3- Peripheral vascular diseases.

➔ such as Raynaud's disease.

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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.

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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

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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:


➢ They blocks β2 receptors in the smooth muscle of the bronchioles.

➔ Produces constriction of bronchioles (bronchial asthma).

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❑ 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. !!!!!!!!!!

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❖ 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.


➢ 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.


➢ They blocks β2 receptors so reduce the process of glycogenolysis in liver and

skeletal muscles.

➔ Decrease the blood glucose level (hypoglycemia)

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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.

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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.

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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

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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.

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❑ 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.

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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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