Adrenergic Agonists 2013

Adrenergic Agonists

Release primary neurotransmitter i.e. nor epinephrine. · Found in central nervous system and sympathetic nervous system, where they serve as a link between ganglia and effector organs.

Adrenergic neurons and receptors located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs.

Neurotransmission at adrenergic neurons:

The process involves 5 steps:

1. Synthesis of nor-epinephrine:

Tyrosine is transported by Na+ linked carrier into the axoplasm of the neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.

DOPA is decarboxylated by dopa decarboxylase to form dopamine in the cytoplasm of presynaptic neuron.

2. Storage of nor-epinephrine in vesicles:

Dopamine is transported into synaptic vesicles by an amino transporter system i.e. also involved in reuptake of performed nor epinephrine.

This carrier system is blocked by reserpine.

Dopamine is hydroyxlated to form nor-epinephrine by dopamine beta-hydroxylase.

Synaptic vesicles contain dopamine or nor-epinephrine, ATP and beta-hydroxylase, co-transmitters.

2. Release of nor-epinephrine:

An action potential arriving at nerve junction triggers an influx of calcium ions from extracellular fluid into cytoplasm of neuron. Due to increase in calcium influx vesicle fuses with neuron cell membrane and expel contents into synapses.

This release is blocked by guanethidine.

3. Binding to receptors:

Nor epinephrine releases into synaptic space and binds to either postsynaptic receptors on effector organ or to presynaptic receptors on the nerve ending.

When nor-epinephrine is recognized by the receptors a cascade of events are started.

4. Removal of nor-epinephrine:

Nor-epinephrine may;

· Diffuse out of synaptic space and enter the general circulation,

· Metabolized by COMT in synaptic space,

· Reuptake system that pumps it back into neuron.

The uptake by neuronal membrane involves a Na+/K+ ATPase i.e.

inhibited by tricyclic antidepressants or cocaine.

Nor-epinephrine can be oxidized by MAO present in neuronal mitochondria, so it is taken up by vesicles via amine transporter system and release upon another action potential.

The inactive metabolites of nor-epinephrine are excreted in the urine as vanillylmandelic acid, metanephrine and normetanephrine.

Adrenergic receptors:

In sympathetic nervous system, two families of receptors alpha2and2beta2are initially identified on the basis of their response to the adrenergic agonists.

For alpha-receptors, the rank order of potency is epinephrine ≥ nor-epinephrine >> isoproterenol.

For beta-receptors, the rank order of potency is isoproterenol > epinephrine > nor-epinephrine.

Desensitization of receptor involves 3 mechanisms(مستقبلات إزالة التحسس):
1. Sequestration of receptors so that they are unavailable for interaction with ligand.
2. Down regulation i.e. destruction or decrease synthesis of receptors.
3. Receptor phosphorylation by protein kinase or beta-adrenergic receptor kinase.
Characteristics of adrenergic agonists(خصائص المثبطات)
· Mostly are derivatives of beta-phenyl ethylamine.
· Substitution on benzene ring or ethylamine side chains produce compounds with varying abilities to differentiate receptors and to penetrate CNS.
· Two important structural features of these drugs are:
Ø Number and location of OH substitutions on benzene ring.
Ø Nature of substituent on the amino nitrogen.

CATECHOLAMINES.	NONCATECHOLAMINES.
Sympathomimetic amines that contain the 3, 4-dihydroxybenzene group are called catecholamine.	Sympathomimetic amines that contain not 3, 4-dihydroxybenzene group are called noncatecholamine.
Catecholamines cannot be given by mouth.	Catecholamines can be given by mouth.
Catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, but they are also metabolized in other tissues.	Noncatecholamines are not metabolized by COMT.
Short duration of action.	Long duration of action.
Catecholamines are polar; therefore, do not readily penetrate into the CNS.	Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS.
e.g. epinephrine, nor-epinephrine, isoproterenol, dopamine, dobutamine.	e.g. oxymetazoline, phenylephrine, methoxamine, clonidine, metaproterenol, amphetamine, albuterol, terbutaline, salmeterol, formoterol.

Classification of adrenergic agonist:

Direct-acting drugs:
Ø Epinephrine.
Ø Nor-epinephrine.
Ø Isoproterenol.
Ø Dopamine.
Ø Dobutamine.
Ø Oxymetazoline.
Ø Phenylephrine.
Ø Methoxamine.
Ø Clonidine.
Ø Metaproterenol.
Ø Albuterol.
Ø Pirbuterol.
Ø Terbutaline.
Ø Salmeterol.
Ø Formoterol.
Indirect-acting drugs:
· Amphetamine.
· Tyramine.
· Cocaine.
Mixed action drugs:
· Ephedrine.
· Pseudoephedrine.
Mechanism of action of the adrenergic agonists(آلية عمل المثبطات)
1. Direct-acting drugs: These drugs act directly on alpha2or beta receptors. Effect produces similar to those that occur in stimulation of sympathetic nerves or release of hormone epinephrine from adrenal medulla.
These drugs bind to the adrenergic receptors. The activated receptor initiates synthesis of second messengers. Examples are epinephrine, nor-epinephrine, isoproterenol and phenylephrine.
2. Indirect-acting drugs: These drugs are uptake blockers and cause the release of neurotransmitter from the vesicles of the adrenergic neuron.
These drugs cause nor-epinephrine release from presynaptic terminals or inhibit the uptake of nor-epinephrine. They potentiate the effect of nor-epinephrine but these drugs do not directly affect the postsynaptic receptors. Examples are amphetamine, tyramine and cocaine.
3. Mixed action drugs: These drugs have both effects to stimulate adrenoreceptors directly and to release nor-epinephrine from adrenergic neuron.
Examples are ephedrine and pseudo-ephedrine.

DIRECT-ACTING AGONISTS(مثبطات مباشرة المفعول:

DRUGS	ACTION	USES	ADRS	PHARMACOKINETICS
Epinephrine	a_{1 ,} a_{2 ,} b_{1 ,} b₂agonist.	Acute asthma, treatment of open angle glaucoma, anaphylactic shocks, local anesthetic to increase duration of action, cardiac arrest, haemostatic.	Excessive sympathomimetic effects: hypertension arrhythmia, stroke myocardial infarction, pulmonary edema. CNS disturbance: anxiety, fear, tension, headache & tremor.	Rapid onset, short duration of action; given by I/V, subcutaneously, endotracheal tube, inhalational, topically, oral administration; metabolites excreted in urine; inactivated by intestinal enzymes, duration of action is 1-15 minutes, does not enter CNS.
Nor-epinephrine	a_{1 ,} a_{2 ,} b₁agonist.	Treatment of shock.	Extreme vasospasm, tissue necrosis, excessive blood pressure, arrhythmias, infarction, blanching and sloughing of skin along injected vein.	Given by I/V for rapid onset of action, duration of action is 1 to 2 minutes, poorly absorbed by oral, rapid removal by tissues, metabolized by MAO and COMT
Isoproterenol	b_{1 ,} b₂agonist. (non-selective).	Acute asthma, as a cardiac stimulant.	Tachycardia, dysrhythmias. Excessive sympathomimetic effects: hypertension arrhythmia, stroke myocardial infarction, pulmonary edema. CNS disturbance: anxiety, fear, tension, headache & tremor.	Given by sublingual, parenterally, inhaled aerosols, it is a marginal substrate for COMT and is stable to MAO action, plasma half life ~ 2hours.
Dopamine	Dopaminergic, a₁, b₁agonist.	Treatment of shock; especially with renal shutdown, treatment of congestive heart failure, raise blood pressure.	Cardiovascular disturbance, arrhythmias, nausea, hypertension.	Not administered orally, does not enter CNS, duration: 1-15 minutes, I/V route only, rapid onset of action.
Dobutamine	b₁agonist (non-selective).	Cardiogenic shock.	Dsyrhythmias, tremor, headache, tachycardia, CNS disturbance, nausea, increase in arterioventricular conduction, tolerance may develop on prolonged use.	I/V route only, plasma half life ~ 2 minutes.
Oxymetazoline	a₁agonist.	As a nasal decongestant.	Nervousness, headache, trouble sleeping, burning of mucosa and sneezing when administered in nose.	Nasal spray, ophthalmic drops,
Phenylephrine	a₁agonist.	As a nasal decongestant, raise blood pressure, treatment of paroxysmal supraventricular tachycardia.	Large dose cause hypertension, reflex bradycardia, cardiac irregularities.	Oral, inhalant, topical, parenteral, duration: 15-60 minutes, metabolized by MAO.
Methoxamine	a₁agonist (non-selective).	Treatment of supraventricular tachycardia, nasal decongestant.	Hypertension, headache, vomiting, reflex bradycardia.	Given intranasally, metabolized by MAO, plasma half life~ 1 hour.
Clonidine	a₂partial agonist	Hypertension, migraine.	Nasal decongestant, hypertension, migraine.	Well absorbed orally, excreted as unchanged and as conjugate, plasma half life ~ 12 hours.
Metaproterenol	b₂>b₁	Treatment of bronchospasm and asthma.	Nausea, vomiting, headache.	Resistant to methylation by COMT, administered orally or by inhalation.
Albuterol, Pirbuterol, Terbutaline	b₂agonist.	Treatment of bronchospasm (short acting).	Tachycardia, tremor, dsyrhythmias, peripheral vasodilation.	Poorly absorbed orally, given by aerosol, and mainly excreted unchanged, plasma half life ~ 4 hours.
Salmeterol, Formoterol	b₂agonist.	Treatment of bronchospasm (long acting), agent of choice for treating nocturnal asthma in symptomatic patients taking other asthma medication.	Tachycardia, tremor, dsyrhythmias, peripheral vasodilation.	Slow onset, long action, given by aerosol
Clenbuterol	b₂agonist.	Anabolic action to increase muscle strength.	Tachycardia, tremor, dsyrhythmias, peripheral vasodilation.	Active orally, long acting.
Salbutamol	b₂agonist.	Asthma, premature labour.	Tachycardia, tremor, dsyrhythmias, peripheral vasodilation.	Given orally or by aerosol, mainly excreted unchanged, plasma half life~ 4 hours.
Ritodrine	b₂agonist.	Delay of parturition.	Tachycardia, tremor, dsyrhythmias, peripheral vasodilation.	Poorly absorbed by mouth, given I/V.

INDIRECT-ACTING AGONISTS(مثبطات غير مباشرة المفعول:

DRUGS	ACTION	USES	ADRS	PHARMACOKINETICS
Amphetamine	alpha, beta3 CNS effects. (nor-epinephrine release enhance and also inhibit MAO so high level of catecholamine release into synaptic spaces).	As a CNS stimulant in treatment of children with attention deficient syndrome, narcolepsy, appetite control, suppressant and drug abuse.	Hypertension, tachycardia, insomnia, acute psychosis with overdose, dependence, Avoid in pregnancy because adverse effects on development of fetus	Oral and parenteral route. Well absorbed orally. Penetrate freely into brain and excreted unchanged in urine. Plasma half life~ 12 hours depending on urine flow and pH.
Tyramine	Displaces stored catecholamine.	No clinical use it is found in fermented food.	Hypertension, vasoconstriction, arrhythmias, stroke, myocardial infarction.	Normally high first-pass effect. Normally inactivated by MAO in gut.
Cocaine	It has ability to block Na⁺/K⁺ activated ATPase required for cellular uptake of nor-epinephrine on cell membrane of adrenergic neuron.	Local anesthetic with intrinsic haemostatic action.	Very high addiction liability, hypertension, arrhythmias, seizure.	Parenteral only, duration: 2 hours

MIXED-ACTION AGONIST:

DRUGS	ACTION	USES	ADRS	PHARMACOKINETICS
Ephedrine & Pseudoephedrine.	Release nor-epinephrine, alpha3 beta2agonist, Weak CNS stimulant.	Nasal decongestant, treatment of asthma, raise blood pressure, enhance contractility & improve motor function in myasthenia gravis when used in conjunction with anticholinesterases, mild stimulation of CNS; increase alertness, decrease fatigue, prevents sleep, improve athletic performance.	Hypertension, tachycardia, insomnia, acute psychosis with overdose, dependence.	Well absorbed orally. Penetrate freely into brain and excreted unchanged in urine. Plasma half life~ 12 hours depending on urine flow and pH. Poor substrate of COMT & MAO, have a long duration of action. Pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine.

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