Adrenergic neuron blocking drugs
Adrenergic neuron blocking drugs act on pre junctional adrenergic neurons to interfere with or adrenaline synthesis, storage or release. Some drugs also affect the reuptake of the released nor adrenaline from synaptic cleft.
Adrenergic neuron blocking drugs are classified in-
- Drugs that affect nor-adrenaline synthesis– α-methyl-p-tyrosine, Carbidopa, α- methyldopa
- Drugs that affect noradrenaline storage– Reserpine.
- Drugs that affect noradrenaline release– Guanethedine, Guanadral, Reserpine, Bretylium
- Drugs that inhibit noradrenaline reuptake– Tricyclic antidepressants like imipramine, amitriptyline, cocaine etc.
1. Drugs that affect nor-adrenaline synthesis
α – methyl-p- tyrosine: (Metyrosine)
It is a structural analogue of tyrosine. On administration it is taken up by the adrenergic neurons and adrenal medulla where it blocks the enzyme tyrosine hydroxylase. This results in failure of synthesis of noradrenaline, adrenaline and dopamine.
Carbidopa
It is a dopa derivative that inhibits dopa-decarboxylase enzyme peripherally. Central dopamine synthesis is unaffected as it cannot cross blood brain barrier.
α-methyl dopa
It is an analogue of l-dopa, the precursor of dopamine and noradrenaline.
α-methyl dopa is taken up by adrenergic neurons, mainly CNS, where it is decarboxylated and then dehydroxylated to from α-methyl noradrenaline is a potent α2– receptor agonist and thus inhibits sympathetic discharge from the brain, which in turn causes peripheral vasodilation and reduction of total peripheral resistance.
It indirectly also causes reduced synthesis of true transmitter i.e., noradrenaline.
2. Drugs that affect noradrenaline storage
Reserpine
Reserpine is a alkaloid obtained from the plant Rauwolfia serpentina. This blocks the transport of noradrenaline and other biogenic amines into synaptic vesicles, apparently by binding to the transport system. Thus the noradrenaline in the neuronal cytoplasm is metabolized by the enzyme MAO and is not stored in the synaptic vesicles.
Mechanism of action of reserpine– Reserpine irreversibly binds to the storage vesicle in central and peripheral adrenergic neurons and blocks Mg++-ATP dependant transport of biogenic amines-noradrenaline and dopamine from cytoplasm into the storage vesicles. Thus adrenergic nerve terminals cannot concentrate noradrenaline and its precussor dopamine in storage vesicles.
In addition it also causes leakage of stored noradrenaline into cytoplasm, where it is stored by MAO. Ultimately reserpine causes depletion of noradrenaline in sympathetic nerve endings.
Pharmacological effects of reserpine– Reserpine produces slowly developing fall in blood pressure, decrease in peripheral resistance and bradycardia. Renal and cerebral blood flow is unchanged due to suppressed sympathetic activity. High doses of reserpine causes depletion of catecholamines and 5HT in brain an produces sedation an depression.
Side/adverse effects of reserpine– Because of suppressed overall sympathetic activity, there is predominance of parasympathetic over activity in many systems. This causes bradycardia, diarrhea, increased gastric acid secretion an miosis.
Clinical uses of reserpine– Rarely used because of adverse effects.
3. Drugs that affect noradrenaline release
The mechanisms by which these drugs interfere with release of noradrenaline include-
- inhibition of noradrenaline release in response to depolarization of the nerve terminal and/or
- complete depletion of noradrenaline from its storage sites
Guanethidine
Guanethidine is selectively inhibits release of noradrenaline from peripheral postganglionic adrenergic neurons, with no effect on adrenal medulla.
Mechanism of action of Guanethidine– Guanethidine has complex mechanism of action. It has bretylium like effect-blocks nerve impulse coupled release of stored noradrenaline
Tyramine like effect- displaces noradrenaline from storage vesicles
Reserpine like effect- causes gradual depletion of noradrenaline in storage vesicles
Blocks uptake1 carrier transport system for noradrenaline
When chronically administered guanethidine acts as a “substitute neurotransmitter”, as it is stored noradrenaline storage vesicles and is released by stimuli that normally release noradrenaline.
Guanethidine has some local anesthetic like action but Guanethidine in large doses caused structural damage to adrenergic neurons.
Pharmacological effects of Guanethidine– Following oral administration, guanethidine produces fall in blood pressure and bradycardia, because of decreased release of noradrenaline. However, after IV administration, it produces characteristic triphasic response in blood pressure.
Initially it produces decrease in blood pressure (due to decreased peripheral resistance an cardiac output, resulting from initial noradrenaline blockade).
The fall is then followed by increase in blood pressure (due to release of noradrealine) and then finally there is fall in blood pressure ( due to depletion of noradrenaline).
Clinical uses of Guanethidine– Seldom used in veterinary practice
Bretylium
Bretylium inhibits the release of noradrenaline, accumulates in nerve terminals and exerts a selective local anesthetic effect on sympathetic nerve terminals. It does not block release of catecholamines from adrenal medulla and does not affect nerve terminals other than those that release nor adrenaline. Bretylium also has effect on K+ channels in myocardium and exerts anti arrhythmic effect.
4. Drugs that inhibit noradrenaline reuptake
Neuronal reuptake of released noradrenaline (uptake1) is the most important mechanism by which sympathetic neurotransmission is terminated. thus drugs that inhibit this uptake1 process cause accumulation of noradrenaline in synaptic cleft, which results in enhancement of sympathetic activity.
Tricyclic antidepressants
Drugs like imipramine and desimipramine block noradrenaline and 5HT uptake by nerurons. Major effects are seen in the central nervous system with this group of drugs.
Cocaine
Cocaine is an alkaloid obtained from Erythroxylum coca with local anaesthetic alkaloid. Besides the local anesthetic action, cocaine also blocks Na+-K+-activated ATPase required for transport of noradrenaline into neurons across the cell membrane (uptake1)