Lecture 1 (Drugs Acting on Autonomic Ganglia)

8/8/2019 Lecture 1 (Drugs Acting on Autonomic Ganglia)

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Drugs that affectsneurotransmitter Release,

Synthesis or Uptake


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OBJECTIVE S

Identify different types of drugs thatinterefer with synthesis, storage or uptake of NAUnderstand the mechanism of actionof :E -methyldopa

ReserpineGuanethidine


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The drugs in this group block the adrenergic

neurons, by interference with NA release,storage, synthesis or alter the uptake into theadrenergic nerve.

They could be classified into:

Drugs that affect NA synthesis:(E -methyldopa)

Drugs that affect NA storage:

(Reserpine)Adrenergic neuron blockers:(Guanethidine)


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Drugs that affect NA synthesisE -methyldopa

It is a dopa decarboxylase inhibitor.It inhibits NA biosynthesis.It is metabolized to E - methyl NA, whichcan be stored in the sympathetic nerveendings, therefore, displacing NA andacting as a false transmitter.E -

methyl NA stimulates presynapticE

2-

receptors in brain leading to inhibition of sympathetic outflow.


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USES:

Treatment of hypertension

Contraindications:Pheochromocytoma

Active liver diseases


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Drugs that affect NA storage:Reserpine:

It blocks the magnesium/ATP -dependent transport of biogenicamines from the cytoplasm into thestorage vesicles in the adrenergicnerves.This causes an ultimate depletion of

NA levels in the adrenergic neurons.


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The amine -depleting action of reserpine results in:

Sedation and tranquilizing action bydepleting catecholamines and 5 -H Tstores in the brain.H ypotension and bradycardia


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The rap eu tic u s e s: H ypertension (in combination with other drugs) except in case of phaeochromocytoma

Sid e effe cts:- Postural hypotension, Failure of ejaculation ,

Diarrhea, Nasal congestion, Miosisweight gain, activations of peptic ulcer, CNS

effects .


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Adrenergic neuron blockers:Guanethidine:

Guanethidine inhibits the response of adrenergic nerve to stimulation or toindirectly acting sympathomimeticamines.


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GUAN ETHI D I N E

Inhibit uptake

InhibitRelease

Storedinsteadof NA


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M e c h anism o f action:

Guanethidine acts by blocking therelease of stored NA and also inhibitsthe uptake of NA.

Guanethidine is taken up by adrenergicnerves by the same mechanismsinvolved in NA uptake (uptake 1).


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M e c h anism o f action:

Subsequently, it accumulates in thestorage granules and displaces NA,thus producing a transient increase in

blood pressure.Furthermore, it prevents further release of NA in response to neuronal depolarization

(leading to prolonged fall in blood pressure).


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The adrenergic receptors are notblocked and therefore the drug does

not antagonize the circulatingcatecholamine but may potentiatetheir effects as it preventing theuptake.


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The rap eu tic u s e s: Treatment of severe hypertensionexcept in case of phaeochromocytoma

Sid e effe cts:Postural hypotension, Diarrhea,

Miosis, Nasal congestion, Failure of ejaculation


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Drugs Acting O nDrugs Acting O n

Autonomic GangliaAutonomic Ganglia


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Ov er v iew

Review ganglionic transmission

Definition and Classification Ganglionic Stimulants Ganglionic Blockers


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Ganglionic T ransmission

Primary neurotransmitter at allganglia and the adrenal medulla is

Ach

Receptor mediating the effects of Ach is nicotinic receptor

ACh binding results in an increased

permeability to Na+ (mainly) resultingin an EPSP


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Autonomic Ganglia

ACH

Nn


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Ganglion Stimulants

Stimulates nicotinic receptors insympathetic and parasympatheticganglia.

Nicotine (low concentration)Tetramethylammonium (TMA)Dimethylphenylpiperazinium (DMPP)


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N ICOTI N E

Stimulates at low dosesStimulates then blocks at high doses

Clinical uses: restricted to nicotinedependence (i.e. nicotine patches)

Tolerance developed after repeatedsmall doses of nicotine


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Pharma cologic al a ction:

It acts on:Sympathetic & parasympathetic ganglia

Nicotinic receptors of muscle (Nm)

In larger doses, the initial stimulation isfollowed very rapidly by depolarizationblockade


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Cardiovascular system:

Small dose; increased H R,vasoconstriction (stimulation of sympathetic ganglia).

Large dose; initially an increase then adecrease in H R, vasodilation (ganglionicblockade)

Similar to sympathetic stimulation


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Gastrointestinal tract actions :

(Parasympathetic stimulation)Increased tone and motility of the intestine.

Central nervous systemVomiting

Antidiuretic effectIncreased drive to respiration


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Ganglion Blockers

Depolarizing Non-Depolarizing

Competitive Non-Competitive


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Non-Depolarizing ganglion block

Competitive ganglion blocker:Mechanism of action:

No initial stimulation on Nn

receptor

Compete with acetylcholine for N nreceptor in the autonomic ganglia.

It blocks both sympathetic andparasympathetic ganglia


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Eff ect will always appear to be

opposite to the predominate ANS tone

Ganglionic blockade will alwayslower blood pressure (why?)

At rest, PS tone predominates in organs andglands jointly innervated by PS and S f ibers;

the e ff ect o f blockade looks like mildsympathetic activation


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Ex amples o f competitive ganglion

blockers:Te tra e t hyl ammoni u m.

M e cam yl amin e s

P e mpidin e

T rim e tap h an


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N on-competitive Ganglion

BLOCKERS:HEXAM T HONIUM

Blocks the response of acetylcholine at theautonomic ganglia

Does not depolarize or stimulate the ganglion

It blocks the associated ion channels with thereceptor, while the receptor was opened.


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Th erapeutic Uses:

Use of the ganglion blockers isinfrequent because more selectiveautonomic blocking agents areavailable.

Mecamylamine is being studied for possible use in reducing nicotine

craving in patients attempting to quitsmoking.


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Trimethaphan is occasionally usedin the treatment of hypertensiveemergencies and dissecting aorticaneurysm to produce controlled

hypotension.Electroconvulsive therapy.


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G ang l ionic b l ock e rs: sid e effe cts

Orthostatic hypotension

Blurred vision

Urinary retention, constipation

Sexual dysfunction

Lecture 1 (Drugs Acting on Autonomic Ganglia)

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