DR . TUSHAR S DHAWALE

ASSO. PROFESSOR

DEP. OF PHARMACOLOGY

PRATIBHA MEDICAL COLLEGE

TRICHUR

“Cholinergic

transmission and drugs

“

25/02/15

Acetycholine

It is also the preganglionic neurotransmitter for

both the sympathetic and parasympathetic

nervous system.

Acetylcholine (ACh) is the postganglionic

neurotransmitter in the parasympathetic nervous

system

.

Cholinergic fibre means

All such fibre that release the acetycholine as

the neuro transmitter

1 all the somatic motor neuron to the skeletal

muscle

2 all preganglionic sympathetic and

parasympathetic fibre

3All the parasympathetic fibre to the neuro-

effectors junction

4 post ganglionic sympathetic fibre to sweat

gland

Para sympathetic nervous

system

Distribution of parasympathetic

nervous system

Comparison of the pre and post

ganglionic fibre

Acetycholine synthesis

Muscarinic receptor

Features M1 M2 M3

Location Autonomic and enteric

ganglia

Paracrine cell gastric gland

CNS

SA node , AV node ,

presynaptic terminal

Exocrine gland ,

smooth muscle ,

vascular endothelium

Function Gastric acid

Cns excitation

Gi motility

Dercrase rate of impulse

generation

Velocity of conduction

Bradycardia

contractility

Increase in exocrine

secretion , smooth

muscle contraction

Mechanism ip3 , DAG ,

increase in ca 2+ conc.

Inhibition of adenyl cyclase

, decrease CAMP opening

of k+ channel

Same as the M1

receptor

Agonist Oxotremorine Methacholine Bethacholine

Antagonist Pirenzepine

Telenzepine

Triptramine Tolterodine

Darifenacin

Eyes: contraction of ciliary muscle and smooth muscle of the

iris sphincter (miosis)

Heart : Bradycardia (possibly preceded by tachycardia),

decrease force of conytraction

Blood vessel : vasodilation ( EDRF)

Lung : bronchoconstriction and increase secretion

Pancreas : increased pancreatic juice

Urinary bladder : voiding of urine ( detrusor and spincter)

Sweat gland : increased sweating

Acetylcholine – muscarinic

action

Acetycholine : nicotinic action

Neuro-muscular Junction: nicotinic Nm receptor

Stimulation lead to muscle contraction

Sympathetic And P. Sympathetic Ganglia: Nn

receptor

Release of NE and Ach

Adrenal Medulla : Nn receptor

Release of adrenaline

Location of nicotinic receptor

In sympathetic and parasympathetic ganglia

in the adrenal medulla

in the neuromuscular junction of the skeletal

muscle

in the central nervous system.

Cholimimetic drugs

Directly acting ( acetylcholine is prototype)

Synthetic Natural alkaloid Miscellaneous

Methacholine Muscarine Tremorine

Bethanchol Nicotine Oxy tremorine

Carbachol Pilocarpine Cevimeline

Arecoline

Directly acting cholimimetic drug

(synthetic )

Synthetic cholinester

Bethanchol

Long acting drug

Resistant to true and pseudo cholinesterase

Indication

Atony of bladder Urinary retention

Git atony

Xerostomia

Bethanchol

Side effect

Cns stimulation, Miosis

Spasm of accomodation for distant vision

Abdominal cramps

Flushing, Salivation

Contraindication

*Hyperthyroidism ,Asthma

Peptic ulcer ,My . Infarction

Preparation : urotonin , bethacol 25 mg tab.

Directly acting cholimimetics

Pilocarpine

Natural alkaloid

Tertiary amine in nature

Dominat m3 action

Mild nicotinic action

Indication

1 Open glaucoma 0.5-4 % solution

2 Xerostomia 5- 10 mg

3 stimuation of salivary secretion in post-op. Patient

Miscellaneous cholimimetic drug

Cevimiline

Indication

Xerostomia in chemotherapy patient

Sjogren syndrome

Tremorine & oxytremorine

To produce parkinsonism in animal

Indirectly acting cholimimetic

drugs

Mechanism

They prevent the degradation/ hydrolysis of the

acetylcholine and analogue

Further divided into

Reversible Irreversible

Cholimimetic cholimimetic

Indirectly acting cholimimetic

drug

Reversible Irreversible

Natural Quaternary

compound

Organophosphate Carbamate

Physiostigmi

neEdophronium Isoflurophate Propoxur

Neostigmine Ecothiophate

Pyridostigmin

e

Parathion

Demercarium Malathion

Rivastgmine Diazinon

ambernonium Paraxon

Pathology : myashtenia gravis

• Autoimmune disorder

• Incidence- 1 in 10000

• Auto antibodies against the ach receptor

Response failed to incite contraction

Myashtenia Gravis Sign & Symptoms

Tensilon test

A Diagnostic Test For Myasthenis Gravis

Drug Used- Edophronium chloride

Dose – Given 0.3 Mg

Ultra Short Duration Of Action

it differentiate between the cholinergic crisis and

the myashtenic crisis

Cause worsening of symptoms in cholinergic crisis

Myasthenia Gravis Treatment

Pyridostigmine – 60 mg tds

Neostigmine - 15-30 mg per day orally

0.5 -2.5 mg IM/SC

prolonged treatment with the AChE drug,

Myasthenia cholinergic

Crisis crisis

(Therapeutic (over treatment)

Failure )

Treatment of toxic effects

Atropine 0.5 mg /sc

* Tolerance developed to muscarinic S/E effects

Myasthenia gravis treatment

Algorithm for M. Gravis

treatment

Cholimimetic drugs

Irreversible Anticholinestarases

Organophoshates carbamate

Isoflurophate propxur

Ecothiophate

Parathion

Malathion

Irreversible AchE blocker

phosphorylate the esteric site of the

AChE by forming the coavalent bond

The AChe become inactive

Resistant to hydrolysis

Ectothipate have additional quaternary nitrogen

That bind with the anionic site of the enzyme

Hence slow hydrolysis can be still possible with ecothiopate binding

After the phosphorylation of the enzyme

undergoes

Molecular arrangement

, become completely resistant to the hydolysis

Loss of one alkyl or alkoxy group .

Organophosphates having di- isopropyl group (

DFP)

Are more prone to ageing than parathion (

diethyl)

Malathion ( dimethyl)

Irreversible AchE blocker

Organo phosphorus poisoning

Agent causing

• Malathion

• Parathion

• Ectothiopate

• Diazion

• Diflos ( DFP)

• Carbate derivatives

• Propoxur and carbaryl

organophosphorus poisoning

1)Accidental , occupational hazard

2)Suicide

Treatment option

Atropine ache reactivating drug

To counter the pralidoxime 2- PAM

Antimuscarinic drug

Organophosphate poisoning

initially

Atropine in dose of the 2 mg i.v is

administered

Every 15 min till the sign of the atropinisation

appear

pralidoxime in dose of the 1-2 g

Given via iv infusion of over 15-20 min

For reactivation of the enzyme

Ache Reactivator

Pralidoxime activate the enzyme by

Binding to the anionic site of the enzyme

the phosphorylated esteric site now attract the

Oxime group of PAM

The phosphate – oxime group seperate out

Leaving the enzyme in the active form

DAM ( diacetyl mono oxime )

Has an advantage since it cross the blood brain barrier

Limitation of the oxime therapy

Shortcoming

No reactivation after the Ageing

Not effective in carbamate group insecticide

PAM and OBIDOXIME do not cross the blood

brain

Organophosphate therapeutic indication

Ectothiopate

It is quaternary ammonium compound

Hence does not cross blood brain barrier

Water soluble

0.05-0.25 % solution are used

Topically as miotic and glaucoma

Longer acting 1-2 weeks

Carbaryl

Carbamate derivative

Used topically for the control of the head lice

Antimuscarinic drugs

Natural

alkaloids

Semisynthetic

derivatives

Synthetic derivatives

Atropine Homatropine Eucatropine Oxybutinin

Atropine methionitrate Cyclopentolate Telenzepine

Scopolami

ne Hyoscine Tropicamide Pirenzepine

Ipratropium Dicylomine trihexyphenidyl

Tiotropium Flavoxate propantheline

Glycopyrrolate Clidinium

Tolterodine Valethamate

Atropine mechanism of action

Competitive antagonist of the acetylcholine at the

M1 to M5 receptor

Antagonism is reversible

Proposed mechanism blockade of the inhibition of

release of the ip3 m1 and m3

M2 receptor mediated action causing inhibition of

The adenyl cyclase

Antagonism is more pronounce for the

Exogeneolsly administed choline ester

Atropine effect

Central nervous system

Central excitation

Restlessness, irritabilty , disorientation ,

Hallucination and delirum

Scopolamine

Low dose

Drem like state, amnesia, drowsiness

Depression of emetic centre

High dose hallucination

Excitment , agitation

Large dose

Stimulation followed by depression

Effect of atropine

Salivary gland : dry mouth, difficult swallowing

Gastric: reduces volume secretion & total acidity

Others:

Reduces secretion in nose, mouth, pharynx, bronchi

(viscid)

formation of mucus plug

Decrease sweating

Effect of atropine

GI:Reduces tone & motility (antispasmodic)

Biliary tract : weak anti spasmodic

Urinary tract: reduce tone of fundus of bladder &

enhance tone of trigonal sphincter -- uri

retention

Bronchi: relaxes musc of bronchi & bronchioles

Eye: mydriasis (sphincter of iris & ciliary musc) –

paralysis of accomodation or cyclopegia

effect of atropine on cvs

Initially decreases HR – partial agonist of Ach

or stimulation of vagal nuclei

Followed by tachycardia (↑ by 30-40 bpm) –

blocking of M2 ® in SA node

Toxic doses: dilatation of cutaneous blood

vessels – atropine flush & hypotension)

Atropine p/k

Distribution

Widely distributed

Scopolamine has wide distribution and distributed into

The brain parenchyma as well

Metabolism

By phase 2 reaction in the liver ( conjugation )

Species variation – like rabbit due to inherent active enzyme the atropine esterase that degrade the atropine rapidly

Excretion via renal route

t1/2 is 3 hrs

Except in eye it is around 72 hrs

Atropine p/k

atropine pk properties

Tertiary amine like atropine and hyoscine and scopolamine

Absorbed well from gut and mucous membrane

Drug like scopolamine absorbed from skin also

Quaternary compound like

Poor lipid solubilty and

Poor penetration into the brain

ACUTE BELLADONA

POISONING

Peripheral Muscarinic Blockade Dryness Of Mouth, Difficult Swallowing, Thirst

Tachycardia , Palpitations

Hyperpyrexia (Inhibition Of Sweating)

Mydriasis, Blurred Vision, Photophobia

Difficult Micturation, Retention

Central Actions Excitement, Restlessness

Motor Incoordination

Slurring Of Speech, Memory Disturbance

Confusion, Hallucination, Mania, Delirium

Coma,

Belladona poisoning

management

Ingestion: gastic lavage

Physostigmine 1-4mg (children 0.5-1mg) IV (pref.

in CNS symp)

Neostigmine 2-5mg s.c.

Repeated at intervals of 1-2hrs

Other symptomatic mgmt (dark room, tepid

sponging, oxygen, artificial vent, catheterization)

ADVERSE EFFECTS

Dryness of mouth, difficult swallowing

tachycardia

Fever

Constipation

Blurring of vision, ppts glaucoma (elderly)

Retention of urine (elderly)

Local allergy: dermatitis, conjunctivitis, swelling of

eyelids

Effect of the atropine

effect of the atropine on the eye

Passive mydriasis

Paralysis of accomodation ( cycloplegia )

Photophobia

Drynesss of eyes ( sandy eye )

Atropine therapeutic application in

the eye

Testing of the refractive errors

For othalmoscopic examination

To break adhesions along with the miotics

Most preffered combination is

Homatropine and pilocarpine

Uses of atropine and analogue

Drug indication

Atropine Malathion poisoning

Scopolamine Motion sickness

Benzotropine parkinson’s disease

Trihexyphenidyl Parkinson’s disease

Biperiden Parkinson’s disease

Tropicamide Measurement of refractory

error

Cyclopentolate Ophthalmic examination

Uses of atropine and analogue

Drugn Indication

Homatropine To break adhesion iris and

anterior surface of lens

Oxybutyrin In eneures, involuntary

bladder

Glycopyrrolate To reduce the secretion

Pirenzepine and

telenzepine

In control of gastric acid

secretion

Skeletal muscle relaxant

Peripheral acting skeletal muscle relaxant

This act peripherally at neuro-muscular

junction .

Act on nicotinic Nm receptor

Divided into –

non depolarising muscle relaxant

( d- tubocurarine is prototype)

depolarising muscle relaxant

( succinycholine )

non depolarising muscle

blocker

Long acting – tubocurarine

Mid acting - pancurorium

pipecurorium

atracurirum

cisacurirum

rocurirum

Short acting - mivacurium

rapacurium

Non depolaring muscle blocker

Affinity for the Nm receptor

Prevent binding of the ach to this receptor

failure to open the sodium channel

Failure to produce end plate potential

Failure to elicit contraction

Skeletal muscle relaxation occcur

Produce surmountable antagonism

p/k property of the non depolarising

mjuscle relaxant

Quaternary ammonium compound

Remain ionised at the physiological ph

Volume of distribution

Smaller volume of distribution

Confined to extracellular fluid

Don to cross bb ( exc. Atracurium )

Reversal of neuro- muscular

blockade

1)Neostigmine / pyridostigmine

availability of ach

2)Sugammadex

It is ý – clycodextrin compund

form water soluble complex with the steroidal n-m blocker

favour movement of steroidal n-m blocker from n-m junction in plasma , excreted via urine .

Succinylcholine

Action on the ganglia

Agonist action the nn receptor

Cause histamine release

Vagal ganglia – bradycardia

sympethetic gangia- tachycardia and

hypertension

Also act on the muscarinic receptor to reduce

b.p

Hence ther net no effect on the blood pressure is

seen

Succinycholine

Mechanism of action

Succinycholine

at the nmj it act on the nm receptor lead to opening of the na channel

Cause depolarisation

Produce repetitive excitation and relaxation

Produce muscle fasciculation . When acetylcholine bind with it it can not elicit any response hence an flaccid paralysis ensure

Succinylcholine

Pharmacodynamics

Single iv dose

Fasciculation over chest and abdomen

Complete relaxation with in the 1-2 min

Sequence of paralysis

Cheek and abdomenn –

Neck – limb – face- trunk –respiratory paralysis

Succinylcholine

Pharmacokinetic

Brief duration of the action

5-10 min

Dose 0.75-1.5 mg/ kg iv

Cause : rapid hydolysis by the plasma pseudo

cholinesterase

Move from motor end plate into the extracellular

fluid

Dibucaine No.

dibucaine and local anaesthetic

Reduce activity of the true cholinesterase by 80%

and pseudo cholinesterase by 20 % hence the

dibucaine no. Of less than 80 indicate activity of

the atypical enzyme

Succinycholine

Adverse effect

Muscle soreness

Malignat hyperthermia

Masseter muscle rigidity

Hyperkalemia

Rise in iop

Prolonged apnoea

Incresed intragastric pressure

Malignat hypertension

Succinylcholine

Adverse effect

Hyperkalemia

Efflux of k+ occur during the depolarisation

blockade

Target group –

Burn , spinal injury , uremia

Precipitation of arrythmia ,

Even cardiac arrest

Succinylcholine

Malignat hyperthermia

Autosomal dominant condition

calcium channel rynodine calcium channel

On administration of the SCh

Persistent release of the ca2+ from the sarcoplasmic reticulum

Cause persistent muscle contraction

Incresed heat production

Increased suseptibility following admininstration of the halothane along with the succinycholine

Depolarising v/s non depolarising muscle

blocker

Monitoring of neuro-muscular

blockade

Therapeutic use of n-m blockers

For brief procedure like

Endotracheal intubation

Laryngoscopy

Bronchoscopy

Combined with diazepam to prevent the

injury due excess convulsion

In spastic condition like tetanus , status

epilepticus

Difference between the competitive and

depolarisinng muscle blocker

parameter D tubocurarine Succinylcholine

Blockade type Competitive blockade Depolarising blockade

Type of relaxation Flaccid paralysis Fasciculation followed by

paralysis

Neostigmine addition + antagonism Potentiation

Effect of other

neuromuscular blocking

drug

Decreased effect Increases effect

Histamine release ++ release negligible

Serum k+ level No change Hyperkalemia

Pharmocogenetic

variation

nil pesudocholinesterase

Cardiac M2 receptor No effect stimulate (bradycardia )

Nicotine

Alkaloid in nature

Stimulate cns

Low dose depolarise N-M junction

High dose paralysis

Stimulation of sympathetic and Para sympathetic ganglia

Adverse effect

• High incidence of hypertension

• Chronic bronchitis

• Tobacco ambylopia

• Lung cancer

Clinical use of nicotine

Nicotine transdermal patch

As an aid to quit smoking

Ganglionic blocker

Block the transmission from the pre to post ganglionic

neuron

Block both the sympathetic as well as parasympathetic

ganglia

Inhibition of release of ach and ne

Persistent depolarising blocker

Nicotine , carbachol

Non – depolarising blocker

Trimethapan, hexamethonium, mecamyline

Therapeutic use

Hy. tension in dissecting aneurysm

Hypertensive emergency

Thank .... U

Nervi erigentes

Terminal ganglia

Vagus nerve lie within

Short post ganglionic fibre

Non mylinated except the ciliary

parasympaathetic post ganglionic fibre r

mylianated

Location Of Ach Receptor

Nicotinic receptor

1. Neuromuscular junction

2. All the autonomic ganglia

3. In the brain

Muscarinic receptor

Parasympathetic neuro-effector junction

1. M1 – sympathetic ganglia , gastric parietal cell , cerebral cortex(+)

2. M2 – myocardium , smooth muscle (-), presynapticnerve terminal

3. M3- glandular and visceral smooth muscle (+)

Degradation acetycholine

Acetyl choline is hydrolysed by the acetycholine

esterase

True acetycholineesterase

Cholinergic synaptic cleft

Methacholine

Succinyl choline , butyryl choline

Neuronal membrane

Rbc and placenta

Degradation acetycholine

Plasma cholinesterse / pseudo cholineesterase

from in Liver

Location : plasma and Intestine

Hydrolyses benzocholine and butyrylcholine

esters

Genetic variation found

Succinycholine

This case have denervated muscle and Nm

receptor show denervated supersensitivity

nasuea and vomitting occur due to rise in intra

gastric pressure