7. cholinergic drugs

7/22/2019 7. Cholinergic Drugs

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Asmah Nasser, M.D.


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M1 Secretory

glands

salivation, stomach acid, sweating, lacrimation

M2 Heart Decreases heart rate bradycardia

M3 Smooth

muscle

(GI/GU/Resp)

Contraction of smooth muscles (some)

diarrhea, bronchospasm, urination

M3 Pupil and

ciliary

muscle

Contracts Miosis

Increased flow of aqueous humor

Nm Skeletal

muscle end

plate

Contraction of skeletal muscle

Nn Autonomic

ganglia,

Adrenal

Medulla

Secretion of Epinephrine

Controls ANS


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Classification and examples of direct and

indirect acting Cholinergic agonists Brief discussion of few of the above

examples

Pathophysiology, diagnosis, andManagement of Myasthenia gravis and tensilon test

Glaucoma

Alzheimer's disease

Organo Phosphorus compound poisoning


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Heart: Cardiac suppressantBradycardia,

hypotension,

Eye: Miosis, cycloplegia, facilitates aqueoushumour drainage, lacrimation

Bronchospasm

Excess secretion from glands.salivary, bronchial,lacrimal glands etc..

GIT /bladder smooth muscle contraction andrelaxation of sphincters, increased motility,

diarrhea, vomiting , increased micturation (urinaryurgency)


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Often called parasympathomimetic drugs,

because their action mimics the action of thePSNS commonly

Also called as Cholinergic drugs or

cholinomimetricCholinergic agonists are two types :

1.Direct acting

2.Indirect acting


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They act by binding directly to cholinoceptors

Acetylcholine (Synthetic analogue of ACH)

Carbachol

Bethanechol

Pilocarpine(naturally occurring alkaloid)


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They act through inhibition of Acetyl

cholinesterase enzyme.so increasesAcetylcholine level in the synapse

Reversible: Neostigmine Physostigmine Pyridostigmine Edrophonium Tacrine

Danopezil

Irreversible :

Ecothiophate

Malathion

Parathion

Sarin


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It is a quaternary ammonium compound soCannot penetrate the membrane

Does not have any therapeutic importance,because of multiplicity of actions & rapid

inactivation by acetylcholinesterases It has both Muscarinic & Nicotinic actions

Neurotransmitter for pre-ganglionic neuron


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Not hydrolyzed by acetylcholinesterases

It has strong Muscarinic action & no Nicotinic action Actions

Directly stimulates M receptors causing increasedintestinal motility & tone

It stimulates detrusor muscle of the bladder whiletrigone & sphincters are relaxed causing expulsion ofurine

Therapeutic Uses:

Paralytic ileus Urinary retentions


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An alkaloid, lipid soluble & is stable to hydrolysis by

cholinsterases It has Muscarinic activity only .ActionsWhen applied locally to cornea Produces rapidmoisis & contraction of ciliary muscle produces ofspasm of accommodation & vision is fixed at

particular distance making it impossible to focusfor far situated objectsTherapeutic Use: In GlaucomaIt opens trabecular meshwork around schlemms

canal

causes drainage of aqueous humor IOP immediately decreases.


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Cholinesterase inhibitors. Can be reversibleor irreversible.

Reversable: Neostigmine

Physostigmine

Edrophonium

Tacrin

Danopezil

Irreversible Malathion and Parathion

Sarin

Ecothiopate


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Neostigmine in M.gravis Physostigminein Glaucoma, atropine overdose

Ecothiopate in glaucoma

Edrophonium in M.gravis to test

Tacrin, Danopezil in Alzheimer's

Malathion, Parathion as insecticides


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An autoimmune process causes production of

antibodies that decrease the number of functional

nicotinic receptors on the postjunctional end plates.

Frequent findings are

Double vision.diplopia,

Drooping of eyelids. ptosis,

Dysarthria Difficulty in speaking

Dysphagia ..difficulty swallowing,

Difficult in Daily routines

Day passes, limb weakness increases. Difficulty in respiration Severe disease may affect all the

muscles, including those necessary for respiration.

Death


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Immunosuppressantdrugs

Thymectomy

Acetyl Cholinesterase inhibitors Neostigmine

Pyridostigmine

Ambenonium

Edrophonium

Other supportive measures


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NeostigmineHas a strong influence at theneuromuscular junction

Pyridostigmine:Has a longer duration of actionthan neostigmine

Ambenonium :Available only in oral form;cannot be used if patient is unable to swallowtablets

Edrophonium: Diagnostic agent for myastheniagravis and to diffrentiate myasthenic andcholinergic crisis ( ensilon test)


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Clinical situations in which severe myasthenia

(myasthenic crisis) must be distinguished fromexcessive drug therapy (cholinergic crisis) usuallyoccur in very ill myasthenic patients

If excessive amounts of cholinesterase inhibitorhave been used, patients may become

paradoxically weak because of nicotinicdepolarizing blockade of the motor end plate.

Small doses of edrophonium (12 mgintravenously) will produce no relief or even worsenweakness if the patient is receiving excessivecholinesterase inhibitor therapy.

On the other hand, if the patient improves withedrophonium, an increase in cholinesteraseinhibitor dosage may be indicated.


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A progressive disorder involving neural

degeneration in the cortex Leads to a marked loss of memory and of the

ability to carry on activities of daily living

Cause of the disease is not yet known ?????? There is a progressive loss of ACh-producing

neurons and their target neurons


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Tacrine Side effect: HepatoToxicity First drug to treat Alzheimers dementia

Rivastigmine Available in solution for swallowing ease

Donepezil Has once-a-day dosing advantage


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Only Ecothipate is used clinically inGlaucoma. This is the long acting drug usedin glaucoma

Rest of the drugs are used as pesticides or war

gases or poisons: Malathion and Parathion


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The dominant initial signs are those of

muscarinic excess: miosis, salivation, sweating,

bronchial constriction, vomiting, and diarrhea.

Central nervous system involvement usuallyfollows rapidly, accompanied by peripheral

nicotinic effects, especially depolarizing

neuromuscular blockade.


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(1) maintenance of vital signsrespiration in particular may be

impaired;

(2) decontamination to prevent further absorptionthis may

require removal of all clothing and washing of the skin in

cases of exposure to dusts and sprays; and

(3) Atropine parenterally in large doses, given as often as

required to control signs of muscarinic excess stimulation .

(4)Therapy often also includes treatment with pralidoxime(Acetylcholinesterase reactivator)


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Irreversible cholinesterate inhibitor. LONG acting

Used in Glaucoma


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Direct/indirect acting cholinergic drugsactions, adverse effects, toxicity features ofOP poisoning

In OP poisoning atropine used to reverseonly the muscarinic effects..

Pralidoxime used to reactivate the enzyme


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Miosis Excessive salivation

Bradycardia

Bronchospasm Abdominal cramps, vomiting, diarrhea,

urination

Sweating


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Asmah Nasser, M.D.


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About 70 million people are affectedWorldwide 10% of these (~7 million) are blind from glaucoma

US data: > 40 yrs of age, 3 million about 120, 000 Americans are blind from it.

Most common cause of blindness amongBlack-Americans.

50% of all patients, are not awarethey have it,until late


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Types of Glaucoma:1. Open Angle Glaucoma Excessive production ofAqueous Humour2. Closed Angle Glaucoma Outflow obstruction ofAqueous Humour

Two Therapy aimed at:1. Reduce (Production, Synthesis or Secretion)

Dorzolamide, Acetazolamide, Timolol, Betoxolol andApraclonidine

2.Facilitate the drainage: Pilocarpine, Carbachol,

Ecothiopate ,Mannitol and Latanoprost


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Courtesy : Katzung


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Mannitol

reduces IOP by reducing vitreous volume byinhibiting the enzyme carbonic anhydrase

Reduces the secretion/synethesis

Timolol topical eye drops Non-selective blockade

Betaxolol eye drops Selective 1 blockade

Reduces the synthesis

Acetazolamide (oral), Dorzolamide (topical):

reduces the synthesis of aqueous humour,inhibits the enzyme carbonic anhydrase

2 receptor agonist (apraclonidine1%, topical

drops).


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1. Pilocarpine, Carbachol, Ecothiopateand

Physostigmine :Causes Ciliary muscle contraction,

increases Irido-corneal angle and open trabecularmeshwork.

2. Prostaglandins : Latanoprost: increase the outflow

through uveoscleral meshwork


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Excessive adrenergic receptor mediatedproduction and secretion of aqueous humorfrom the ciliary body epithelium.

Best treated with betablockers


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Results from obstruction of canal ofSchlemmthrough which aqueous humorwas supposed to be filtrated out .

Caused by1. Mydriatics : Anti-cholinergic drugs

2. Antidepressants : SSRI drugs

Treatment: Pilocarpine, Carbachol , ecothiopateand physostigmine

7. cholinergic drugs

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