الحلقة 4 من كورس كلنيكال فارما (ANS)

 الحلقة 4 من كورس كلنيكال فارما ( من جزء الجهاز العصبي اللاإرادي)

Indirect-Acting (Anticholinestrase)

Don’t act on receptors but act on cholinesterase enzymeinhibit AChE  Increase ACh.

A.Reversible Anticholinesterase (AChE inhibitors)

- Binds reversibly to the active center of acetyl cholinesterase (ACHE) enzyme by

hydrogen bond (Short acting) and weak covalent bond (Medium acting) inactivate

cholinesterase enzyme due to conformational change.

- It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors.

1- short-acting AChE inhibitor:-

Edrophonium (Enlon®)(Enlon-Plus®)

Pharmacokinetics

- Edrophonium quaternary amine actions are limited

to the periphery (not pass BBB).

- It is rapidly absorbed and has a short duration of

action due to rapid renal elimination.

- Onset of action IV (30 to 60 seconds), IM (2 to 10

minutes).

Duration of action IV (5 to 10 minutes), IM (5 to 30

minutes).

-Half-life 7 to 12 minutes,

-Elimination time  33to 110minutes.

Uses 1: Diagnosis of myasthenia gravis  IV injection of

Edrophonium  rapid increase in muscle strength.

- N.B: - Excess of drug may provoke a cholinergic crisis

(is an over- stimulation at a neuromuscular junction

due to an excess of ACh)  Atropine is the antidote.

- Enlon-Plus® Edrophonium + Atropine

- Because of its short duration of action, it is not

recommended for maintenance therapy in myasthenia

gravis.

2: Antidote for curare or curare like agents

(Neuromuscular blockers) to reverse the effects of

certain medications used to prevent muscle

contractions during surgical procedures

3: Unaccepted uses: Edrophonium has been used to

terminate supraventricular tachycardia but has

generally been replaced by other antiarrhythmic

agents.

2.Medium-Acting AChE inhibitors:-

Neostigmine (Prostigmin®) Physostigmine (Antilirium®)

- Synthetic quaternary amine

compound.

-Naturally tertiary amine alkaloid.

- Polar Not Lipid soluble  Not

Pass BBB No CNS effect

- Effect on skeletal muscle (+++)

-Moderate duration of action (0.5

to 2 hours).

Non polarLipid solublePass

BBB → CNS effects.

- Effect on skeletal muscle (+)

- Moderate duration of action (0.5

to 2 hours).

Uses

- Manage symptoms of myasthenia

gravis.

- Stimulate the bladder and GIT in

paralytic ileus and atony of urinary

bladder after surgery.

- Curare poisoning (antidote for

curare or curare like agents)

Uses

- Antidote for atropine to reverse

the central and peripheral side

effect of atropine e.g. dry mouth,

blurred vision, Flushing, etc.

- Increase GIT motility and

stimulate bladder.

- Used in glaucoma and Alzheimer's

Disease but * not recommended

(Unspecific)

Adverse Effects

Include those of generalized

cholinergic stimulation e.g.

salivation, hypotension, nausea,

flushing, abdominal pain and

diarrhea.

- Not cause CNS side effects.

- CI in intestinal or urinary bladder

obstruction.

Adverse Effects

- Convulsion and bradycardia.

-Paralysis of skeletal muscle (rarely)

due to accumulation of ACh at the

skeletal neuromuscular junction as

a result of inhibition of AChE.

Pyridostigmine (Mestinon®) Ambenonium (Mystelase®)

Information Pyridostigmine and ambenonium are quaternary

ammonium compounds Polar (Not cross BBB).

- Slightly longer duration of action than neostigmine

{Pyridostigmine (3 to 6 hours), Ambenonium (4 to 8

hours)}.

Uses - Used in the chronic management of myasthenia gravis.

Adverse

effect

- Similar to neostigmine.

Distigmine Bromide (Ubretid®)

- Distigmine is similar to neostigmine but has a longer

duration of action.

-Distigmine has a greater risk of causing cholinergic crisis

so, rarely used as a treatment for myasthenia gravis.

- Used in paralytic ileus and increase atony of urinary

bladder after surgery.

Demecarium Bromide (Humorsol Ocumeter)

Demecarium is a drug that used topically in eye drops for

treatment of glaucoma in cats, dogs, and other animals

(rarely used in human due to may cause retinal

detachment).

3. Anticholinesterase with Selective CNS effects :-

Tacrine Donepezil

(Alzepizil®)

Rivastigmine

(Exelon®)

Galantamine

(Reminyl®)

Information

- Tacrine was the first to become available, but it

has been replaced by others because of its

hepatotoxicity. Despite the ability of donepezil,

rivastigmine , galantamine.

Uses - Delay the progression of Alzheimer's disease

(Deficiency of cholinergic neurons in the CNS).

Adverse

effect

- GI distress is their primary adverse effect.

Irreversible Anticholinesterase (Organophosphate Compounds)

- A number of synthetic organophosphate compounds have the capacity

to bind covalently to ACHE.

-The result is a long-lasting increase in ACh at all sites where it is released.

- Many of these drugs are extremely toxic and were developed by the

military as nerve agents.

Diisopropyl fluorophosphate (DFP)

- May used in treatment of chronic open-angle glaucoma (rarely used).

- It is highly lipid soluble and is well absorbed across all membranes.

Echothiophate (Phospholine)

-Echothiophate is an organophosphate that covalently binds via phosphate

group at the active site of ACHE the enzyme is permanently inactivated

restoration of via its ACHE activity requires the synthesis of new enzyme.

- Used topically in treatment of open-angle glaucoma.

Insecticides (For Example)

Malathion (Ovide®) Parathion (Folidon®)

-They are highly absorbed via skin, mucous membranes, and orally.

- Malathion is less toxic than parathion in mammalian species.

war Gases (Toxic Gases)

- Organophosphate nerve gases such as sarin, tabun and soman are used

as agents of warfare.

- Nerve gases binds covalently to ACHE the enzyme is permanently

inactivated Acetylcholine accumulates  nerve impulses cannot be

stopped, causing prolonged muscle contraction Paralysis occurs and

death may result since the respiratory muscles are affected (respiratory

arrest).

- Signs includes (DUMBBELS) Diarrhea, Urination, Miosis, Bradycardia,

Bronchoconstriction, Emesis, Lacrimation and Salivation.

Treatment of Toxicity of Irreversible Anticholinesterase:-

1) Pralidoxime (Protopam®) :

 Pralidoxime reactivates inhibited ACHE by displaces the phosphate group of

the organophosphate and regenerates the enzyme.

It is unable to penetrate into the CNS (not useful in treating the CNS side

effects).

- Initial dose: 1 to 2 g as an IV infusion in 100 mL of normal saline, over 15 to

30 Pralidoxime IV dose: (25- 50 mg/kg) minutes.

- Second dose: 1 to 2 g may be indicated after about 1 hour.

-Additional doses: may be given every 10 to 12 hours if muscle weakness

persists.

2) Atropine (Atropine sulphate®) :

Blocking muscarinic receptors (Prevent peripherally and centrally muscarinic side

effect due to it pass BBB) (seen later).

DuoDote Atropine + Pralidoxime in one ampoule for injection

3) Diazepam (Valium®) :

Anticonvulsant (reduce the persistent convulsion)(seen later).

4) Oxygen supply Artificial respiration.

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