ملخص

Anticholinergic Drugs

In contrast to cholinergic agonists which have limited usefulness therapeutically, the cholinergic blockers are beneficial in a variety of clinical situations
Antimuscarinic Agents:
1- M1 Selective.
2- Non selective.
Tertiary amine
1- Atropine prototype. 2- Hemoatropine 3- Scopolamin

quaternary amine

produce more peripheral effects with decrease CNS effect.
Include: Propantheline , Ipratropium , Clidinium bromide.

They are absorbed from GIT, mucus membrane , skin and eye .

Scopolamine has greater effect on CNS & eye than atropine.
- Atropine has greater effect on heart, intestine, bronchi and urinary tissue than scopolamine
Atropine has a high affinity for muscarinic receptors, where it binds competitively & reversiblely,preventing Ach from binding to that site.

Atropine is both a central and peripheral muscarinic blocker.

Atropine opposes the effects of all cholinergic drug
minimal stimulant effect and slow sedation.
1- CNS:


a- Mydriasis (dilated pupil) b- Cycloplegia: By weakening the contraction of ciliary muscle , so causing loss of ability to accommodate for near vision c- Reduction of lachrymal secretion, causing dry or sandy eyes.
d- Increase intraocular pressure
2- On eye
block the cardiac receptors on the SA node to vagus nerve so the cardiac rate increases modestly (tachycardia). with poisoning, there is marked vasodilatation.
3- On CVS
bronchial dilatation , decrease secretion
4- On Respiratory
a- Antispasmodic due to reduction of GIT motility.
b- Block salivary glands secretion
5- Gastrointestinal (GlT):

smooth muscles of ureter and bladder wall are relaxed and urination is slowed

6-genito-urinary tract
All decrease (exceptMilk) dry mouth, dry eyes, dry skin (inhibit sweating), bronchial secretion decrease & become viscid.

7- Exocrine glands secretions

Actions of Atropine

Poisoning with Atropine

Features:
- Dry mouth with dysphasia.
- Mydriasis, blurred vision.
- Hot flushes , dry skin with hyperthermia (CNS effect - absence of sweating).
- Restlessness ,anxiety, excitement hallucinations, delirium, mania.
- The cerebral excitation is followed by depression and coma.
Treatment:
- By giving activated charcoal to adsorb the drug.
- Diazepam is given for excitement.
Clinical uses of antimuscarinic drugs


1. On CNS:
a- Benzhexol , against rigidity and tremor in parkinsonism.
b- Hyoscine,: used as antiemetic. And prevent or reduce motion sickness.

2. Ophthalmologic disorders:

used in cases that need mydriasis with cycloplagia or prolonged action .
-Tropicamide is the short acting mydriatic drug.
3. Respiratory disorder :

a. Preoperative: To decrease bronchial secretion & spasm

b- Ipratropium is useful in the treatment of asthma and COAD in patients unable to take adrenergic agonists.
4. CVS disorders:

a. Myocardial infarction (MI) because it block reflex vagal stimulation (bradycardia) accompany pain of inferior MI .
b. Atropine used to treat sinus bradycardia
5. GIT disturbances:
a. Propantheline (Duspataline): used as antispasmodic
Hyosine butyl bromide (Buscopan): effective relaxant of the
sm.m .
b- Peptic ulcer : M1 inhibitor (Pirenzepine).
c- In preanesthesia: they reduce salivation and gastric secretion.
d. Clidinium bromide: used in treatment of gastric disorders.
6. Urinary disorder
- Flavoxate, propantheline and oxybutynin, are used to relieve m-spasm
7. Atropine used as antidotes to cholinergic and anticholinesterase agent, it is drug of choice to treat poisoning from organophosphate pesticides.
- Its also used to block muscarinic effects due to cholinergic drugs such a neostigmine are used.


Adverse effects of antimuscarinic drugs
In the infants even ordinary dose could result in antimuscarinic fever, while in adults it depends on the dose :
1. Small dose: decrease salivation , decreased bronchial secretion, decrease sweating .
2. medium dose: pupil dilation visual accommodation decreased and heart rate is increased .
3. Largest dose: inhibition to the urination and intestinal motility and this is followed by decrease in gastric section and motility .
4. over dose: all above are exaggerated , with CNS excitation , restlessness , irritability and hallucination.

II- Antinicotinic Agents:

1- Ganglionic Blocking Agents.
2- Neuromuscular Blocking Agents.

1- Ganglionic Blocking Agents

Hexamethionin, mecamylamine and other ganglion-blockers were mainly used in the treatment of hypertension.
, the adverse effect of ganglion blocked are so severe (both sympathetic and parasympathetic divisions are blocked), so that patients are unable to tolerate long term treatment with them

Trimethaphan

It is the only Ganglion-blocker still in clinical use
It is used IV to treat severe accelerated hypertension (malignant hypertension).
these drugs cause postural hypotension.


2- Neuromuscular Blocking drug
These drugs are important for producing complete sk-m relaxation in surgery, by specific blockade of the N-M
also relax the vocal cords and allow the passage of a tracheal tube.
- Patients who have received a M-relaxant should always have their respiration assisted or controlled until the drug have been inactivated or antagonized.

Non Depolarizing Competitive N-M blocking agents

Drugs of this group cause N-M block by competing with Ach at the receptor site at the N-M junction so prevent depolarization of muscle cell membrane

Tubocurarine

- Is the prototype it produces a competitive block at the at the motor endplate of the muscle causing flaccid paralysis lasts 30-60 min.
- Tubocurarine blocks autonomic ganglia and causes an initial transient drop in blood pressure & cause histamine release which may induce bronchospasm.

The action of competitive N-M blocking drugs is antagonized by anticholinesterases, like Neostigmine which preceded by atropine to prevent the parasympathetic autonomic effect of Neostigmine (such as bradycardia and salivation)

Depolarizing Non competitive N-M blocking agents

Suxamethonium (Succinylcholine)
- It attaches to the nicotinic receptors and acts like Ach to depolarize the N-M junction.
. Initially this produces short-lasting muscle fasciculation, followed within a few minutes by muscle paralysis.

does not produce a ganglionic block, except in high doses, although it does have weak histamine-releasing action
duration of action of succinylcholine is extremely short so used during anesthesia for brief procedures
the succinylcholine action cannot be reversed by other drug
undergo rapid hydrolysis by plasma pseudo cholinesterase enzyme


its persistence in the body is increased by
1- Neostigmine, which inactivate that enzyme.
2- In patient with hepatic disease or severe malnutrition, whose plasma concentration of enzyme may be lower than normal.
3- Procaine also is destroyed by this enzyme and so by competing with suxamethonium for the enzyme, may prolong its action.
4- There are persons with hereditary defects in amount or kind of enzyme, who cannot destroy the drug as rapidly as normal

Adverse effects of Succinylcholine

1- Hyperthermia
2- Apnea: A genetically related deficiency of plasma pseudo cholinesterase enzyme can lead to apnea due to paralysis of the diaphragm
3- Cardiovascular
a- Repeated injections of suxamethonium can cause bradycardia and even cardiac arrest
b-It causes release of K from muscle which can be enough to cause cardiac arrest in patients with already hyperthermia
4- Muscle pain lasting 1-3 days due to muscle fasciculation preceded the paralysis by Suxamethonium.
5- High dose can stimulate the uterus

Contraindication of succinylcholine

1- Hypersensitivity to suxamethonium.
2- Severe liver disease
3- Burned patient
4- Pregnancy


Uses of N-M blocking agents
- The main use of these drugs is the producing complete skeletal muscle relaxation in surgery.
Other uses:
1- Control Ventilation:
- In respiratory failure due to obstructive airway disease.
2- Treatment of convulsion:
- By decrease peripheral manifestation of convulsion

Myasthenia Gravis

It is a disease affecting neuromuscular junctions of skeletal muscle.
special autoimmune antibodies (Abs), which either block or causes lyses of the Ach receptors.
- Cholinoceptors exist for about 7days in normal individuals but for only 1day in MG patient.
The characteristic symptoms of weakness and fatigability that decrease with rest and worsen with exercise
Severe disease may affect all the muscles, including muscles necessary for respiration.

Edrophonium is used as a diagnostic test for MG.

2 mg dose is injected IV after baseline measurements of muscle strength have been obtained. If no response occurs after 45 seconds, an additional 8 mg may be injected.
- If the patient has MG an improvement in the strength of muscles last for 15 minutes ( this differentiate MG from cholinergic crisis due to excessive drug therapy in which there will be worsening of the condition)

myasthenia gravis Treatment of

1- Chronic long-term therapy of MG is usually accomplished with neostigmine, pyridostigmine.
The doses are titrated to optimum levels based on changes in muscle strength
If muscarinic effects of such therapy are prominent, they can be treated by atropine (antimuscarinic drugs)
Longer-acting cholinesterase inhibitors such as the organophosphorous agents are not used. ?? because ther are very long acting agent

2- Thymectomy

3- Adreno corticosteroid, (prednisolone), induce improvement in 80% of cases.
4- Immunosuppressive therapy . Aim is to eliminate Ach. Receptor auto-antibody.

Clinical indications of the cholinergic drugs (agonists)

1. Reduce IOP in patients with glaucoma and during ocular surgery.
2. Treatment of atony of (GIT & bladder).
3. Diagnose & treatment of myasthenia gravis.
4. Minor uses: as antidotes to:
a- Neuromuscular blocking agents (muscle relaxants), tubocurarine.
b- Drugs with anticholinergic effects such as tricyclic antidepressant, belladonna alkaloid.

Tacrine: The newest anticholinesterase agent used for treatment of mild to moderate dementia associated with Alzheimer's disease

Adverse Reactions of all the cholinergic drugs

blurred vision , decrease accommodation and meiosis.

1. On eye

Increase sweating .

2. On skin

Increase salivation , belching , nausea , vomiting , intestinal cramps (abdominal colic) and diarrhea .
3. On GIT
vasodilatation , decrease heart rate
4. On CVS :
hyperpolarization of the skeletal muscle which will reduce contraction .

5. At motor end plate

irritability , anxiety and fear , some of them causes seizures.
6. On CNS