Al-Bayan University
Pharmacy college
3rd stage
pharmacy
5th lecture
Drugs acting on ANS
Part 1
Dr.Khulood Saadoon
Nervous system
Nervous system can be divided into :
1- Central nervous system( Brain and spinal cord).
2- Peripheral nervous system( somatic and autonomic).
Somatic nervous system: It controls the motor
functions of the body(axons from the spinal cord to the
skeletal muscles).
Autonomic nervous system can be divided into:
1- Sympathetic nervous system(SNS).
2- Parasympathetic nervous system(PNS).
• Autonomic nervous system: Its activity is not
under direct conscious control.
It regulates the involuntary functions(hear beat,
Bp, respiration, digestion, elimination-------)
Parasympathetic nervous system
(PNS)
Neurotransmitter of PSN is acetylcholine(Ach).
Acetylcholine is also a neurotransmitter in all preganglionic
nerves( sympathetic and parasympathetic).
Neurotransmitter is a chemical mediator that transmit nerve
impulse across junctions or synapses.
It is synthesized in the nerve ending and release to act on
different organs. Then it is hydrolyzed by special enzymes.
Synthesis and hydrolysis of Acetylcholine
Synthesis: Acetate + Co-A → Acetyl Co-A + choline →→ Acetylcholine + Co-A
Ch. Acetylase
Storage:
It is stored together with ATP & Ca in small membrane bound vesicle in cholinergic
neurons.
Enzymatic destruction:
There are two types of enzymes:
a- True choline esterase: It is found in tissues, CNS, RBCs & NMJ. It is specific &
regenerates within 3 months.
b- Pseudocholinesterase enzyme(butyrlcholinesterase): It is found in liver &
plasma, it is not specific (destroys other drugs), it regenerates within 3 weeks.
The end product of ACh destruction is acetic acid & choline. It is metabolized
mainly by true cholinesterase enzyme & to a lesser extent by pseudocholinesterase.
It is excreted by renal route.
Cholinergic receptors
Acetylcholine acts on
1- Muscarinic receptors (M1,M2,M3). This receptor
family earned its name because it was first identified
using muscarine, an alkaloid isolated from mushroom
Amanita muscaria. It is responsible for mushroom
poisoning.
2- Nicotinic receptors (Nn, Nm). They get their name
from nicotine which selectively bind to these receptors.
Distribution of cholinergic receptors
Muscarinic receptors (M1 –M5): .
• M1 (neural)- CNS & stomach (Excitatory)
• M2 (cardiac)- Heart (SA node), presynaptic (decrease ACh)
(inhibitory)
• M3 (glandular& smooth muscle endothelium)- Glands,
visceral smooth muscle & BV endothelium (Excitatory)
Nicotinic receptors:
• Nn- Autonomic ganglia, suprarenal medulla.
• Nm- Neuromuscular junction (NMJ).
Pharmacological actions of ACh
A. Muscarinic activation:
1- EYE:
a- It contracts the circular smooth muscle fibers of the ciliary muscle &
iris causes spasm of accommodation & ↑ outflow of aqueous humour
into the canal of Schleme & ↓intraocular pressure (IOP).
b- It causes ↓ in pupil size because contracts circular smooth muscle of
the iris & causes miosis.
2-CVS:
a- It produces – ve chronotropic effect (↓ SA node activity). It ↓
conductive velocity through AV node, it has no effect on force of
contraction, because there are no muscarinic receptors, or
parasympathetic innervation of ventricles.
b- It produces vasodilation. It results primarily from its action on endothelial
cells to promote the release of (NO) which diffuses to the vascular smooth
muscle & produces relaxation (endothelium derived relaxing factor EDRF).
c-It causes hypotension.
3-GIT:
a- It ↑ smooth muscle contraction, ↑ peristaltic activity & motility →
diarrhea.
b- It ↑ watery salivation & gastric acid secretion.
c-Tone in sphincters ↓ → defaecation or oesophageal acid reflex.
4- Urinary tract:
It ↑ contraction of bladder smooth muscle & ↑relaxation of sphincter
→urination.
5- Bronchial smooth muscle:
It ↑ bronchial constriction & secretion.
6- CNS: It produces tremor & ataxia.
7- It ↑ tears from lachrymal glands.
8- It ↑ sweat gland secretion.
Nicotinic receptors activation:
1- Nm (NMJ). It ↑skeletal muscle contraction.
2-Nn(Autonomic ganglia).It stimulates both sympathetic &
parasympathetic activity.
Note:
Acetylcholine is not used clinically because:
1. Easily hydrolyzed.
2. Not specific (acts on M & N), so it has huge variety of effects.
3.Irregular absorption
Pharmacological actions of ACh
• ACh actions and its side effects can be summarized by
DUMBLES
• D=Diarrhea
• U= Urination
• M=Miosis
• B= Bronchospasm, Bradycardia
• L= Lacrimation
• E= Excitation of Skeletal muscles
• S= Salivation and Sweating
Drugs acting on Parasympathetic division
• Drugs that act on parasympathetic division are either
1- Cholinergic drugs( parasympathomimetics) : They
act as agonists on cholinergic receptors( M&N), they
bind with the receptors and activate them.
2- Anticholinergics drugs( parasympatholytics): They
act as antagonists on cholinergic receptors, they bind
with the cholinergic receptors(M&N) and block them.
Classification of cholinergic drugs
Bethanchol
• It acts primarily on muscarinic receptors
• Therapeutic action: It increases intestinal motility,
especially after surgery.
• It also stimulates the detrusor muscle of the bladder.
• Clinical uses:
• Paralytic ileus and urinary retention after surgery.
Carbachol
• It acts on muscarinic and nicotinic receptors.
• It is rarely used clinically because of its high potency,
receptor nonselectivity, and long duration of action.
• It is mainly used in ophthalmic for treatment of
glaucoma( decrease intraocular pressure).
• It stimulates miosis during ophthalmic surgery.
• It is used topically as eye drops
Pilocarpine
• It is an alkaloid that extracted from leaves of Pilocarpus
Jaborandi. It acts primarily on muscarinic receptors.
Clinical uses:
1-It causes rapid miosis and decrease intraocular pressure, so
it is drug of choice(DOC) for treatment of glaucoma in the
eye.
2-It is the most potent stimulant of secretions( sweat, saliva,
tears), so it is used for treatment of xerostomia in Sjogen
syndrome.
.
Indirect acting cholinergic drugs
• They inhibit acetylcholinesterase enzyme which is responsible for
the hydrolysis of acetylcholine. This will increase the
concentration of acetylcholine indirectly. Accumulation of Ach in
the synaptic space will provoke response at all cholinoceptors in
the body.They can be classified into
1- Reversible( bind weakly with the enzyme)
A- Short acting (edrophonium)
B- Intermediate acting(physostigmine, neostigmine,)
2- Irreversible or long acting ( bind covalently with the enzyme)
(Organophosphates)
Short acting(Edrophonium)
• It has short duration of action(5-15 minutes). It is used
I.V for diagnosis of myasthenia gravis, an autoimmune
disease caused by antibodies to the nicotinic
receptors at the NMJ. This cause skeletal muscle
weakness and fatigue.
• I.V injection of edrophonium leads to a rapid increase
in muscle strength.
Intermediate acting
( physostigmine and neostigmine)
• Physostigmine: It is tertiary amine found in plants. It
reversibly bind with AChE enzyme and potentiate cholinergic
activity throughout the body. Its duration of action (30
minutes -2 hours).
• It can enter and stimulate the cholinergic sites in the CNS.
• Neostigmine: It is quaternary nitrogen, synthetic compound.
It is polar, so it is absorbed poorly from GIT and does not
enter CNS.
Physostigmine Neostigmine
Natural( calabar bean) Synthetic
Tertiary ammonium Quaternary ammonium
Well absorbed Poorly absorbed
Cross BBB Cannot
Actions: Eye,CNS indirectly GIT, NMJ indirectly
Uses: Uses:
1-Glaucoma 1-Myasthenia gravis
2-Atropine poisoning 2-Postoperative urinary retention &
3-Alzheimer disease constipation
Side effects: 3-Antidote to NM blockers
1-Lacrimation,miosis Side effects;
2-Bradycardia and hypotension 1-Nausea,vomiting& diarrhea.
3- Convulsion 2-Bronchospasm.
Long acting(irreversible)
organophosphates
Echothiophate
• It causes phosphorylation of AChE ,with time ,the
strength of the bond increases(aging)& AChE become
irreversibly inhibited.
• It is poorly absorbed from GIT And has negligible
distribution into CNS
• It is used for treatment of glaucoma when other
drugs are ineffective.
Malathion(insecticide)
Sarin(nerve gas)
They are( OP) highly lipid soluble & well absorbed from all sites (skin & lung)
& can cross BBB. So they cause cholinergic intoxication.
Toxicity:
Acute poisoning with OP leads to excessive muscarinic & nicotinic effects, in
addition to CNS effects.
Muscarinic effects include: (Bronchospasm, hypotension, bradycardia, miosis, ↑
acid secretion, urination, and diarrhea).
Nicotinic effects, include (muscular fasciculation, paralysis)
CNS effects include, (insomnia, restlessness, tremor, confusion, ataxia, and
convulsion)
Death is due to CNS effects & respiratory paralysis by depolarizing NM blockade &
excessive bronchial secretion & respiratory failure.
• Symptoms of toxicity is called DUMBELS
Treatment of toxicity:
1- Maintenance of vital signs (aspiration of bronchial secretion
& artificial
respiration).
2- Prevent further absorption by removal of contaminated
clothes &
washing the skin.
3- Atropine in large doses to combat CNS & muscarinic
effects. The patient is fully atropinized for at least 24 hours.
4- Cholinesterase reactivators (pralidoxime).
5- Diazepam may be needed for convulsion.
Tacrine and Donepezil
• They are used for treatment of Alzheimer's disease.
Patient with this disease have a deficiency of
cholinergic neurons in the CNS.
• These drugs inhibit the AChE enzyme and increase the
level of ACh in the brain and thereby help to relieve
the symptoms of Alzheimer's disease.
Side effects & contraindications of cholinergic drugs
Side effects:
1- Bronchospasm.
2- Nausea, vomiting & diarrhea.
3- Salivation, lacrimation & sweating.
4- Vasodilatation and transient hypotension.
Contraindications:
1-Peptic ulcer.
2- Bronchial asthma.
3-Parkinsonism
