drugs acting on the parasympathatic nervous system
DESCRIPTION
DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM. Dr. Naila Abrar. Parasympathetic Nervous System. Muscarinic Nicotinic Autonomic neuroeffector Ganglia & NMJ junctions Acetylcholine. GPCR. Ion Channels. CHOLINOCEPTORS. Nicotinic Ion channel. Muscarinic - PowerPoint PPT PresentationTRANSCRIPT
DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM
Dr. Naila Abrar
Parasympathetic Nervous System
Muscarinic Nicotinic
Autonomic neuroeffector Ganglia & NMJ junctions
Acetylcholine
GPCRIon
Channels
CHOLINOCEPTORS
NicotinicIon channel
Muscarinic GPCR
Receptor Type
Other Names Location Structural Features
Postreceptor Mechanism
M1
Nerves Seven
transmembrane segments, Gq/11 protein-linked
IP3, DAG cascade
M2 Cardiac M2
Heart, nerves, smooth muscle
Seven transmembrane segments, Gi/o protein-linked
Inhibition of cAMP production, activation of K+ channels
M3
Glands, smooth
muscle, endothelium
Seven transmembrane segments, Gq/11 protein-linked
IP3, DAG cascade
M4 CNS Seven transmembrane segments, Gi/o protein-linked
Inhibition of cAMP production
M5
CNS Seven
transmembrane segments, Gq/11 protein-linked
IP3, DAG cascade
Receptor Type
Other Names Location Structural Features
Postreceptor Mechanism
NM
Muscle type, end plate receptor
Skeletal muscle neuromuscular junction
Pentamer [(1)21)]
Na+, K+ depolarizing ion channel
NN
Neuronal type, ganglion receptor
CNS postganglionic cell body, dendrites
Pentamer with and subunits only, eg, (4)2(2)3 (CNS) or 3 5(2)3 (ganglia)
Na+, K+ depolarizing ion channel
PARASYMPATHOMIMETIC
DRUGS
or
CHOLINERGIC DRUGS
or
CHOLINOMIMETIC DRUGS
CLASSICIFICATION
A.Directly Acting
B. Indirectly Acting
A. Directly Acting Cholinergic Drugs
I.CHOLINE ESTERS
II.CHOLINOMIMETIC ALKALOIDS
I.CHOLINE ESTERS
- Acetylcholine
- Methacholine
- Carbachol
- Bethanechol
II.CHOLINOMIMETIC ALKALOIDS
a. Mainly Muscarinic Agonists
Natural Alkaloids: - Muscarine - Pilocarpine - Arecholine Synthetic Alkaloid:
- Oxotremorine
b. Mainly Nicotinic Agonists
Natural Alkaloids: - Nicotine - Lobeline
Synthetic Alkaloids:
- Dimethylphenyl-piperazinium(DMPP)
B. Indirectly Acting Cholinergic Drugs
(Anticholinesterases)I- REVERSIBLE
Carbamates Tertiary amines-
physostigmine Quaternary ammonium
compounds- neostigmine, pyridostigmine, tacrine, ambenonium, demecarium
Alcohols- edrophonium Miscellaneous- tacrine,
galantamine, rivastigmine, donepezil
II- IRREVERSIBLE Organophosphates Therapeutically
useful-ecothiopate War gases-sarin, tuban, soman Insecticides-parathion, malathion,
DFP, TEPP, OMPA
PHARMACOKINETICS
• Esters-Quaternary ammonium gp• Choline esters are poorly absorbed
and poorly distributed into CNS• Methacholine is resistant to
hydrolysis by cholinesterase• Carbamic acid esters carbachol and
bethanechol- most resistant-longer duration of action
Pharmacokinetic (contd.)
• Pilocarpine, nicotine, lobeline-tertiary natural compounds- well absorbed
• Muscarine, quaternary amine is toxic when ingested present in certain mushrooms
• Excretion chiefly through kidneys
MECHANISM OF ACTION of directly acting
cholinomimetics
1. Activation of muscarinic receptors on effector cells directly to alter organ function
2. Interaction with muscarinic receptors on nerve terminals to inhibit release of their neurotransmitter
MECHANISM OF ACTION of directly acting cholinomimetics
Muscarinic- GPCRInhibitory effects (M2 & M4)
Inhibition of adenylyl cyclase- decrease of cAMP (GPCR-Gi/Go)
Excitatory effects (M1,M3,M5)
Increase activity of IP3 & DAG (GPCR-Gq/11)
MECHANISM OF ACTION of directly acting cholinomimetics
Nicotinic – pentameric ion channelNa+ & K+ move down conc. gradient DepolarizationSkeletal muscle-Action potential
propagation-contractionProlonged agonist occupancy-
depolarizing blockade
ACETYLCHOLINE
CHEMISTRYAn ester of acetic acid and choline
SYNTHESIS, STORAGE, RELEASE & INACTIVATION
Pharmacological actions/ Organ system effects:
Muscarinic Actions
Nicotinic Actions
EYE:M3
Miosis (constriction of pupil)- contraction of papillary sphincter ms.
Spasm of accommodation (contraction of ciliary muscle)- eye fixed for near vision • Decrease in intraocular pressure• Conjunctival hyperemia• Lacrimation
CVS (Heart & Blood Vessels)
Negative chronotropic effect-bradycardia M2
-Decreases rate of spontaneous depolarization
Negative dromotropic effect- decrease in conduction velocity in AV node-(inhibiting Ca channels)
Negative inotropic effect- decreased cardiac output (hyperpolarization, decrease cAMP & epinephrine release)
Vasodilation- fall in blood pressure- NO
RESPIRATORY SYSTEM
M3
Bronchial muscle contraction
Bronchial gland stimulation-
increase tracheobronchial secretions
GIT
M3
Increase motility
Relaxation of sphincters
Increase tone of LES
URINARY BLADDER
M3
Detrusor muscle contraction
Relaxation of sphincters
Promote micturition
Exocrine glands- M3
- Increase in salivation, sweat, lacrimation
Central Nervous System - M1
- Cortical arousal, or activation
Peripheral nervous system - Stimulation of ganglia both the
systems are activated
Neuromuscular junction- Na+ and K+ entry into cell-
depolarization- Skeletal muscle contraction
THERAPEUTIC USES• Glaucoma (pilocarpine)• Accommodative estropia• Induction of miosis (Ach, carbachol)• Postoperative ileus (bethanechol)• Congenital megacolon (bethanechol)• Atony of urinary bladder – post op,
diabetic autonomic neuropathy (bethanechol)
THERAPEUTIC USES (contd.)
• Dry mouth with Sjogren’s syndrome (pilocarpine, cevimeline)
• Diagnosis of bronchial airway hyperreactivity (methacholine)
ADVERSE EFFECTS
• Signs of muscarinic excess.• Salivation, sweating• Difficulty in visual accommodation• NVD, abd. cramps• Urinary urgency• Cutaneous vasodilatation• Bronchoconstriction• Hypotension
CONTRAINDICATIONS
• Bronchial asthma• GI or urinary tract obstruction• Peptic ulcer• Recent myocardial infarction• Coronary insufficiency• Hyperthyroidism
MUSHROOM POISONING
• Signs of muscarinic excess-salivation, sweating, NVD, visual disturbances, headache, abd. Colic,urinary urgency, bradycardia, bronchospasm, hypotension, shock
• Atropine (1-2mg I/M every 30mins)
ACUTE NICOTINE TOXICITY
A. CNS stimulation, cause convulsions, coma and respiratory arrest.
B. Skeletal muscle depolarization and respiratory paralysis.
C. Hypertension and cardiac arrhythmia.
CHRONIC TOBACCO USE
• Increased risk of vascular disease.• Sudden coronary death.• Aggravation of peptic ulcer in
smokers.
Other Choline Esters
Methacholine
Carbachol
Bethanechol
METHACHOLINE
• Both muscarinic and nicotinic actions.
• Muscarinic actions are more prominent on CVS than on GIT and urinary bladder.
• Duration of action 30 min.• Paroxymal atrial tachycardia.
CARBACHOL
• Not destroyed by cholinesterase.• Longer duration of action and potent
than methacholine.Therapeutic uses• Post operative abdominal distention,
paralytic ileus, urinary retention and glaucoma.
BETHANECHOL
• Weak but prolonged effect
Therapeutic uses• Difficulty in micturition, gastric
distention following surgery.
PILOCARPINE
• Pilocarpus microphyllus (jaborandi)• Tertiary amine-enters CNS• More muscarinic effectsTherapeutic uses• Glaucoma (other options available)• Reverse effects of mydriatics• Xerostomia • Break adhesions