DRUGS acting on the PARASYMPATHATIC NERVOUS SYSTEM

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DRUGS acting on the PARASYMPATHATIC NERVOUS
SYSTEM

• Dr. Naila Abrar

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Parasympathetic Nervous System

• Muscarinic Nicotinic
• Autonomic neuroeffector Ganglia NMJ
• junctions
• Acetylcholine

GPCR
Ion Channels
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CHOLINOCEPTORS

• Nicotinic
• Ion channel

• Muscarinic
• GPCR

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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 
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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 
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• PARASYMPATHOMIMETIC DRUGSor CHOLINERGIC
  DRUGSor
• CHOLINOMIMETIC DRUGS

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CLASSICIFICATION

• Directly Acting
• Indirectly Acting

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A. Directly Acting Cholinergic Drugs

• CHOLINE ESTERS
• CHOLINOMIMETIC ALKALOIDS

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• CHOLINE ESTERS
• - Acetylcholine
• - Methacholine
• - Carbachol
• - Bethanechol

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II.CHOLINOMIMETIC ALKALOIDS

• a. Mainly Muscarinic Agonists
• Natural Alkaloids
• - Muscarine
• - Pilocarpine
• - Arecholine
• Synthetic Alkaloid
• - Oxotremorine

• Mainly Nicotinic Agonists
• Natural Alkaloids
• - Nicotine
• - Lobeline
• Synthetic Alkaloids
• - Dimethylphenyl-piperazinium(DMPP)

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B. Indirectly Acting Cholinergic Drugs
(Anticholinesterases)

• I- REVERSIBLE

• II- IRREVERSIBLE

• Carbamates
• Tertiary amines-physostigmine
• Quaternary ammonium compounds- neostigmine,
  pyridostigmine, tacrine, ambenonium, demecarium
• Alcohols- edrophonium
• Miscellaneous- tacrine, galantamine,
  rivastigmine, donepezil

• Organophosphates
• Therapeutically useful
• -ecothiopate
• War gases
• -sarin, tuban, soman
• Insecticides
• -parathion, malathion, DFP, TEPP, OMPA

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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

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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

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MECHANISM OF ACTION of directly acting
cholinomimetics

• Activation of muscarinic receptors on effector
  cells directly to alter organ function
• Interaction with muscarinic receptors on nerve
  terminals to inhibit release of their
  neurotransmitter

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MECHANISM OF ACTION of directly acting
cholinomimetics

• Muscarinic- GPCR
• Inhibitory 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)

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MECHANISM OF ACTION of directly acting
cholinomimetics

• Nicotinic pentameric ion channel
• Na K move down conc. gradient
• Depolarization
• Skeletal muscle-Action potential
  propagation-contraction
• Prolonged agonist occupancy-depolarizing blockade

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ACETYLCHOLINE

• CHEMISTRY
• An ester of acetic acid and choline

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SYNTHESIS, STORAGE, RELEASE INACTIVATION
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Pharmacological actions/ Organ system effects

• Muscarinic Actions
• Nicotinic Actions

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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

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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

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RESPIRATORY SYSTEM

• M3
• Bronchial muscle contraction
• Bronchial gland stimulation- increase
  tracheobronchial secretions

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GIT

• M3
• Increase motility
• Relaxation of sphincters
• Increase tone of LES

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URINARY BLADDER

• M3
• Detrusor muscle contraction
• Relaxation of sphincters
• Promote micturition

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• 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

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• Neuromuscular junction
• - Na and K entry into cell- depolarization
• - Skeletal muscle contraction

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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)

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THERAPEUTIC USES (contd.)

• Dry mouth with Sjogrens syndrome (pilocarpine,
  cevimeline)
• Diagnosis of bronchial airway hyperreactivity
  (methacholine)

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ADVERSE EFFECTS

• Signs of muscarinic excess.
• Salivation, sweating
• Difficulty in visual accommodation
• NVD, abd. cramps
• Urinary urgency
• Cutaneous vasodilatation
• Bronchoconstriction
• Hypotension

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CONTRAINDICATIONS

• Bronchial asthma
• GI or urinary tract obstruction
• Peptic ulcer
• Recent myocardial infarction
• Coronary insufficiency
• Hyperthyroidism

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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)

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ACUTE NICOTINE TOXICITY

1. CNS stimulation, cause convulsions, coma and
   respiratory arrest.
2. Skeletal muscle depolarization and respiratory
   paralysis.
3. Hypertension and cardiac arrhythmia.

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CHRONIC TOBACCO USE

• Increased risk of vascular disease.
• Sudden coronary death.
• Aggravation of peptic ulcer in smokers.

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Other Choline Esters

• Methacholine
• Carbachol
• Bethanechol

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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.

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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.

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BETHANECHOL

• Weak but prolonged effect
• Therapeutic uses
• Difficulty in micturition, gastric distention
  following surgery.

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PILOCARPINE

• Pilocarpus microphyllus (jaborandi)
• Tertiary amine-enters CNS
• More muscarinic effects
• Therapeutic uses
• Glaucoma (other options available)
• Reverse effects of mydriatics
• Xerostomia
• Break adhesions