Cholinergics PDF

Parasympathetic System Cholinergic Agonists Characteristics Acetylcholine, neurotransmitter of Cholinergic Neuron Acetylcholine (Ach) Synthesis Storage Release Binding to receptor Degradation Recycling Cholinergic Neuron Receptors Muscarinic Found primarily in the neuro-effector junction of the Para...

Parasympathetic System Cholinergic Agonists Characteristics Acetylcholine, neurotransmitter of Cholinergic Neuron Acetylcholine (Ach) Synthesis Storage Release Binding to receptor Degradation Recycling Cholinergic Neuron Receptors Muscarinic Found primarily in the neuro-effector junction of the Parasympathetic nervous system As a group found in: Ganglia of PNS Autonomic effector organs Heart Smooth muscle Brain Receptors Muscarinic M1 - brain, exocrine glands and autonomic ganglia and stomach (gastric parietal cells) M2 - Heart, brain, autonomic ganglia and smooth muscle M3 - Exocrine glands & smooth muscle, brain and endothelial cells M4 –basal ganglia, amygdala, hippocampus (areas involved in mood, emotions, limbic system) M5 – substantia nigra (midbrain) function unclear Receptors Nicotinic Weak muscarinic activity CNS Adrenal medulla Autonomic ganglia Neuromuscular junction Receptors Acetylcholine Signal Transduction Activation of 2nd messenger (protein G) Increased intracellular [Ca] May stimulate or inhibit a secondary secondary enzyme M2 in the heart stimulates protein G which inhibits adenylcyclase thus increasing K conductance with decreased heart rate and force of contraction. Direct Acting Agents Acetylcholine Therapeutically of no importance (multiplicity of actions and rapid inactivation) Has muscarinic and nicotinic actions: decreased heart rate (vagal stimulation) decrease blood pressure (vasodilation) increase salivary secretions and motility in the eye causes contraction of ciliary muscles with miosis (constriction of pupil) Bethanecol Structurally related to acetylcholine but not destroyed by acetylcholinesterase No nicotinic action Strong muscarinic action Actions Increased intestinal motility and tone Stimulate detrusor muscle of bladder promoting urination Applications Urology (stimulation of bladder tone) Adverse effects Generalized cholinergic stimulation sweating Decreased blood BP Nausea Abdominal pain/diarrhea Bronchospasm Carbachol Muscarinic and nicotinic actions may last up to 1 hr Actions: Systemic use cause profound effect on cardiovascular and gastrointestinal systems Promotes release of epinephrine from adrenal medulla On available for ophthalmic use to to reduce IOP Pilocarpine Stable to hydrolysis by acetylcholinesterase Actions: Ocularly produces miosis and enhances accommodation Stimulates sweat, tears and saliva production Pilocarpine Therapeutic use POAG Acute angle close Pigmentary glaucoma Sjogren’s syndrome (oral administration) – xerostomia/xerophthalmia Adverse reactions: potent stimulator of secretion od sweat glands Indirect Acting Agents Acetylcholinestrase Inhibitors Inhibits acetylcholinesterase enzyme responsible for the breakdown of used acetylcholine By interfering with the metabolism of acetylcholine, they indirectly stimulates both nicotinic and muscarinic receptors due to the consequential increase in available acetylcholine at the synapses site Reversible Inhibitors Physostigmine Actions wide range of actions; stimulates muscarinic and nicotinic receptors with duration of 2-4 hrs Therapeutic use Atony of intestines and bladder, it promotes motility Decrease intraocular pressure (topical) Overdose: atropine, phenothiazine, Tricyclic antidepressants Adverse effects: convulsions bradycardia Reversible Inhibitors Pyridostigmine and Ambenonium Use in myasthenia gravis (active 3-6 hrs) and (4-8hrs.) Neostigmine Doesn’t cross BBB, but has greater effect in skeletal muscle Used in myasthenia gravis Tx and antidote for tubocurarine and neuromuscular blockers Reversible Inhibitors Demecarium Similar action as Neostigmine Old drug to Tx POAG Edrophonium Like neostigmine but shorter duration Use IV in the Dx of myasthenia gravis Tacrine, Donepezil, Rivastigmine and Galantamine Used in the treatment of Alzheimer’s disease Irreversible Inhibitors Synthetic organophosphate compounds most extremely toxic and developed by the military as nerve gases Related agents are use as insecticides (parathion, malathion) Irreversible Inhibitors Echothiophate Covalently binds to active site of acetylcholinesterase and permanently inactivates it Generalized cholinergic stimulation, paralysis of motor function, convulsions and miosis Therapeutic use Ophthalmic ointment for chronic treatment of open angle glaucoma * Pralidoxime Used for organo-phosphate poisoning Reactivation of acetylcholinesterase Muscarinic Agonists Side Effects Diarrhea Diaphoresis Miosis Nausea Urinary urgency Transient myopia Brow pain