Pharm Exam 2 PDF

Parasympathetic System Cholinergic Agonists Acetylcholine, neurotransmitter of parasympathetic system Cholinergic neuron Acetylcholine (Ach) synthesis Storage release Binding to receptor degradation Recycling Muscarinic receptors Found primarily in the neuro-effector junction of the parasympathetic...

Parasympathetic System Cholinergic Agonists Acetylcholine, neurotransmitter of parasympathetic system Cholinergic neuron Acetylcholine (Ach) synthesis Storage release Binding to receptor degradation Recycling Muscarinic receptors Found primarily in the neuro-effector junction of the parasympathetic nervous system 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 As a group found in: ○ Ganglia of PNS ○ Autonomic effector organs ○ Heart ○ Smooth muscle ○ Brain Nicotinic receptors Weak muscarinic activity CNS Adrenal medulla Autonomic ganglia Neuromuscular junction Ach is dependent on nicotinic receptors Acetylcholine signal transduction Activation of 2nd messenger (protein G) Increased intracellular [Ca] May stimulate or inhibit a secondary enzyme M2 in the heart stimulates protein G which inhibits adenyl cyclase thus increasing K conductance with decreased heart rate and force of contraction Direct acting agents Acetylcholine ○ Therapeutically of no importance ○ 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) Bethanechol ○ 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 Nause Abdominal pain/diarrhea Bronchospasm Carbachol ○ Muscarinic and nicotinic actions may last up to 1 hr ○ Actions: Systemic use cause profound effect on cardiovascular and GI systems Promotes release of epinephrine from adrenal medulla On available for ophthalmic use to reduce IOP Pilocarpine ○ Stable to hydrolysis by acetylcholinesterase ○ Actions: Ocularly produces miosis and enhances accommodation (Vuity) Stimulates sweat, tears, and saliva production ○ Therapeutic use: POAG Acute angle closure Pigmentary glaucoma Sjogren’s syndrome (oral admin) - xerostomia/xerophthalmia Adverse reactions: potent stimulator of secretion of sweat glands (body odor) Indirect-acting agents: Acetylcholinesterase Inhibitors Inhibits acetylcholinesterase - enzyme responsible for the breakdown of used acetylcholine By interfering with the metabolism of acetylcholine, they indirectly stimulate 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 IOP (topical) Overdose: atropine, phenothiazine, tricyclic antidepressants ○ Adverse effects: convulsions bradycardia Pyridostigmine and Ambenonium ○ Use in myasthenia gravis (active 3-6 hrs) and (4-8 hrs) Neostigmine ○ Doesn’t cross BBB, but has greater effect in skeletal muscle ○ Used in myasthenia gravis tx and antidote for tubocurarine and neuromuscular blockers 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 tx of Alzheimer's disease (loss of Ach dumping for thinking is not there) Irreversible inhibitors Synthetic organophosphate compounds most extremely toxic and developed by the military as nerve gases Related agents are used as insecticides (parathion, malathion) 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