Parasympathomimetic Drugs PDF

# Parasympathomimetic Drugs Drugs affecting the autonomic nervous system (ANS) are divided into two groups: - Sympathomimetic - Parasympathomimetic ## Parasympathomimetic Drugs These drugs act on receptors that are activated by acetylcholine (ACh) and mimic the same actions. ### Cholinergic...

# Parasympathomimetic Drugs Drugs affecting the autonomic nervous system (ANS) are divided into two groups: - Sympathomimetic - Parasympathomimetic ## Parasympathomimetic Drugs These drugs act on receptors that are activated by acetylcholine (ACh) and mimic the same actions. ### Cholinergic Agonists #### Directly Acting - Choline esters - Ach - Bethanechol - Carbachol - Methacholine - Alkaloids - Pilocarpine - Muscarine - Arecoline #### Indirectly Acting (Anticholinesterases) - Reversible - Acridine Carbamates - Tacrine - Irreversible - Organophosphorous (OP) - Parathion - Propoxur (Baygon) - Malathion - Carbamates - Physostigmine - Neostigmine - Pyridostigmine - Cararyl - Edrophonium - Rivastigmine - Donepezil - Nerve Gases - Dyflos - Echothiophate  ## The Cholinergic Neurons - Postganglionic fibers of the parasympathetic division use ACh as a neurotransmitter. - The postganglionic sympathetic division of sweat glands also uses acetylcholine. - Cholinergic neurons innervate the muscles of the somatic system and also play an important role in the central nervous system (CNS). ### Neurotransmission at Cholinergic Neurons The action of cholinergic neurotransmitters through neurons involves six sequential steps: 1. Synthesis 2. Storage 3. Release 4. Binding of ACh to a receptor 5. Degradation of the neurotransmitter in the synaptic cleft 6. Recycling of choline and acetate.  ## Types of Cholinergic Receptors ### Muscarinic Receptors - Muscarinic receptors are G protein-coupled receptors. - These receptors are able to bind with ACh, also recognize muscarine. - The muscarinic receptors show only a weak affinity for nicotine. - There are five subclasses of muscarinic receptors: M1, M2, M3, M4 and M5. - M1, M2, and M3 receptors have been functionally characterized. | Receptors | Organs | | :---------- | :-------------------------------------------------------------------- | | M1 | Gastric parietal cells, cardiac cells and smooth muscle | | M2 | Bladder, exocrine glands, and smooth muscle | | M3 | Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these tissues, but at high concentration, they may show some activity at nicotinic receptors. |  ### Mechanisms of Acetylcholine Signal Transduction - A conformational change and interacts with a G protein, designated Gq, that in turn activates phospholipase C. - Production of the second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 causes an increase in intracellular Ca2+. - Ca2+ interact to stimulate or inhibit enzymes or to dohyperpolarization, secretion, or contraction. - Diacylglycerol activates protein kinase C, an enzyme that phosphorylates numerous proteins within the cell. ### Muscarinic Agonists - Pilocarpine is an example of a nonselective muscarinic agonist. - M1 receptor agonists are being investigated for the treatment of Alzheimer's disease. - M3 receptor antagonists for the treatment of chronic obstructive pulmonary disease. - Currently, no clinically important agents interact solely with the M4 and M5 receptors. ### Nicotinic Receptors - The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel. - Binding of two ACh molecules leads to a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell。 ### Nicotinic Receptors Are Located in: - CNS - Adrenal medulla - Autonomic ganglia - Neuromuscular junction (NMJ) in skeletal muscles. - Ganglionic receptors are selectively blocked by mecamylamine. - NMJ receptors are specifically blocked by atracurium. ## Direct Acting Cholinergic Agonists - Endogenous choline esters, which include Ach and synthetic esters of choline, such as carbachol and bethanechol. - Naturally occurring alkaloids, such as nicotine and pilocarpine. All of the direct-acting cholinergic drugs have a longer duration of action than ACh. The more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. ### Acetylcholine - Heart rate and cardiac output via stimulation of vagal stimulation. - Blood pressure: ACh causes vasodilation and lowering of blood pressure by an indirect mechanism of action by action of M3 receptors found on endothelial cells lining the smooth muscles of blood vessels. - NO from arginine that diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation via phosphodiesterase-3 inhibition ### Acetylcholine - Atropine blocks these muscarinic receptors and prevents ACh from producing vasodilation. - In the gastrointestinal (GI) tract, acetylcholine stimulates intestinal secretions and secretion. - Bronchiolar secretions, the tone of the detrusor muscle, causing urination. ### Acetylcholine - In the eye, stimulation of ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle, causing miosis. - ACh (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery. ## Bethanechol ### Action - Acts mainly on smooth muscles of the bladder and GIT. - It has about a 1-hour duration of action. - Directly stimulates M3 receptors, causing intestinal motility and tone. - It also stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter muscles are relaxed. These effects produce urination. ### Therapeutic Uses - In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. - Bethanechol may also be used to treat neurogenic atony as well as megacolon. ### Adverse Effects - Cholinergic stimulation such as sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm. - Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent.