Lecture 6: Parasympathetic Nervous System (Muscarinic Agonists) PDF

Pharmacology-1 (PPT301) Fall Semester (2024-2025) Lecture 6 Parasympathetic nervous system (Muscarinic agonists) Associated Prof. Ahmed Esam Khodir Academic E-mail : [email protected] Quiz  JIJILOs (Intended learning Outcomes) Learning Obj...

Pharmacology-1 (PPT301) Fall Semester (2024-2025) Lecture 6 Parasympathetic nervous system (Muscarinic agonists) Associated Prof. Ahmed Esam Khodir Academic E-mail : [email protected] Quiz  JIJILOs (Intended learning Outcomes) Learning Objectives ¶¶ By the end of this Lecture, the student will be able to 1. Describe the neuronal release and inactivation of acetylcholine. 2. List the three types of cholinergic receptors and the tissues where they are located. 3. Compare the pharmacologic actions and uses of the direct-acting and indirect-acting cholinergic (muscarinic) drugs. 4. List and briefly describe the clinical indications for the indirect-acting anticholinesterase drugs. 5. Describe the pharmacologic actions, uses, and adverse effects of anticholinergic drugs. 6. list the preferred drug treatment for the most common conditions affected by parasympathetic activity.  Introduction The autonomic nervous system regulates the functions of the internal organs and glands. The sympathetic division controls activity during physical exertion and stress (fight or flight). The parasympathetic division regulates body functions mainly during rest, digestion, and waste elimination. Parasympathetic stimulation increases the activity of the gastrointestinal and genitourinary systems and decreases the activity of the cardiovascular system. ! Drugs that increase parasympathetic activity (cholinergic) are used in the treatment of Alzheimer’s disease, glaucoma, myasthenia gravis, and urinary and intestinal stasis. ! Drugs that decrease parasympathetic activity (anticholinergics) are indicated for the treatment of overactive urinary and intestinal conditions, asthma and COPD, motion sickness, and during various ophthalmic procedures.  ! Key Terms ! Øacetylcholinesterase: an enzyme that inactivates acetylcholine. anticholinergic: refers to drugs or effects that reduce the activity of the parasympathetic nervous system. Øcholinergic: refers to the nerves and receptors of the parasympathetic nervous system; also refers to the drugs that stimulate this system. Ømuscarinic receptor: an older but more specific term for the cholinergic receptor on smooth and cardiac muscle. Ønicotinic-muscle (Nm) receptor: cholinergic receptor located at the neuromuscular junction of skeletal muscle. Ønicotinic-neural (Nn) receptor: cholinergic receptor located on both sympathetic and parasympathetic ganglia. Øparasympatholytic: refers to drugs (anticholinergic) that decrease activity of the parasympathetic nervous system. Øparasympathomimetic: refers to drugs (cholinergic) that mimic stimulation of the parasympathetic nervous system. The nervous system  parasympathetic nervous system — The parasympathetic nervous system refers to nerves that originate in the brain and the sacral portion of the spinal cord and are active when the body is at rest or trying to restore body energy and function. (Rest and Digest) — Acetylcholine is the neurotransmitter of parasympathetic nerves. — When the body is at rest, the parasympathetic nervous system is active. — Parasympathetic nerves are more active during periods of rest. Parasympathetic nerves release acetylcholine — Unlike sympathetic nerves, parasympathetic nerves do not innervate many blood vessels.  Cholinergic transmission Ach is located at the following sites: Somatic N.S. at the neuromuscular junction. Sympathetic ganglia. Sympathetic postsynaptic fibre to sweat gland & medulla. All ganglia of parasympathetic system. Postganglionic parasympathetic nerve.  ! Two major classes of Ach receptors ! 1- Nicotinic receptors: The nicotinic receptor functions as a ligand-gated ion channel — Skeletal muscle 2- Muscarinic receptors : Muscarinic receptors belong to the class of G protein–coupled receptors q M1 receptors found mainly in CNS , peripheral neurons & gastric parietal cells. q M2 receptors (cardiac) occur in peripheral neurons as well as in the heart. q M3 receptors (glandular/smooth muscle) Action of Ach can be divided into: Muscarinic actions on smooth muscle, cardiac muscle and glands and this action can be blocked or antagonized by atropine. Nicotinic action at all autonomic ganglia which can be blocked by hexamethonium and at neuromuscular junction which can be blocked by d.tubocurarine. Acetylcholine ** Synthesis of acetylcholine: -- Widely distributed in nervous tissues, motor fibres, ganglia and also in brain. --Ach is synthesized within the nerve terminal from choline. -- Free choline within the nerve terminal is acetylated by the cytosolic enzyme choline acetyl transferase (CAT). --The source of acetyl group is acetyl-CoA. CAT Choline + Acetyl-CoA Acetylcholine — Choline is taken up into the nerve ending and combined with acetyl-CoA to form acetylcholine (ACH). ACH is stored in vesicles and upon stimulation is released into the synaptic cleft to stimulate muscarinic receptors (M) on internal organs and glands, nicotinic receptors (Nn) on autonomic ganglia, and nicotinic receptors (Nm) on skeletal muscle. ACH is inactivated enzymatically by acetylcholinesterase. — Binding to the receptor: — The postsynaptic cholinergic receptors on the surface of the effector organs are divided into two classes: 1- Muscarinic 2- Nicotinic. — Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells, as mediated by second-messenger molecules. — Recycling of choline: Choline may be re-captured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron. There, it is acetylated into ACh that is stored until released by a subsequent action potential. Degradation of acetylcholine: -- The released Ach is hydrolyzed very rapidly (within 1 ms), so it acts very briefly. -- Hydrolysis occurs by Ach esterase enzyme, which present in the presynaptic nerve terminal. Two types of acetylcholine esterase: True cholinesterase found in nerve ending, neuromuscular junction and RBCs. Specific, very slow turnover. Pseudocholinesterase, non-specific found in plasma, intestine, liver and skin.  Cholinergic Receptors — (a) Illustrates a parasympathetic neuron with pre- and postganglionic nerve fibers innervating smooth or cardiac muscle via the muscarinic receptor. (b) Illustrates the nicotinic-n receptor located on the ganglia of both parasympathetic and sympathetic neurons. (c) Illustrates a somatic neuron that innervates skeletal muscle via nicotinic-m receptors Muscarinic actions give reason Cardiovascular effects: Heart: Decrease force of contraction (mainly in atria), inhibition of AV conduction and cardiac slowing and reduced automaticity. Blood pressure: Ach decreases blood pressure due to vasodilatation and decreased cardiac output. Vasodilatation is due to the release of NO from endothelium.  Smooth muscles: -- GIT: Ach increases tone and motility of the small and large intestine and relaxes the sphincters. -- Urinary bladder: Ach contracts the muscles of the urinary bladder & relaxes sphincter. -- Respiration: Ach increases bronchial secretions and produces contraction and spasm of bronchioles. -- Exocrine glands: Ach and related drugs stimulate secretions of all glands that receive parasympathetic innervation Eye: If the parasympathetic nerves are stimulated, the pupil is constricted (Active miosis). Atropine will paralyses the muscle and thus, radial muscle (Sympathetic) tone predominate, producing (Passive mydriasis).  Ach also causes contraction of ciliary muscle allowing the lens to become more convex and the accommodation becomes fixed to near vision (Spasm of accommodation). Atropine paralyzes the ciliary muscle, lead to loss of accommodation or cycloplegia. Nicotinic actions: A) Skeletal muscles: Ach causes muscle twitching due to depolarization of motor end plate. B) Autonomic ganglia: Ach in the presence of atropine will lead to an increase in blood pressure rather than decrease. Unwanted effects of Ach : Sweating, salivation, lacrimation, intestinal pain, cramps diarrhea, flushing, difficult breathing and hypotension.