Sheet 4 cholinergic agonists (2).pptx

Cholinergic Agonists Pharmacology lecture 4 Pharmacology, Lecture 4 Cholinergic Agonists Dr 1 Salem Abukres II. THE CHOLINERGIC NEURON ACh as a neurotransmitter in: Preganglionic fibers in the adrenal medulla...

Cholinergic Agonists Pharmacology lecture 4 Pharmacology, Lecture 4 Cholinergic Agonists Dr 1 Salem Abukres II. THE CHOLINERGIC NEURON ACh as a neurotransmitter in: Preganglionic fibers in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division postganglionic sympathetic division of sweat glands Muscles of the somatic system In the central nervous system (CNS) Pharmacology, Lecture 4 Cholinergic Agonists Dr 2 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 3 Salem Abukres A. Neurotransmission at cholinergic neurons Neurotransmission in cholinergic 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 (that is, the space between the nerve endings and adjacent receptors located on nerves or effector organs), and 6) recycling of choline and acetate Pharmacology, Lecture 4 Cholinergic Agonists Dr 4 Salem Abukres Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form ACh increase in intracellular calcium promotes the fusion of synaptic vesicles and releases ACh Pharmacology, Lecture 4 Cholinergic Agonists Dr 5 Salem Abukres  III. CHOLINERGIC RECEPTORS (CHOLINOCEPTORS) A. Muscarinic receptors Binding Ach, recognize muscarine, an alkaloid that is present in certain poisonous mushrooms Only a weak affinity for nicotine Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. M1 receptors are also found on gastric parietal cells, m2 receptors on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine glands, and smooth muscle Drugs with muscarinic actions at high concentration they may show some activity at nicotinic receptors Pharmacology, Lecture 4 Cholinergic Agonists Dr 6 Salem Abukres G protein coupled-receptors Classified into three categories: Gq, Gi, or Gs. Gq and Gs are stimulatory receptors whereas Gi is inhibitory. Gq activates the phospholipase C (PLC) pathway and Gs activates the cAMP and, subsequently, protein kinase C (PKC) pathway. Gi inhibits several signaling cascades in the cells Pharmacology, Lecture 4 Cholinergic Agonists Dr 7 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 8 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 9 Salem Abukres  2. Mechanisms of acetylcholine signal transduction: A number of different molecular mechanisms For example: when the M1 or M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, designated Gq, that in turn activates phospholipase C. This leads to the hydrolysis of phosphatidylinositol- bisphosphate to yield diacylglycerol and inositol trisphosphate. Inositol trisphosphate causes an increase in intracellular Ca2+ Ca2+ interacts to stimulate or inhibit enzymes or to cause hyperpolarization, secretion, or contraction. Diacylglycerol activates protein kinase C Pharmacology, Lecture 4 Cholinergic Agonists Dr 10 Salem Abukres  In contrast, activation of the M2 subtype on the cardiac muscle stimulates a G protein, designated Gi, which inhibits adenylyl cyclase2 and increases K+ conductance The heart responds with a decrease in rate and force of contraction. Pharmacology, Lecture 4 Cholinergic Agonists Dr 11 Salem Abukres B. Nicotinic receptors also recognize nicotine but Nicotine at low concentration show only a weak affinity stimulates the receptor, and at for muscarine high concentration blocks the receptor as a ligand-gated ion The nicotinic receptors of channel autonomic ganglia differ from Binding of two ACh molecules those of neuromuscular elicits a conformational junction NMJ. For example, change that allows the entry ganglionic receptors are of sodium ions, resulting in selectively blocked by the depolarization of the hexamethonium, whereas NMJ effector cell receptors are specifically blocked by tubocurarine Pharmacology, Lecture 4 Cholinergic Agonists Dr 12 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 13 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 14 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 15 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 16 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 17 Salem Abukres IV. DIRECT-ACTING CHOLINERGIC AGONISTS also known as parasympathomimetics Choline esters: carbachol and bethanechol. Alkaloids, such as pilocarpine, All of the direct-acting cholinergic drugs have longer durations of action than ACh. Some of the more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness Pharmacology, Lecture 4 Cholinergic Agonists Dr 18 Salem Abukres A. Acetylcholine 1. Decrease in heart rate and cardiac output: 2. Decrease in blood pressure 3. Other actions: increases salivary secretion and stimulates intestinal secretions and motility Pharmacology, Lecture 4 Cholinergic Agonists Dr 19 Salem Abukres  IV. DIRECT-ACTING CHOLINERGIC AGONISTS B. Bethanechol (muscranic C. Carbachol (mus+ nic) resp) Increased intestinal motility and tone Profound effects: because of its Stimulates the detrusor muscle of the bladder, ganglion-stimulating activity, it may first whereas the trigone and sphincter are relaxed. stimulate and then depress these So increase voiding pressure and decrease systems bladder capacity to cause expulsion of urine. Therapeutic applications:used to stimulate the Cause release of epinephrine from the atonic bladder, particularly in postpartum or adrenal medulla by its nicotinic action. postoperative, nonobstructive urinary Miosis and a spasm: ciliary muscle of retention the eye remains in a constant state of Adverse effects: generalized cholinergic contraction. stimulation, sweating, salivation, flushing, decreased blood pressure, nausea, abdominal Used as: a miotic agent to treat pain, diarrhea, and bronchospasm glaucoma Atropine sulfate may be administered to 3. Adverse effects: At doses used overcome severe cardiovascular or ophthalmologically, little or no due to bronchoconstrictor responses lack of systemic penetration Pharmacology, Lecture 4 Cholinergic Agonists Dr 20 Salem Abukres  D. Pilocarpine Exhibits muscarinic activity and 2. Therapeutic use: is used primarily in In glaucoma: and is the drug of ophthalmology choice in the emergency lowering of intraocular pressure Produces rapid miosis and The miotic action of pilocarpine is also contraction of the ciliary useful in reversing mydriasis due to muscle atropine. The drug is beneficial in 3. Adverse effects: parasympathetic promoting salivation in effects, including profuse sweating patients with xerostomia and (diaphoresis) and salivation sjögren’s syndrome, which Parenteral atropine is administered is characterized by dry mouth to counteract the toxicity of and lack of tears pilocarpine Pharmacology, Lecture 4 Cholinergic Agonists Dr 21 Salem Abukres V. INDIRECT-ACTING CHOLINERGIC AGONISTS: ACETYLCHOLINESTERASE INHIBITORS (REVERSIBLE) A. Edrophonium Short-acting ACETYLCHOLINESTERASE INHIBITOR (ACHE inhibitor) Used in the diagnosis of myasthenia gravis Excess drug may provoke a cholinergic crisis (atropine is the antidote). Used to assess cholinesterase inhibitor therapy And for reversing the effects of nondepolarizing neuromuscular blockers after surgery. Pharmacology, Lecture 4 Cholinergic Agonists Dr 22 Salem Abukres B. Physostigmine Intermediate-acting agent ACHE INHIBITOR Has a wide range of effects as a result of its action, and stimulates not only the muscarinic and nicotinic sites of the ANS but also the nicotinic receptors of the NMJ. 2. Therapeutic uses: The drug increases intestinal and bladder motility, to treat glaucoma, but pilocarpine is more effective. Overdoses of drugs with anticholinergic actions, atropine, phenothiazines, and tricyclic antidepressants. Side effects: bradycardia and a fall in cardiac output, paralysis of skeletal muscle. Rarely seen with therapeutic doses Pharmacology, Lecture 4 Cholinergic Agonists Dr 23 Salem Abukres C. Neostigmine Used to stimulate the bladder and GI tract, as an antidote for tubocurarine and other competitive neuromuscular blocking agents Also used symptomatically to treat myasthenia gravis. Side effects: generalized cholinergic stimulation, Neostigmine is contraindicated when intestinal or urinary bladder obstruction is present. Pharmacology, Lecture 4 Cholinergic Agonists Dr 24 Salem Abukres E. Tacrine, donepezil, rivastigmine, and galantamine Patients with alzheimer disease have a deficiency of cholinergic neurons in the CNS This observation led to the development of anticholinesterases as possible remedies for the loss of cognitive function Donepezil Pharmacology, Lecture 4 Cholinergic Agonists Dr 25 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 26 Salem Abukres VI. INDIRECT-ACTING CHOLINERGIC AGONISTS: ANTICHOLINESTERASES (IRREVERSIBLE) A number of synthetic organophosphate compounds have the capacity to bind covalently to AChE. The result is a long-lasting increase in ACh at all sites where it is released. Many of these drugs are extremely toxic and were developed by the military as nerve agents. Related compounds, such as parathion, are used as insecticides. Pharmacology, Lecture 4 Cholinergic Agonists Dr 27 Salem Abukres VII. TOXICOLOGY OF ACETYLCHOLINESTERASE INHIBITORS A. Reactivation of acetylcholinesterase: Pralidoxime can reactivate inhibited AChE. However, it is unable to penetrate into the CNS. B. Other treatments: Atropine is administered to prevent muscarinic side effects of these agents. Such effects include increased bronchial secretion and saliva, bronchoconstriction, and bradycardia. Diazepam is also administered to reduce the persistent convulsion caused by these agents. Supportive measures, such as maintenance of patent airway, oxygen supply, and artificial respiration, may be necessary as well. Pharmacology, Lecture 4 Cholinergic Agonists Dr 28 Salem Abukres Pharmacology, Lecture 4 Cholinergic Agonists Dr 29 Salem Abukres