Lec 6 Pharmacology I PDF

PCT312 Pharmacology I CHOLINERGIC AGONISTS Assoc. Prof. Mennatallah Ali  PCT 312 Pharmacology I “Cholinergic agonists” By the end of the lecture: 1. Classify cholinergic agonists. 2. Identify th...

PCT312 Pharmacology I CHOLINERGIC AGONISTS Assoc. Prof. Mennatallah Ali  PCT 312 Pharmacology I “Cholinergic agonists” By the end of the lecture: 1. Classify cholinergic agonists. 2. Identify the action of acetylcholine on different organs. 3. Recognize different cholinergic agonists and their therapeutic use. 4. Distinguish the different uses of anticholinesterases. 5. Outline the mechanism of organophosphates, their symptoms and management strategy. Cholinergic agonists or cholinomimetics or parasympathomimetics are drugs that mimic the endogenous acetylcholine on its receptors. Acetylcholine is the physiological transmitter at both muscarinic and nicotinic receptors. Cholinergic agonists can be classified into: I. Directly acting agonists: bind to and activate muscarinic or nicotinic receptors. They can be divided on the basis of chemical structure into a. Choline Esters (including acetylcholine) b. Cholinomimetic Alkaloids (such as muscarine and nicotine). II. Indirectly acting agents: produce their effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline & acetate. 1  I- Directly acting agonists: Choline esters Cholinomimetic alkaloids Others (synthetic) Acetylcholine Muscarine Carbachol Varnenciline Nicotine Bethanechol Cevimeline Pilocarpine Methacholine A. Choline esters: The choline esters include acetylcholine and synthetic acetylcholine analogs, such as carbachol, bethanechol and methacholine. 1- Acetylcholine Neurotransmission at cholinergic neurons 1. Synthesis of acetylcholine: Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium as choline has a quaternary nitrogen. This step can be inhibited by hemicholinium. This uptake of choline is the rate-limiting step in ACh synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA, from mitochondria) to form ACh in the cytosol. 2. Storage of acetylcholine in vesicles: ACh is packaged and stored into presynaptic vesicles by an active transport process vesicular ACh transporter (VAChT). The mature vesicle contains ACH, adenosine triphosphate (ATP, cotransmitter) and proteoglycan. 3. Release of acetylcholine: Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of contents into the synaptic space. This release can be blocked by botulinum toxin. 4. Binding to the receptor: ACh released from the synaptic vesicles diffuses across the synaptic space and binds to postsynaptic receptors on the target cell, and to presynaptic receptors. Binding to a receptor leads to a biologic response within the cell, as mediated by second messenger molecules. 2 5. Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly terminated, because acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the synaptic cleft. There are two types of cholinesterase: a. True cholinesterase (Specific cholinesterase): Responsible for the hydrolysis of Ach released at the cholinergic sites. b. Pseudocholinesterase (Butyrylcholinesterase): Nonspecific it occurs in the liver and plasma. The molecule of the cholinesterase enzyme possesses 2 active sites. Attachment of acetyl choline molecule at these 2 sites induces its hydrolysis by the enzyme into choline and acetate. 6. Recycling of choline: Choline may be recaptured back into the neuron. There, it is available to be acetylated into ACh. 3 Absorption and Fate: - Ach is a quaternary ammonium compound that cannot penetrate membranes, thus, it is ineffective orally and should be given parenterally. - It has no therapeutic effect as it has short duration of action (5-20 seconds) as it is rapidly hydrolyzed in the blood and tissues by the cholinesterase enzyme. Pharmacological actions of acetylcholine: Acetylcholine has two main pharmacological actions: I- Muscarinic -Like actions: a- Cardiovascular System: - Heart: (M2 receptors): Ach on the heart produces bradycardia (-ve chronotropic), decrease cardiac output and decrease conductivity. - Blood vessels: Vasodilatation Stimulation of the M3 receptors in the endothelial cells of the blood vessels and the subsequent release of (EDRF= endothelium derived relaxing factor) NO, which activates guanylate cyclase leading to the formation of the second messenger cGMP Decrease Blood pressure: due to bradycardia & vasodilatation b- Gastrointestinal tract: Stimulation of tone and motility and sphincters are relaxed. c- Urinary tract: (Evacuation of the bladder): Stimulation of the M3 detrusor muscle and relaxation of the internal urethral sphincter. d- Bronchioles: Bronchoconstriction and M 3 increased secretions 4  e- Eye: Miosis due to stimulation of the constrictor pupillae muscle (Circular muscle). Stimulation of the ciliary muscle resulting in accommodation for near vision. f- Exocrine glands: Stimulation of secretions (Salivary, gastric, bronchial, lachrymal and sweat). The muscarinic actions of Ach are blocked by atropine. 2- Nicotine - like actions is due to stimulation of the nicotinic receptors present in the autonomic ganglia, adrenal glands (NN) and skeletal muscles (NM). a- Action on the autonomic ganglia (NN): Acetylcholine reversal (in presence of atropine); acetylcholine produce an increase in blood pressure instead of a decrease. This is due to: - Stimulation of the sympathetic ganglia leading to a release of noradrenaline. - Stimulation of the adrenal medulla leading to the release of adrenaline and noradrenaline. b- Action on the skeletal muscles (NM): Acetylcholine stimulates nicotinic receptors (NM) at the motor endplate causing contraction (muscle twitches), this action is blocked by neuromuscular blockers, e.g. d-tubocurarine. 5 Therapeutic uses of acetylcholine: It is not used therapeutically due to 1. Multiplicity in action. 2. Rapid inactivation by cholinesterase enzyme. 3. Ineffective orally. Only use to produce immediate brief miosis during ophthalmic surgery and as an experimental tool Synthetic Choline esters Carbachol, Bethanechol, and Methacholine They are positively charged quaternary ammonium compounds that are poorly absorbed from GIT and are not distributed to the CNS. These have the following advantages over acetylcholine: - They have a longer duration of action. - They are effective orally & parenterally. - Some are more selective in action (bethanechol and methacholine only activate muscarinic receptors) Choline ester Susceptibility Muscarinic Nicotinic cholinesterase action action Acetylcholine ++++ +++ +++ Carbachol Negligible ++ +++ Bethanechol Negligible ++ None Methacholine + ++++ None 2- Carbachol (carbamylcholine)  It is not affected by both types of cholinesterase (it is stable and has a long duration of action.  It has nicotinic action similar to ACh.  It exerts muscarinic effects mainly in the eye, GIT and urinary bladder. Uses: Because of its high potency, nonselectivity, and relatively long duration of action, carbachol is rarely used. Carbachol is only used intraocularly to produce miosis during ophthalmic surgery, such as cataract surgery. It was also used in glaucoma treatment. 6  Glaucoma is characterized by a progressive damage of optic nerve, leading to irreversible sight loss. The main cause is the increase in the intraocular pressure (IOP), due to resistance to the drainage of aqueous humor through outflow pathways 3- Bethanechol  Bethanechol selectively activates muscarinic receptors, particularly in urinary bladder or gastrointestinal muscle (M3)  Therapeutic doses of bethanechol given orally or subcutaneously have little effect on blood pressure, but the drug should never be administered intravenously because this can cause hypotension and bradycardia. Uses: Bethanechol can be given postoperatively or postpartum to increase bladder muscle tone in patients with nonobstructive urinary retention. It can be used to increase GIT motility in gastric atony, and paralytic ileus. 4- Methacholine  It is more stable than acetylcholine (hydrolyzed only by true cholinesterase).  It has a prominent muscarinic action Uses: It is primarily used in the diagnosis of “bronchial airway hyperreactivity” due to its bronchoconstricting properties. B. Cholinomimetic Plant Alkaloids: The cholinergic plant alkaloids include muscarine, nicotine, and pilocarpine. 1- Muscarine is found in some mushrooms, can stimulate muscarinic receptors at effector organs. Muscarine has no current medical use. 2- Nicotine is derived from Nicotiana plants and is contained in cigarettes and other tobacco products; it is highly addictive. Low concentrations of nicotine stimulated autonomic ganglia and skeletal muscle neuromuscular junctions but not autonomic effector cells. Nicotine is available in chewing gum, transdermal patches, and other products designed for use in smoking cessation programs. 3- Pilocarpine  Pilocarpine is a tertiary amine alkaloid that is obtained from Pilocarpus, a small shrub.  Pilocarpine, is stable to hydrolysis by AChE, absorbed from GIT.  Compared with ACh and its derivatives, it is far less potent but is uncharged and can penetrate the CNS at therapeutic doses.  Pilocarpine exhibits muscarinic activity. 7 Pilocarpine is extremely effective in miosis (miotic effect) and contraction of the ciliary muscle and widening of the filtration angle and opening the trabecular meshwork around the Schlemm canal, causing an immediate drop in intraocular pressure because of the increased drainage of aqueous humor and induce accommodation for near vision. Uses: 1- It is used in the treatment of acute angle-closure glaucoma (short-term under controlled conditions), a medical emergency in which blindness can result if the intraocular pressure is not lowered immediately. It is also used for the treatment of chronic open-angle glaucoma (not first-line treatment). Main side effects are decreased night vision, caused by miosis, and difficulty in focusing on distant objects (blurred vision). 2- Pilocarpine also increases the secretion of the exocrine glands especially salivary (sialagogue action) and sweat (diaphoretic action). In patients with xerostomia (dry mouth), pilocarpine is administered orally to stimulate salivary gland secretion. Pilocarpine toxicity is characterized by exaggeration of various parasympathetic effects, including profuse body secretions: sweating (diaphoresis) and salivation, etc. (DUMBBELS) C. Synthetic other agents: 1- Cevimeline is a synthetic direct-acting muscarinic receptor agonist that selectively activates M3 receptors. It is administered orally to treat dry mouth in patients who have had radiation therapy for head and neck cancer and to patients with Sjögren syndrome (autoimmune disease characterized by dry eyes, dry mouth, and arthritis) to increase salivary (sialogogue activity) and lacrimal secretion. 8 2- Varenicline is a partial agonist at the nicotinic receptor subtype found in the brain that mediates the reinforcing effects of nicotine in smokers. It is used as an aid to smoking cessation. Contraindications Acetylcholine receptor agonists are contraindicated in  Bronchial asthma  Bradycardia and cardiac block  Peptic Ulcers  Urinary or bowel obstruction II. Indirectly acting agents: Anticholinesterases (Inhibitors of AChE or cholinesterase inhibitors) indirectly provide cholinergic action by preventing the degradation of ACh. This leads to accumulation of acetylcholine at cholinergic sites. According to the nature of the binding of the drug with the enzyme, they can be classified into: Anticholinesterases Reversible (Physostigmine, Neostigmine, Irreversible Pyridostigmine, Edrophonium, (Organophosphorous and Donepezil/ compounds) galantamine/rivastigmine) A- Reversible anticholinesterases: They compete with acetylcholine for the active sites on the true and pseudo- cholinesterase (AChE) forms a temporary carbamoylated intermediate, which then becomes reversibly inactivated. The result is potentiation of cholinergic activity throughout the body. 9  1- Physostigmine (Eserine) and 2- Neostigmine Physostigmine (Eserine) Neostigmine Source Natural plant alkaloid Synthetic Quaternary ammonium Chemistry Tertiary amine compound GIT Absorption Complete Poor and irregular Penetration of Reach the CNS to produce It does not cross the blood brain lipid barriers central stimulation barrier Peripheral AChEI and a direct Inhibition of AChE leading to stimulant action on skeletal accumulation of acetyl choline at muscle. Pharmacologic different sites producing: actions a- Muscarinic action Its muscarinic effects are more b- Nicotinic action marked on GIT and urinary c- CNS stimulation bladder Locally on the eye, it produces:  Miosis and decreased IOP by Action on skeletal muscle: the same mechanism as  Stimulation through inhibition pilocarpine. of cholinesterase at the Special effects  Contraction of the ciliary myoneural junction. muscle leading to  Direct stimulant action. accommodation for near objects.  Lacrimation.  It is used to stimulate the bladder and GlT (as bethanechol, in paralytic ileus,  Physostigmine has been used postoperative urinary to treat glaucoma, but other retention) drugs are employed today.  Neostigmine is also used to  It is available for parenteral Therapeutic uses manage symptoms of administration as an antidote myasthenia gravis (with to the adverse effects caused atropine: to block M by an overdose of atropine or receptors) other antimuscarinic drugs.  An antidote for competitive neuromuscular-blocking agents (NMBs). 10 Myasthenia Gravis It is an autoimmune disease caused by antibodies to the nicotinic (NM) receptors, which are stimulated by acetylcholine released at neuromuscular junctions. This causes their degradation, and thus makes fewer receptors available for interaction with the neurotransmitter. Myasthenia gravis is characterized by muscle weakness and rapid fatigability of skeletal muscles, and most often affects the muscles of the face, throat, and neck 3- Pyridostigmine is another cholinesterase inhibitor used in the chronic management of myasthenia gravis. Its duration of action is intermediate (3 to 6 hours) but longer than that of neostigmine. When used in the long-term treatment of myasthenia gravis, neostigmine and pyridostigmine symptomatically improve muscle tone and reduce facial and eyelid ptosis. Corticosteroids and other immunosuppressant drugs are also used in treating myasthenia to reduce the formation of antibodies to the nicotinic receptor. They are often used in combination with cholinesterase inhibitors. 4- Edrophonium (tensilon): It has more selective action on the skeletal muscle, however, it reversibly binds to a negatively charged (anionic) site on cholinesterase resulting in having a very short duration of action (10 min). Edrophonium is used for:  Edrophonium is used in the diagnosis of myasthenia gravis, (as its effect lasts for 5 minutes only).  It is used for differentiating cholinergic and myasthenic crises  It also used for reversing the effects of nondepolarizing competitive neuromuscular blockers (NMBs) (similar to neostigmine). Muscle weakness may be experienced due to either undertreatment or overtreatment. Undertreatment, where patients are receiving adequate doses of the drug, muscle weakness is caused by an acetylcholine deficiency and is called a myasthenic crisis. Overtreatment can be caused by an excessive amount of acetylcholine at the neuromuscular junction, causing sustained depolarization neuromuscular blockade (muscle fatigue). This condition is called a cholinergic crisis. 5- Centrally acting, reversible AChEIs Donepezil, galantamine, and rivastigmine are centrally acting, reversible cholinesterase inhibitors that readily cross the blood-brain barrier and act to increase the concentration of acetylcholine at central cholinergic synapses. These drugs are used in the treatment of Alzheimer’s disease. In addition to an old drug called tacrine, which was withdrawn due to liver toxicity 11 Alzheimer’s disease It is neurodegenerative brain disease of unknown cause that leads to dementia. It is characterized by a relative lack of the neurotransmitter acetylcholine, and by the presence of plaques of amyloid proteins. The predominant early features are memory loss and personality changes. The disease is progressive, leading to impairment of higher cerebral and cognitive function. 2- Irreversible anticholinesterases: Organophosphorus compounds (OPs):  Insecticides (Parathion, Malathion)  Nerve gases (Sarin & Soman)  Echothiophate: rarely used as eye drops in the treatment of glaucoma due to its very long duration of action (2 weeks duration of action), side effect profile, including the risk of cataract They are highly lipid-soluble and are effectively absorbed from all sites in the body, including the skin, mucous membranes, and GIT. Toxicity can occur after exposure by any route. The organophosphates form a tight, covalently bound intermediate with the catalytic site of cholinesterase. The covalently bound intermediate is further stabilized by a spontaneous process called aging, in which a portion of the drug molecule is lost. Organophosphate compounds augment cholinergic neurotransmission at both central and peripheral cholinergic synapses. Systemic exposure to these compounds can produce all of the effects of muscarinic receptor activation, including salivation, lacrimation, miosis, bronchoconstriction, intestinal cramps, and urinary incontinence. Excessive activation of nicotinic receptors by organophosphate compounds leads to a depolarizing neuromuscular blockade and muscle weakness. Seizures, respiratory depression, and coma can result from the overactivation of acetylcholine receptors in the CNS. Management of this toxicity involves the following: - Decontamination of the patient, support of cardiovascular and respiratory function. - Atropine effectively counteracts the muscarinic effects caused by organophosphates and other cholinesterase inhibitors. High dose 2 mg I.V. or I.M. repeated every 5-10 min. till the pupil dilates, and heart rate (about 80 beats/min) occur 12 - Pralidoxime is used to regenerate cholinesterase after organophosphate poisoning. The high affinity of pralidoxime for phosphorus enables it to break the phosphorus bond with cholinesterase and thereby regenerate the enzyme. It is important to administer pralidoxime as soon as possible after organophosphate exposure (within 12 hours) because enzyme “aging”. - Anticonvulsants e.g. diazepam 13