Parasympathetic Nervous System Drugs (Lecture 6) PDF

Cholinergic Nerve Activity Release of acetylcholine: — When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. — E...

Cholinergic Nerve Activity Release of acetylcholine: — When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. — Elevated calcium levels promote the release of the contents of synaptic vesicles into the synaptic space. This release can be blocked by botulinum toxin. — ! " The toxins of certain bacteria can cause food poisoning, referred to as botulism. Some of these toxins can inhibit the release of ACH from the cholinergic nerve ending to produce a flaccid type of skeletal muscle paralysis. — In recent years, preparations of these toxins ( Botox ) have been injected into skeletal muscle to produce temporary paralysis in a variety of conditions. The cholinergic receptors at the neuromuscular junction (NMJ) of skeletal muscle are known as nicotinic-muscle (Nm) receptors. Drugs that block the effects of ACH at the NMJ are referred to as neuromuscular blockers or skeletal muscle relaxants. Clinical Indications for Anticholinesterase Drugs q Clinical Use of Botulinum Toxin Botulinum toxin is derived from the toxin produced by the bacterium Clostridium botulinum. q The toxin inhibits the release of ACH from cholinergic nerve endings. q In skeletal muscle this action results in muscle paralysis. ü Local intradermal injections of the toxin ( Botox Cosmetic ) are used to temporarily decrease the wrinkling around the eyes, forehead, and face that occurs with aging). ü Other preparations of the toxin (Botulinum toxin type A, Botox, Dysport, and Botulinum toxin type B, Myobloc ) are injected intramuscularly in muscle disorders such as migraine headache prevention, other spastic conditions to provide muscle relaxation. Injections usually last 1 to 3 months. (Woman Receiving Botox Injection to Lessen Skin Wrinkling for Cosmetic Purposes)  Cholinergic Drugs üCholinergic drugs mimic the actions of ACH at the cholinergic (muscarinic) receptors. Another term with essentially the same meaning is parasympathomimetic. üCholinergic drugs are subdivided into two groups: 1. Direct-acting 2. Indirect-acting drugs. üThe direct-acting drugs bind to the cholinergic (muscarinic) receptors and produce effects similar to those of ACH. üThe indirect-acting drugs inhibit the enzyme acetylcholinesterase. The indirect- acting drugs that inhibit acetylcholinesterase increase the concentration and actions of ACH at all muscarinic and nicotinic receptor sites. ü The direct-acting drugs only increase activity at the cholinergic (muscarinic) sites. Multiple Choice Use your critical-thinking skills to answer the following questions. Select the correct answer. 1. Parasympathetic receptors located on the membranes of the internal organs are classified as: a) alpha-1 b) nicotinic-neural (Nn) c) nicotinic-muscle (Nm) d) muscarinic e) ganglionic 2. Select the pharmacologic effect produced by cholinergic drugs. a) increased heart rate b) increased gastrointestinal motility c) decreased urination d) pupillary dilation e) bronchodilation  Muscarinic agonists “Cholinergic drugs” A- Direct acting: ** Choline esters , which include ACh, and synthetic esters of choline, such as carbachol ** Naturally occurring alkaloids as pilocarpine. B- Indirect acting: Cholinesterase inhibitors such as -- Reversible anticholinesterase e.g. physostigmine and pyridostigmine. -- Irreversible anticholinesterase such as organophosphorous compounds used as insecticides and war gases.  Carbachol (carbamylcholine) — Carbachol has both muscarinic as well as nicotinic actions. It is biotransformed by other esterases but at a slower rate. — Actions: Carbachol has profound effects on both the cardiovascular and GI systems because of its ganglion-stimulating activity. It can cause release of epinephrine from the adrenal medulla by its nicotinic action. — Locally instilled into the eye, it causes miosis and a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction. — Therapeutic uses: Because of its high potency, receptor non- selectivity, and relatively long duration of action, carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma. Onset of action for miosis is 10 to 20 minutes and intraocular pressure is reduced for 4 to 8 hours. — Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration.  Pilocarpine - The alkaloid pilocarpine is a tertiary amine - It will penetrate the CNS at therapeutic doses. — Actions: ** Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug is beneficial in promoting salivation in patients -- Applied topically to the cornea, pilocarpine produces rapid miosis and contraction of the ciliary muscle. When the eye undergoes this miosis, it experiences a spasm of accommodation. The vision becomes fixed at some particular distance, making it impossible to focus. — Therapeutic use in glaucoma: - Pilocarpine is used to treat glaucoma and is the drug of choice in the emergency lowering of intraocular pressure of both narrow-angle/closed-angle) and wide-angle (also called open-angle) glaucoma. - The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine. — Adverse effects: # Pilocarpine can enter the brain and cause CNS disturbances. # Poisoning with this agent is characterized by exaggeration of various parasympathetic effects, including profuse sweating (diaphoresis) and salivation. Parenteral atropine, at doses that can cross the blood-brain barrier, is administered to counteract the toxicity of pilocarpine  Indirectly acting cholinergic agents Anticholinesterase: Are drugs, which lead to accumulation of large amount of Ach at different tissues, due to inhibition of cholinesterase. -- Reversible cholinesterase inhibitors: Drugs of therapeutic importance like Neostigmine , physostigmine. -- Irreversible cholinesterase inhibitors: Very long duration of action and toxicity. used as insecticides e.g. organophosphorus comps. A) Reversible cholinesterase inhibitors: 1- Neostigmine: Muscarinic actions: Bradycardia, hypotension, vasodilatation. Increases GI motility and gastric secretion. Local application causes miosis and decrease of IOP. Stimulates all smooth muscles & secretions. Nicotinic actions: Small dose stimulate, large dose block ganglia. Stimulate skeletal muscle by increasing Ach and by direct action on muscle and by direct action on the receptors.  Uses of Neostigmine : --Diagnosis and treatment of myasthenia gravis. -- Treatment of urinary retention. --Treatment of Alzheimer disease — Adverse effects: Adverse effects of neostigmine include those of generalized cholinergic stimulation, such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm. Neostigmine is contraindicated when intestinal or urinary bladder obstruction is present. It should not be used for patients who have inflammatory bowel disease. Myasthenia gravis A disorder that specifically affect neuromuscular junction, affects about 1:2000 individuals who show weakness of skeletal muscles of the face and. neck followed by other muscle and increase fatigability. The myasthenia gravis is due to ! More cholinesterase enzyme ! Abnormal motor end plate ! Presence of a curare like substance in plasma ! Reduction in the number of ACh receptors due to the production of antibodies that decrease the number of nicotinic receptors. *** Given Neostigmine (prostigmine) 1-2 mg IM, if the condition improved, so it is myasthenia gravis and it will respond to neostigmin. If not respond so it is cholinergic crisis (More ACh). 2- Physostigmine (Eserine) - Natural alkaloid, its affinity to cholinesterase enzyme is 10,000 times greater than Ach.. - Physostigmine is a tertiary amine, makes it readily absorbed from GIT and can penetrate BBB and has CNS effects. - Acts on both muscarinic and nicotinic receptors. - Used as miotic and in treatment of glaucoma. - Adverse effects: The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia and a fall in cardiac output may also occur. 3- Edrophenium (Tensilon): Edrophonium is the prototype short-acting AChE inhibitor - Similar to neostigmine in structure but differ in 1- rapid onset and short duration 2- weak as anticolinesterase but more selective for myasthenia gravis 3- Used for diagnosis of maysthenia gravis B) Irreversible cholinesterase inhibitors: Irreversible cholinesterase inhibitors: Very long duration of action and toxicity. used as insecticides e.g. organophosphorus comps - They are organophosphorous compounds, because of their toxicity, they have little use clinically and used as insecticides. - They are ester of phosphoric acid, they react with cholinesterase enzyme as does Ach, but the phosphorylated enzyme is inactive and can not hydrolyse Ach. The hydrolysis of the ester bond by water is very slow compared to the carbamylated enzyme. - Examples are serine, parathion, and malathion. - Hydroxylamine and oxime are found capable to increase the rate of hydrolysis of the ester bond. They considered as a reactivator or regenerator of the enzyme. Example is pyridine-2-aldoxime-methiodide (2-PAM). Actions: Muscle fasciculation, miosis, salivation, sweating,. cramps, abdominal and respiratory distress due to cholinesterase inhibition in the periphery. Anxiety, restlessness, convulsion due to CNS effects. Neuro-toxicity, which is long lasting with varying degree of severity.  Treatment: ** Remove toxic agent. ** Atropine, every 30 min IM until muscarinic symptoms disappear or full atropinization. ** PAM 1-2 g. repeated every 20-30 min I.V. ** Remove secretions to allow free air passage and artificial respiration. ** Diazapam to control convulsion. ** Gastric lavage if taken orally.