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1 number 21 Done by Corrected by Dania Alkouz Doctor Malik
2 Dr. Malik is going to repeat what Dr. Omar said about the cholinergic agonists and antagonists. The Autonomic Nervous system (ANS) (Just a quick revision) As we know, the ANS is divided into sympathetic and parasympathetic systems (and enteric system). In the sympathetic system the preganglionic nerurons are short while the postganglionic ones are long. In the parasympathetic system the preganglionic neurons are long (ganglia in the effector organs or close to them) and the postganglionic neurons are short. These arrangements allow the sympathetic system to give a wide-range effect by the preganglionic neurons being highly branched and allow the parasympathetic system to be highly discrete as there is almost no branching seen in the preganglionic neurons. For the receptors, in the ganglia the receptors in both the sympathetic and parasympathetic systems are cholinergic nicotinic receptors (on the postsynaptic membrane). On the effector organs the receptors in the parasympathetic system are also cholinergic but muscarinic. In the sympathetic system there are various types: adrenergic receptors (most common), dopaminergic receptors and cholinergic receptors (sweat glands and adrenal medulla). Note: In the somatic nervous system a single neuron runs from the CNS to the skeletal muscles where nicotinic receptors are present. Of all the receptors mentioned above only the nicotinic receptors act ionotrophically (when activated, they change the permeability of the postsynaptic membrane to certain ions) and have no sub-types. All the other receptors act via the second messenger system (IP3 and DAG or camp) and do have subtypes. There are M₁, M₂, M₃, M₄ and M₅ muscarinic receptors. We will not pay much attention to the subtypes of the muscarininc receptors as we rarely find drugs that are actually selective to one type over the others here. For adrenergic receptors we can find α₁, α₂, β₁, β₂ and β₃ receptors. It is important to know the differences between these sub-types here as many drugs are indeed selective to some over others. Dopaminergic receptors are divided into D₁, D₂, D₃, D₄ and D₅ receptors. Differentiating between these sub-types can also have important clinical applications here.
3 As for the neurotransmitters, all cholinergic receptors are stimulated by acetylcholine while all adrenergic receptors are stimulated by epinephrine (adrenaline) and norepinephrine (noradrenaline). Dopaminergic receptors are stimulated by dopamine. Following we discuss the locations of all the receptors we just mentioned (I am not sure if the doctor expects us to know about the locations of the muscarinic receptors, they were mentioned to be on the safe side). α₁: There main locations are the eyes, the sphincter muscles of the bladder and the blood vessels. α₂: Mainly work as feedback inhibitors for α₁ adrenergic neurons and for some β₁ adrenergic neurons (in the heart). β₁: Found mainly in the heart. β₂: Found mainly in the lungs, smooth muscles of the blood vessels vasculating the skeletal muscles. (the coronary arteries contain both α₁ and β₂ receptors so that a balance is maintained and that changes in neurotransmitters concentrations do not have drastic effects on the coronary arteries). β₃: Found in the adipose tissue mainly (lipolysis). M₁: In the CNS, peripheral neurons and gastric parietal cells. M₂: In the cardiac tissue mainly (inhibitory effect) and in the CNS. M₃: In the CNS and in the eyes (miosis), the lungs (bronchospasm), the GI (increase motility) and the sphincter muscles (decrease their tone). M₄: In the CNS. M₅: In the CNS. All the dopaminergic receptors : In the coronary arteries, renal and mesenteric blood vessels (cause vasodilation in kidneys and mesenteric). Note: in many organs more than one sub-type of receptors of the same receptor type (e.g. β₁ and β₂ in the heart) but one of those sub-types seems to dominate. Cholinergic Agonists These are drugs that activate the cholinergic receptors, knowing that we can predict a lot of their actions. The main actions of these drugs are: lowering heart rate, lowering blood pressure, increasing GI motility, miosis (glaucoma treatment) and increased salivation. We will discuss two direct acting
4 cholinergic agonists (they activate the receptors) and two indirect acting ones (they increase the amount of available neurotransmitters). Bethanecol This drug is a direct cholinergic agonist. It can only be administered orally (if given IM or IV it would cause severe hypotension and can cause a cardiac arrest and even death). It is often used in urologic treatments especially a non-obstructive urinary tract retension after an operation or during postpartum (first 6 weeks after birth). There are other rare cases it can be used with like neurogenic bladder (a problem in the nervous signals sent to the bladder) and diabetic autonomic neuropathy (diabetes can decreases the efficacy of the nervous control of the bladder). Another disease it can be used with is the paralytic ileus (paralysis of the muscles of the intestine causing its obstruction). This disease can cause abdominal distention (substances accumulate in the intestines so causing the abdomen to appear expanded outwards). The side effects of bethanecol are those of activated cholinergic receptors; sweating, salivation, decreased blood pressure and bronchospasm. Note: The amount of drug given to the patient gives it some kind of selectivity towards the abnormal region/receptor only and there is only a low chance of side effects appearing (this amount is a setpoint by the body itself). If we exceed this set-point then this selectivity of the drug is lost and the adverse effects are likely to be seen, that s why this drug is never to be given IM or IV as the dose reaching the blood increases a lot. Pilocarbine This is another cholinergic agonist (direct). It activates muscarininc receptors and is used in ophthalmology العيون).(طب It is often used in the treatment of acute open angle glaucoma (administered as eye drops); it causes miosis so the aqueous humor can drain out from the eye decreasing the interocular pressure in the eye. It stimulates secretions (saliva, sweat,etc.), but has a limited use due to its low selectivity. Still, it can be used as a mouth wash للفم) (غسول to treat xerostomia (dry mouth) (can be caused by head and neck radiation and by Sjörgen s syndrome). This drug can cross the blood brain barrier and cause disturbances.
5 Anti-cholinesterases These are indirect agonists of the cholinergic receptors. They inhibit the acetylcholinesterase enzyme and so inhibit the break down of acetylcholine causing a prolonged effect (this is used in chemical war weapons like the sarin gas). They cause the activation of all the cholinergic receptors (muscarinic and nicotinic). Physostigmine This is one of the anti-cholinesterases. It is very lipophilic and so can easily cross the blood brain barrier making it able to oppose the action of atropine (a cholinergic antagonist) and it is indeed used in opposing the effect of atropine poisoning (if too much atropine was taken) (also with overdoses of antimuscarininc drugs like tricyclic antidepressants and antihistamines (H1)). It can be used as an eye drop to treat glaucoma but pilocarbine does this job better. (cholinergic drugs decrease the visual acuity البرص) (قوة on the longterm). Neostigmine Produce a more nicotinic effect than physostigmine and so has a greater effect on skeletal muscles. Mainly used to reverse the effects of neuromuscular blocking drugs (muscle relaxants) which are often used in surgeries to induce muscle paralysis (if the patient stays for too long after the operation without being able to move his muscles easily then neostigmine is given). Also used to treat the symptoms of myasthenia gravis (an autoimmune disease). Myasthenia gravis ( عضل (وهن happens when the immune system attacks the nicotinic receptors and so muscles cannot contract (e.g. patient can t open his eyelids or can do so only slowly). Giving neostigmine increases the concentration of acetylcholine available so the remaining nicotinic receptors are activated to the most causing some action to be seen. Usually when neostigmine is given atropine is also used to avoid muscarinic adverse effects of neostigmine. Donepezil A drug that was found to be able to improve the condition of patients with Alzheimer s disease. This drug can cross the blood-brain barrier and their it blocks the acetylcholinesterase bringing about this effect.
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