Pharmacology - CHOLINERGIC DRUGS (MADE EASY)

in this lecture I want to talk about cholinergic agonist so let's jump right into it as you may recall from my previous video cholinergic neurons are primarily found within parasympathetic system however it's important to remember that they also participate in sympathetic innervation of sweat glands and blood vessels in skeletal muscle now cholinergic neurotransmission can be broken down into six major steps in the first step choline molecule is transported into the neuron by energy and sodium dependent transport system once inside choline reacts with acetyl coenzyme A to form acetyl choline the enzyme responsible for catalyzing this reaction is choline acetyl transferase in the second step acetyl choline gets transported into pre synaptic vesicle where it's protected from degradation in the third step the action potential causes the voltage-sensitive calcium channels to open thus allowing calcium to enter the axon this in turn leads to the fusion of the vesicle with the membrane and release of the acetylcholine from the terminal in the fourth step acetylcholine binds to postsynaptic receptor which leads to cholinergic response acetylcholine also binds to presynaptic receptors and inhibit the release of more acetylcholine this serves as a negative feedback loop in the fifth step the enzyme called acetylcholinesterase terminates acetylcholine function at the synaptic cleft by breaking it down to acetate and choline and finally in the sixth step the free choline is taken up again by the presynaptic neuron and the whole cycle gets repeated now let's talk about the receptors in more details there are two types of cholinergic receptors first there are muscarinic receptors and the second are the nicotinic receptors and as you can probably tell from their names muscarinic receptors have high affinity for muscarine and nicotinic receptors have high affinity for nicotine now there are five distinct subtypes of muscarinic receptors known as M1 M2 M3 M4 and M5 out of these the first three M1 2 and 3 have been functionally defined therefore we generally focus just on them as far as their location besides being found on neurons M1 receptors are located in gastric glands M2 receptors are located on cardiac cells and M3 receptors are found in numerous places on smooth muscle in the eye lungs digestive tract as well as exocrine glands such as sweat and salivary now as you may remember muscarinic receptors are members of the G protein-coupled receptors you may also recall that there are different types of G protein so the receptors M1 and M3 are coupled to G protein of type Gq as a quick reminder stimulation of Gq leads to increase in intracellular levels of calcium this is important to remember because increasing intracellular calcium content can trigger processes such as contraction secretions and neurotransmission on the other hand M2 receptors are coupled to G protein of type Gi and stimulation of Gi can lead to opening of potassium channels which in turn causes hyperpolarization and reduction of heart rate now let's talk about the second major type of cholinergic receptors which are the nicotinic receptors nicotinic receptors are ligand-gated ion channels now when acetylcholine binds to them these receptors will undergo conformational change that allows sodium ions to flow into the cells there are two types of nicotinic receptors first those receptors that are found on at the neuromuscular junction are classified as Nm and they're responsible for muscle contraction the second receptors that are found in the central nervous system and autonomic ganglia are classified as Nn and they're mainly involved in transmission of cholinergic signals so now let's talk about the actual drugs we can divide cholinergic agonists into three different groups number one direct acting number two indirect acting reversible and number three indirect acting irreversible so let's start with direct acting cholinergic agonists they simply mimic the effects of acetylcholine by binding to either muscarinic or nicotinic receptors the first drug that belongs to this group is not surprisingly Acetylcholine now the biggest problem with Acetylcholine is that it produces nonspecific cholinergic effects and it's rapidly inactivated by cholinesterases therefore its clinical use is very limited in general when administered intravenously Acetylcholine decreases cardiac output and heart rate decreases blood pressure and increases GI activity Acetylcholine is available in ophthalmic solution which is sometimes used to produce miosis during eye surgery the next drug is Carbachol which is structurally similar to acetylcholine and thus effectively mimics effects of acetylcholine and along with that goes its limited therapeutic use however Carbachol is not very susceptible to acetylcholinesterases therefore it has fairly long duration of action as far as its therapeutic use Carbachol is sometimes used only locally to constrict pupil during eye surgery and to decrease intraocular pressure now another drug in this group that's also used ophthalmically is Pilocarpine Pilocarpine acts on smooth muscle of the eye to constrict the pupil and more importantly it increases aqueous outflow which results in rapid drop in intraocular pressure this is why Pilocarpine is very useful in treating acute glaucoma attack the last drug that I wanted to mention is Bethanechol unlike the other drugs in this group Bethanechol selectively stimulates urinary and gastrointestinal tract therefore it is sometimes given orally or subcutaneously to treat urinary retention or to treat gastrointestinal lack of muscular tone now let's talk about the second group of cholinergic agonists which are the indirect acting agonists these simply work by binding to acetylcholinesterase enzyme which as you may remember catalyzes breakdown of acetylcholine this in turn results in buildup of acetylcholine in the synaptic cleft and corresponding effects so now let's talk about reversible agents first and let's start with Edrophonium Edrophonium reversibly binds to acetylcholineesterase it has a very short duration of action only about 10 to 20 minutes and its use is typically restricted to diagnosis of myasthenia gravis myasthenia gravis is a neuromuscular disease which is caused by antibodies that block acetylcholine receptors which leads to muscle weakness so when Edrophonium is administered to a patient with myasthenia gravis we observe rapid increase in muscle strength next we have Physostigmine Physostigmine stimulates both nicotinic and muscarinic receptors and it's an intermediate acting agent with duration of action of about 30 minutes to 2 hours it's been historically used in the treatment of overdoses of anticholinergic drugs such as Atropine next we have Neostigmine Neostigmine is another intermediate acting agent but unlike Physostigmine its structure is more polar therefore it does not absorb well from the GI tract and does not enter the CNS it is typically used for symptoms of myasthenia gravis it can also be used to stimulate bladder and GI tract and to reverse the effects of anesthesia from neuromuscular blocking agents also I wanted to mention Pyridostigmine which is another agent that is very similar to Neostigmine and it produces very similar effects lastly I wanted to mention some agents that are used to ease the symptoms of Alzheimer's disease and these are Donepezil Rivastigmine and Galantamine reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease therefore use of these agents can enhance cholinergic effects and lead to somewhat improved cognitive function unfortunately none of these agents can stop the progression of Alzheimer's disease now that we covered the reversible anticholinesterase agents I wanted to briefly mention the irreversible ones many of these drugs are extremely toxic and were developed by the military as nerve agents and best example of that is sarin gas because of that the only agent that you might still encounter in medical practice is Echothiophate Echothiophate forms covalent bonds with acetylcholinesterase leading to a very strong cholinergic stimulation its therapeutic use is restricted to treatment of open-angle glaucoma only however it is rarely used at all due to its side effect profile I would like to end this video by sharing some of the side effects associated with cholinergic agonists now the adverse effects that can result from use of these agents are due to overstimulation of cholinergic receptors and there are as follows diarrhea urination miosis and muscle weakness bronchorrhea bradycardia emesis lacrimation and salivation now how can you remember all of these well the great mnemonic is right in front of you "DUMBBELLS" it's all you need to know to remember the common side effects associated with cholinergic agonists thank you for watching make sure you subscribe and stay tuned to the part 2 where I'll be discussing cholinergic antagonists

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Keywords: cholinergic, parasympathomimetic drugs, cholinergic system and drugs, cholinergic pharmacology, cholinergic transmission, Cholinomimetic, cholinergic system, cholinergic drugs, cholinergic receptors, cholinergic agonists, muscarinic, cholinergic and anticholinergic drugs, muscarinic receptors, cholinergic and adrenergic receptors, acetylcholine receptors, anticholinergic drugs, acetylcholine, ans pharmacology, muscarinic and nicotinic receptors, anticholinesterases, nicotinic, atropine

Id: r-gJaMoMon0

Length: 10min 38sec (638 seconds)

Published: Sun May 01 2016