L17 Autonomic Pharmacology PDF

Autonomic pharmacology 30 November 2024 19:56 Drugs which target the entire autonomic nervous system Both the sympathetic and parasympathetic nervous systems use nicotinic ACh receptors at synapses between preganglionic and postganglionic neurones. These receptors are also present on skeletal muscl...

Autonomic pharmacology 30 November 2024 19:56 Drugs which target the entire autonomic nervous system Both the sympathetic and parasympathetic nervous systems use nicotinic ACh receptors at synapses between preganglionic and postganglionic neurones. These receptors are also present on skeletal muscles, however the structure is different/ Generally a nicotinic AChR is pentameric transmembrane ion channel with 5 subunits. In skeletal muscle, the AChR uses α1 subunits, whereas the nicotinic AChRs of the ANS use α2-7 subunits. This allows drugs to be used that specifically target the subunits of ANS receptors. One drug is hexamethonium. This is a non-competitive antagonist of ANS NAChRs (nicotinic ACh receptors). It blocks all the effects of autonomic stimulation, both sympathetic and parasympathetic, while not affecting skeletal muscle. It has anti-hypertensive effects. It is no longer used due to the large number of side effects, as it blocks all aspects of sympathetic and parasympathetic transmission. Drugs which target the parasympathetic nervous system Postganglionic neurones of the PaNS exert their effects on effectors via muscarinic ACh receptors. Drugs that specifically target the PaNS will target these rceptors. Muscarinic ACh receptors are G-protein coupled receptors, consisting of 7 transmembrane domains. There are 5 types of muscarinic receptors, most importantly ​ M1 - Present in the stomach and salivary glands. It is a Gq receptor, so achieves its effect by activating phospholipase C (PLC) ​ M2 - Present in cardiac muscle. It is a Gi receptor, so achieves its effect by inhibiting adenylyl cyclase, reducing cAMP levels. ​ M3 - Present in smooth muscle (e.g. eyes, bronchi) and exocrine glands. It is a Gq receptor, so achieves its effect by activating PLC. Muscarinic agonists/parasympathomimetic drugs These are drugs that activate muscarinic ACh receptors, achieving same effects as parasympathetic stimulation, such as: ​ Decreased heart rate ​ Vasodilation ​ Smooth muscle contraction, e.g. in gut or respiratory tract ​ Salivation ​ Lacrimation (tearing up) ​ Bronchial mucous secretions Muscarine poisoning can occur due to over-consumption of muscarine containing mushrooms. In this case, extreme parasympathetic effects occur, such as bradycardia, hypotension, increased gut motility and pain, bronchoconstriction and miosis of pupils (abnormal constriction) This poisoning can be reversed by atropine, which is a competitive antagonist for muscarine. An example of a muscarinic agonist is pilocarpine, which is used to treat glaucoma of the eyes by topical administration directly into the eye via eyedrops. This way, only the M3 receptors of ciliary muscles are targeted, preventing side effects caused by parasympathetic effects across the entire body. Muscarinic antagonists Used to treat: ​ Asthma (ipratropium/tiotropium) - Relax smooth muscles of bronchi, to widen airway ​ Bradycardia (atropine) - Increases heart rate ​ Constricted pupils (tropicamide) - Relaxes iris sphincter muscle, which normally constricts pupil ​ Urinary incontinence (oxybutynin/tolterodine) - Relaxes smooth muscle of bladder ​ Motion sickness (hyoscine) ​ Cyclopentolate can also be used to dilate the pupil in diagnostic procedures. Muscarinic agonists can also be used to counter the effects of ACh esterase inhibitors. ​ ACh esterase inhibitors are administered after operations to stop the paralysis by anaesthesia, by causing ACh build up in the synaptic clefts ​ However this can cause unwanted PaNS stimulation causing side effects such as bronchoconstriction, drugs such as atropine can be administered to prevent these side effects ​ AChE inhibitors are also administered as treatment for myasthenia gravis and could be used as a weapon (nerve gas). Drugs which target the sympathetic nervous system Sympathetic postganglionic neurones use noradrenaline (NA) as neurotransmitter, allowing them to be specifically targeted. Adrenoceptors are G-protein coupled receptors, there are 5 types: ​ α1 - Causes contraction of smooth muscle (e.g. vasoconstriction). It is a Gq receptor so achieves its effects by activating phospholipase C ​ α2 - Causes direct vasoconstriction, as well as inhibition of NA release and sympathetic outflow from CNS. It is a Gi receptor so achieves its effects by inhibiting adenylyl cyclase ​ β1 - Increases heart rate and contractility. It is a Gs receptor, so it activates adenylyl cyclase and increases cellular cAMP levels.  ​ β2 - Causes relaxation of smooth muscle, for example in bronchi and blood vessels of skeletal muscle. It is a Gs receptor so it achieves its effect by activating adenylyl cyclase and increasing cellular levels of cAMP ​ β3 - Causes smooth muscle to relax, for example in the bladder. Also stimulates lipolysis. It is a Gs receptors so achieves its effects by activating adenylyl cyclase. Drugs which target adrenoceptors can either be adrenergic agonists or adrenergic antagonists. They can be further categorised based on what type of adrenoreceptor they act on. α-adrenoceptor agonist Uses: ​ Vasoconstrictors (adrenaline, noradrenaline) - Coupled with local anaesthetics to prevent its spread into the general circulation and prolong action. Target α1 receptors. ​ Nasal decongestant (phenylephrine) - Target α1 receptors. ​ Hypertension treatment - Targets α2 receptors of the CNS. ​ Facial erythema treatment - Stimulate direct vasoconstriction. Target α2 receptors. α-adrenoceptor antagonists (alpha-blockers) Uses: ​ Hypertension treatment (doxazosin) - Targets α1 receptors, stimulating vasodilation ​ Benign prostatic hyperplasia treatment (tamsulosin) - Targets α1 receptors of the prostate and urethra, stimulating them to relax to alleviate urinary difficulties. β-adrenoceptor agonists ​ Cardiogenic shock (adrenaline/dobutamine) - Heart cannot pump blood efficiently. Targets β1 receptors on heart to increase heart rate and contractility. ​ Anaphylactic shock (epinephrine/adrenaline) - As a response to low blood pressure due to allergic reaction. Targets α and β1 receptors to restore blood pressure. ​ Asthma (salbutamol) - Targets β2 receptors to relax bronchial smooth muscle. Salbutamol can also be injected intravenously to delay premature labour. β-adrenoceptor antagonists (beta-blockers) ​ Angina, cardiac arrhythmias and heart failure ​ Hypertension treatment ​ Anxiety treatment ​ Glaucoma treatment (timolol) Another example is metoprolol, which targets β1 receptors. Drugs which target the SyNS via catecholamine regulation Regular noradrenaline regulation 1.​ Noradrenaline (NA) is synthesised from tyrosine in a multi-step mechanism which involves dopamine as an intermediate. 2.​ It is then stored in secretory vesicles and is released into the synapse when an action potential reaches the pre-synaptic bulb 3.​ NA then acts on its receptors. The NA is eventually reabsorbed into the presynaptic bulb via the action of NAT (noradrenaline transporter) protein. This terminates the action of NA. 4.​ In the neurones, some NA may be broken down by mono-amine oxidase (MAO) enzymes into other metabolites. Drugs that target SyNS via catecholamine regulation will interfere with this process, there are 3 main types NAT inhibitors ​ By inhibiting action of NAT, less NA is reabsorbed by neurones. More NA remains in synaptic cleft for longer, leading to prolonged sympathetic activation ​ Examples include desipramine (used as an antidepressant), and cocaine (used as local anaesthetic) ​ DAT (dopamine transporter) and SERT (serotonin transporter) proteins have similar structures to NAT, therefore these drugs will also have side effects due to the buildup of dopamine and serotonin in the synapses of the CNS. This is how cocaine leads to feelings of euphoria and excitement. ​ Other side effects include tachycardia and dysrhythmia MAO inhibitors ​ By inhibiting MAO which normally breaks down NA, levels of NA in the presynaptic neurones are elevated.  ​ MAO inhibitors also lead to increased levels of dopamine and serotonin in the CNS and PNS. ​ Side effects include hypotension, weight gain, restlessness, insomnia. ​ MAO also breaks down tyramine (present in cheese), which has sympathomimetic effects. Therefore, eating cheese while under influence of MAO inhibitors leads to a 'cheese reaction' with effects such as headaches, palpitations and hypertensive crisis (severe increase in blood pressure). ​ Examples include moclobemide and phenelzine Sympathetic amines ​ These are drugs that are structurally similar to NA. therefore, they are transported into neurones by NAT protein, and into secretory vesicles (VMAT) ​ Therefore, they displace NA from vesicles, and NA leaks out the neurone into the synaptic cleft via the NAT protein. ​ They have effects such as bronchodilation, vasoconstriction, increasing blood pressure (hypotension treatment) ​ It also has a similar effect on serotonin and dopamine, therefore having excitatory and euphoric effects on the CNS, leading to them being common drugs in substance abuse. ​ Examples include amphetamine, ephedrine, tyramine.