Autonomic Nervous System Agents PDF

AUTONOMIC NERVOUS SYSTEM AGENTS The central nervous system (CNS) is the body's primary nervous system, consisting of the brain and spinal cord. The peripheral nervous system (PNS), located outside the brain and spinal cord, is made up of two divisions: the autonomic and the somatic. After i...

AUTONOMIC NERVOUS SYSTEM AGENTS The central nervous system (CNS) is the body's primary nervous system, consisting of the brain and spinal cord. The peripheral nervous system (PNS), located outside the brain and spinal cord, is made up of two divisions: the autonomic and the somatic. After interpretation by the CNS, the PNS receives stimuli and initiates responses to these stimuli. The autonomic nervous system (ANS), also called the visceral system, acts on smooth muscles and glands. Its functions include control and regulation of the heart, respiratory system, gastroin- testinal tract, bladder, eyes, and glands. The ANS is an involuntary nervous system over which we have little or no control. We breathe, our hearts beat, and peristalsis continues without our realizing it. However, unlike the ANS, the somatic nervous system is a voluntary system that innervates skeletal muscles over which there is control. The two sets of neurons in the autonomic component of the PNS are the (1) afferent (sensory) neurons and the (2) efferent (motor) neurons. The afferent neurons send impulses to the CNS, where they are interpreted. The efferent neurons receive the impulses (information) from the brain and transmit these impulses through the spinal cord to the effector organ cells. The efferent pathways in the ANS are divided into two branches: the sympathetic and the parasympathetic nerves. Collectively, these two branches are called the sympathetic nervous system and the parasympathetic nervous system. The sympathetic and parasympathetic nervous systems act on the same organs but produce opposite responses to provide homeostasis (balance). Drugs act on the sympathetic and parasympathetic nervous systems by either stimulating or depressing responses. SYMPATHETIC NERVOUS SYSTEM The sympathetic nervous system is also called the adrenergic system because at one time it was believed that adrenaline was the neurotransmitter that innervated smooth muscle. The neu- rotransmitter, however, is norepinephrine. The adrenergic receptor organ cells are of four types: alpha1, alpha2, beta1, and beta2. Norepinephrine is released from the terminal nerve ending and stimulates the cell receptors to produce a response. PARASYMPATHETIC NERVOUS SYSTEM The parasympathetic nervous system is called the cholinergic system because the neurotransmitter at the end of the neuron that innervates the muscle is acetylcholine. The cholinergic receptors at organ cells are either nicotinic or muscarinic, meaning that they are stimulated by the alkaloids nicotine and muscarine, respectively. Acetylcholine stimulates the receptor cells to produce a response, but the enzyme acetylcholinesterase may inactivate acetylcholine before it reaches the receptor cell. Drugs that mimic the neurotransmitters norepinephrine and acetylcholine produce responses opposite to each other in the same organ. For example, an adrenergic drug (sympathomimetic) increases the heart rate, whereas a cholinergic drug (parasympathomimetic) decreases the heart rate. However, a drug that mimics the sympathetic nervous system and a drug that blocks the parasympathetic nervous system can cause similar responses in the organ. For instance, the sympathomimetic and the parasympatholytic (block impulses from PNS drugs both increase heart rate; the adrenergic blockers and the cholinergic drugs both decrease heart rate.  SYMPATHETIC AND PARASYMPATHETIC RESPONSES TO DRUGS SYMPATHETIC PARASYMPATHETIC RESPONSES Sympathomimetic Parasympathomimetic Opposite response Sympatholytic Parasympatholytic Opposite response Sympathomimetic Parasympatholytic Similar response Sympatholytic Parasympathomimetic Similar response ADRENERGIC AGONISTS Drugs that stimulate the sympathetic nervous system are called adrenergics, adrenergic agonists, or sympathomimetics,because they mimic the sympathetic neurotransmitters nor- epinephrine and epinephrine. They act on one or more adrenergic receptor sites located in the effector cells of muscles, such as the heart, bronchiole walls, gastrointestinal (GI) tract, urinary bladder, and ciliary muscle of the eye. There are many adrenergic receptors. The four main receptors are alpha1, alpha2, beta1, and beta2, which mediate the major responses. Sympathetic responses The alpha-adrenergic receptors are located in blood vessels, eye, bladder, and prostate. When the alpha1 receptors in vascular tissues (vessels) of muscles are stimulated, the arterioles and venules constrict, increasing peripheral resistance and blood return to the heart. Circulation is improved, and blood pressure is increased. When there is too much stimulation, blood flow is decreased to the vital organs. The alpha2 receptors are located in the postganglionic sympathetic nerve endings. When stimulated, they inhibit the release of norepinephrine, leading to a decrease in vasoconstriction. This results in vasodilation and a decrease in blood pressure. The beta1 receptors are located in the kidney but primarily in the heart. Stimulation of the beta receptor increases myocardial contractility and heart rate. The beta2 receptors are found mostly in the smooth muscles of the lung and gastrointestinal tract, the liver, and the uterine muscle. Stimulation of the beta, receptor causes (1) relaxation of the smooth muscles of the lungs, resulting in bronchodilation; (2) a decrease in gastrointestinal tone and motility; (3) activation of glycogenolysis in the liver and increased blood glucose; and (4) relaxation of the uterine muscle, resulting in a decrease in uterine contraction. Another adrenergic receptor is dopaminergic and is located in the renal, mesenteric, coronary, and cerebral arteries. When this receptor is stimulated, the vessels dilate and blood flow increases. Only dopamine can activate this receptor. Inactivation of Neurotransmitters After the neurotransmitter (e.g., norepinephrine) has performed its function, the action must be stopped to prevent prolonging the effect. Transmitters are inactivated by (1) reuptake of the transmitter back into the neuron (nerve cell terminal), (2) enzymatic transformation or degradation, and (3) diffusion away from the receptor. The mechanism of norepinephrine reuptake plays a more important role in inactivation than the enzymatic action. Following the reup- take of the transmitter in the neuron, the transmitter may be degraded or reused. The two enzymes that inactivate norepi- nephrine are (1) monoamine oxidase (MAO), which is inside the neuron; and (2) catechol-O-methyltransferase (COMT), which is outside of the neuron. Drugs can prolong the action of the neurotransmitter (e.g., norepinephrine) by either (1) inhibiting the norepinephrine reuptake, which prolongs the action of the trans- mitter or (2) inhibiting the degradation of norepinephrine by enzyme action. Mnemonics: 1. We have one heart and two lungs i.e.beta1, is in heart and beta2, is in lungs (bronchus). 2. Sympathetic system stimulates the heart and inhibits at other places. In the heart, we have beta1 receptor, so its function is to stimulate (i.e. tachycardia etc) whereas at other places, we have ẞ2, so it relaxes (i.e. bronchodilation, tocolytic action, relaxation of GIT and bladder). 3. In emergencies, we require sympathy. Thus, the tremors occurring during fear are due to beta2 receptor stimulation. 4. Blood vessels contain alpha1 receptors (causing vasoconstriction) and beta2 receptors (causing vasodilation). To remember, we have ABCD. A (Alpha 1)→C (Constriction) B (Beta 2) D (Dilation) 5. When the sympathetic system is stimulated, both alpha1 and beta2 receptors are stimulated, so what will happen to blood vessels? It depends upon the relative number of receptors. If a blood vessel contain more alpha1 receptors, it contracts whereas those having more ẞ2 receptors will dilate. To remember this, When we see a lion, we require sympathy, so the sympathetic system is activated. We need to run now, so muscles require more blood. They get this because blood vessels of skeletal muscle contain more ẞ2, receptors. At this time of emergency, blood requirement in skin and internal organs is minimal, so vasoconstriction occurs here due to more alpha1 receptors. 6. Hypoglycemia is an emergency. Sympathetic system protect from it by: -Causing warning symptoms (tachycardia, palpitations via ẞ1 stimulation) and tremors by beta2 activation. -Beta-2 receptor in liver reverse hypoglycemia by increasing the formation (stimulate gluconeogenesis and glycogenolysis) of glucose. Classification of Sympathomimetic Drugs 1. Directly acting - stimulates alpha and beta receptors directly 2. Indirectly acting - increase the amount of NA in the synapse. 3. Mixed action sympathomimetics Mixed acting Directly -possess both of these actions. 1. DIRECTLY ACTING SYMPATHOMIMETICS These drugs may be catecholamines (containing dihydroxybenzene nucleus) or non- catecholamines. A, NA and dopamine (DA) are the endogenous catecholamines whereas isoprenaline, dobutamine, dopexamine and fenoldopam are synthetic catecholamines. Non-catecholamines may act as selective agonists of alpha1, alpha 2' , beta1 and beta2 receptors. A. Catecholamines Adrenaline is the drug of choice for anaphylactic shock. It is given as 0.5 ml of 1:1000 solution (i.e. 0.5 mg) i.m./s.c. injection. Intramuscular route (on Lateral thigh) is preferred because of variability in absorption from s.c. sites. Intravenous route is avoided but can be used rarely in much lower concentration (1:10,000). Adrenaline is also used to prolong the duration of action and decrease the systemic toxicity of local anesthetics.  Adrenaline is also used in patients with cardiac arrest. The preferred route is i.v. followed by intraosseous and endotracheal, Dopamine is the drug of choice for cardiogenic shock with oliguric renal failure. It acts on D₁ (at a dose of 1-2 µg/kg/min.), β₁ (at 2-10 µg/kg/min.) and a₁ (at > 10 µg/kg/min.) receptors. It causes renal vasodilation by acting on D1, receptors and maintains renal perfusion and GFR. Other ionotropic agents like NA cause renal vasoconstriction and thus worsen renal failure. Ibopamine has similar properties as DA. Dobutamine is relatively selective ẞ₁ agonist with no action on DA receptors. It increases cardiac output with little action on heart rate. Dopexamine combines B, and D₁ agonistic activity with NA reuptake inhibitory action. Fenoldopam is D1 agonist useful in hypertensive emergencies. B. Non Catecholamines a1 agonists: These drugs can be used as nasal decongestants like naphazoline, oxymetazoline and xylometazoline. When effect of these drugs subside, after-congestion is seen. If used for prolonged periods, these can result in atrophic rhinitis (Rhinitis medicamentosa). Phenylephrine can also be used as a mydriatic (does not cause cycloplegia). Methoxamine and mephentermine can be used to increase BP in hypotensive states. Midodrine is a prodrug (active metabolite is desglymidodrine) used for the treatment of orthostatic hypotension. Phenylpropanolamine was banned due to risk of hemorrhagic stroke a2 agonists: Clonidine and a methyldopa (a prodrug) are a2 agonists that can be used for the treatment of hypertension. Other uses of clonidine include: ○ To control diarrhea in diabetic patients with autonomic neuropathy. ○ Prophylaxis of migraine. ○ Management of withdrawal symptoms of alcohol, nicotine and opioids. ○ Epidurally, in combination with opioids for relief of pain. ○ For treatment of ADHD [as monotherapy or adjunctive to other drugs] Apraclonidine and brimonidine are selective a, agonists used topically for the treatment of glaucoma. Dexmeditomidine (central a2 agonist) is used for pre-anaesthetic medication. It is also indicated for sedation of initially intubated and mechanically ventilated patients during treatment in ICU. Guanfacine and guanabenz are a, agonists similar to clonidine and are rarely used now. Tizanidine is used as a muscle relaxant. B₁ agonists: Prenaltrenol is the only non-catecholamine ẞ1 selective agent. It has been promoted recently for the reversal of ẞ blockade. B₂ agonists: Salbutamol (albuterol), levalbuterol, bitolterol, fenoterol, metaproterenol, terbutaline, pirbuterol, salmeterol, formoterol, arformoterol, carmoterol and indacterol are selective ẞ2 agonists useful in bronchial asthma. Ritodrine and isoxsuprine are agonists useful as tocolytic (uterine relaxant) agents. B3 agonists: Mirabegron is a new drug that acts by stimulating ẞ3 receptors in urinary bladder. It is indicated for treatment of overactive bladder. 2. INDIRECTLY ACTING SYMPATHOMIMETICS These drugs act by increasing the release of NA in the synaptic cleft or by inhibiting the reuptake of NA. These agents enter the neuronal cytoplasm by the same transporter that is responsible for the reuptake of NA. From the cytoplasm, these drugs enter the storage vesicles and displace and release the stored NA (because each vesicle has fixed storage capacity). Released NA activates adrenergic receptors. On repeated dosing at short intervals, tachyphylaxis (rapid development of tolerance) is seen with these drugs. Tyramine is normally present in certain foods and can lead to cheese reaction in patients taking MAO inhibitors Methylphenidate is the preferred drug for the treatment of attention deficit hyperkinetic disorder (ADHD). Other drugs used for this indication are amphetamines, atomoxetine and pemoline. Pemoline has been withdrawn due to life threatening hepatotoxicity. Amphetamines are addictive substances and can result in tolerance and dependence. As these are basic drugs, urinary acidification (with NHCl) is employed for the treatment of their toxicity. On the other hand, amphetamine addicts use sodium bicarbonate to obtain the "kick". Modafinil is approved for treatment of narcolepsy, in shift workers, to relieve fatigue in multiple sclerosis and as an adjunt in obstructive sleep apnea. 3. MIXED ACTION SYMPATHOMIMETICS These drugs enhance the release of NA (like indirectly acting drugs) apart from activating a and ẞ receptors directly. Ephedrine and pseudoephedrine are present in the cold remedies for nasal decongestant and bronchodilator action. Ephedrine can also be used for the treatment of bronchial asthma. It is the vasopressor of choice in pregnancy because due to B2 mediated vasodilatory action, it does not interfere with placental circulation [methoxamine, mephetermine and other selective a1 agonists can cause placental vasoconstriction and compromise fetal circulation]. SYMPATHOLYTIC DRUGS These drugs may act by blocking alpha and/or Beta-adrenergic receptors. 1. ALPHA BLOCKERS a. Nonselective Alpha-Blockers Phenoxybenzamine is an irreversible antagonist whereas phentolamine and tolazoline are reversible blockers of a1 and a2, receptors. These agents result in vasodilation and postural hypotension (due to antagonism of vasoconstrictor a, receptors). Reflex increase in sympathetic discharge and increased sympathetic outflow (due to blockade of a, receptors) are responsible for marked tachycardia seen with the use of these agents. Use of these drugs before adrenaline results in vasomotor reversal of Dale. Intravenous injection of adrenaline normally causes increase in blood pressure (a effect) followed by prolonged fall (B, effect). If it is administered after giving a blockers, only fall in BP is seen (vasomotor reversal of Dale). Phenoxybenzamine is used to prevent hypertensive episodes during operative manipulation of tumor in pheochromocytoma. Phentolamine and tolazoline are preferred agents for the treatment of hypertensive crisis in clonidine withdrawal and cheese reaction. b. Selective alpha1 -Blockers These drugs (prazosin, terazosin, doxazosin and alfuzosin) cause decrease in blood pressure with lesser tachycardia than non selective blockers (due to lack of a2 blocking action, sympathetic outflow is not increased). Selective a1, blockers have favorable effect on lipid profile (increase HDL and decrease LDL and TG) Due to relaxation of smooth muscle in the neck of urinary bladder and prostatic urethra, urinary flow is improved by these drugs. Therefore, selective a1 blockers are drugs of choice for patients with hypertension and benign hyperplasia of prostate (BHP). Prazosin (and other a, blockers) are useful for the treatment of scorpion sting. Major adverse effect of these drugs is postural hypotension. It is seen with first few doses or on dose escalation (First dose effect). If used continuously, tolerance develops to this adverse effect. Inhibition of ejaculation is another side effect of these agents. Tamsulosin and Silodosin selectively inhibits subtype of a receptors present in the prostate (a) without affecting those present in the blood vessels. These are therefore preferred for the treatment of BHP because of their reduced propensity to cause postural hypotension. These has been found to cause intra-operative 'floppy iris syndrome' during cataract surgery. Indoramin and urapadil are occasionally used for hypertensive emergencies.