Autonomic Drugs Chapter 6 PDF

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 6 ADRENERGIC AGONISTS ...

Autonomic Drugs UNIT 2- DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHAPTERS 3, 4, 5, 6, & 7 © 2022-2024, Dr. Susan Wrenn, All rights reserved Whalen, K., Lerchenfeldt, S., Giordano, C. (2023). Lippincott  Chapter 6 ADRENERGIC AGONISTS  Adrenergic drugs affect receptors that are stimulated by norepinephrine (noradrenaline) or epinephrine (adrenaline). Overview Drugs that activate adrenergic receptors are termed sympathomimetics. Direct-acting agonists directly activate adrenergic receptors Indirect-acting agonists act indirectly by enhancing release or blocking reuptake of norepinephrine Drugs that block activation of The Adrenergic Neuron ◦ Adrenergic neurons release norepinephrine as the primary neurotransmitter. ◦ These neurons are found in the central nervous system (CNS) and in the sympathetic nervous system where they serve as links between ganglia and the effector organs. ◦ Adrenergic drugs act on adrenergic receptors, located either presynaptically on the neuron or postsynaptically on the effector organ. The Adrenergic Neuron Neurotransmission at adrenergic neurons 6 sequential steps: 1. Synthesis of Norepinephrine 2. Storage 3. Release 4. Binding to receptors 5. Removal of norepinephrine 6. Potential fates of recaptured norepinephrine (including metabolism) The Adrenergic Neuron Neurotransmission at adrenergic neurons 1. Synthesis of norepinephrine ◦ Tyrosine is transported by a carrier into the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. ◦ This is the rate-limiting step in the formation of norepinephrine. ◦ DOPA is then decarboxylated by the enzyme aromatic l-amino acid decarboxylase to form dopamine in the presynaptic neuron. Tyrosine DOPA Dopamin e The Adrenergic Neuron Neurotransmission at adrenergic neurons 2. Storage of norepinephrine in vesicles ◦ Dopamine is transported into synaptic vesicles. ◦ Next, dopamine is hydroxylated to form norepinephrine by the enzyme dopamine β- hydroxylase. Dopamine Norepinephrine The Adrenergic Neuron Neurotransmission at adrenergic neurons 3. Release of norepinephrine ◦ An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. ◦ The increase in calcium causes synaptic vesicles to fuse with the cell membrane and to undergo exocytosis and expel their contents into the synapse. The Adrenergic Neuron Neurotransmission at adrenergic neurons 4. Binding to receptors ◦ Norepinephrine released from the synaptic vesicles diffuses into the synaptic space and binds to postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. ◦ Binding of norepinephrine to receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. ◦ Norepinephrine also binds to presynaptic receptors (mainly α2 subtype) that modulate the release of the neurotransmitter. The Adrenergic Neuron Neurotransmission at adrenergic neurons 5. Removal of norepinephrine ◦ Norepinephrine may 1. Diffuse out of the synaptic space and enter the systemic circulation 2. Be metabolized to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space, or 3. Undergo reuptake back into the neuron ◦ Reuptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of its effects. The Adrenergic Neuron Neurotransmission at adrenergic neurons 6. Potential fates of recaptured norepinephrine ◦ Once norepinephrine reenters the adrenergic neuron, it may be taken up into synaptic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool in the cytoplasm. ◦ Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The Adrenergic Neuron Adrenergic receptors (adrenoceptors) 2 main families- α and β ◦ α-Adrenoceptors ◦ Weak response to isoproterenol (synthetic) ◦ Responsive to epinephrine and norepinephrine, naturally occurring catecholamines ◦ α1 receptors ◦ Present on the postsynaptic membrane of effector organs ◦ Activate second messengers ◦ Cause constriction of smooth muscle The Adrenergic Neuron Adrenergic receptors (adrenoceptors) 2 main families- α and β ◦ α-Adrenoceptors ◦ α2 receptors ◦ Present on sympathetic presynaptic nerve endings ◦ Control the release of norepinephrine ◦ Stimulation of α2 receptors by norepinephrine inhibits the further release of norepinephrine ◦ Binding at α2 receptors decreases intracellular cAMP ◦ Also found on parasympathetic presynaptic nerve endings- inhibit the release of ACh ◦ Further subdivisions ◦ Useful for more selective drug targets ◦ Example: Tamsulosin- α1A antagonist for BPH The Adrenergic Neuron Adrenergic receptors (adrenoceptors) 2 main families- α and β ◦ β-Adrenoceptors ◦ Strong response to isoproterenol (synthetic) ◦ Less responsive to epinephrine and norepinephrine (natural) ◦ 3 types of β-receptors ◦ β1 – equal affinity for epinephrine and norepinephrine ◦ β2 – higher affinity for epinephrine ◦ β3 –? ◦ Binding of a neurotransmitter at any of the 3 types results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell The Adrenergic Neuron Adrenergic receptors (adrenoceptors) ◦ Distribution of receptors ◦ Adrenergically innervated organs and tissues usually have a predominant type of receptor ◦ Characteristic responses mediated by adrenoceptors ◦ In general- stimulation of α1 receptors produces vasoconstriction and increase in total peripheral resistance and blood pressure ◦ Stimulation of β1 receptors causes cardiac stimulation (increase in heart rate and contractility) (1=heart) ◦ Stimulation of β2 receptors produces vasodilation (skeletal muscle vascular beds) and bronchial smooth muscle relaxation (2=lungs) ◦ β3 receptors are involved in lipolysis (found in adipose tissue) and have affects on the bladder The Adrenergic Neuron Adrenergic receptors (adrenoceptors) ◦ Desensitization of receptors ◦ Prolonged exposure to the catecholamines reduces the responsiveness of these receptors- desensitization ◦ 3 mechanisms involved 1. Sequestration of the receptors make them unavailable for interaction 2. Down-regulation – disappearance by destruction or decreased synthesis 3. Inability to couple to G-protein due to phosphorylation on the cytoplasmic side The Adrenergic Neuron Characteristics of Adrenergic Agonists Catecholamines ◦ Sympathomimetic amines that contain the 3,4- dihydroxybenzene group and have the following characteristics: ◦ Show the highest potency in directly activating α or β receptors ◦ Are metabolized by COMT and MAO- have only a brief period of action when given parenterally and are completely inactivated if given orally ◦ Are polar and do not cross the CNS well. Have few CNS effects. Noncatecholamines ◦ Have longer half-lives- prolonged duration of action ◦ Not inactivated by COMT, poor substrates for MAO ◦ Increased lipid solubility permits greater access to the CNS Characteristics of Adrenergic Agonists Substitution on the amine nitrogen ◦ The nature of the substituent on the amine nitrogen is important for determining β selectivity Mechanism of action of adrenergic agonists ◦ Direct-acting agonists- act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of epinephrine from the adrenal medulla. ◦ Indirect-acting agonists- may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron ◦ Mixed-action agonists- both stimulate adrenoceptors directly and enhance release of norepinephrine from the adrenergic neuron Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine – Nasal spray, injection, inhalation ◦ In the adrenal medulla, norepinephrine is methylated to yield epinephrine. ◦ On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine ◦ Epinephrine interacts with both α and β receptors. ◦ A low doses, β effects (vasodilation) on the vascular system predominate ◦ At high doses, α effects (vasoconstriction) are the strongest Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine ◦ Actions ◦ Cardiovascular- primary site of action ◦ Strengthens contractility of the myocardium (positive inotrope: β1)(↑ force) ◦ Increases rate of contraction (positive chronotrope: β1)(↑ rate) ◦ Overall, cardiac output increases and oxygen demands on the myocardium increase ◦ β1 receptors cause the kidneys to release renin, which leads to production of angiotensin II, a potent vasoconstrictor and results in decreased renal blood flow ◦ Constricts arterioles in the skin, mucous membranes, and viscera and dilates vessels going to the liver and skeletal muscles ◦ Cumulative effect is an increase in systolic blood pressure and a slight decrease in diastolic pressure Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine ◦ Actions ◦ Respiratory ◦ Powerful bronchodilation ◦ Inhibits the release of allergic mediators such as histamine from mast cells ◦ Hyperglycemia ◦ Produces significant hyperglycemic effect through increased glycogenolysis, increased release of glucagon, and decreased release of insulin Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine ◦ Therapeutic Uses ◦ Bronchospasm ◦ The primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function. ◦ Drug of choice for anaphylactic shock ◦ Anaphylactic shock ◦ Drug of choice for type I hypersensitivity reactions ◦ Cardiac arrest ◦ May be used to restore cardiac rhythm in patients with cardiac arrest (ACLS) ◦ Local anesthesia ◦ Increases the duration of local anesthesia by producing vasoconstriction at the site of injection, reduces systemic absorption of the anesthetic, and promotes local hemostasis ◦ Intraocular surgery ◦ Used to induce and maintain mydriasis during surgery Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine ◦ Pharmacokinetics ◦ Rapid onset but brief duration of action due to rapid degradation ◦ Preferred route in outpatient setting is intramuscular due to rapid absorption ◦ In emergencies, it may be given IV (fastest) or by intraosseous, subcutaneous, endotracheal tube, or inhalation routes ◦ Rapidly metabolized by MAO and COMT Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Epinephrine ◦ Adverse effects ◦ Can produce CNS effects such as anxiety, fear, tension, headache and tremor ◦ Can trigger cardiac arrythmias and angina, especially in patients with coronary artery disease or hypertension ◦ Can induce pulmonary edema ◦ Patients with hyperthyroidism may have enhanced response due to increased receptors ◦ Hyperglycemia may occur and insulin may be required ◦ Tachycardia may occur with coadministration of inhaled anesthetics ◦ Increased blood pressure and peripheral vascular resistance may occur when given with nonselective β-blockers Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Norepinephrine- injection ◦ α-adrenergic receptor is most affected ◦ Cardiovascular actions ◦ Vasoconstriction ◦ Causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effects) (little to no β2 activity) ◦ Both systolic and diastolic pressures increase ◦ Baroreceptor reflex ◦ Increases blood pressure, which stimulates the baroreceptors, which creates a rise in vagal activity ◦ Increased vagal activity produces a reflex bradycardia, which is sufficient to counteract the local action of norepinephrine on the heart. (lowers rate, not force) Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Norepinephrine ◦ Therapeutic uses ◦ Used to treat shock (septic shock) because it increases vascular resistance and, therefore, increases blood pressure ◦ Pharmacokinetics ◦ Given IV for rapid onset of action- duration of action is 1-2 minutes- given as continuous infusion ◦ Rapidly metabolized by MAO and COMT ◦ Adverse Effects ◦ Similar to epinephrine ◦ Potent vasoconstrictor- may cause blanching and sloughing of skin along an injected vein ◦ Extravasation can cause tissue necrosis ◦ Avoid peripheral veins- central line preferred ◦ Impaired circulation caused by norepinephrine may be treated with phentolamine Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Dopamine- injection ◦ Immediate metabolic precursor of norepinephrine and occurs naturally in the CNS and adrenal medulla ◦ Can activate both α- and β-adrenergic receptors ◦ At higher doses, causes vasoconstriction by activating α1 receptors ◦ At lower doses, it stimulates β1 cardiac receptors ◦ Has additional actions at D1 and D2 dopaminergic receptors which are found in the peripheral mesenteric and renal vascular beds and cause vasodilation. D2 receptors located on presynaptic adrenergic neurons interfere with norepinephrine release. ◦ Actions ◦ Stimulates β1 cardiac receptors, both inotropic and chronotropic ◦ Dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Dopamine ◦ Therapeutic uses ◦ Can be used for cardiogenic and septic shock and is given by continuous infusion ◦ Raises blood pressure by stimulating β1 receptors on the heart to increase cardiac output and α1 receptors on blood vessels to increase total peripheral resistance. ◦ Enhances perfusion to the kidney and splanchnic areas ◦ Increased blood flow to the kidney enhances the glomerular filtration rate and causes diuresis ◦ Used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments ◦ Adverse effects ◦ Produces same effects as sympathetic stimulation ◦ Rapidly metabolized by MAO and COMT- adverse effects are short lived Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Phenylephrine- nasal, ophthalmic, injection, oral, topical ◦ Synthetic agonist ◦ Binds primarily to α1 receptors ◦ Vasoconstrictor that raises both systolic and diastolic blood pressures ◦ Induces reflex bradycardia- useful for the treatment of paroxysmal supraventricular tachycardia* ◦ Used to treat hypotension in hospitalized or surgical patients (especially those with a rapid heart rate) ◦ Also acts as a nasal decongestant (poor) an is used in ophthalmic preparations for mydriasis Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Naphazoline (O), oxymetazoline (O, N, T), and tetrahydrozoline (O, N) ◦ Synthetic agonists ◦ Stimulate both α1 and α2 receptors ◦ Found in OTC nasal sprays and ophthalmic drops ◦ Directly stimulate α receptors on blood vessels supplying the nasal mucosa and conjunctiva, thereby producing vasoconstriction and decreasing congestion. ◦ Oxymetazoline is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. ◦ Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur (Rhinitis medicamentosa) Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Midodrine- oral ◦ Selective α1 agonist ◦ Acts in the periphery to increase arterial and venous tone ◦ Used in the treatment of orthostatic hypotension ◦ Given 3 times daily at 3–4-hour intervals- avoid within 4 hours of bedtime to avoid supine hypertension Direct-acting Adrenergic Agonists Clonidine (and guanfacine)- oral ◦ α2 agonist ◦ Used in the treatment of hypertension ◦ Also used to minimize symptoms of withdrawal from opiates, tobacco smoking, and benzodiazepines ◦ Both clonidine and guanfacine are useful in the management of attention deficit hyperactivity disorder (ADHD) ◦ Acts centrally on presynaptic α2 receptors to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery ◦ Abrupt discontinuation must be avoided to prevent rebound hypertension Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Dobutamine- injection ◦ Synthetic catecholamine ◦ Primarily a β1 receptor agonist ◦ Increases heart rate and cardiac output with few vascular effects ◦ Used to increase cardiac output in acute heart failure ◦ Does not elevate oxygen demands of the myocardium as much as other sympathomimetics ◦ Increases atrioventricular (AV) conduction- use with caution in atrial fibrillation Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Isoproterenol- injection ◦ Synthetic catecholamine ◦ Stimulates both β1 and β2 receptors ◦ Nonselectivity is a disadvantage- rarely used ◦ Actions ◦ Produces intense stimulation of the heart, increasing heart rate, contractility, and cardiac output ◦ Dilates the arterioles of skeletal muscle, resulting in decreased peripheral resistance ◦ May decrease systolic blood pressure slightly, but greatly reduces mean arterial and diastolic blood pressures Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Albuterol (I, O), levalbuterol (I), metaproterenol, and terbutaline (Inj, O) ◦ Short-acting β2 agonists (SABAs) ◦ Albuterol and levalbuterol are the SABA of choice for the management of acute bronchospasm ◦ Effects last about 3 hours ◦ Injectable terbutaline is used off-label as a uterine relaxant to suppress premature labor and cannot be used more than 72 hours ◦ The most common side effect is tremor ◦ Other adverse effects are restlessness, apprehension, and anxiety ◦ Monoamine oxidase inhibitors (MAOIs) increase the risk of adverse cardiovascular effects and concomitant use should be avoided. Direct-acting Adrenergic Agonists Bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron Formoterol, indacaterol, olodaterol, and salmeterol ◦ Long-acting β2 agonists (LABAs) ◦ Used for the management of respiratory disorders such as asthma and chronic obstructive pulmonary disease ◦ Effects last about 12 hours ◦ Salmeterol has a delayed onset of action ◦ Not recommended as monotherapy for asthma because they have been shown to increase the risk of asthma-related deaths Mirabegron and vibegron- oral ◦ β3 agonists that relax the detrusor smooth muscle and increases bladder capacity ◦ Used for overactive bladder ◦ Mirabegron may increase blood pressure- do not use in patients with uncontrolled hypertension Indirect-acting Adrenergic Agonists Cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine. Potentiate the effects of endogenous epi or norepi, but do not directly affect postsynaptic receptors. Amphetamine- oral ◦ Has central stimulatory action- used in ADHD ◦ Can increase blood pressure significantly by α1 agonist activity on the vasculature and β1 stimulatory effects on the heart ◦ Actions are mediated through the increase on nonvesicular release of norepinephrine and dopamine ◦ Also inhibits MAO Tyramine ◦ Not a drug, but is found in fermented foods ◦ Normally oxidized by MAO- causes serious vasopressor episodes in patients taking MAOIs Indirect-acting Adrenergic Agonists Cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine. Potentiate the effects of endogenous epi or norepi, but do not directly affect postsynaptic receptors. Cocaine ◦ Blocks the sodium-chloride (Na+/Cl-)-dependent norepinephrine transporter required for cellular uptake of norepinephrine into the adrenergic neuron. ◦ This results in the accumulation of norepinephrine in the synaptic space and increased sympathetic activity. ◦ Can increase blood pressure by α1 agonist activity and β1 stimulatory effects. ◦ Small doses of catecholamines produce greatly magnified effects and prolonged duration of action in an individual taking cocaine. Mixed-action Adrenergic Agonists Enhance release of norepinephrine and directly stimulate adrenergic receptors ◦ Less potent than epinephrine ◦ Poor substrates for COMT and MAO, have a long duration of action ◦ Excellent oral absorption and penetrate the CNS Ephedrine – injection, oral ◦ Raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation ◦ Indicated in anesthesia-induced hypotension ◦ Produces bronchodilation, but slower and less potent than other agents ◦ Produces mild CNS stimulation- increases alertness, decreases fatigue, and prevents sleep ◦ Improves athletic performance, but not safe Pseudoephedrine- oral ◦ Used for nasal and sinus congestion- OTC ◦ Fewer CNS effects ◦ Sales limited due to use in production of methamphetamine