Lecture 5: Adrenergic Drugs PDF

3rd Year Dental Students pharmacology Dr. Duaa Nidhal Adrenergic drugs Adrenergic drugs interact with receptors sensitive to norepinephrine and epinephrine. These receptors, known as adrenergic or adrenoceptors, can be activated by sympathomimetic dru...

3rd Year Dental Students pharmacology Dr. Duaa Nidhal Adrenergic drugs Adrenergic drugs interact with receptors sensitive to norepinephrine and epinephrine. These receptors, known as adrenergic or adrenoceptors, can be activated by sympathomimetic drugs and inhibited by sympatholytics. Sympathomimetics can either directly activate adrenergic receptors (direct- acting agonists) or indirectly influence them by enhancing norepinephrine release or blocking reuptake (indirect-acting agonists). Adrenergic neurons release norepinephrine (noradrenaline, NE) as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also 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. Neurotransmission at adrenergic neurons Neurotransmission involves the following steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap. 1- Synthesis of NE: In the process of synthesizing NE, Tyrosine is transported to the adrenergic neuron and converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase, which is a crucial, rate-limiting step. DOPA is then transformed into dopamine by aromatic L-amino acid decarboxylase in the presynaptic neuron (Figure 1). 2- Storage of NE in vesicles: After dopamine is synthesized, it is transported into synaptic vesicles by the amine transporter system (a process blocked by reserpine). Then, dopamine is hydroxylated to form NE with the help of the enzyme dopamine β-hydroxylase (figure 1). 1  3rd Year Dental Students pharmacology Dr. Duaa Nidhal 3- Release of norepinephrine: NE release is initiated when an action potential reaches the nerve junction, causing calcium ions to enter the neuron's cytoplasm. The increased calcium levels prompt synaptic vesicles to fuse with the cell membrane and undergo exocytosis, releasing their contents into the synapse (figure 1). Drugs such as guanethidine block this release. 4- Binding to receptors: NE is released from synaptic vesicles and can bind to postsynaptic receptors on effector organs or presynaptic receptors on nerve endings. Adrenergic receptors utilize both the cAMP second messenger system and the phosphatidylinositol cycle to transmit signals for various effects. NE also binds to presynaptic receptors, particularly the α2 subtype, which influences neurotransmitter release modulation. 5- 5- Removal of NE may be by: 1) Diffusing out of the synaptic space and entering the systemic circulation 2) Metabolising to inactive metabolites by catechol-O-methyltransferase (COMT) in the synaptic space 3) Undergoing reuptake back into the neuron. The reuptake by the neuronal membrane involves a sodium-chloride (Na+/Cl-)-dependent norepinephrine transporter (NET) that can be inhibited by tricyclic antidepressants (TCAs), 2 such as imipramine, by serotonin–norepinephrine reuptake inhibitors such as duloxetine, or by cocaine (figure 1). Reuptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of its effects. 6- Potential fates of recaptured NE: Once NE re-enters 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, NE can be oxidised by monoamine oxidase (MAO) present in neuronal mitochondria (figure 1). 2  3rd Year Dental Students pharmacology Dr. Duaa Nidhal figure 1: Synthesis and release of norepinephrine from the adrenergic neuron. MAO = monoamine oxidase, SNRI = serotonin norepinephrine reuptake inhibitor. Adrenergic receptors (adrenoceptors) In the sympathetic nervous system, there are different classes of adrenoceptors classified based on their responses to adrenergic agonists like epinephrine, norepinephrine, and isoproterenol. The two main families of these receptors are labeled as α and β, each consisting of several specific receptor subtypes. 1- α-Adrenoceptors: they respond weakly to the synthetic agonist isoproterenol but are sensitive to the natural catecholamines, epinephrine (EPI) and NE, 3  3rd Year Dental Students pharmacology Dr. Duaa Nidhal with EPI having the highest potency and affinity. These receptors are divided into α1 and α2 subgroups based on their affinities for agonists and blocking drugs. α1 receptors have a greater affinity for phenylephrine, while α2 receptors are selectively bound by clonidine, with minimal impact on α1 receptors. a- α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects, originally designated as αadrenergic, involving constriction of smooth muscle b- α2 Receptors: α2 receptors are primarily found on sympathetic presynaptic nerve endings and serve as important regulators of NE release. When stimulated by NE, they initiate feedback inhibition, reducing further NE release from the stimulated 3 adrenergic neuron. These receptors act as inhibitory autoreceptors in this context. α2 receptors are also located on presynaptic parasympathetic neurons, where NE can inhibit acetylcholine release, functioning as inhibitory heteroreceptors. c- Further subdivisions: The α1 and α2 receptor families have subtypes, such as α1A, α1B, α1C, α1D, α2A, α2B, and α2C. This classification is important for understanding drug selectivity. Tamsulosin, for example, is a selective α1A antagonist used for treating benign prostatic hyperplasia. It has fewer cardiovascular side effects because it specifically targets α1A receptors in the urinary tract and prostate, without affecting α1B receptors found in blood vessels. 2. β-Adrenoceptors (β-AR): β-AR exhibit distinct responses compared to α receptors. They strongly respond to isoproterenol and are less sensitive to epinephrine (Epi) and then to norepinephrine (NE). There are three major subtypes of β-ARs: β1, β2, and β3, based on their affinities for adrenergic compounds. β1 receptors equally favor Epi and NE, while β2 receptors have a higher preference for Epi over NE. Tissues rich in β2 receptors, like skeletal 4  3rd Year Dental Students pharmacology Dr. Duaa Nidhal muscle vasculature, are highly responsive to circulating Epi from the adrenal medulla. β3 receptors play a role in lipolysis and affect the bladder's detrusor muscle. Activation of any of these β receptors triggers adenylyl cyclase stimulation and an increase in intracellular cAMP levels. The main effects mediated by adrenoceptors are as follows: 1. Stimulation of α1 receptors primarily leads to vasoconstriction, especially in the skin and abdominal viscera, resulting in increased total peripheral resistance and blood pressure. 2. Activation of β1 receptors typically results in cardiac stimulation, including an increase in heart rate and contractility. 3. Stimulation of β2 receptors tends to produce vasodilation in skeletal muscle vascular beds and relaxation of smooth muscle. Figure 2: Major effects mediated by α- and β-adrenoceptors. Desensitisation of receptors: Continuous exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitisation. Many mechanisms have been suggested to explain this phenomenon such as: 5  3rd Year Dental Students pharmacology Dr. Duaa Nidhal 1- Sequestration of the receptors so that they are unavailable for interaction with the ligand. 2- Down-regulation, that is, a disappearance of the receptors either by destruction or by decreased synthesis. Catecholamines such as EPI, NE, isoproterenol, and dopamine share the following properties: 1. High potency: Catecholamines show the high potency in directly activating α or β receptors 2. Rapid inactivation: Catecholamines are metabolised by COMT postsynaptically and by MAO intraneuronally, as well as by COMT and MAO in the gut wall, and by MAO in the liver. Thus, catecholamines have only a brief period of action when given parenterally, and they are inactivated when administered orally. 3.Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most catecholamines have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. Noncatecholamines Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. These agents are poor substrates for MAO (an important route of metabolism) and, thus, show a prolonged duration of action. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. 6  3rd Year Dental Students pharmacology Dr. Duaa Nidhal Adrenergic agonists classification: Adrenergic agonists can be classified according to their mechanism of action to three types as demonstrated in table 1. Table 1: Summary about the adrenergic agonist compounds. 7  3rd Year Dental Students pharmacology Dr. Duaa Nidhal DIRECT-ACTING ADRENERGIC AGONISTS Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron. As a group, these agents are widely used clinically. Epinephrine Epi is one of the four catecholamines (Epi, NE, dopamine, and dobutamine) commonly used in therapy. The first three are naturally occurring neurotransmitters, and the latter is a synthetic compound. In the adrenal medulla, NE is methylated to yield Epi. On stimulation, the adrenal medulla releases about 80% Epi and 20% NE directly into the circulation. Epi interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are the strongest. Epinephrine actions: A- Cardiovascular: The major actions of Epi are on the cardiovascular system as It strengthens the contractility of the myocardium (positive inotrope: β1 action) and increases its rate of contraction (positive chronotrope: β1 action) hence cardiac output increases. 1- It activates β1 receptors on the kidney to cause renin release. Renin is an enzyme involved in the production of angiotensin II, a potent vasoconstrictor. 2- 2-Epi constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects). Renal blood flow is decreased. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure due to β2 receptor–mediated vasodilation in the skeletal muscle vascular bed 8  3rd Year Dental Students pharmacology Dr. Duaa Nidhal Figure 3: Cardiovascular effects of intravenous infusion of low doses of epinephrine. B- Respiratory: Epi causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action). It also inhibits the release of allergy mediators such as histamines from mast cells. C- Hyperglycemia: Epi has a significant hyperglycaemic effect because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect). D. Lipolysis: Epi initiates lipolysis through agonist activity on the β receptors of adipose tissue. Increased levels of cAMP stimulate a hormone-sensitive lipase, which hydrolyses triglycerides to free fatty acids and glycerol Therapeutic uses: 1- Epi is the preferred drug for treating acute asthma and anaphylactic shock due to type I hypersensitivity reactions. It acts rapidly (within minutes) to improve respiratory function when administered subcutaneously. However, for chronic asthma treatment, selective β2 agonists like albuterol are favored due to their longer duration of action and minimal cardiac stimulatory effects. 9  3rd Year Dental Students pharmacology Dr. Duaa Nidhal 2- Treating Cardiac arrest 3- In anaesthesia: Local anaesthetic solutions may contain low concentrations (for example, 1:100,000 parts) of Epi, which can greatly increase the duration of local anaesthesia by producing vasoconstriction at the site of injection. Pharmacokinetics: Main pharmacokinetics aspects were summarised in figure 4. Figure 4: Pharmacokinetics of epinephrine. CNS = central nervous system. Adverse effects: 1-It can cause anxiety, fear, tension and headache 2- It can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. 3- It can induce pulmonary oedema. 4- It can lead to tachycardia. 5-It can cause Hyperglycaemia and increment in blood pressure. 10  3rd Year Dental Students pharmacology Dr. Duaa Nidhal Norepinephrine Because NE is the neurotransmitter of adrenergic nerves, it should, theoretically, stimulate all types of adrenergic receptors. However, when administered in therapeutic doses, the α-adrenergic receptor is most affected. A- Cardiovascular actions: 1- Vasoconstriction: NE causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). Both systolic and diastolic blood pressures increase. [Note: NE causes greater vasoconstriction than Epi, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles. The weak β2 activity of NE also explains why it is not useful in the treatment of asthma or anaphylaxis.] 2- Baroreceptor reflex: NE raises blood pressure, activating baroreceptors and causing an increase in vagal activity. This vagal response results in reflex bradycardia, counteracting NE's heart effects. However, NE's positive inotropic effects remain unaffected. When atropine, a vagal blocker, is given before NE, the heart is stimulated by NE, leading to tachycardia. Therapeutic uses: NE is used to treat shock, because it increases vascular resistance and, therefore, increases blood pressure. It has no other clinically significant uses. Pharmacokinetics: NE is given IV for rapid onset of action. The duration of action is 1 to 2 minutes, following the end of the infusion. It is rapidly metabolised by MAO and COMT, and inactive metabolites are excreted in the urine. Adverse effects: These are similar to Epi. In addition, NE is a potent vasoconstrictor and may cause blanching and sloughing of skin along an injected vein. If extravasation (leakage of drug from the vessel into tissues surrounding the injection site) occurs, it can cause tissue necrosis. It should 11  3rd Year Dental Students pharmacology Dr. Duaa Nidhal not be administered in peripheral veins, if possible. Impaired circulation from NE may be treated with the α receptor antagonist phentolamine. Isoproterenol: It is a direct-acting synthetic catecholamine that stimulates both β1- and β2- adrenergic receptors. Because of its nonselectivity, it is rarely used therapeutically. Dopamine It is the immediate metabolic precursor of NE, occurs naturally in the CNS. Dopamine can activate α- and β-adrenergic receptors but this depends on the dopamine dose, for example: At higher doses, it causes vasoconstriction by activating α1 receptors, whereas at lower doses, it stimulates β1 cardiac receptors. In addition, D1 and D2 dopaminergic receptors, distinct from the α- and β-adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation. Actions a. Cardiovascular: Dopamine exerts a stimulatory effect on the β1 receptors of the heart, having both positive inotropic and chronotropic effects. At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction. b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera. Therapeutic uses: Dopamine is the drug of choice for cardiogenic and septic shock and is given by continuous infusion. It raises blood pressure by stimulating the β1 receptors on the heart to increase cardiac output and α1 receptors on blood vessels to increase total peripheral resistance. In addition, it enhances perfusion to the kidney and splanchnic areas. Increased blood flow to the kidney enhances the glomerular filtration rate and causes diuresis. In 12  3rd Year Dental Students pharmacology Dr. Duaa Nidhal this regard, dopamine is far superior to NE, which diminishes blood supply to the kidney and may cause renal shutdown. It is also used to treat hypotension and severe heart failure. Adverse effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolised by MAO or COMT, and its adverse effects (nausea, hypertension, and arrhythmias) are, therefore, short-lived. There are more adrenergic agonist drugs that can be used in different medical situation to save peoples’ life. The most important ones are summarised in table 2. Table 2: A summary about the direct-acting adrenergic agonists drugs 13  3rd Year Dental Students pharmacology Dr. Duaa Nidhal INDIRECT-ACTING ADRENERGIC AGONISTS Indirect-acting adrenergic agonists (IAAA) cause the release, inhibit the reuptake, or inhibit the degradation of EPI or NE. They potentiate the effects of Epi or NE produced endogenously, but do not directly affect postsynaptic receptors. Indirect-acting adrenergic agonists properties are summarised in table 3. Table 3: Properties of indirect-acting adrenergic agonists. Mixed- Acting Agonists: Ephedrine and pseudoephedrine are adrenergic drugs with dual actions. They not only release stored NE and directly stimulate both α and β receptors but also produce a range of adrenergic effects similar to Epi, albeit less potent. Their extended duration of action is due to the fact that they are not catechols and are not efficiently broken down by enzymes like COMT and MAO. 14  3rd Year Dental Students pharmacology Dr. Duaa Nidhal Both these drugs are effectively absorbed when taken orally and can enter the central nervous system (CNS). However, pseudoephedrine has fewer effects on the CNS. Ephedrine is primarily excreted in urine without significant changes, while pseudoephedrine undergoes incomplete hepatic metabolism before being eliminated through urine. Ephedrine can raise blood pressure by causing blood vessels to constrict and stimulating the heart, making it a potential treatment for low blood pressure. It also relaxes the bronchi, although it is less potent and acts more slowly than Epi. Ephedrine also mildly stimulates the CNS, promoting alertness, reducing fatigue, and preventing sleep, in addition to enhancing athletic performance. It's worth noting that the clinical use of ephedrine is on the decline because better and safer agents with fewer side effects are now available. Ephedrine- containing herbal supplements have been banned by the U.S. FDA due to the risk of life-threatening cardiovascular reactions. Pseudoephedrine is mainly used orally to alleviate nasal and sinus congestion but has also been illicitly used in the production of methamphetamine. As a result, products containing pseudoephedrine are subject to restrictions and must be kept behind the sales counter in the United States. 15