5-sympathomimetic-and-sympatholytic-drugs-2.pdf

# Introduction to sympathomimetic and sympatholytic drugs This section introduces drugs that modulate the autonomic nervous system by targeting adrenergic receptors, classifying them as either sympathomimetic (enhancing sympathetic effects) or sympatholytic (blocking sympathetic effects) [2](#page=2). ### 1.1 The sympathetic nervous system The sympathetic nervous system, often referred to as the "fight or flight" system, utilizes norepinephrine (NE) as its primary neurotransmitter. Drugs affecting adrenergic receptors can either mimic or block the actions of NE and epinephrine (Epi) [3](#page=3). #### 1.1.1 Sympathetic neuron network structure Sympathetic neurons are organized into a network. A preganglionic neuron synapses with a postganglionic neuron within a ganglion. Both the preganglionic and postganglionic neurons release acetylcholine (ACh) at the ganglion, which acts on nicotinic receptors. Adrenergic receptors are located at the junction between the postganglionic neuron and the effector organ, where NE is released. Notably, eccrine sweat glands receive sympathetic stimulation via muscarinic receptors, while the adrenal medulla and kidney are exclusively innervated by sympathetic nerves [4](#page=4). #### 1.1.2 Neurotransmission in the sympathetic neuron The synthesis and release of NE in sympathetic neurons involve several steps: 1. Tyrosine uptake into the neuron [5](#page=5). 2. Synthesis of L-DOPA [5](#page=5). 3. Synthesis and storage of dopamine (DA) in vesicles, which is then converted to NE [5](#page=5). 4. Arrival of an action potential, leading to calcium ion ($Ca^{2+}$) entry into the cell [5](#page=5). 5. Release of NE into the synaptic cleft [5](#page=5). 6. Interaction with adrenergic receptors on the effector organ [5](#page=5). 7. Termination of NE's effect through reuptake mechanisms (uptake-1 or uptake-2) [5](#page=5). Uptake-1 is inhibited by drugs like cocaine and tricyclic antidepressants (TCAs), while uptake-2 is inhibited by corticosteroids. NE is metabolized by monoamine oxidase A (MAO-A) within the presynaptic neuron and by catechol-O-methyltransferase (COMT) in surrounding tissues [5](#page=5). ### 1.2 Adrenergic receptors Adrenergic receptors are classified into alpha ($\alpha$) and beta ($\beta$) subtypes. These receptors are G protein-coupled receptors [6](#page=6): * $\alpha$1 receptors are coupled to Gq proteins and mediate vasoconstriction [6](#page=6). * $\alpha$2 receptors are coupled to Gi proteins and act as autoreceptors, inhibiting neurotransmitter release [6](#page=6). * $\beta$1, $\beta$2, and $\beta$3 receptors are coupled to Gs proteins and generally mediate stimulation and relaxation [6](#page=6). $\alpha$ receptors are primarily affected by NE and Epi, while $\beta$ receptors are affected by Epi and synthetic agonists like isoproterenol. Different subtypes are distributed in various tissues and elicit distinct physiological responses [6](#page=6): * $\alpha$1 receptors are found in blood vessels, the internal sphincter of the bladder, and the ductus deferens [6](#page=6). * $\beta$1 receptors are located in the heart and kidneys (involved in renin release) [6](#page=6). * $\beta$2 receptors are present in the bronchi, blood vessels, and uterus [6](#page=6). * $\beta$3 receptors are located in the detrusor muscle of the bladder [6](#page=6). #### 1.2.1 Adrenergic effects The activation of specific adrenergic receptor subtypes results in various physiological effects: * **$\alpha$1:** Causes mydriasis (dilation of the pupil via the radial muscle), vasoconstriction, pilomotor erection (goosebumps), and ejaculation [7](#page=7). * **$\alpha$2:** Inhibits NE release and insulin release [7](#page=7). * **$\beta$1:** Increases myocardial contractility (+ inotropy), heart rate (+ chronotropy), and conduction velocity (+ dromotropy). It also increases renin synthesis and contributes to lipolysis (in conjunction with $\beta$3) [7](#page=7). * **$\beta$2:** Promotes bronchodilation and vasodilation, causes uterine relaxation, and stimulates glycogenolysis [7](#page=7). * **D1 receptors:** Relax renal blood vessels [7](#page=7). #### 1.2.2 Receptor desensitization Continuous and prolonged exposure to adrenergic agonists or antagonists can rapidly alter receptor activity. Agonists tend to decrease the number of receptors through down-regulation, while antagonists can increase receptor numbers via up-regulation [8](#page=8). > **Tip:** Due to receptor desensitization, it is crucial that patients do not abruptly stop taking these medications without medical advice [8](#page=8). --- # Sympathomimetic drugs: direct, indirect, and mixed acting Sympathomimetic drugs enhance adrenergic activity by interacting with the sympathetic nervous system [9](#page=9). ### 2.1 Classification of sympathomimetic drugs Sympathomimetic drugs are classified into three main categories based on their mechanism of action [9](#page=9): * **Direct-acting agonists:** These drugs mimic the effects of endogenous neurotransmitters like epinephrine (Epi) and norepinephrine (NE) by binding directly to adrenergic receptors [10](#page=10). * **Indirect-acting agonists:** These drugs do not bind directly to adrenergic receptors. Instead, they produce their effects by increasing the levels of endogenous neurotransmitters, primarily NE, in the synaptic cleft [21](#page=21). * **Mixed-action agonists:** These drugs possess a dual mechanism, both directly stimulating adrenergic receptors and indirectly increasing the release of NE [26](#page=26). ### 2.2 Direct-acting agonists Direct-acting agonists bind to adrenergic receptors, thereby activating the sympathetic nervous system. They are widely utilized in clinical practice [10](#page=10). #### 2.2.1 Catecholamines Catecholamines, such as dopamine (DA), NE, Epi, and isoproterenol, are endogenous or synthetic compounds that are rapidly degraded by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) enzymes. They typically do not cross the blood-brain barrier (CNS) [9](#page=9). * **Adrenaline (Epinephrine)** * Synthesized in the adrenal medulla within chromaffin cells [11](#page=11). * Released alongside NE when stimulated [11](#page=11). * Acts on all adrenergic receptors (α and β) [11](#page=11). * At low doses, β effects are dominant, while at high doses, α effects become more prominent [11](#page=11). * Administered via intramuscular (IM), intravenous (IV), and subcutaneous (SC) routes, with a rapid onset of action [11](#page=11). * Metabolized by MAO to vanillylmandelic acid (VMA) and by COMT to metanephrine [11](#page=11). * **Effects:** Vasoconstriction, increased renin secretion, increased peripheral resistance, heart stimulation, bronchodilation, relaxation of bladder detrusor muscle, contraction of internal bladder sphincter, decreased gastrointestinal (GI) motility, lipolysis, hyperglycemia, and vasodilation in skeletal muscle [12](#page=12). * **Clinical Use:** Bronchodilation in anaphylactic shock, cardiac arrest, prolonging the duration of action (DOA) in local anesthesia, and intraocular surgery [12](#page=12). * **Side Effects:** Cardiac arrhythmias, increased afterload (leading to pulmonary edema), potentiated effects in hyperthyroidism, increased glucose levels (caution in diabetics), and excessive α activity when combined with non-selective beta blockers [13](#page=13). * **Noradrenaline (Norepinephrine)** * Primarily affects α adrenergic receptors, with β activity seen at high doses [14](#page=14). * Administered intravenously only [14](#page=14). * Degraded by COMT and MAO [14](#page=14). * **Effects:** Potent vasoconstriction (more than adrenaline), and reflex bradycardia mediated by baroreceptors [14](#page=14). * **Clinical Use:** Treatment of shock and hypotension. It is ineffective for bronchospasm and anaphylactic shock [14](#page=14). * **Side Effects:** Similar to adrenaline. Extravasation outside the vein can cause necrosis. Its effects can be antagonized by phentolamine or nitroglycerin [14](#page=14). * **Isoproterenol (Isoprenaline)** * Stimulates both β1 and β2 adrenergic receptors [15](#page=15). * **Effects:** Cardiac stimulant, relaxation of skeletal muscle blood vessels, and bronchodilation [15](#page=15). * **Side Effects:** Similar to adrenaline via β receptor activation [15](#page=15). * **Clinical Use:** Hypovolemic shock, cardiogenic shock, septic shock, and congestive heart failure [15](#page=15). * **Dopamine (DA)** * Stimulates β1 receptors at low doses and α1 receptors at high doses [16](#page=16). * Primary effects mediated through D1 and D2 receptors [16](#page=16). * D1 receptors: Relax mesenteric and renal vessels, increasing blood supply [16](#page=16). * D2 receptors: Inhibit NE release from adrenergic presynaptic neurons [16](#page=16). * **Clinical Use:** Septic shock and cardiogenic shock [16](#page=16). * **Side Effects:** Overdose mimics sympathetic overstimulation, causing hypertension and nausea/vomiting (NV) [16](#page=16). * **Fenoldopam / Dobutamine** * **Fenoldopam:** A D1 receptor agonist used as a fast-acting vasodilator, particularly effective on coronary, renal, and mesenteric arteries. Side effects include headache, flushing, nausea, and tachycardia (due to hypotension) [17](#page=17). * **Dobutamine:** A β1 receptor agonist used to increase cardiac contractility (inotropy) and heart rate (chronotropy) in acute heart failure and post-cardiac surgery [17](#page=17). #### 2.2.2 Non-catecholamines Non-catecholamines are generally more lipophilic and can cross the CNS [9](#page=9). * **Oxymetazoline / Phenylephrine** * **Oxymetazoline:** Stimulates α1 and α2 receptors. It is used as a nasal decongestant. Systemic absorption can lead to irritability, headache, and sleep disturbances; it should not be used for more than three days [18](#page=18). * **Phenylephrine:** Stimulates α1 receptors, causing vasoconstriction. Used in hypotension treatment and as a nasal decongestant. It has no direct effect on the heart but can cause reflex bradycardia [18](#page=18). * **Midodrine / Mirabegron** * **Midodrine:** An α1 agonist that increases peripheral arterial and venous tone. Used to treat orthostatic hypotension [19](#page=19). * **Mirabegron:** A β3 agonist that relaxes the bladder detrusor muscle. Used to treat overactive bladder [19](#page=19). #### 2.2.3 Beta-2 Receptor Agonists * **Characteristics:** β2 receptors are predominantly found in the bronchi. Agonists of these receptors cause bronchodilation and are used in the management of asthma and chronic obstructive pulmonary disease (COPD) [20](#page=20). * **Classification:** * Short-acting β2 agonists (SABA): Useful for acute relief in crisis situations. Examples include Salbutamol, terbutaline, and metaproterenol. SABAs can also relax the uterus and are used to prevent preterm labor [20](#page=20). * Long-acting β2 agonists (LABA): Used for prophylaxis and maintenance therapy. Examples include Salmeterol, formoterol, and indacaterol [20](#page=20). * **Ritodrine:** Specifically used in obstetrics as a uterine relaxant to prevent preterm labor [20](#page=20). ### 2.3 Indirect-acting agonists Indirect-acting agonists exert their sympathomimetic effects by increasing the concentration of endogenous neurotransmitters, particularly norepinephrine, at the synapse, without directly binding to adrenergic receptors [21](#page=21). * **General Mechanism:** These drugs interfere with the reuptake or promote the release of neurotransmitters from presynaptic terminals [23](#page=23). * **Examples:** Amphetamines, cocaine, and tyramine are common indirect-acting sympathomimetics [21](#page=21). #### 2.3.1 Amphetamines * **Mechanism:** Increase the release of norepinephrine (NE) and dopamine (DA) from neuron axon terminals [22](#page=22). * **CNS Penetration:** They readily cross into the CNS, leading to potential abuse and addiction [22](#page=22). * **Effects:** Primarily mediated by increased levels of NE, DA, and serotonin (5-HT) [22](#page=22). * **Clinical Use:** Attention-deficit/hyperactivity disorder (ADHD), obesity, narcolepsy, and depression (off-label). Methylphenidate is a primary drug for ADHD treatment [22](#page=22). #### 2.3.2 Cocaine * **Mechanism:** Primarily blocks the reuptake of NE [23](#page=23). * **Historical Use:** Previously used as a local anesthetic [23](#page=23). * **Current Use:** Rarely used today, primarily in otolaryngology clinics [23](#page=23). * **Abuse Potential:** Frequently abused [23](#page=23). * **Effects:** Similar to amphetamines but with a shorter duration of action (DOA) [23](#page=23). #### 2.3.3 Tyramine * **Mechanism:** Causes sympathetic stimulation by inducing the release of NE from storage vesicles [24](#page=24). * **Clinical Significance:** Consumption of tyramine-rich foods by individuals taking MAO inhibitors (MAOIs) is risky due to the potential for a hypertensive crisis [24](#page=24). ### 2.4 Mixed-acting agonists Mixed-acting agonists possess a dual mechanism of action, simultaneously stimulating adrenergic receptors directly and enhancing the release of NE from presynaptic terminals [26](#page=26). * **Examples:** Ephedrine and pseudoephedrine are the primary mixed-acting sympathomimetics [26](#page=26). * **Absorption:** Complete absorption occurs with oral administration [26](#page=26). * **CNS Penetration:** They can cross into the CNS, with ephedrine having a greater CNS effect [26](#page=26). * **Effects:** Can increase attention and athletic performance. They are used to treat hypotension caused by anesthesia, act as nasal decongestants, and possess bronchodilator effects [26](#page=26). * **Pseudoephedrine Control:** Pseudoephedrine is a controlled substance due to its illicit use in the synthesis of methamphetamine [26](#page=26). --- # Sympatholytic drugs and their classifications Sympatholytic drugs, also known as adrenergic blockers or antagonists, function by binding to receptors and preventing the effects of sympathetic stimulation. They are categorized based on the specific receptors they target, including alpha-blockers, beta-blockers, and VMAT inhibitors, and are primarily utilized in the management of cardiovascular diseases [28](#page=28). ### 3.1 Alpha blockers Alpha blockers are classified according to their affinity for $\alpha$1 and $\alpha$2 receptors. $\alpha$1 receptors are predominantly located in blood vessels, and their antagonism leads to a decrease in blood pressure. These receptors are also present in the seminal tract, eye, skin, and bladder. $\alpha$2 receptors function as autoreceptors; their blockade results in stimulation. Alpha blockers can be selective for $\alpha$1 receptors or non-selective, affecting both $\alpha$1 and $\alpha$2 receptors. The clinical use of selective $\alpha$2 antagonists is limited [29](#page=29). #### 3.1.1 Alpha 1 selective blockers Selective antagonists of $\alpha$1 receptors are primarily used in the treatment of hypertension (HT) and urinary problems. Examples include Prazosin, terazosin, and doxazosin, which are employed as antihypertensives. Tamsulosin, alfuzosin, and silodosin are used to alleviate urinary difficulties associated with prostatic hyperplasia. Common side effects of $\alpha$1 blockers include reflex tachycardia, first-dose syncope, erection problems, nasal congestion, and loose iris syndrome [30](#page=30). #### 3.1.2 Non-selective alpha blockers Non-selective alpha blockers interact with both $\alpha$1 and $\alpha$2 receptors [31](#page=31). * **Phentolamine** is a competitive antagonist of both $\alpha$1 and $\alpha$2 receptors and is used in the diagnosis of pheochromocytoma and for hypertensive crises [31](#page=31). * **Phenoxybenzamine** binds irreversibly to $\alpha$1 and $\alpha$2 receptors and is used in the treatment of pheochromocytoma [31](#page=31). * **Tolazolin** is indicated for neonatal pulmonary hypertension [31](#page=31). Side effects of non-selective blockers are primarily due to $\alpha$1 blockade, but $\alpha$2 blockade can lead to an increase in norepinephrine (NE) levels, stimulating the heart via $\beta$1 receptors and causing evident reflex tachycardia [31](#page=31). #### 3.1.3 Alpha 2 blockers **Yohimbine** specifically blocks $\alpha$2 autoreceptors. Inhibition of these receptors increases NE levels, leading to sympathetic stimulation. It is used off-label as an aphrodisiac and may be beneficial in treating erectile dysfunction [32](#page=32). ### 3.2 Beta blockers Beta blockers antagonize the effects of epinephrine (Epi) by blocking $\beta$ receptors. Those with high $\beta$1 affinity are termed cardioselective. Non-selective blockers can cause a range of side effects. Some $\beta$-blockers exhibit partial agonist activity, meaning they have intrinsic sympathomimetic activity (ISA). A few agents affect both $\alpha$ and $\beta$ receptors [33](#page=33) [37](#page=37). Clinical applications of $\beta$-blockers are broad and include the treatment of hypertension, chronic heart failure (CHF), myocardial infarction (MI), angina, glaucoma, migraines, and hyperthyroidism. They do not typically cause postural hypotension and should not be discontinued abruptly [33](#page=33). > **Tip:** Sudden discontinuation of beta-blockers can lead to arrhythmias due to rebound sympathetic activity [34](#page=34). #### 3.2.1 Non-selective beta blockers **Propranolol** is the prototype non-selective $\beta$-blocker. It undergoes significant first-pass metabolism and can penetrate the central nervous system (CNS). Propranolol exerts negative inotropic and chronotropic effects, reducing cardiac output, workload, and myocardial oxygen demand. Its side effects include bronchoconstriction, arrhythmias upon sudden withdrawal, sexual problems, hypoglycemia, and central nervous system effects [34](#page=34). Other non-selective $\beta$-blockers include **Nadolol, timolol, and pindolol**. Timolol is useful in the chronic management of glaucoma, though pilocarpine is preferred for acute attacks. Unlike cholinergic drugs used for glaucoma, $\beta$-blockers do not impair the eye's focusing ability or pupil size. These drugs are contraindicated in patients with asthma and COPD due to the risk of bronchoconstriction. Pindolol is noted for having partial agonist activity [35](#page=35). #### 3.2.2 Beta 1 selective blockers $\beta$1-selective blockers are also known as cardioselective agents. Examples include **Atenolol, acebutolol, esmolol, nebivolol, metoprolol, bisoprolol, and betaxolol**. They are preferred antihypertensives for patients with asthma because they have less impact on respiratory function. These drugs are primary agents in the chronic treatment of stable angina. They also cause fewer disruptions to carbohydrate metabolism compared to non-selective blockers. Nebivolol has the additional benefit of increasing nitric oxide (NO) levels. Esmolol is characterized by its ester structure, which contributes to its short duration of action [36](#page=36). #### 3.2.3 Beta blockers with partial agonist activity (ISA positive) Agents with partial agonist activity, such as **Acebutolol and Pindolol**, possess intrinsic sympathomimetic activity (ISA). They tend to lower blood pressure less significantly than other $\beta$-blockers and also reduce HDL levels to a lesser extent. These drugs may be used in patients with moderate bradycardia as antihypertensives. However, they are not recommended for patients with chronic angina or arrhythmias and are not widely used in practice [37](#page=37). #### 3.2.4 Alpha and beta blockers **Labetalol and Carvedilol** are unique as they block both $\alpha$1 and $\beta$ receptors. Labetalol is particularly useful in treating pregnancy-induced hypertension (preeclampsia) and is a preferred agent for hypertensive emergencies. Carvedilol, along with bisoprolol and metoprolol, is a crucial component in the treatment of CHF, although they are not used during acute exacerbations. Common side effects include orthostatic hypotension and dizziness [38](#page=38). ### 3.3 VMAT inhibitors Vesicular monoamine transporter (VMAT) inhibitors reduce the levels of all monoamines by inhibiting the VMAT transporter [39](#page=39). * **Reserpine** lowers blood pressure by decreasing NE levels. Its side effects stem from the deficiency of other amine neurotransmitters, such as dopamine (DA) and serotonin (5-HT) [39](#page=39). * **Guanethidine and Guanadrel** are peripherally active drugs that also act as NE-depletors [39](#page=39). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Sympathomimetic drugs | These drugs increase adrenergic activity by mimicking the effects of norepinephrine and epinephrine at adrenergic receptors. | | Sympatholytic drugs | Also known as adrenergic blockers or antagonists, these drugs bind to adrenergic receptors and prevent their activation, thereby reducing sympathetic tone. | | Adrenergic receptors | Receptors in the sympathetic nervous system that bind to catecholamines like norepinephrine and epinephrine. They are classified into alpha (α) and beta (β) subtypes. | | Norepinephrine (NE) | A primary neurotransmitter of the sympathetic nervous system, synthesized in postganglionic neurons and released at the junction with effector organs. | | Epinephrine (Epi) | A hormone produced by the adrenal medulla that acts as a neurotransmitter in the sympathetic nervous system, affecting all adrenergic receptors. | | G proteins | Guanine nucleotide-binding proteins that act as signal transducers in cellular communication, coupling receptor activation to intracellular responses. | | Down-regulation | A cellular process where continuous exposure to an agonist leads to a decrease in the number of available receptors, reducing the cell's sensitivity to the agonist. | | Up-regulation | A cellular process where continuous exposure to an antagonist leads to an increase in the number of available receptors, enhancing the cell's sensitivity to agonists. | | Catecholamines | A group of monoamine-based neurotransmitters and hormones, including dopamine, norepinephrine, and epinephrine, which are degraded by MAO and COMT enzymes. | | Non-catecholamines | Drugs that are structurally different from catecholamines and are often lipophilic, allowing them to readily cross the blood-brain barrier and affect the central nervous system. | | Vasoconstriction | The narrowing of blood vessels, typically caused by the contraction of smooth muscle in their walls, leading to increased blood pressure and reduced blood flow. | | Bronchodilation | The widening of the airways in the lungs, which helps to improve airflow and is often achieved by relaxing the smooth muscles in the bronchial tubes. | | MAO (Monoamine Oxidase) | An enzyme responsible for the degradation of monoamine neurotransmitters like norepinephrine, serotonin, and dopamine. MAO-A specifically degrades NE. | | COMT (Catechol-O-Methyltransferase) | An enzyme that catalyzes the methylation of catecholamines and their metabolites, playing a role in their inactivation and metabolism. | | Baroreceptors | Sensory receptors located in the walls of blood vessels that detect changes in blood pressure, initiating reflex responses to maintain homeostasis. | | VMAT (Vesicular Monoamine Transporter) | A protein found in the membranes of synaptic vesicles that is responsible for transporting monoamine neurotransmitters from the cytoplasm into the vesicles for storage and release. | | Preeclampsia | A serious pregnancy complication characterized by high blood pressure and signs of damage to other organ systems, most often the liver and kidneys. | | Orthostatic hypotension | A form of low blood pressure that occurs upon standing up from a sitting or lying position, often leading to dizziness or lightheadedness. | | Pheochromocytoma | A rare tumor of the adrenal gland that produces excess hormones, leading to symptoms such as high blood pressure, headaches, and sweating. |