Autonomic Pharmacology Quick Reference
Parasympathetic vs Sympathetic overview
Parasympathetic Nervous System (PNS): Often termed "rest and digest" or "feed and breed" system. Primarily responsible for conserving energy and slowing down body functions. Activated during periods of calm and relaxation.
Neurotransmitter: Acetylcholine (ACh) is the primary neurotransmitter. It is released from both preganglionic and postganglionic parasympathetic nerve terminals.
Receptors: Postganglionic parasympathetic effects on target organs are primarily mediated by muscarinic cholinergic receptors.
Muscarinic Receptors (M1, M2, M3, M4, M5): These are G protein-coupled receptors. For instance, M2 receptors in the heart decrease heart rate, while M3 receptors in smooth muscle (e.g., GI, bladder, bronchi) cause contraction and glandular secretions (e.g., salivary, lacrimal).
Organ Effects: Decreased heart rate, increased gastrointestinal motility and secretion, bladder contraction, pupil constriction (miosis), increased salivation, and bronchial constriction.
Sympathetic Nervous System (SNS): Known as the "fight or flight" or "stress response" system. Prepares the body for immediate, vigorous activity in response to stress or danger.
Neurotransmitters:
Primary Postganglionic Transmitter: Norepinephrine (NE; also known as noradrenaline) is released from most postganglionic sympathetic nerve terminals.
Adrenal Medulla: Releases epinephrine (EPI; adrenaline) and NE directly into the bloodstream, acting as hormones.
Exception (Sweat Glands): While part of the sympathetic system, sweat glands are innervated by postganglionic sympathetic neurons that release acetylcholine (ACh), mediating their effects via muscarinic receptors.
Receptors: Effects are primarily mediated by adrenergic receptors (alpha and beta types) which bind NE and EPI.
Organ Effects: Increased heart rate and contractility, vasoconstriction in many vascular beds (e.g., skin, GI), vasodilation in skeletal muscle, bronchodilation, pupil dilation (mydriasis), glucose release from the liver, and decreased GI motility.
Key terms:
Cholinergic: Refers to physiological effects or drugs that mimic or affect acetylcholine. Often associated with parasympathetic stimulation (e.g., increased salivation, bradycardia).
Anticholinergic: Refers to drugs that block acetylcholine receptors, primarily muscarinic. Produces effects opposite to cholinergic stimulation (e.g., dry mouth, blurred vision, tachycardia).
Adrenergic: Refers to physiological effects or drugs that mimic or affect norepinephrine and epinephrine. Associated with sympathetic stimulation (e.g., increased heart rate, vasoconstriction).
Cholinergic and Anticholinergic Drugs
Cholinergic Drugs (Parasympathomimetics): These agents enhance the effects of acetylcholine, thereby stimulating parasympathetic responses (often described as "rest and digest" effects).
Direct-acting cholinergic agents: These drugs directly bind to and activate cholinergic receptors, predominantly muscarinic receptors (e.g., bethanechol, pilocarpine). Their effects tend to last longer compared to endogenous ACh because many are not readily hydrolyzed by acetylcholinesterase, or have a slower metabolism.
Examples: Bethanechol (stimulates bladder and GI smooth muscle), Pilocarpine (increases glandular secretions, used for glaucoma by causing miosis and improving aqueous humor outflow).
Indirect-acting parasympathomimetics (Cholinesterase Inhibitors): These drugs do not directly interact with ACh receptors. Instead, they inhibit the enzyme acetylcholinesterase (AChE), which is responsible for breaking down acetylcholine in the synaptic cleft. By inhibiting AChE, they increase the concentration and prolong the action of endogenous ACh at all cholinergic sites (nicotinic and muscarinic receptors at the neuromuscular junction, ganglia, and parasympathetic target organs).
Nonselective action: Because AChE is present throughout the nervous system, cholinesterase inhibitors are nonselective and affect all cholinergic synapses.
Prototype indirect-acting: Mestinon (pyridostigmine). It is a reversible cholinesterase inhibitor primarily used in the management of myasthenia gravis, where it improves muscle strength by increasing ACh at the neuromuscular junction. It is also used as a prophylactic or therapeutic agent in nerve gas exposure to protect AChE from irreversible binding.
Cholinesterase Inhibitors (Indirect-Acting Parasympathomimetics) – mechanism
Mechanism of Action: Cholinesterase inhibitors function by preventing the enzymatic breakdown of acetylcholine (ACh) by acetylcholinesterase (AChE). AChE is typically found in cholinergic synapses and hydrolyzes ACh into acetate and choline, thereby terminating its action. By inhibiting AChE, these drugs allow endogenous ACh to persist in the synaptic cleft for a longer duration and bind to both muscarinic and nicotinic receptors more effectively and repeatedly.
Effects: This prolonged presence of ACh enhances cholinergic signaling, amplifying parasympathetic effects throughout the body. The effects are systemic and broader than direct-acting agents, affecting:
Ganglia: Both sympathetic and parasympathetic ganglia (nicotinic receptors).
Neuromuscular Junction (NMJ): Nicotinic receptors on skeletal muscle, improving muscle contraction (as seen in myasthenia gravis).
Parasympathetic Organ Receptors: Muscarinic receptors on effector organs, producing classical rest-and-digest responses.
Common example: Mestinon (pyridostigmine), used for its reversible action to manage conditions like myasthenia gravis and as a protective agent against organophosphate nerve agents.
Cholinergic Crisis (SLUDGE) and Antidote
Cholinergic Crisis: This is a life-threatening condition resulting from excessive stimulation of muscarinic and, to some extent, nicotinic cholinergic receptors due to an overdose of cholinergic drugs (e.g., cholinesterase inhibitors) or exposure to organophosphate poisons. It represents a severe exaggeration of parasympathetic activity.
Clinical Manifestations (SLUDGE):
Salivation: Profuse drooling dueased salivary gland secretion (M3).
Lacrimation: Excessive tearing due to increased lacrimal gland secretion (M3).
Urination: Involuntary voiding due to bladder detrusor muscle contraction and sphincter relaxation (M3).
Diaphoresis/Diarrhea: Profuse sweating (sympathetic cholinergic M3 receptors) and increased GI motility leading to diarrhea (M3).
GI upset: Abdominal cramping, nausea, vomiting due to increased smooth muscle contraction and gastric secretions (M3).
Emesis: Vomiting.
Additional Symptoms: Bradycardia, miosis (pinpoint pupils), bronchoconstriction, and respiratory distress. At high nicotinic stimulation, muscle weakness, paralysis, and fasciculations can occur, eventually leading to respiratory failure.
Antidote for Cholinergic Crisis: The primary treatment involves addressing the underlying cause and administering specific antidotes.
Atropine: This is the competitive antagonist for muscarinic cholinergic receptors. It effectively blocks the excessive muscarinic effects of ACh, thereby reducing salivation, bronchorrhea, bradycardia, and GI hypermotility. It does not reverse nicotinic effects (e.g., muscle paralysis).
Pralidoxime (2-PAM): Specifically used in cases of organophosphate poisoning (which irreversibly bind to AChE). Pralidoxime is an oxime that can reactivate acetylcholinesterase if administered early enough, before "aging" of the enzyme occurs. It works by breaking the bond between the organophosphate and the AChE, thus restoring enzyme function and reversing both muscarinic and nicotinic effects.
Adrenergic Drugs (Sympathomimetics) – Overview
Adrenergic drugs (also known as sympathomimetics) are agents that mimic the effects of endogenous catecholamines (adrenaline/epinephrine and norepinephrine). They stimulate the sympathetic nervous system, preparing the body for a "fight or flight" response.
Physiological Response: When stimulated, the sympathetic nervous system triggers a cascade of bodily changes:
Increased heart rate and force of contraction (to deliver more blood).
Vasoconstriction in non-essential organs (e.g., GI tract, skin) to redirect blood flow.
Vasodilation in essential organs (e.g., skeletal muscles, heart, lungs) to enhance oxygen and nutrient delivery.
Bronchodilation (to increase oxygen intake).
Pupil dilation (mydriasis, to enhance vision).
Redirection of energy resources (e.g., breakdown of glycogen for glucose).
Suppression of non-essential functions (e.g., digestion, urination).
Receptors involved: Adrenergic drugs exert their effects primarily by acting on various subtypes of alpha (\alpha)-adrenergic and beta (\beta)-adrenergic receptors located throughout the body. These are G protein-coupled receptors.
Two Main Actions:
Adrenergic agonists (Sympathomimetics): These drugs directly stimulate adrenergic receptors or increase the release or inhibit the reuptake of NE/EPI. Their effects include increased heart rate and contractility, bronchodilation, altered vascular tone, and mobilization of energy stores.
Adrenergic antagonists (Sympatholytics): These drugs block adrenergic receptors, thereby decreasing or inhibiting sympathetic effects. They are often used to reduce blood pressure, slow heart rate, or manage conditions involving excessive sympathetic activity.
Adrenergic Receptor Families and Effects
Adrenergic receptors are G protein-coupled receptors that are categorized into alpha (\alpha) and beta (\beta) families, each with specific subtypes and physiological effects:
eta-adrenergic and ext{alpha}-adrenergic receptors; effects on heart, lungs, vessels, GI, eyes, etc.
Alpha1 (\alpha_1) Receptors: Located primarily on postsynaptic effector cells (e.g., smooth muscle, glands).
Activation leads to: Vasoconstriction (in arterioles and veins, increasing blood pressure), pupil dilation (mydriasis via radial muscle contraction), contraction of bladder trigone and sphincter, prostate contraction, and increased glycogenolysis in the liver.
Location: Found abundantly in many vascular beds (e.g., skin, mucous membranes, visceral organs), bladder, prostate, and eye.
Alpha2 (\alpha_2) Receptors: Primarily located on presynaptic nerve terminals (autoreceptors) and also found postsynaptically in some areas (e.g., brain, pancreas).
Activation leads to: Inhibition of norepinephrine release from nerve terminals (negative feedback), decreased sympathetic outflow from the CNS, and inhibition of insulin release from the pancreas.
Clinical Relevance: Agonists like clonidine are used for hypertension due to their central \alpha_2 effects, which reduce sympathetic outflow.
Beta1 (\beta_1) Receptors: Primarily located in the heart and kidneys.
Activation leads to: Increased heart rate (chronotropy), increased force of myocardial contraction (inotropy), increased conduction velocity through the AV node (dromotropy), and increased renin release from the kidneys.
Clinical Relevance: Targeted by drugs for cardiac conditions.
Beta2 (\beta_2) Receptors: Primarily located in the lungs, uterine smooth muscle, skeletal muscle arteries, and liver.
Activation leads to: Bronchodilation (relaxation of bronchial smooth muscle), uterine relaxation (tocolysis), vasodilation in selected vascular beds (e.g., skeletal muscle and coronary arteries), and glycogenolysis in the liver.
Clinical Relevance: Targeted by bronchodilators for asthma and drugs to prevent premature labor.
Beta3 (\beta_3) Receptors: Primarily found in adipose tissue, responsible for lipolysis (breakdown of fats). Also found in the detrusor muscle of the bladder, causing relaxation.
Activation leads to: Lipolysis and relaxation of the detrusor muscle, used in drugs for overactive bladder.
Adrenergic Agonists (Sympathomimetics) – examples & uses
Adrenergic agonists are drugs that stimulate adrenergic receptors, mimicking the effects of the sympathetic nervous system. Their selectivity for specific receptor subtypes determines their clinical applications.
Epinephrine (Adrenaline): A nonselective agonist, acting on \alpha1, \alpha2, \beta1, and \beta2 receptors.
Uses: Drug of choice for anaphylaxis (potent bronchodilation, vasoconstriction, increased cardiac output), cardiac arrest (restores cardiac rhythm), and can be used as a local vasoconstrictor with anesthetics.
Norepinephrine (Levophed): Predominantly an \alpha1 agonist with some \beta1 activity, but very little \beta_2 effect.
Uses: A potent vasopressor for the treatment of severe hypotension and shock states (e.g., septic shock) due to its strong vasoconstrictive properties, which increase systemic vascular resistance.
Dopamine: Its effects are dose-dependent.
Low Doses (D1, D2 receptors): Primarily stimulates dopaminergic receptors, leading to renal vasodilation, improving renal perfusion and urine output.
Moderate Doses (\beta1 receptors): Stimulates \beta1 receptors, increasing heart rate and contractility (cardiac stimulant).
High Doses (\alpha1 receptors): Stimulates \alpha1 receptors, causing generalized vasoconstriction and increasing blood pressure, similar to norepinephrine.
Uses: Treatment of shock (cardiogenic, hypovolemic, septic) and heart failure.
Isoproterenol: A nonselective \beta agonist (stimulates both \beta1 and \beta2 receptors).
Uses: Primarily increases heart rate and contractility (via \beta1 ) and causes bronchodilation (via \beta2 ). Historically used for asthma and bradycardia, but largely replaced by more selective agents due to significant cardiac side effects.
Dobutamine: A relatively selective \beta_1 agonist.
Uses: Primarily used as a cardiac stimulant in acute heart failure and cardiogenic shock, where it increases myocardial contractility and stroke volume without significantly increasing heart rate or causing major peripheral vasoconstriction.
Phenylephrine: A selective \alpha_1 agonist.
Uses: Potent vasoconstrictor used to increase blood pressure in hypotension (e.g., during spinal anesthesia), topical nasal decongestant (reduces mucosal swelling), and ophthalmic agent for pupil dilation.
Albuterol (Salbutamol): A selective \beta_2 agonist.
Uses: Most commonly used as a bronchodilator for the relief of acute bronchospasm in asthma and COPD (Short-Acting Beta Agonist - SABA). It causes relaxation of bronchial smooth muscle.
Ephedrine: A mixed-acting adrenergic drug. It directly stimulates \alpha and \beta receptors and also promotes the release of endogenous norepinephrine.
Uses: Historically used as a bronchodilator, decongestant, and for weight loss. Due to its broad effects and CNS stimulation, its use is now more limited, but it can be used for hypotension.
Adrenergic Receptors – Selectivity and Clinical Use
The concept of receptor selectivity is crucial in adrenergic pharmacology, as it dictates the therapeutic effects and potential side effects of drugs.
Cardioselective (\beta1 ) blockers: These drugs primarily antagonize \beta1 receptors in the heart. This selectivity means they have a reduced likelihood of affecting \beta_2 receptors in the lungs (causing bronchoconstriction) or in peripheral blood vessels. They are generally preferred for patients with coexisting respiratory conditions like asthma or COPD.
Example: Atenolol (Tenormin), Metoprolol (Lopressor/Toprol XL). These are selective \beta_1 blockers often used for hypertension, angina, and post-MI management.
Nonselective \beta blockers: These drugs block both \beta1 and \beta2 receptors. While effective in cardiac conditions, their blockade of \beta_2 receptors can lead to significant adverse effects, particularly in the respiratory system.
Example: Propranolol. This is a nonselective \beta1 and \beta2 blocker. Besides its cardiac effects, it can cause bronchoconstriction and can also interact with \alpha receptors at higher doses, though this is less common.
Implications: The blockade of \beta_2 receptors can cause bronchoconstriction, which is particularly problematic and potentially life-threatening in patients with asthma or COPD. Therefore, nonselective \beta blockers are generally contraindicated or used with extreme caution in these patient populations.
Dose-dependence and selectivity: It is important to note that receptor selectivity is often dose-dependent. A drug considered selective at therapeutic doses may lose its selectivity and affect other receptor subtypes at higher doses, leading to a broader range of effects and potential side effects.
Adverse effects when \beta2 is blocked (nonselective): The most critical adverse effect is bronchoconstriction, which can exacerbate asthma or COPD. Other potential effects include peripheral vasoconstriction and impaired metabolic responses (e.g., delayed recovery from hypoglycemia as \beta2 receptors are involved in glycogenolysis).
Adrenergic Blockers (Sympatholytics) – alpha vs beta blockers
Adrenergic blockers reduce sympathetic activity by antagonizing adrenergic receptors. They are categorized based on the receptor subtype they block.
Alpha Blockers (primarily \alpha1 blockers): These drugs selectively block \alpha1 adrenergic receptors, leading to relaxation of smooth muscle and vasodilation.
Mechanism and Effects: Blocking \alpha_1 receptors in blood vessels causes arterial and venous vasodilation, thereby lowering systemic vascular resistance and blood pressure. This can lead to several side effects:
Orthostatic Hypotension (First-dose Phenomenon): A sudden drop in blood pressure upon standing, especially with the first dose, due to impaired venoconstriction and pooling of blood in the periphery.
Reflex Tachycardia: The drop in blood pressure can trigger a compensatory increase in heart rate via the baroreceptor reflex.
Nasal Congestion: Due to vasodilation in the nasal mucosa.
Impotence: Can interfere with erectile function.
Fluid Retention: May occur due to compensatory activation of the renin-angiotensin-aldosterone system.
Example: Prazosin (Minipress). Used mainly for hypertension, especially when combined with other antihypertensive agents. It is also highly effective in relieving symptoms of Benign Prostatic Hyperplasia (BPH) by relaxing the smooth muscle in the bladder neck and prostate capsule, improving urine flow.
Other examples: Terazosin, Doxazosin (longer acting).
Beta Blockers: These drugs block \beta adrenergic receptors, primarily affecting the heart and sometimes the lungs.
Mechanism and Effects: By blocking \beta_1 receptors in the heart, they reduce heart rate, decrease myocardial contractility, and slow conduction through the AV node, leading to decreased cardiac output and typically lower blood pressure. Renin release from the kidneys is also inhibited, contributing to blood pressure reduction.
Cardioselective (\beta1 selective) Beta Blockers: These agents preferentially block \beta1 receptors at lower doses, minimizing effects on \beta_2 receptors.
Example: Atenolol (Tenormin), Metoprolol. Preferred for patients with respiratory conditions and diabetes.
Fewer noncardiac effects: Lower risk of bronchoconstriction and metabolic disturbances compared to nonselective blockers.
Nonselective Beta Blockers (\beta1 and \beta2 ): These block both \beta1 and \beta2 receptors.
Example: Propranolol. Can cause bronchoconstriction (contraindicated in severe asthma/COPD) and may mask symptoms of hypoglycemia. Some nonselective beta-blockers may also have alpha-blocking activity (e.g., Carvedilol, Labetalol), offering additional vasodilation.
Common Uses:
Hypertension: Reduces blood pressure by decreasing cardiac output and renin release.
Angina Pectoris: Decreases myocardial oxygen demand by reducing heart rate and contractility.
Myocardial Infarction: Reduces infarct size, prevents arrhythmias, and improves long-term survival.
Heart Failure: Certain beta-blockers (e.g., carvedilol, metoprolol succinate, bisoprolol) are proven to reduce morbidity and mortality in chronic heart failure (after initial stabilization).
Migraine Prophylaxis: Nonselective beta-blockers like propranolol are effective in preventing migraine headaches.
Other uses: Tremor, anxiety (performance anxiety), hyperthyroidism (to control symptoms like tachycardia).
Clinical Considerations and Safety
Thorough clinical assessment is paramount before initiating and throughout adrenergic or cholinergic drug therapy due to their potent and widespread effects on various organ systems.
Before giving drugs:
Patient History: Obtain a comprehensive medical history, including pre-existing conditions (e.g., asthma, COPD, heart failure, diabetes, glaucoma, BPH), allergies, and previous adverse drug reactions.
Current Medications: Review all current prescription, over-the-counter, and herbal medications to identify potential drug-drug interactions (e.g., tricyclic antidepressants and nonselective beta-blockers).
Laboratory Values: Assess relevant lab tests (e.g., renal and liver function, electrolytes, blood glucose).
Baseline Vitals: Establish baseline heart rate, blood pressure, respiratory rate, and oxygen saturation. Note any arrhythmias or abnormal breathing patterns.
Monitor during therapy: Continuous and regular monitoring is essential to assess therapeutic efficacy and detect adverse effects early.
Cardiovascular: Heart rate (for bradycardia/tachycardia), blood pressure (for hypotension/hypertension), EKG (for arrhythmias), and signs of heart failure exacerbation.
Respiratory: Respiratory status (for bronchospasm, dyspnea), oxygenation (SpO2).
Renal/Fluid Balance: Urine output, fluid balance (especially with drugs affecting blood pressure or volume).
Neurological: Mental status changes, tremor, dizziness.
Gastrointestinal/Genitourinary: Bowel sounds, urinary retention or urgency (cholinergic/anticholinergic effects).
Special cautions:
Nonselective Beta Blockers in Asthma/COPD: These agents can critically cause bronchospasm by blocking \beta_2 receptors in the lungs, potentially leading to severe respiratory distress. They are generally contraindicated or should be used with extreme caution and at the lowest possible dose with close monitoring in patients with reactive airway diseases.
Alpha Blockers and Orthostatic Hypotension: Patients on \alpha_1 blockers are at significant risk for orthostatic hypotension, particularly with the first dose or dose increases. Educate patients to change positions slowly and be aware of symptoms like dizziness or lightheadedness, which could lead to falls. Initial dosing should often be at bedtime.
Beta Blockers and Diabetes: Beta-blockers (especially nonselective ones) can mask the adrenergic symptoms of hypoglycemia (e.g., tachycardia, tremor) in diabetic patients, making it harder for them to recognize and treat low blood sugar. They can also inhibit glycogenolysis, thereby delaying recovery from hypoglycemia. Use with caution, and educate diabetic patients about alternative signs of hypoglycemia (e.g., sweating, hunger).
Abrupt Withdrawal: Do not abruptly discontinue beta-blockers, especially in patients with ischemic heart disease, as this can lead to rebound hypertension, angina exacerbation, or myocardial infarction due to up-regulation of adrenergic receptors during chronic blockade.
Test-style Quick Recall
Primary action of adrenergic drugs: To mimic adrenaline/norepinephrine, stimulating the sympathetic nervous system to prepare the body for a "fight or flight" state (sympathomimetics). This involves increasing heart rate, bronchodilation, and vasoconstriction in many areas.
Nonselective beta blockers: These drugs block both \beta1 and \beta2 adrenergic receptors. The blockade of \beta2 receptors carries a significant risk of bronchospasm in patients with asthma or COPD. Cardioselective (\beta1 ) blockers, such as atenolol or metoprolol, primarily affect the heart and are generally safer for patients with coexisting respiratory conditions, though selectivity can be lost at higher doses.
Prazosin (Minipress): This is a selective \alpha_1 blocker. Its primary uses are for hypertension (by causing vasodilation) and for relieving urinary outflow symptoms in Benign Prostatic Hyperplasia (BPH) by relaxing smooth muscle in the prostate and bladder neck. A key adverse effect to monitor for is orthostatic hypotension, particularly with the first dose.
Dobutamine: This is a relatively selective \beta_1 agonist. It acts as a cardiac stimulant, primarily increasing contractility and cardiac output with less effect on heart rate or peripheral vascular resistance. It is often utilized in the management of decompensated heart failure or cardiogenic shock.
Albuterol: A selective \beta_2 agonist. Its main therapeutic effect is bronchodilation, making it a first-line rescue medication for acute asthma attacks and COPD exacerbations. Common adverse effects, resulting from some systemic absorption and potential loss of selectivity at higher doses, include tachycardia, tremors, and nervousness.
Cholinergic crisis treatment: The immediate antidote for the excessive muscarinic effects of a cholinergic crisis is Atropine, which competitively blocks muscarinic receptors. In cases of organophosphate poisoning, Pralidoxime (2-PAM) can be administered in addition to atropine to reactivate acetylcholinesterase and reverse both muscarinic and nicotinic effects, if given early enough.
Quick clinical case cue
Clinical Scenario: A patient presenting with hypertension and a history of mild intermittent asthma is prescribed a nonselective beta blocker (e.g., propranolol). During therapy, they develop new or worsening wheezing and shortness of breath.
Expectation and Management: This presentation is a classic indicator of potential bronchospasm induced by the nonselective beta-blocker blocking \beta_2 receptors in the airways. The presence of asthma significantly increases this risk. The nurse or clinician should immediately:
Stop or hold the nonselective beta-blocker.
Assess respiratory status thoroughly, including auscultating lung sounds, checking oxygen saturation, and asking about symptom severity.
Administer a short-acting bronchodilator (e.g., albuterol) if ordered or per protocol.
Notify the prescriber to reassess the patient's medication regimen. A switch to a cardioselective (\beta_1 ) beta-blocker (e.g., metoprolol, atenolol, bisoprolol) might be considered as a safer alternative for managing hypertension in this patient, or an entirely different class of antihypertensive medication.
Educate the patient about the importance of reporting respiratory symptoms immediately if they recur with any medication changes.