Autonomic Drugs & Nervous System

Autonomic Drugs Objectives

• The sympathetic nervous system controls heart rate and blood pressure
• The parasympathetic nervous system controls heart rate and blood pressure

Autonomic Nervous System

• Cardiac output is CO
• Blood pressure is BP
• Stroke volume is SV

Autonomic Nervous System Functions

• Regulates heart rate and contraction force
• Constricts and dilates blood vessels
• Contracts and relaxes smooth muscle in various organs
• Supports Visual accommodation, controls pupillary size, regulates secretions from exocrine and endocrine glands

Sympathetic Nervous System

• Facilitates fight, fright, or flight responses
• Facilitates arousal responses
• Releases neurotransmitters like norepinephrine from postganglionic sympathetic fibers
• Releases neurotransmitters like epinephrine (E) from the adrenal medulla

Sympathetic Nervous System Receptors

• a₁ receptors are found on blood vessels, smooth muscles, bronchi, GIT, uterus, bladder, and iris
• a2 receptors are primarily on the GIT, pancreas, and minimally on blood vessels
• β1 receptors mainly affect the heart, kidneys, and salivary glands
• β2 receptors are on blood vessels, bronchi, GIT, uterus, bladder, iris, and ciliary muscle

Adrenergic Agonists: Epinephrine/Adrenaline

• Epinephrine is a non-selective adrenergic agonist, affecting both α and β receptors

Epinephrine/Adrenaline CVS Effects

• Increases heart rate (HR) and contraction force through β1 receptors
• Affects blood pressure with a biphasic response

Epinephrine Low Dose Effects

• Vasodilation occurs through β2 receptors, decreasing blood pressure and causing a reflex increase in heart rate
• Reflex increase in heart rate, plus stimulation of the heart via β1 receptors, can significantly raise heart rate and cardiac output, leading to a potent increase in blood pressure

Epinephrine High Dose Effects

• Vasoconstriction occurs through α1 receptors, increasing blood pressure and causing a reflex decrease in heart rate
• The reflex decrease in heart rate, combined with direct heart stimulation via β1 receptors, results in a net increase in heart rate, increasing cardiac output and potently increasing blood pressure
• The increase in blood pressure due to α1 receptors overshadows any fall in blood pressure from β2 receptors

Epinephrine Other Effects

• Relaxes bronchial muscles via β2 receptors
• Relaxes smooth muscles via β2 receptors and constricts sphincters via α1 receptors in the GIT
• Relaxes the pregnant uterus via β2 receptors
• Relaxes bladder smooth muscle via β2 receptors
• Contracts sphincter via α1 causing urinary retention
• Contraction of iris radial muscle triggers pupil dilation (mydriasis) via β2 receptors
• Decrease in insulin, increase in glycogenolysis (β2) causes hyperglycemia

Epinephrine, Clinical Uses & Adverse Effects

• Is used to treat cardiac arrest, nasal congestion, and acute asthma and to reverse low blood pressure in anaphylactic shock
• Can adverse effects such as cardiac arrhythmias, cerebral hemorrhage, headaches, anxiety, tremors, and palpitations

Epinephrine/Adrenaline Administration

• Ineffective when taken orally
• Slowly absorbed from subcutaneous tissue
• Absorbed faster from intramuscular sites
• Effective via inhalation locally, but not usually given intravenously due to rapid liver inactivation
• Rapidly inactivated in the liver by Monoamine Oxidase (MAO) and Catechol-o-methyl-transferase (COMT)

Norepinephrine/Noradrenaline

• Non-selective adrenergic agonist, targets alpha and beta-1 receptors
• Is an endogenous neurotransmitter
• Produces similar effects to epinephrine, affecting alpha receptors on blood vessels
• Acts on β1 receptors but has insignificant effects on β2 receptors
• Is unlikely to cause vasodilation

Norepinephrine/Noradrenaline Cardiovascular

• Vasoconstriction is facilitated by (α₁) increasing BP and triggering a reflex decrease in HR
• There is a reflex decrease in HR combined with direct heart stimulation (β₁) resulting in a net increase in HR which increases CO and increases BP
• Vasoconstriction increasesTPR as well as stroke volume resulting in increased systolic and diastolic BP and increased mean and pulse pressure

Norepinephrine/Noradrenaline Other Effects, Uses and Administration

• Increase coronary blood flow
• Hyperglycemia effect occurs at large doses
• Contraction in pregnant uterus
• Used vasopressor agent for hypovolemic shock and other hypotensive states administered with Noradrenal bitartrate via slow IV infusion at 2-4 mg/minute

Norepinephrine/Noradrenaline, Pharmacokinetics & Side Effects

• Poor absorption with ineffective oral and subcutaneous administration
• Administered intravenously
• Metabolized by MAO and COMT resulting in short duration of action
• Can cause anxiety, palpitation and respiratory difficulty
• Can cause headaches
• Extravasation causes necrosis, gangrene, severe hypertension, anginal pain

Propranolol

• Non-selective β antagonist (beta blocker)

Propranolol Cardio Vascular Effects

• Decreases heart rate, is less pronounced at resting heart rate
• Reduces coronary blood flow and oxygen consumption
• Reduces renin secretion from juxtaglomerular cells in the kidneys and the renin-angiotensin pathway that increases BP

Propranolol Uses & Adverse Effects

• Used to treat hypertension, prevent myocardial infarction, angina pectoris, arrhythmias, migraines, and stage fright
• Can induce heart failure, fatigue, depression, hypoglycemia especially for patients on insulin, and Bradycardia

Parasympathetic Nervous System

• Releases Acetylcholine (ACh) as a neurotransmitter
• Controls restorative, vegetative, and housing responses known as the rest and digest system

Parasympathetic Nervous System Receptors

• Includes both Muscarinic (M) and Nicotinic (N) receptors
• M1 receptor is mainly located in autonomic ganglia in the CNS and on presynaptic nerves for the ANS system
• M2 receptor is mainly located on the heart in nodes, GIT and the CNS system
• M3 receptor is located on glands, vasculature and smooth muscles
• Nicotinic receptors are in autonomic ganglia, NMJ for skeletal muscles, and the CNS

Muscarinic Receptor Subtypes

• M1 (Neural): Modulates neurotransmission
• M1 and M3 have activation coupled to a Gq protein to stimulate PLC, then increasing IP3 and DAG from membrane phospholipids thus increasing Ca2+
• M2 (Cardiac): Decreases heart rate and conduction.
• Activation coupled with Gai protein inhibiting adenylate cyclase, thus decreasing CAMP or increasing K+ efflux
• M3 (Muscular): Stimulates glandular secretion, contracts smooth muscles, and dilates blood vessels
  • M3 (on blood vessels) results in activation that increases nitric oxide which activates guanylate cyclase, increasing cGMP

Parasympathetic Regulations of the Heart

• Utilizes Vagus nerves for the parasympathetic innervation of the heart
• Innervates the SA node, AV node, and atrial myocardium
• Employs acetylcholine (Ach) as the parasympathetic neurotransmitter
• Features M2 muscarinic receptors as the primary cholinergic receptors

Parasympathetic Activity Effects

• Does not contribute to or control the tone of blood vessels with M3 receptors presented on vessels
• M3 receptors affects vasculature that responds to circulating Ach and/or injected M3 agonists resulting in vasodilation and reduced BP
• Vascular effects associated with M3 agonists are not clinically exploited, but occur during drugs used for other purposes

Cholinergic Agonist: Acetylcholine (ACh)

• Non-selective Muscarinic & Nicotinic agonist

Acetylcholine (ACh) Cardio Vascular Effects

• Decrease in heart rate and force of cardiac contraction of the heart through M2 receptor
• Vasodilation is facilitated via a NO pathway on vascular endothelium which decreases BP through M3 receptors

Acetylcholine (ACh) Other Effects and Pharmacokinetics

• Includes increased contraction of smooth muscles, increased motility in GIT and secretion activity
• Other effects are increased uterine activity, bronchial tone as well as increased contractility of bladder
• Contraction of pupil and constriction of ciliary muscles
• Effects involve salivary, sweat and lacrimal gland stimulation
• Rapidly hydrolyzed by cholinesterase with short duration of action
• Effects are also non-specific due to targeting M and N receptors due to clinical application

Cholinergic Antagonist: Atropine

• Is a Non-selective muscarinic antagonist
• Competitively inhibits the actions of ACh at muscarinic receptor sites M2 & M3

Atropine - Cardio Vascular Effects

• Blocks vagal nerve effects to the heart at M2 causing increased HR and increased conduction
• If given intravenously it causes initial transient bradycardia at low dose.

Atropine - Other Effects

• Includes Relaxation of smooth muscles
  • Includes of bronchial muscles and decreasing secretions
• Reduction in motility of GIT
• Relaxation of smooth muscle in bladder
• Relaxation of ciliary muscle causing cycloplegia
• Relaxation of sphincter pupillae causing mydriasis
• Decrease in salivary, gastric and sweat gland secretion

Atropine- Therapeutic Use & Adverse Effects

• Used for Sinus bradycardia and heart block
• Opthamology and Pre-operative medication to decrease secretions
• Used as a Prophylaxis of motion sickness
• Includes tachycardia constipation, blurry vision, dry mouth and urine retention