Pharmacology of Sympathomimetics

Introduction to Autonomic Pharmacology

• The autonomic nervous system (ANS) maintains homeostasis, regulating nearly every organ system in the body.
• Autonomic drugs make up 10-15% of the top 200 drugs.
• Drugs that aren't autonomic can still affect the ANS, sometimes causing adverse effects.

Divisions of the Nervous System

• The nervous system is divided into the central nervous system (CNS) and peripheral nervous system (PNS).
• The PNS is further divided into the somatic nervous system and the autonomic nervous system.
• The somatic system controls skeletal muscles and is a one-neuron system, releasing acetylcholine at the neuromuscular junction.
• The autonomic system controls smooth muscle, cardiac muscle and glands; composed of two neuron systems with preganglionic and postganglionic neurons.

The Autonomic Nervous System (ANS)

• The ANS has two major divisions: parasympathetic and sympathetic.
• The parasympathetic system (craniosacral) has long preganglionic and short postganglionic nerves, synapsing near the effector organ, typically releasing acetylcholine. Its role is to conserve energy ("rest and digest").
• The sympathetic system (thoracolumbar) has short preganglionic and long postganglionic nerves, synapsing in ganglia near the spinal cord, typically releasing norepinephrine. These responses are associated with the "fight or flight" response.
• The two divisions often have opposing roles in controlling the same target organs in the body.

Properties of the ANS

• Involuntary (automatic) control.
• Two-neuron system (pre- and postganglionic neurons).
• Preganglionic nerves originate in the CNS and terminate in ganglia.
• Sympathetic division originates in the thoracic and lumbar regions.
• Parasympathetic division originates in the cranial and sacral regions.
• Synapses occur in ganglia; the sympathetic uses the paravertebral (and prevertebral) ganglia, while the parasympathetic uses terminal ganglia.
• Postganglionic nerves are non-myelinated and innervate effector cells at the neuroeffector junction.

Peripheral Nerve Innervation of Effectors

• Autonomic nerves innervate effector organs through two neuron systems (pre- and postganglionic).
• The preganglionic neuron releases acetylcholine.
• The postganglionic neuron releases either acetylcholine (parasympathetic) or norepinephrine (sympathetic).

Peripheral Location of Autonomic Receptors (Drug Targets)

• Acetylcholine receptors affect effector organs involved in processes like controlling the eye, heart, gut-bladder, lung etc.
• Norepinephrine receptors affect similar organs, but have an opposing effect to parasympathetic effects on those organs.

Sites of Neurotransmitter Action

• Acetylcholine acts at neuromuscular junctions, parasympathetic ganglia, sympathetic ganglia, and parasympathetic and sympathetic neuroeffector junctions.
• Norepinephrine acts primarily at most sympathetic neuroeffector junctions, while epinephrine is released from chromaffin cells in the adrenal gland.

Location of Autonomic Receptors

• Nicotinic receptors are located in parasympathetic and sympathetic ganglia, chromaffin cells, and skeletal muscle.
• Muscarinic receptors are located in effector organs innervated by postganglionic parasympathetic nerves and in some postganglionic cholinergic fibres of the sympathetic system (e.g. sweat glands).
• a and β adrenergic receptors are located on most effector organs innervated by postganglionic sympathetic nerves.

Direct effects of autonomic nerve activity

• Autonomic effects are generally similar for agonists and antagonists affecting the same systems.

Patterns of autonomic innervation of effector organs

• Some organs, for example the heart and blood vessels, have dual opposing innervation from both the sympathetic and parasympathetic system
• Others are innervated by sympathetic nerves but have little to no parasympathetic innervation, or vice-versa.

Cholinergic Agonists & Antagonists

• Cholinergic agonists mimic acetylcholine's action.
• Cholinergic antagonists block acetylcholine's action.

Cholinergic Agonists and Antagonists

• Cholinergic agonists can be choline esters (acetylcholine, methacholine, carbachol, and betanechol) or naturally occurring alkaloids (muscarine, arecoline, pilocarpine) , or more synthetic ones like cevimeline.
• Cholinergic antagonists include atropine, scopolamine, and others.

Cholinesterase Inhibitors

• Acetylcholinesterase breaks down acetylcholine, thus limiting its effect. Inhibitors prolong the effect at target organs and tissues.
• Butyrylcholinesterase is found in plasma and on platelets and breaks down choline esters.

Mechanism of Action of Cholinesterase Inhibitors

• Direct acting agonists bind to and activate muscarinic and nicotinic receptors.
• Indirect acting inhibitors inhibit acetylcholinesterase, prolonging acetylcholine effects at the neuroeffector junction.

Pharmacological Effects of Cholinesterase Inhibitors

• Cholinesterase inhibitors cause similar effects to muscarinic agonists (e.g., eye, heart, gut-bladder, lung)
• They can also cause unique systemic effects from nicotinic actions, such as muscle fasciculations, tremor, and depolarizing block.

Therapeutic Use of Cholinesterase Inhibitors

• Myasthenia Gravis (MG) treatment.
• Reversal of neuromuscular blockade (e.g., after surgery).
• Antidote for atropine poisoning.
• Alzheimer's disease.

Adverse Effects of Cholinesterase Inhibitors

• Similar to muscarinic receptor agonists: ocular effects (miosis), respiratory effects (bronchoconstriction), cardiovascular effects (bradycardia), GI effects (diarrhea), genitourinary effects (urination), and diaphoresis.
• Can cause a cholinergic crisis when used at high doses.

Parasympatholytics (Anticholinergics)

• Drugs that reduce or inhibit parasympathetic actions.
• Muscarinic receptor antagonists.
• Ganglionic blocking drugs.

Mechanism of Action of Parasympatholytics

• Competitive antagonism of muscarinic receptors; blocking the actions of acetylcholine.

Ocular Effects of Atropine

• Iris muscle relaxation (mydriasis); the pupil dilates.
• Cycloplegia (loss of accommodation). The eye loses the ability to change its focus, usually for near vision.
• Decreased lacrimal secretions (dry eyes).

Cardiovascular Effects of Atropine

• Tachycardia (increased heart rate).
• Mild increase in force of atrial contraction.

Respiratory Effects of Atropine

• Bronchodilation.
• Inhibition of respiratory tract secretions.
• Decreased ciliary mucous clearance.

GI Effects of Atropine

• Xerostomia (dry mouth).
• Reduced gastric acid secretion.
• Reduced GI motility.

Genitourinary Effects of Atropine

• Impaired micturition (difficulty urinating).
• Blockade of detrusor contraction.
• Contraction of trigone and urinary sphincter muscles.

CNS Effects of Atropine

• Effects in low or medium doses include effects like sedation, while high doses can cause effects like excitement, hallucinations, delirium, and amnesia.

Other Effects of Atropine

• Inhibition of sweat gland secretion.

Drugs for Overactive Bladder/Incontinence

• M3-muscarinic cholinergic receptor antagonists: Oxybutynin, Darifenacin, Solifenacin, Tolterodine, Trospium.

Therapeutic Uses of Muscarinic Cholinergic Antagonists in the CNS

• Motion sickness prophylaxis (Scopolamine).
• Parkinson's disease (Benztropine).
• Antidotes for organophosphate poisoning.

Therapeutic Uses of Muscarinic Cholinergic Antagonists in the Periphery

• Respiratory disorders (e.g., asthma). Surgical adjuncts, ophthalmologic examinations, treatment of diseases like irritable bowel.

Adverse Effects of Muscarinic Cholinergic Antagonists

• Ocular: blurred vision.
• Cardiovascular: tachycardia.
• Gastrointestinal (GI): xerostomia, constipation, and dyspepsia.
• CNS effects can include sedation, excitement, hallucinations, delirium, and amnesia

Overview of Adrenergic Agonists

• These agents mimic the actions of the sympathetic nervous system.
• Types include: directly acting, indirectly acting, and mixed acting sympathomimetics.
• Examples of these sympathomimetic agents include epinephrine, norepinephrine, isoproterenol, phenylephrine, brimonidine, clonidine, dobutamine, albuterol, and others.

Overview of Adrenergic Antagonists

• These agents block the actions of the sympathetic nervous system.
• Adrenergic receptor blockers (block receptors), and adrenergic neuron blockers.
• Examples of these antagonists include carvedilol, propranolol, metoprolol, atenolol, terazosin, prazosin, and others.

Mechanism of Action of a Blockers

• Competitive antagonism of alpha 1 adrenergic receptors.
• Effects on sympathetic nerve-mediated vasoconstriction.

Therapeutic Use of Alpha Blockers

• Hypertension
• Benign Prostatic Hyperplasia (BPH)
• Peripheral Vascular Disease (PVD) like Raynaud's phenomenon
• Impotence.

Adverse Effects of Alpha Blockers

• Orthostatic hypotension
• Reflex tachycardia and palpitations
• Fluid retention and edema
• Inhibition of ejaculation
• Dizziness, drowsiness, constipation, and diarrhea.

Therapeutic use of Beta Blockers

• Hypertension
• Angina Pectoris
• Arrhythmias
• Chronic Congestive Heart Failure (CHF)
• Glaucoma
• Muscle tremor.

Adverse effects of β Blockers

• Central nervous system (CNS) effects: lethargy, depression, fatigue, vivid dreams.
• Respiratory effects: wheezing and bronchoconstriction.
• Cardiac effects: Cardiac suppression, bradycardia, AV node block.
• Rebound effects (angina, hypertension, arrhythmias) with acute drug withdrawal.

Other Sympathomimetic Drugs

• Indirect Acting —Release of norepinephrine from sympathetic nerves (e.g., tyramine, amphetamine, methylphenidate, phenentermine).
• Block the neuronal uptake of norepinephrine (e.g., tricyclic antidepressants, cocaine, serotonin and norepinephrine reuptake inhibitors).
• Mixed Acting —Both direct and indirect action (e.g., ephedrine, pseudoephedrine).

NE Releasing Drugs and MAO Inhibitors

• Drugs that release NE from nerves often interact dangerously with MAO inhibitors.
• Overuse/abuse can cause dangerous, even life-threatening, responses.

Summary of adrenergic agonists and antagonists

• Sympathomimetic (agonist): Mimic sympathetic effects.
• Adrenergic blocking (antagonist): Block sympathetic effects.
• Mechanism of action relies on receptor binding (either activating or blocking), causing either direct or indirect effects.

Test your knowledge on sympathomimetic drugs, including their mechanisms, effects, and interactions. This quiz covers critical concepts related to neurotransmitters, drug classifications, and the sympathetic and parasympathetic nervous systems. Perfect for students of pharmacology or health sciences.