Pharmacology Quiz: Adrenergic Drugs

Drugs Affecting the Autonomic Nervous System

• This topic covers drugs that influence the autonomic nervous system, a crucial part of the body's involuntary functions.
• The autonomic nervous system has two main branches: the parasympathetic and sympathetic sectors.
• The parasympathetic sector uses acetylcholine (ACh) as its neurotransmitter.
• The sympathetic sector primarily uses norepinephrine and epinephrine (from the adrenal gland).
• Acetylcholine and its associated systems are critical for many body functions, such as digestion and relaxation.
• Norepinephrine and epinephrine are involved in "fight-or-flight" responses and other crucial systems like heart rate and blood pressure regulation.

Learning Objectives

• Understanding the role of acetylcholine as a neurotransmitter, including its biosynthesis, stereochemistry, storage, and metabolism.
• Identifying and comparing muscarinic and nicotinic cholinergic receptors.
• Recognizing the mechanisms of action of cholinergic drugs (agonists, antagonists, direct and indirect acting).
• Identifying the structure-activity relationships (SARs) of cholinergic drugs.
• Understanding the pharmacokinetic aspects of cholinergic drugs and their clinical applications.

Parasympathetic Drugs

• Agonists: Parasympathomimetics(Cholinomimetics) and Choline esters.
• Antagonists: Parasympatholytics (anticholinergics).
• Acetylcholine is a crucial endogenous neurotransmitter at both preganglionic and postganglionic parasympathetic nerve endings.

Acetylcholine Analogs

• The chemical instability of Ach, the positively charged nictrogen has electronic effects, which are offset by modifications like methyl group substitution (e.g., to make Methacholine).
• The methyl group shields the carbonyl oxygen, reducing interaction with positively charged nitrogen and enhancing stability for sustained parasympathetic stimulation at muscarinic receptors. Different isomers have different effects on the receptor.
• Substituting CH3 with NH2 gives carbamate group and resists hydrolysis

Muscarinic Receptors

• Muscarinic receptors (mAChRs) are distributed in the central nervous system and peripheral tissues.
• They consist of seven transmembrane helical domains.
• Different subtypes of muscarinic receptors (M1 to M5) exist.

Nicotinic Receptors

• Nicotinic receptors (nAChRs) are located in skeletal muscle neuromuscular junctions, adrenal medulla, and autonomic ganglia.
• They function as ligand-gated ion channels, with acetylcholine acting as the gatekeeper.
• The ion channel created by this receptor allows the passage of relevant ions.

Molecular Characteristics of Ach

• The acetylcholine molecule can exist in different conformations due to bond rotations.
• The orientation of the ester group and the quaternary nitrogen is crucial for its interaction with both muscarinic and nicotinic receptors.
• The distance between these groups differs between these receptors.

Acetylcholine as a Poor Therapeutic Agent

• Ach has low chemical stability and poor oral bioavailability due to interactions with various body systems.
• Modifications to improve stability and selectivity are needed for therapeutic applications.

Noncholine Derivatives

• Natural and synthetic compounds directly impacting cholinergic receptors.
• They are important for therapeutic applications such as glaucoma and Alzheimer's disease treatment.
• Chemical stability and specific receptor targeting (e.g., pilocarpine)
• Epimerization in alkaline pH can affect their effectiveness.

Acetylcholinesterase Inhibitors

• Acetylcholinesterase inhibitors interfere with the breakdown of acetylcholine, prolonging its action.
• They are used in treating myasthenia gravis, open-angle glaucoma, and potentially to enhance cognitive function in Alzheimer's disease.
• Enzyme inhibition can be reversible or irreversible.

Reversible AChEls

• Physostigmine is a crucial example of a reversible acetylcholinesterase inhibitor.
• The structural features, along with the presence of both a urethane group and a benzene ring, are key for its activity.

Synthesis of Neostigmine

• The chemical synthesis of Neostigmine is a multi-step process, often involving reactions like alkylation and condensation.
• Information about the specific chemical processes are included.

AChEls for Management of Alzheimer's Disease

• Drugs like rivastigmine and donepezil are also used in treating Alzheimer's disease.
• Details of their action mechanisms and differences in their action on the enzyme Achase, are included.

Irreversible AChEls

• Organophosphates are a major class of irreversible AChEls.
• These compounds are used in warfare and insecticides.
• These inhibitors' effects on acetylcholine and its role in the neuromuscular system and associated processes.

Important Aspects of drugs that act by direct interaction with receptors

• The chemical structure of the drug that binds to the receptor directly.
• The location of the specific receptor.
• The binding site for the drug to the receptor.
• Types of receptors of the drug, including α and β receptors relevant to sympathetic system.
• How the chemical structure of a drug determines which receptor it will bind.
• The physiological responses (e.g., increased blood pressure in response to noradrenaline).
• How the drug interacts with sympathetic receptors such as α and beta receptors on cardiovascular and gastrointestinal systems.
• Methods used to analyze the effects of the drug and its interactions.

Direct Acting Sympathomimetics

• Phenylethylamines are an important sub-class of directly-acting sympathomimetics that act on adrenergic receptors
• They are directly influencing the activity of adrenergic receptors.
• They use catecholamines as endogenous substrates.

General methods of Assays.

• The use of non-aqueous titrations. (e.g. crystal violet as indicator).
• The use of spectrophotometric methods (colorimetric method), including measurement of specific wavelengths (e.g. 550nm).

Chemical Derivatives

• Specific derivatives of epinephrine or norepinephrine used medically.
• They are used to treat glaucoma and other systemic conditions.
• Chemical modifications affecting drug activity, stability, and receptor selectivity.

SAR of muscarinic antagonists and nicotinic Antagonists

• Important features of the drug that allows for their interactions with the receptor.

Nonselective α- and β-Antagonists

• These drugs can block a variety of receptors and thus have wider effects.
• Examples of drugs in these classes are reviewed.

Selective β₁- and β₂-Agonists

• These are important drugs focused on stimulating particular activity in specific tissues (e.g., bronchodilation).

Stereochemical Aspects

• Stereochemical aspects of the ligands are of importance.
• Importance of chirality in drugs affecting sympathetic system.

Synthesis of important drugs.

• Information on the chemical reactions and synthesis methods of various drugs is reviewed.
• Specific example of methods are included for synthesizng some of the drugs.

Cardiovascular Drugs and their Target Sites

• Specific classes of drugs are reviewed for activity on cardiovascular system.
• The specific site for the drugs within the system are included (eg: cardiac vessels).
• Their pharmacological activity is explained.

Antihypertensive Agents

• Drugs for hypertension control, including their modes of action.
• Classification of drugs based on their chemical structure.
• Includes sympatholytics such as Clonidine; a2-agonist.
• Also includes direct vasodilators such as sodium nitroprusside.
• Also includes drugs for renin-angiotensin system (RAS) such as ACEIs and ATII antagonists.
• Diuretic agents are used.

Calcium Channel Blockers

• Mechanisms of action of these drugs.
• Classification into four chemical classes, explaining differences in structure and effects.
• Drug examples.

Antianginal Drugs

• The physiological mechanisms and therapeutic rationale behind these drugs are reviewed.
• Includes the mechanistic roles of organic nitrates, calcium channel blockers, and β-blockers in relieving angina.

Antiarrhythmic Drugs

• The classification of these drugs according to their mechanism of action, are reviewed
• Examples of drugs from each class.
• The use of drugs for targeting specific types of cardiac arrhythmias.

Cardiotonics

• The mechanisms of action of these drugs on the heart muscle.
• Use of drugs like Inamrinone or Milrinone to treat specific cardiac conditions.

Anticoagulants

• Different types of drugs used to prevent blood clots.
• The chemical structure of heparin, along with its mechanisms for disrupting coagulation processes.
• How low molecular weight heparins function.
• Oral anticoagulants, like warfarin, and their modes of action.
• The mechanism of action of Dabigatran etexilate is discussed.
• Chemical features of important anticoagulants are given.

Antihyperlipidemics

• Overview of these drugs and their applications.
• Therapeutic classes and mechanism of action.
• Included are drugs affecting lipoprotein lipase for lowering lipid levels.

Other information

• Important information about the various drugs and their pharmacological effects.
• Chemical structures of several compounds are included.
• Mechanisms of drug action (e.g., blocking sodium channels, altering neurotransmitter levels).
• Pharmacokinetic and pharmacodynamic information regarding some drugs.
• The synthesis information of many drugs.
• The potential chemical structures of related compounds.
• A detailed look at the chemical structure-activity relationship of different classes of drugs is reviewed.
• The potential for side effects.