Pharmacology Quiz on Drug Actions and Effects

General Principles of Pharmacology

• Pharmacology is the study of the effect of drugs on the body and the effect of the body on drugs.
• It investigates how drugs work at the molecular level, and how the body's physiology responds to them.

Learning Outcomes

• Learning outcomes for the lecture include describing drug targets and receptor-effector mechanisms activated by agonists.
• Key learning points include outlining drug sources, pharmacodynamics, pharmacokinetics, main drug target classes, agonist/antagonist definitions, receptor subtypes, and principles of drug actions.

Session Outline

• Sources of drugs include natural (plants and fungi) and synthetic sources.
• Students should understand the terms pharmacodynamics (drug effects on the body) and pharmacokinetics (body effects on the drug).
• The lecture defines and describes four major drug target classes (receptors, ion channels, carrier molecules, and enzymes).
• Students are expected to know how drugs interact with their targets and how they work there.
• The key terms agonist (mimicking endogenous signals) and antagonist (blocking endogenous signals) are essential.
• Receptor subtypes are also discussed as they contribute to variations in drug action.
• Drug action at the target, specifically focusing on the interactions with the receptor.

Sources of Drugs

• Drugs originate from various sources, including plants (aspirin from willow bark), opium poppies (morphine), and fungi (psilocybin).
• Modern drug research continues to explore natural sources.
• Synthetic drugs are derived from novel medicinal chemistry approaches; also synthetic-biologics, are crucial in pharmacology.

Pharmacodynamics

• Pharmacodynamics refers to the molecular interactions by which drugs exert their effects on the body.
• Drug targets include proteins (receptors, ion channels, enzymes, etc.) which are the binding sites for medications.
• The effects of drugs on the body can be dependent on drug concentration and may vary from therapeutic to toxic effects.

Pharmacodynamics (Continued)

• Drug effect on patients correlates to the dosage level.
• Comparing one drug (Drug A) to another (Drug B) can help measure the efficacy and safety margin.
• The therapeutic window is the dose range between minimal therapeutic effect and minimal toxicity (important to note for comparing drugs).

Pharmacokinetics

• Pharmacokinetics describes how the body affects a drug.
• Key processes include absorption, moving the drug from its site of administration into the bloodstream.
• Drug distribution, which is the movement of a drug from the bloodstream to tissues of the body
• Metabolism, where the body inactivates the drug using enzymes.
• Excretion, where the drug is eliminated from the body (urine, bile, feces)
• Pharmacokinetics determines the optimal route, frequency, and duration of treatment.

PK/PD Case Study

• Real-world examples, such as hay fever medications, explore the connection between drug action, and the body's response mechanisms.
• Key considerations include drug mechanisms (as with Benadryl), the body's pharmacokinetic processes, and reasons for treatment repetition.

Drug Interaction With Targets

• Drug interaction with their targets depends on shape compatibility ("lock and key"), charge distribution causing bonds formation, and the types of bonds that form (e.g., van der Waals, hydrogen).
• The specific structure of drug molecules and their target molecules (particularly proteins), are key factors for drug-target interactions
• Additional factors relevant to drug interactions, such as hydrophobicity, ionization status (pKa), and conformations of target molecules, help define the nature of drug-target interactions.

Drug Target Classes

• Drugs act on specific protein targets, and there are four critical types.

Targets For Drug Action

• Four major drug targets: receptors, ion channels, carrier molecules, and enzymes.
• The specific targets influence the way in which drugs are designed to interact with the corresponding systems of the body.

Signal Transduction

• Signal transduction is the process by which cells receive and act on external signals (hormones, neurotransmitters, growth factors).
• Steps include reception, transduction (conversion of a signal), and response (causing biological effects).

Signal Transduction: Agonist

• An agonist mimics the action of an endogenous chemical messenger, initiating a normal cellular response.
• A drug acting as an agonist usually binds to the receptor, thereby activating the receptor.

Signal Transduction: Antagonist

• An antagonist blocks the action of an endogenous chemical messenger and thus inhibits the signal transduction pathway..
• This type of drug effectively inhibits the signaling pathway when binding to a receptor, preventing the activation of an endogenous messenger.

A Typical Enzymatic Reaction

• In normal enzymatic reactions, substrates bind to the active site of an enzyme, forming an enzyme-substrate complex, and the enzyme facilitates the substrate transformation to yield products.
• Antagonists inhibit enzymatic reactions.
• Agonists work as pseudsubstrates to mimic the normal enzymatic reactions.

Competitive Inhibition

• Competitive inhibitors bind to the enzyme's active site, blocking the substrate from binding, which prevents the reaction.
• Blocking the active site of the enzyme thereby prevents substrates from binding effectively to the enzyme in order to be converted into products.

Non-Competitive Inhibition

• Non-competitive inhibitors bind to an allosteric site on the enzyme and thereby change the shape of the active site, which reduces its ability to bind to substrates.

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

• NSAIDs block the cyclooxygenase enzyme, reducing prostaglandin production, which in turn lessens inflammation, pain, and fever.

Allosteric Drug Action at Ion Channels

• Allosteric regulation at ion channels causes drug binding at a site distinct from the main (orthosteric) binding site that influences channel function, enhancing or reducing the ion channel's function.
• Benzodiazepines are examples of drugs that work through allosteric regulation of GABA receptors, increasing inhibition and potentially reducing anxiety.

Overview: Drug Action at Target

• Agonists stimulate or activate receptors; antagonists block receptor activation, by the endogenous ligand itself or other external agents.
• Agonists acting at ion channels either open or close channels; antagonists may block channel function.

Signal Transduction—Receptors

• Receptor activation following signal binding leads to changes in receptor properties and the activation of cellular responses.
• The receptor with bound agonist initiates multiple intracellular signaling events that lead to cellular responses.

Receptor Subtypes- Signal Transduction

• Ligand-gated ion channels, G-protein coupled receptors, and enzyme-linked receptors have different structures and signaling pathways, which determine how they respond to drugs and impact responses.

Heterotrimeric G-Proteins

• G proteins are composed of three subunits (alpha, beta, gamma), which interact with receptors and effectors.
• G proteins transmit extracellular signals to various intracellular mediators and thus trigger biological reactions for mediating responses.

Diversity of G-Protein Subunits and Effector Proteins

• Different G-protein subunits and effector proteins mediate diverse cellular responses.
• Specificity in the G-protein configuration triggers various physiological effects within the cell.

Examples: Adrenoreceptors

• Adrenoreceptors are protein targets activated by adrenaline and noradrenaline which impacts response differences in different cells.
• The type of response is determined by the specific adrenoreceptor at the target site.

Kinase-Linked Receptors

• Kinase-linked receptors are transmembrane proteins with intracellular kinase domains.
• Their structure allows ligand binding, and dimerization leading to autophosphorylation events, which initiates downstream signaling pathways.

Insulin Receptor

• Insulin binding to the insulin receptor leads to the autophosphorylation of tyrosine residues in the receptor's intracellular domain.
• This activation subsequently triggers various intracellular signaling pathways which ultimately results in biological effects; such as the lowering of blood glucose.

Nuclear Receptors

• Nuclear receptors are located within the cell cytoplasm or nucleus and regulate gene expression.
• These receptors act by binding to ligands, and by binding with specific DNA regions, which modifies gene expressions, thus triggering response expressions.

Class I Nuclear Receptor Signal Transduction

• mRNA from modified gene expression is subsequently translated into proteins, leading to biological effects in the body.