Pharmacology Quiz on Therapeutic Index and Dosage

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Questions and Answers

What does the Therapeutic Index (TI) indicate about a drug?

The speed at which the drug is metabolized.

The potential effectiveness and safety of the drug. (correct)

The time required for the drug to take effect.

The likelihood of drug addiction.

How is the Therapeutic Index calculated?

TI = LD50 + ED50

TI = ED99 / LD1

TI = ED50 - LD50

TI = LD50 / ED50 (correct)

Which of the following factors does NOT modify the dosage and action of drugs?

Gender

Weather conditions (correct)

Age

Genes

What is the Median Lethal Dose (LD50) primarily used to determine?

The dose required to kill 50% of a test population. Signup and view all the answers

What is the risk-benefit ratio used to assess?

The estimated harm versus expected advantages of drug use. Signup and view all the answers

If a patient has a Body Weight (BW) of 140 kg, how would their individual dose be calculated based on the average adult dose?

Individual dose = 140/70 × average adult dose. Signup and view all the answers

Which of the following is NOT a method to understand the dose-response relationship?

Combination therapy response. Signup and view all the answers

What does the Margin of Safety measure?

LD1/ED99. Signup and view all the answers

What effect does urine pH have on the clearance of weak bases?

Weak bases ionize more and are less reabsorbed in alkaline urine. Signup and view all the answers

Which of the following substances is primarily excreted through the lungs?

Alcohol Signup and view all the answers

What happens to drugs that undergo enterohepatic cycling after being excreted into the bile?

They can be reabsorbed into the portal vein. Signup and view all the answers

Which of the following drugs can darken stool color?

Ferrous sulfate Signup and view all the answers

In which order of kinetics does the rate of drug elimination remain constant irrespective of drug concentration?

Zero-order kinetics Signup and view all the answers

Which type of drugs is likely to be harmful to breastfeeding infants due to excretion in breast milk?

Opioids like Codeine Signup and view all the answers

What is a characteristic of first-order kinetics in drug elimination?

Elimination rate varies based on drug concentration. Signup and view all the answers

What type of substances are likely to be excreted in sweat?

Metalloids and certain antibiotics Signup and view all the answers

What factor is crucial for the effect of drugs on cells or tissues?

Drug binding specificity Signup and view all the answers

What is a common consequence of higher drug doses?

Side effects from alternate targets Signup and view all the answers

How do drugs typically interact with ion channels?

By binding to receptor sites or other parts of the channel Signup and view all the answers

What type of ion channels open in response to cell polarization?

Voltage-gated ion channels Signup and view all the answers

What role do carrier molecules play in drug action?

Transporting ions and small organic molecules across membranes Signup and view all the answers

Which drug is known to inhibit the angiotensin-converting enzyme?

Enalapril Signup and view all the answers

What type of proteins do most drugs bind to for effect?

Common protein molecules like enzymes and receptors Signup and view all the answers

What is an example of a drug that functions by inhibiting a proton pump?

Omeprazole Signup and view all the answers

What is the primary role of a receptor in drug interactions?

To receive chemical signals from outside a cell Signup and view all the answers

Which of the following statements about drug-receptor interaction is true?

Drugs can only modify ongoing cellular functions Signup and view all the answers

What is the main site for drug metabolism in the body?

Liver Signup and view all the answers

What is the difference between potency and efficacy in the context of drugs?

Potency is the amount of drug required for effect, whereas efficacy describes the ability to produce an effect Signup and view all the answers

Which of the following represents a pro-drug that is activated through metabolism?

Sulindac Signup and view all the answers

Which concept emphasizes the relationship between the concentration of a drug and its response?

Dose-response relationship Signup and view all the answers

Which type of reaction is categorized as a Phase 1 biotransformation?

Oxidation Signup and view all the answers

What defines the maximal efficacy of a drug?

The largest effect that a drug can produce Signup and view all the answers

What is the primary purpose of drug metabolism?

To transform lipophilic drugs into more polar excretable products Signup and view all the answers

What does the term 'intrinsic activity' refer to in pharmacology?

The degree to which a drug can induce effects at its receptor Signup and view all the answers

What is not a function of Phase 1 reactions in drug metabolism?

Conjugation with endogenous substances Signup and view all the answers

Which theory suggests that drug response depends on the proportion of receptors occupied by drugs?

Occupation theory Signup and view all the answers

Which enzyme system is primarily responsible for catalyzing oxidation in Phase 1 reactions?

Cytochrome P-450 mono-oxygenase Signup and view all the answers

Which of the following is NOT a correct characteristic of receptors?

They can impart entirely new cell functions Signup and view all the answers

Which of the following is a characteristic of Phase 2 biotransformation reactions?

They involve conjugation with endogenous substances. Signup and view all the answers

Which of the following drugs undergoes biotransformation to form an active metabolite?

Amitriptyline Signup and view all the answers

What is the primary role of cytochrome P-450 mono-oxygenase?

Catalysis of drug metabolism Signup and view all the answers

Which of the following factors can influence drug metabolism?

Age Signup and view all the answers

Which is a consequence of enzyme induction by certain drugs?

Increased biotransformation of drugs Signup and view all the answers

Which CYP isozyme is NOT among the six isozymes responsible for most P450-catalyzed reactions?

CYP1A1 Signup and view all the answers

What type of reactions are most cytochrome P-450 enzymes involved in?

Phase I reactions Signup and view all the answers

Which of the following conditions may require enzyme induction for treatment?

Congenital non-haemolytic jaundice Signup and view all the answers

What effect can an active metabolite have on drug activity?

Enhance drug action Signup and view all the answers

Which of the following is NOT a physiological factor that can depress microsomal enzyme systems?

Increased hydration Signup and view all the answers

Study Notes

Drug Metabolism/Biotransformation

Enzymatically mediated alteration in drug structure
Transforms lipophilic drugs into more polar, excretable products (inactivation)
Essentially, metabolism is a mechanism of drug elimination, leading to:
- Reduced lipid solubility - increased polarity.
- Reduced biological activity.

Main Site - Liver

Major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues like the kidney, intestines, and skin (minor).
Biotransformation is catalyzed by specific enzymes (hepatic microsomal systems), which also catalyze the metabolism of endogenous substances (e.g., steroids).
Some agents are initially administered as inactive compounds (prodrugs) and require metabolism to their active forms.

Metabolism May Results

Active & More Active Metabolite:
- Chloroquine → Hydroxychloroquine
- Amitriptyline → Nortriptyline
- Diazepam → Oxazepam
Activation of Inactive Drugs:
- Sulindac → Sulindac sulfide
- Enalapril → Enalaprilat
Inactivation of Drugs:
- Propranolol
- Lidocaine

Phases of Biotransformation Reactions

Phase 1 (Non-synthetic reactions)
Phase 2 (Synthetic reactions)

Phase 1 (Non-synthetic reactions)

Involve enzyme-catalyzed biotransformation of the drug without any conjugations.
Includes oxidations, reductions, and hydrolysis reactions.
Introduce a functional group (e.g., OH, -COOH, -SH, -NH2) which serves as an active site for conjugation in phase II reactions.
Examples of enzymes include:
- Cytochrome P-450 mono-oxygenase system (mixed-function oxidase)
- Aldehyde/alcohol dehydrogenase
- Aldehyde dehydrogenase
- Deaminase
- Esterase
- Amidases
- Epoxide hydratases

Phase II (Synthetic) reactions

Conjugation reactions involving enzyme-catalyzed combination of a drug (or metabolite) with an endogenous substance (e.g., glucuronide, sulfate, amino acids, glutathione, methyl groups, acetyl groups, etc.).
Enzymes used in phase II reactions include:
- Glucoronyl transferase (glucuronide conjugation)
- Sulfotransferase (sulfate conjugation)
- Transacylase (amino acid conjugation)
- Acetylases
- Ethylases
- Methylases

Cytochrome P-450 Mono-oxygenase/Mixed Function Oxidase

Primarily located in the liver.
Plays a vital role in drug metabolism.
Large variety of P-450 exists, each catalyzing metabolism of a unique spectrum of drugs with some overlaps in substrate specificities.
Six isozymes responsible for the vast majority of P-450-catalyzed reactions: CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2.
Most involved in phase I reactions
Catalyses reactions such as aromatic & aliphatic hydroxylation, dealkylations at nitrogen, sulfur, & oxygen atoms, heteroatom oxidations at nitrogen, sulfur atoms and reductions at nitrogen atoms.

Factors that Influence Metabolism

Physiological Factors: starvation, obstructive jaundice, liver diseases, cardiovascular problems.
- These depress microsomal enzyme systems.
Age: people in extreme ages (young/elderly) have decreased metabolism due to immature/degenerative enzyme systems.
Genetically determined differences: variations in acetylation (e.g., isoniazid, procainamide, hydralazine) can lead to drug toxicity.
Prior administration of other drugs: Repeated administration can induce or inhibit microsomal enzymes.

Inducers

Cytochrome P450 enzymes are an important target for pharmacokinetic drug interactions.
Drugs like phenobarbital, rifampin, and carbamazepine increase the synthesis of one or more CYP isozymes.
This results in increased drug biotransformation, leading to:
- Decreased plasma drug concentrations.
- Decreased drug activity (if metabolite is inactive).
- Increased drug activity (if metabolite is active).
- Decreased therapeutic drug effects.

Possible Uses of Enzyme Induction

Congenital non-haemolytic jaundice: phenobarbitone hastens bilirubin clearance.
Cushing's syndrome: phenytoin reduces steroid degradation.
Chronic poisonings: faster metabolism of accumulated substances.
Liver disease: drug elimination is often affected.

Inhibitors

Inhibition of CYP isozyme activity is another source of drug interactions leading to adverse effects.
Inhibition is often through competition. For example, omeprazole inhibits CYP isozymes responsible for warfarin metabolism. Increase in warfarin concentrations increase risk of bleeding.
CYP inhibitors include erythromycin, cimetidine, ketoconazole, and ritonavir.

Onset of Effect

Inhibitors: enzyme inhibition is fast (within hours).
Inducers: induction takes 4-14 days to reach a peak, and is maintained while the inducing agent is given, then returns to original value over 1-3 weeks.

Drug Excretion

Removal of a drug from the body.
Major routes include renal excretion, hepatobiliary excretion, and pulmonary excretion.
Minor routes include saliva, sweat, tears, breast milk, vaginal fluid, and hair.
Rate of excretion influences duration of drug action.
- Slow excretion leads to prolonged drug actions.

Routes of Drug Excretion (Renal)

For water-soluble & non-volatile drugs
Processes include:
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
Glomerular filtration and active tubular secretion removes drug; passive tubular reabsorption retains the drug.

Various Factors influencing Renal Clearance of Drugs

Age: decreased glomerular filtration rate in older adults affects drug excretion.
Genetics: variations in tubular secretion processes influence drug action duration. (e.g., penicillin, aspirin, cephalosporin)
Urine pH: ionization of weak acids/bases influence absorption in urine.
- Weak bases less reabsorbed in acidic urine.
- Weak acids less reabsorbed in alkaline urine.

Hepatobiliary Excretion

Conjugated drugs are excreted by hepatocytes into bile.
Some drugs may undergo enterohepatic cycling (reabsorption into portal vein) prolonging drug action.
Examples include chloramphenicol and estrogen.

Gastrointestinal Excretion

Drugs not absorbed during oral administration are excreted in the feces.
Drugs that do not undergo enterohepatic cycling appear in the stool.
Examples include aluminum hydroxide (white stool color), ferrous sulfate (darkens stool), and rifampicin (orange-red stool).

Pulmonary Excretion

Many inhalation anesthetics and alcohol are excreted via the lungs.

Sweat Excretion

Rifampicin and metalloids (e.g. arsenic) are excreted via the sweat glands.

Mammary excretion

Many drugs, including Ampicillin, Aspirin, Chlorodizepoxide, and Streptomycin, can be excreted into breast milk.
Lactating mothers should exercise caution regarding drug intake

Kinetics of Elimination

Quantitative aspects of renal drug elimination.
Elimination occurs in two orders:
- First-order kinetics: majority of drugs are eliminated through this, the rate of elimination is directly proportional to the drug concentration (clearance remains constant). - However, with high enough dose, elimination pathways of all drugs saturate.
- Zero-order kinetics: some drugs' elimination kinetics change to zero/higher-order kinetics when drug concentration is constant, meaning a constant amount of drug is eliminated in a set time, while clearance decreases with increasing concentration.

Cont'd... (Elimination/Excretion Rate)

Excretion rate = clearance × plasma concentration
Extraction ratio = decline of drug concentration in the plasma from arterial to venous side of the kidney (= c2/c1)
Clearance (mg/ml) = excretion rate (mg/min)/Cp
Total body clearance: sum of clearances of various drug metabolizing & drug eliminating organs.
- CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
Not possible so CLtotal = k_v*Vd

Kinetics of Following Dosage Forms (Home Exercise)

Kinetics of IV infusion
Kinetics of fixed-dose/fixed-time-interval regimens.

Half-life

Time required for the drug concentration to reduce by one-half.
Plasma half-life depends on how quickly the drug is eliminated from the plasma.

Adjustment in Dosage

T1/2 (half-life) increases/decreases due to various factors:
- diminished renal/hepatic blood flow/extraction ratio or decreased metabolism, or increased protein binding.
- increased hepatic blood flow, decreased protein binding, increased metabolism.

Therapeutic Drug Monitoring

Plasma concentration of drug during treatment essential in:
- Drugs with low safety margins (e.g., digoxin, lithium, cyclosporine)
- Individual variations
- Presence of renal failure
- Poisoning cases
- Failure of response

Pharmacodynamics

Mechanisms of drug actions:
- How drugs act in the body
- Effects (beneficial and harmful)
- What drugs do in the body.
Important note: Drugs modify physiological activity but don't confer new functions on tissues. Drug molecules are few compared to tissue molecules for effects to be significant.

Drug Specificity

Drug specificity is important but no drug is completely specific in its actions.
- At higher doses, some drugs can affect multiple targets leading to side effects.
- Example: TCAs block amine pump reuptake but also affect acetylcholine receptors.
Most drugs produce effects by binding to protein molecules (enzymes, carrier molecules, ion channels, receptors).

Enzyme (Pharmacodynamics) Example

Angiotensin converting enzyme is inhibited by enalapril to reduce angiotensin II formation, leading to vasodilation.

Ion Channels (Pharmacodynamics)

Protein molecules form water-filled pores spanning cell membranes, switching between open and closed states.
Ligand-gated ion channels open upon agonist binding.
Voltage-gated ion channels (e.g., Na+, K+, Ca++) open with membrane polarization.
Drugs may alter channel function directly binding to receptors, or indirectly via intermediaries.

Carrier Molecules (Pharmacodynamics)

Proteins for ion/small molecule transport across cell membranes.
- Examples include renal tubular transport, uptake of neurotransmitter precursors, and effects on C proteins.

Receptor (Pharmacodynamics)

Protein molecules that receive chemical signals from outside the cell, situated either at the cell surface or inside the cell for drug action.
- Drug + Receptor= Drug-Receptor complex for action
Non-receptor mechanisms operate through simple physical/chemical reactions (e.g., antacids neutralizing).

Types of Receptors (Diagram)

Ligand-gated ion channels (e.g., cholinergic receptors)
G protein-coupled receptors (e.g., adrenergic receptors)
Enzyme-linked receptors (e.g., insulin receptors)
Intracellular receptors (e.g., steroid receptors)

Intracellular Receptor (Pharmacodynamics)

Lipid-soluble drugs diffuse across cell membranes and move to the nucleus.
Drugs bind to intracellular receptors, forming a drug-receptor complex.
The complex binds to chromatin activating gene transcription thus producing specific proteins to cause biologic effect.

Induced Fit Model (Pharmacodynamics/Kinetics)

Binding of a substrate to an enzyme is accompanied by a significant change in the enzyme's active site structure.

Different Theories Involved

- Lock-and-key
- Rate theory
- Occupation theory
- Resting state model
- Activated state model

Implications of Drug-receptor Interaction

Drugs alter the rate of bodily functions
Drugs cannot create new functions for cells
Drugs only modify ongoing effects, not create them
Effects can occur beyond normal physiological ranges.

Three Aspects of Drug Receptor Function

Receptors determine the quantitative relationship between drug concentration and response, based on affinity and abundance in target cells.
Receptors as complex molecules that function as regulatory proteins in chemical signalling pathways.
Receptors determine the therapeutic and toxic effects of drugs.

Dose-Response Relationship

Dose: amount of drug required to produce a desired response in an individual.
Dosage: frequency, amount, and duration of drug administration.
Potency: measure of how much drug is required to elicit a given response, less dose more potent.
Efficacy: inherent ability of a drug to produce an effect at receptors
Maximal efficacy: greatest effect attainable by a drug.
Drug response depends on affinity of drug for the receptor and intrinsic/inherent activity.

Agonism and Antagonism

- Agonists facilitate receptor response (keys in a lock).
- Antagonists inhibit receptor response (blocks the lock).

Types of Drug-Receptor Interactions

Agonists: bind to and activate receptors to produce effects. Some inhibit their binding proteins to terminate effect (e.g. cholinesterase inhibitors).
- Example: stopping the breakdown of acetylcholine.
Antagonists: bind to receptors but lack intrinsic activity; prevent other molecules from binding.
- Example: atropine decreasing acetylcholine effects

Partial Agonists and Inverse Agonists

Partial agonists: act as agonist or antagonist, depending on circumstances; lower maximal efficacy, e.g., pindolol.
Inverse agonists: produce an effect opposite to that of an agonist by occupying the same receptor, e.g. metoprolol.

Graded Dose-Response Relations

As drug concentration increases, its pharmacological effect also increases up to maximum effect (when all receptors are occupied).
Used to determine affinity, potency, efficacy, and characteristics of antagonists.

Potency

Effective concentration (EC50): concentration of agonist needed to produce half the maximum biological response.
Potency of an agonist is inversely related to its EC50 value. (The lower the EC50, the higher the potency.)
Higher potency leads to the leftward shift of the DRC (Dose Response Curve).

Efficacy

Maximum possible effect relative to other agents
Determined by the peak (highest level) of the DRC
Full agonist = 100% effect
Partial agonist = 50% effect
Antagonist = 0% effect.
Inverse agonist = - 100%

Quantal (Cumulative) Dose-Response Relationship

Relationship between the dose of a drug and the proportion of a population that responds to it (all or none).
Useful for determining doses where most of the population responds.
Examples: ED50%, TD50%, LD50%, therapeutic index (TI), inter individual variability

Therapeutic Index

Indicator of drug effectiveness and safety
Ratio of lethal dose (LD50) to effective dose (ED50), smaller TI is less safe.
- Margin of safety = LD 1 / ED 99 is another metric.

Risk-Benefit Ratio

Weighing harm (side effects, cost, inconvenience) against benefits (relief, cure, quality of life), difficult to quantify.
Clinicians rely on data from large populations and their own experience.

Factors Modifying Drug Dosages & Actions

- Age, sex/species
- Weight and size
- Genetics
- Route of administration/food/drug-drug interactions
- Physiological state (e.g., pregnancy)
- Disease state/pathology
- Tolerance, natural/acquired
- Psychological factors

Dosage Calculation

- Methods for calculating individual dosages (e.g., Young's rule, Clark's rule, and Fried's rule).

Drug-Drug Interactions

Consequences:
- Additive Effects: similar intrinsic activity with combined effects.
- Synergism: combined drugs have a greater effects than separate effects.
- Potentiation: one substance has no effect alone but increases another's effectiveness.
- Reduction of Effects: diminished beneficial/increased detrimental effect caused by antagonism.

Types of Antagonism

. Chemical: Drug binding . Physical: Drug-property based, e.g. charcoal binding alkaloids . Receptor Block: Drugs binding to receptor sites.
. Competitive: In equilibrium; antagonists compete with agonists for receptor sites. . Non-competitive: Binding not in equilibrium; binds and alters the receptor/binding molecule irreversibly. . Physiological/Functional: Opposing effects from two drugs.

Basic Mechanisms of Drug-Drug Interactions

Drug interactions can result from direct chemical/physical mixing effects or by altering pharmacokinetic features (absorption, distribution, metabolism, excretion. ) or pharmacodynamic features (receptor binding)

Drug-Food Interactions

Impact on drug: -Absorption (can decrease or increase it). -Metabolism (grapefruit juice effect). -Toxicity (e.g., MAOIs and tyramine). -Action (e.g., vitamin K and warfarin).

Adverse Drug Reactions (ADRs)

Any undesirable response a drug might create.
Types: 
Augmentative (side effects) 
Bizarre (allergic, idiosyncratic) 
Chronic (cumulative effects) 
Delayed (teratogenic) 
End-of-use (withdrawal)

Cont'd... (ADRs)

Side Effects: unavoidable secondary drug effects produced even at therapeutic doses (e.g., drowsiness from antihistamines, gastric bleeding from aspirin)
Toxicities: adverse reactions caused by excessive drug levels (e.g. morphine overdose coma.)
Allergic Reactions (type I to IV) occur in immune-sensitive individuals, re-exposure can lead to stronger responses.

Cont'd... (ADRS): Idiosyncratic/Physical/Carcinogenic Effects

Idiosyncratic: unusual response due to predisposition.
Physical dependence, e.g., withdrawal when certain drugs are discontinued, during long-term use (opioids, barbiturates).
Carcinogenicity: some mediators/chemicals cause cancer. Even though numerous compounds have been identified, few are therapeutically used.
Iatrogenic Effects: unwanted responses during treatment, e.g., dermatological reactions, hepatic toxicity, Cushing's syndrome and teratogenic effects.
Teratogenic effects: drug-induced birth defects.

G Protein-Coupled Receptors (GPCRs)

Receptors that interact with G proteins (e.g., Gs, Gq, Gi).
Different G-protein types and associated receptors signal the stimulation of different intracellular pathways.
- The different pathways that signal through respective G proteins initiate different downstream effects / result in different physiological response.

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Description

This quiz tests your knowledge on key pharmacology concepts such as Therapeutic Index, Median Lethal Dose, and the risk-benefit ratio. You'll also explore how factors modify drug dosage and the methods used to understand dose-response relationships. Perfect for students and professionals in the field of pharmacology.