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Questions and Answers
What is the process of glycine conjugation with?
What is the process of glycine conjugation with?
Which of the following is NOT a factor that decreases the first pass effect?
Which of the following is NOT a factor that decreases the first pass effect?
Which enzyme inducer is known to affect the metabolism of benzodiazepines and paracetamol?
Which enzyme inducer is known to affect the metabolism of benzodiazepines and paracetamol?
What is the result of enzyme induction on microsomal metabolizing enzymes?
What is the result of enzyme induction on microsomal metabolizing enzymes?
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Which of the following is an example of intestinal first pass effect?
Which of the following is an example of intestinal first pass effect?
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What is the result of hepatic enzyme inhibition on the first pass effect?
What is the result of hepatic enzyme inhibition on the first pass effect?
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Which of the following is NOT a consequence of enzyme induction?
Which of the following is NOT a consequence of enzyme induction?
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What is the result of saturation of metabolizing enzymes on the first pass effect?
What is the result of saturation of metabolizing enzymes on the first pass effect?
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Which of the following enzymes is induced by cimetidine?
Which of the following enzymes is induced by cimetidine?
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Which of the following is an example of a pro-drug?
Which of the following is an example of a pro-drug?
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Which of the following routes of excretion involves Glomerular filtration?
Which of the following routes of excretion involves Glomerular filtration?
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Which of the following enzymes is responsible for the metabolism of Suxamethonium?
Which of the following enzymes is responsible for the metabolism of Suxamethonium?
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What is the effect of Erythromycin on drug metabolism?
What is the effect of Erythromycin on drug metabolism?
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What is the result of biotransformation of a drug?
What is the result of biotransformation of a drug?
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Which of the following factors can affect drug metabolism?
Which of the following factors can affect drug metabolism?
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What is the term for the time required for the concentration of a drug in the body to decrease by half?
What is the term for the time required for the concentration of a drug in the body to decrease by half?
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What is the term for the fraction of the administered dose that reaches the systemic circulation?
What is the term for the fraction of the administered dose that reaches the systemic circulation?
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Which of the following is NOT a biological factor that determines bioavailability?
Which of the following is NOT a biological factor that determines bioavailability?
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What is the formula to calculate the Volume of Distribution (Vd)?
What is the formula to calculate the Volume of Distribution (Vd)?
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What is the mechanism by which water-soluble drugs cross the blood-brain barrier?
What is the mechanism by which water-soluble drugs cross the blood-brain barrier?
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Which phase of metabolism involves the addition of an endogenous water-soluble group?
Which phase of metabolism involves the addition of an endogenous water-soluble group?
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What is the type of reaction that involves the oxidation of drugs?
What is the type of reaction that involves the oxidation of drugs?
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Which of the following drugs undergoes acetylation in Phase II metabolism?
Which of the following drugs undergoes acetylation in Phase II metabolism?
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What is the purpose of metabolic processes in the body?
What is the purpose of metabolic processes in the body?
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Which of the following factors decreases the rate and extent of renal excretion of drugs?
Which of the following factors decreases the rate and extent of renal excretion of drugs?
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Which route of excretion is responsible for the elimination of basic drugs such as morphine in cases of poisoning?
Which route of excretion is responsible for the elimination of basic drugs such as morphine in cases of poisoning?
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What is the total clearance of a drug equal to?
What is the total clearance of a drug equal to?
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Which of the following drugs has a clearance that is less than the glomerular filtration rate (GFR)?
Which of the following drugs has a clearance that is less than the glomerular filtration rate (GFR)?
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What is the characteristic of a drug that follows zero-order kinetics?
What is the characteristic of a drug that follows zero-order kinetics?
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What determines the duration of the half-life of a drug?
What determines the duration of the half-life of a drug?
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What is the characteristic of a drug that follows first-order kinetics?
What is the characteristic of a drug that follows first-order kinetics?
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What is the expected clearance of a drug that is excreted by renal tubular secretion?
What is the expected clearance of a drug that is excreted by renal tubular secretion?
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What is the primary reason why t ½ is not indicative of duration of action and dosage schedule in the case of 'hit and run' drugs?
What is the primary reason why t ½ is not indicative of duration of action and dosage schedule in the case of 'hit and run' drugs?
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In a two-compartment model, what is the characteristic of the early distribution phase?
In a two-compartment model, what is the characteristic of the early distribution phase?
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What is the primary factor that determines the time to reach steady state levels in a drug that follows first-order kinetics?
What is the primary factor that determines the time to reach steady state levels in a drug that follows first-order kinetics?
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Which of the following is a characteristic of single dose treatment?
Which of the following is a characteristic of single dose treatment?
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What is the primary reason why multiple dosing is preferred over single dose treatment?
What is the primary reason why multiple dosing is preferred over single dose treatment?
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What is the primary factor that determines the steady state level of a drug that follows first-order kinetics?
What is the primary factor that determines the steady state level of a drug that follows first-order kinetics?
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What is the primary difference between a single-compartment model and a two-compartment model?
What is the primary difference between a single-compartment model and a two-compartment model?
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Which of the following is a variant of dosage schedule?
Which of the following is a variant of dosage schedule?
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What is the primary mechanism by which drugs exert their effects on the body?
What is the primary mechanism by which drugs exert their effects on the body?
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Which type of drug action involves the binding of a drug molecule to the target site, making it inactive by sequestration?
Which type of drug action involves the binding of a drug molecule to the target site, making it inactive by sequestration?
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What is the term for a drug that binds to a site on a receptor protein and activates it to initiate a series of reactions?
What is the term for a drug that binds to a site on a receptor protein and activates it to initiate a series of reactions?
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What is the process by which a drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell?
What is the process by which a drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell?
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What is the primary role of receptors in the process of drug action?
What is the primary role of receptors in the process of drug action?
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Which of the following is an example of a drug that exhibits its action by inhibiting a process or selectively deaccelerating a process?
Which of the following is an example of a drug that exhibits its action by inhibiting a process or selectively deaccelerating a process?
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What is the primary mechanism by which deferoxamine exhibits its action?
What is the primary mechanism by which deferoxamine exhibits its action?
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Which of the following is an example of a drug that exhibits its action by neutralizing the action of an existing molecule?
Which of the following is an example of a drug that exhibits its action by neutralizing the action of an existing molecule?
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What is the characteristic of a drug that has intrinsic activity?
What is the characteristic of a drug that has intrinsic activity?
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Which type of drug has affinity to receptors but produces an effect opposite to that of an agonist?
Which type of drug has affinity to receptors but produces an effect opposite to that of an agonist?
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What is the term for the ratio of the range of effective doses to the range of toxic doses?
What is the term for the ratio of the range of effective doses to the range of toxic doses?
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Which mechanism of drug action involves the binding of a drug to a receptor on the surface of a cell?
Which mechanism of drug action involves the binding of a drug to a receptor on the surface of a cell?
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What is the term for the phenomenon where two drugs produce an effect that is greater than the sum of their individual effects?
What is the term for the phenomenon where two drugs produce an effect that is greater than the sum of their individual effects?
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Which type of drug has affinity to receptors but produces a limited response?
Which type of drug has affinity to receptors but produces a limited response?
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What is the term for the range of doses of a drug that produces a therapeutic effect?
What is the term for the range of doses of a drug that produces a therapeutic effect?
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Which mechanism of drug action involves the binding of a drug to a receptor in the nucleus of a cell?
Which mechanism of drug action involves the binding of a drug to a receptor in the nucleus of a cell?
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What is the result of long-term administration of an antagonist on the receptors?
What is the result of long-term administration of an antagonist on the receptors?
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What is the difference between desensitization and tachyphylaxis?
What is the difference between desensitization and tachyphylaxis?
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What is the mechanism of tolerance to a drug?
What is the mechanism of tolerance to a drug?
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What is the result of receptor subtype variation in drug response?
What is the result of receptor subtype variation in drug response?
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What is the effect of competitive antagonists on agonist responses?
What is the effect of competitive antagonists on agonist responses?
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What is stereoselectivity in drug molecules?
What is stereoselectivity in drug molecules?
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What is the relationship between structure and activity of a drug?
What is the relationship between structure and activity of a drug?
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What is the significance of receptor classes in drug response?
What is the significance of receptor classes in drug response?
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What is the primary difference between potency and efficacy of a drug?
What is the primary difference between potency and efficacy of a drug?
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What is the significance of the EC50 value in a graded dose-response curve?
What is the significance of the EC50 value in a graded dose-response curve?
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What is the primary difference between a full agonist and a partial agonist?
What is the primary difference between a full agonist and a partial agonist?
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What is the significance of the Emax value in a graded dose-response curve?
What is the significance of the Emax value in a graded dose-response curve?
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What is the primary advantage of a drug with high efficacy over a drug with high potency?
What is the primary advantage of a drug with high efficacy over a drug with high potency?
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What is the primary difference between the effect of a full agonist and an antagonist on a receptor?
What is the primary difference between the effect of a full agonist and an antagonist on a receptor?
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What is the primary reason why efficacy is a more clinically useful characteristic than potency?
What is the primary reason why efficacy is a more clinically useful characteristic than potency?
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What is the primary difference between the graded dose-response relationships of a full agonist and a partial agonist?
What is the primary difference between the graded dose-response relationships of a full agonist and a partial agonist?
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Which type of receptor is directly linked to an ion channel that opens and closes in response to agonist binding?
Which type of receptor is directly linked to an ion channel that opens and closes in response to agonist binding?
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What is the typical duration of responses triggered by G protein–coupled receptors?
What is the typical duration of responses triggered by G protein–coupled receptors?
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What is the primary function of the intracellular portion of G protein–coupled receptors?
What is the primary function of the intracellular portion of G protein–coupled receptors?
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Which type of receptor undergoes conformational changes to activate intracellular enzymes?
Which type of receptor undergoes conformational changes to activate intracellular enzymes?
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What is the term for the molecules produced by effectors that further activate other effectors in the cell?
What is the term for the molecules produced by effectors that further activate other effectors in the cell?
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Which of the following receptors is an example of a transmembrane ligand-gated ion channel?
Which of the following receptors is an example of a transmembrane ligand-gated ion channel?
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What is the primary function of G proteins in G protein–coupled receptors?
What is the primary function of G proteins in G protein–coupled receptors?
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Which type of receptor family does not involve a G protein in the signal transduction process?
Which type of receptor family does not involve a G protein in the signal transduction process?
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Study Notes
Pharmacokinetics
- Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation
- Factors that determine bioavailability:
- Biological factors: GIT degradation, food and other drugs, absorption, first-pass metabolism, and entero-hepatic circulation
- Pharmaceutical factors: particle size, disintegration agents, and type of excipient
Distribution
- Volume of distribution (Vd) is the apparent volume in which a drug is distributed in the body
- Calculated by: Vd = Volume of distribution / Cp (plasma concentration per liter at the time of plasma-tissue equilibrium after i.v. injection)
- Distribution involves:
- Blood-brain and CSF barriers: water-soluble drugs cannot filter into CSF or brain; crossing occurs by diffusion or carrier-mediated transport
- Placental barrier
- Plasma protein binding
Metabolism (Biotransformation)
- Metabolic processes convert lipid-soluble drugs into water-soluble products for elimination
- Two types of chemical reactions:
- Phase I reaction (non-synthetic): oxidation, reduction, and hydrolysis by microsomal enzymes
- Phase II reaction (synthetic): conjugation involving addition of an endogenous water-soluble group by transferases enzymes (e.g., glucuronidation, acetylation, methylation)
Metabolism (Biotransformation) - First Pass Effect
- Pre-systemic elimination that occurs after oral administration only
- Includes:
- Intestinal first pass effect (intestinal lumen and intestinal wall)
- Hepatic first pass effect (portal circulation and microsomal enzymes)
- Factors affecting the first pass effect:
- Hepatic diseases (decrease first pass effect)
- Hepatic enzyme induction (increase first pass effect)
- Hepatic enzyme inhibition (decrease first pass effect)
- Saturation of metabolizing enzymes (decrease first pass effect)
Enzyme Induction and Inhibition
- Enzyme induction: microsomal metabolizing enzymes increase, reducing drug efficacy and plasma half-life
- Examples of enzyme inducers and affected drugs:
- Cigarettes (benzpyrene): benzodiazepines, paracetamol, propoxyphine, and theophyline
- Barbiturates (phenobarbitone): barbiturates, phenytoin, warfarin, and doxycycline
- ...
- Enzyme inhibition: microsomal metabolizing enzymes decrease, increasing drug efficacy and plasma half-life
- Examples of enzyme inhibitors and affected drugs:
- Cimetidine: diazepam, phenytoin, antidepressants, and theophylline
- Erythromycin: theophylline, warfarin, and cyclosporine
- ...
Factors Affecting Metabolism
- Age and sex
- Diseases
- Drugs
- Genetic factors
Metabolic Products
- Usually biologically active → biologically inactive
- Or active drug → active metabolite (e.g., diazepam → oxazepam and desmethyldiazepam)
- Pro-drug (inactive) → active metabolite (e.g., prednisone → prednisolone)
- Metabolic product can be toxic (e.g., sulphonamides → acetyl derivative)
Elimination
- Routes of excretion:
- Renal
- Liver (bile excretion)
- Lungs (volatile gases, gaseous anesthetics, and few ethanol)
- Gastrointestinal tract (GIT)
- Breast milk
- Miscellaneous (sweat, saliva, hair, nails, skin)
- Clearance:
- Total clearance = Cl renal + Cl liver + Cl others
- Rate of clearance
- Kinetics of clearance (first-order kinetics and zero-order kinetics)
Elimination - Half-Life (t ½)
- Time taken for circulatory plasma concentration to fall by 50%
- Factors affecting t ½:
- Rate of clearance
- Distribution and storage
- Plasma protein binding
- Expectation of t ½:
- Not indicative of duration of action and dosage schedule in certain cases (e.g., active metabolites, "hit and run" drugs, dose-dependent pharmacokinetics, and pathological conditions)
Pharmacokinetic Models
- Multi-compartment distribution: two-compartment model with an early distribution phase followed by a slower elimination phase
- Single-compartment distribution: some drugs behave as if they are distributed to only one compartment
Steady-State Level (SS)
- When intake of a drug is equal to its elimination, reached after 5 half-lives (t ½)
- Two important points:
- Time to reach SS level is a function of t ½ (5 half-lives) irrespective of dose or dose interval
- SS level reached is a function of dose and dose interval, not of t ½
Dosage Regimen
- Variables to consider:
- Amount of single dose
- Route of administration
- Dose interval
- Total duration of therapy
- Single-dose treatment (e.g., hypnotics, analgesics, and purgatives) and multiple dosing
- Variants of dosage schedule:
- Drugs with short plasma t ½ (e.g., dopamine)
Pharmacodynamics
- Describes the actions of a drug on the body
- Most drugs exert effects by interacting with specialized target macromolecules called receptors, which are present on or in the cell
Fundamentals of Drug Action
- Activation: A drug molecule binds to the target site, stimulating a process or selectively accelerating it (e.g., caffeine causes CNS stimulation and increased alertness)
- Inhibition: A drug molecule binds to the target site, inhibiting a process or selectively deaccelerating it (e.g., aspirin inhibits cyclooxygenase, thereby inhibiting the formation of prostaglandins)
- Complexation: A drug molecule binds to the target site, making a complex, thereby making it inactive by sequestration (e.g., deferoxamine chelates iron)
- Neutralization: A drug molecule binds to the target site, neutralizing the action of the existing molecule directly through a chemical reaction or physical interaction (e.g., antacids, polyvalent anti-snake venom)
Signal Transduction
- Drugs act as signals, and receptors act as signal detectors
- An agonist binds to a site on a receptor protein, activating it to initiate a series of reactions that ultimately result in a specific intracellular response
- "Second messenger" or effector molecules are part of the cascade of events that translates agonist binding into a cellular response
Major Receptor Families
- Transmembrane Ligand-Gated Ion Channels: The channel is usually closed until the receptor is activated by an agonist, which opens the channel for a few milliseconds (e.g., cholinergic nicotinic receptor)
- Transmembrane G Protein-Coupled Receptors: The extracellular portion of this receptor contains the ligand-binding site, and the intracellular portion interacts with a G protein when activated (e.g., α and β adrenoceptors)
- Enzyme-Linked Receptors: This family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity (e.g., growth factors and insulin receptors possess tyrosine kinase activity)
Response of Drug-Receptor Interaction
- Agonists: Drugs that bind to receptors and produce a response (e.g., noradrenaline, acetylcholine)
- Antagonists: Drugs that have affinity to receptors without intrinsic activity (e.g., antiadrenergic)
- Partial Agonists: Drugs that have affinity but very low intrinsic activity
- Inverse Agonists: Drugs that produce actions specifically opposite to those of agonists (e.g., B-carbolines)
Combined Use of Drugs
- Synergism: The combined effect of two drugs is greater than the sum of their individual effects (e.g., additive, potentiation)
- Antagonism: The combined effect of two drugs is less than the sum of their individual effects (e.g., naloxone and opioid drugs)
Therapeutic Index (Safety Margin)
- The range of effective doses and the range of toxic doses are determined in humans
- The therapeutic index is a measure of the safety margin of a drug, which is the ratio of the toxic dose to the effective dose
Mechanism of Drug Action
- On Cell Membrane: Action of receptors, enzymes, and pumps, as well as physico-chemical interactions
- On Intracellular Constituents: Action on cytosolic or nuclear receptors, enzymes, DNA or RNA, and transport carrier molecules
- Outside the Cell: Chemical interaction, physical mechanisms, and antimicrobial action
Structure-Activity and Receptor Classes
- Structure-Activity Relationship: The same receptor type may mediate two effects, and a competitive antagonist will inhibit both responses of the agonist
- Stereoselectivity: Drug molecules have more than one 3-dimensional configuration, with different biological activity for each
- Receptor Classes: There are multiple receptor subtypes for each endogenous ligand (e.g., Ach, NA, H, 5-HT)
Quantitative Variation in Drug Response
- Up and Down Regulation of Receptors: The number of receptors can increase or decrease in response to changes in receptor activity
- Desensitization and Tachyphylaxis: A decrease in responsiveness to a drug due to changes in receptors or the loss of receptors
- Tolerance: A gradual decrease in responsiveness to a drug over time, requiring higher doses to achieve the same effect
- Drug Resistance: A decrease in responsiveness to a drug due to genetic changes or other factors
Dose-Response Relationships
- Graded Dose-Response Relations: The pharmacologic effect of a drug increases gradually as the concentration of the drug increases
- Potency: A measure of the amount of drug necessary to produce an effect, determined by the EC50 (the concentration of drug producing 50% of the maximum effect)
- Efficacy: The magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug-receptor complexes formed and the intrinsic activity of the drug
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Description
This quiz covers the concepts of pharmacokinetics and bioavailability, including the factors that determine bioavailability of a drug in the human body.
