Pharmacology Quiz on Therapeutic Index and Dosage

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.