PART 1 — OVERVIEW OF DRUG INTERACTIONS

1. Definition of Drug Interaction

• A drug interaction occurs when one drug alters the pharmacological effect of another drug that is used at the same time.
• The interaction may affect:
• Pharmacokinetics (PK)
• Pharmacodynamics (PD)
• Or occur before either PK or PD (pharmaceutical level).

👉 Key exam logic:

Interaction ≠ adverse effect by itself.

Interaction = one drug modifies another drug.

2. Broad Classification of Drug Interactions

Drug interactions are classified into three major categories:

1. Pharmaceutical interactions
2. Pharmacokinetic interactions
3. Pharmacodynamic interactions

This classification is based on WHERE and HOW the interaction occurs.

3. Pharmaceutical Interactions

(Interaction BEFORE the drug enters systemic circulation)

Definition

• Pharmaceutical interaction occurs when the activity of the object drug is altered at the site of action or formulation level by the precipitant drug.

👉 This happens outside the body or immediately at administration.

3.1 Direct Pharmaceutical Interactions

• Occur when two drugs with similar or opposing pharmacological effects are used together.
• The interaction is due to direct pharmacological action, not metabolism or absorption.

Types of direct interactions

1. Antagonism
• One drug reduces or blocks the effect of another drug.
2. Summation
• Combined effect = sum of individual effects.
3. Potentiation
• One drug with little or no effect alone enhances the effect of another drug.
4. Synergism
• Combined effect is greater than the sum of individual effects.

3.2 Indirect Pharmaceutical Interactions

• One drug affects a precursor or intermediate, which then leads to a pharmacodynamic interaction.
• The drugs do not act on the same receptor directly, but the pathway is shared.

3.3 Physicochemical Pharmaceutical Interactions

• Occur when two intravenous (IV) drugs are mixed together.
• Can result in:
• Precipitation
• Inactivation
• Loss of efficacy
• This is a pure chemical incompatibility, not a biological effect.

4. Transition Point (Exam Anchor)

• Pharmaceutical interactions occur:
• Before absorption
• At formulation or administration level
• Pharmacokinetic interactions occur:
• During ADME
• Pharmacodynamic interactions occur:
• At the receptor / target level

👉 Examiners often ask:

“At what level does this interaction occur?”

PHARMACOKINETICS (PK): CORE FRAMEWORK

(What the body does to the drug)

1. Definition of Pharmacokinetics

• Pharmacokinetics (PK) describes what the body does to the drug after administration.(what will happen to the drug)
• It explains:
• How the drug enters the body
• How it moves within the body
• How it is modified
• How it is removed

2. Components of Pharmacokinetics (ADME)

Pharmacokinetics encompasses four sequential processes:

1. Absorption
2. Distribution
3. Metabolism
4. Elimination

👉 These processes determine:

• Onset of action
• Intensity of effect
• Duration of action
• Risk of toxicity

3. ABSORPTION

(Movement of drug from site of administration into systemic circulation)

Definition

• Absorption is the process by which a drug moves from its site of administration into the bloodstream.

3.1 Mechanisms of Drug Transport Across Membranes

Drugs cross biological membranes by five main mechanisms:

1. Simple (passive) diffusion
2. Carrier-mediated transport
3. Solute Carrier (SLC) transporters
4. ATP Binding Cassette (ABC) transporters
5. Pinocytosis

3.2 Simple (Passive) Diffusion

• Most common mechanism.
• Drug moves:
• From high concentration → low concentration
• Requires:
• Lipid solubility
• Un-ionized form

3.3 Importance of Lipid Solubility

• Lipid solubility is crucial for absorption.
• Lipid-soluble drugs:
• Cross membranes easily
• Are absorbed efficiently

3.4 Acid–Base Nature of Drugs

• Most drugs are weak acids or weak bases.
• Degree of ionization depends on:
• pH of the medium
• pKa of the drug

Ionization rules

• Weak acids
• Ionized in basic medium
• Weak bases
• Ionized in acidic medium

👉 Un-ionized molecules are:

• More lipid soluble
• More easily absorbed

3.5 Lipid-Soluble vs Water-Soluble Drugs

Lipid-soluble drugs

• Cross membranes easily
• Absorbed well from:
• Stomach
• Duodenum

Water-soluble drugs

• Do not cross membranes by diffusion
• Require:
• Facilitated diffusion
• Active transport via carriers
• Example transport pathways:
• Ion channels
• Carrier proteins

4. ROUTES OF ADMINISTRATION

(How drugs are delivered into the body)

Routes are divided into three main groups.

4.1 Systemic Routes

(Drug intended to reach systemic circulation)

A. Enteral routes

• Oral
• Sublingual / Buccal
• Rectal

B. Parenteral routes

• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Transdermal (TD)
• Pulmonary
• Intranasal

4.2 Local Routes

(Systemic absorption not expected)

• Topical
• Intra-articular
• Intrathecal
• Intra-arterial

4.3 Why Most Drugs Are Given Orally

• Oral route is preferred unless:
• Oral intake is impossible (e.g. unconscious patient)
• Drug is destroyed, altered, or not absorbed orally
• Example: insulin

5. Transition Anchor (Exam Logic)

• Absorption determines:
• Whether the drug reaches circulation
• How fast it starts acting
• Failure of absorption = no clinical effect, regardless of dose

DRUG DISTRIBUTION

(Where the drug goes after absorption)

1. Definition of Drug Distribution

• Drug distribution refers to the reversible transfer of a drug from the systemic circulation to different tissues and organs.
• It determines:
• Which tissues the drug reaches
• How much drug reaches each tissue
• Duration of drug action

2. Body Compartments for Drug Distribution

After entering the bloodstream, drugs distribute into two main compartments:

2.1 Central Compartment

• Intravascular compartment
• Includes:
• Blood
• Plasma
• Drugs enter this compartment first after absorption or IV administration.

2.2 Peripheral Compartment

• Extravascular compartment
• Subdivided into:
• Interstitial space
• Intracellular space

3. Purposeful Distribution

• Most drugs are designed to:
• Reach systemic circulation
• Some drugs are deliberately intended to:
• Cross the blood–brain barrier (e.g. meningitis treatment)
• Concentrate in the urinary tract (e.g. UTIs)

👉 Distribution is therefore drug-specific and effect-driven.

4. Factors Affecting Drug Distribution

Distribution is influenced by multiple physiological and drug-related factors:

4.1 Lipid Solubility

• Lipid-soluble drugs:
• Cross membranes easily
• Enter tissues readily
• Water-soluble drugs:
• Remain mainly in plasma/interstitial fluid

4.2 Capillary Permeability

• Highly permeable capillaries:
• Liver
• Kidney
• Poorly permeable capillaries:
• Brain (tight junctions)

4.3 Organ Perfusion

• Organs with high blood flow receive drugs faster:
• Brain
• Liver
• Kidneys
• Heart

4.4 Biological Barriers

Drug movement is restricted by specialized tissue barriers:

• Blood–brain barrier (BBB)
• Blood–CSF barrier
• Placental barrier
• Intercellular tight junctions
• Efflux transporters (e.g. P-glycoprotein)

4.5 Plasma Protein Binding

• Drugs may bind to:
• Albumin
• Other plasma proteins
• Only free (unbound) drug:
• Is pharmacologically active
• Can cross membranes
• Can be eliminated

4.6 Tissue Binding

• Some drugs bind strongly to tissues:
• Fat
• Bone
• Acts as a drug reservoir
• Prolongs duration of action

5. Drug Transport Across the Placenta

Placental transfer depends on:

1. Molecular size
2. Ionization and lipid solubility
3. Plasma protein binding
4. Presence of transporters

👉 Small, lipid-soluble, non-ionized, non–protein-bound drugs cross more easily.

6. Summary of Tissue Barriers (Exam List Reminder)

• Blood–brain barrier
• Blood–CSF barrier
• Placental barrier
• Tight intercellular junctions
• Efflux transporters

7. Transition Anchor (Exam Logic)

• Distribution explains:
• CNS effects
• Placental drug exposure
• Drug accumulation
• Poor distribution = poor therapeutic effect, even with adequate absorption.

BIOAVAILABILITY & VOLUME OF DISTRIBUTION

(Quantifying how much drug reaches circulation and where it resides)

1. BIOAVAILABILITY (F)

Definition

• Bioavailability is the amount or fraction of an administered drug dose that reaches the systemic circulation in an unchanged form.

2. Determinants of Bioavailability

Bioavailability is determined by two main factors:

2.1 Extent of Absorption

• How much of the drug is absorbed from the site of administration into the bloodstream.

2.2 First-Pass Metabolism

• Metabolism of the drug during its first passage through the liver before reaching systemic circulation.

3. Route-Dependent Bioavailability

Intravenous (IV) Drugs

• Bioavailability = 100%
• Reason:
• Drug is delivered directly into systemic circulation
• No absorption barriers
• No first-pass metabolism

4. Factors Affecting Oral Bioavailability

Drug-related factors

• Lipid solubility
• Dissolution rate

Absorption-related factors

• Gastrointestinal pH
• Gastrointestinal motility
• Gastrointestinal disease
• Food
• Drug–drug interactions

Metabolism-related factor

• First-pass hepatic metabolism

5. Clinical Importance of Bioavailability

• Determines:
• Effective oral dose
• Dose adjustments when switching routes
• Poor bioavailability:
• ↓ therapeutic efficacy
• ↑ variability between patients

6. VOLUME OF DISTRIBUTION (Vd)

Definition

• Volume of distribution is the theoretical volume required to contain the entire administered drug dose at the same concentration as that measured in plasma after distribution.

7. Formula for Volume of Distribution

• Vd = Dose / Plasma concentration

8. Interpretation of Volume of Distribution

Large Vd

• Indicates extensive distribution into tissues
• Common with fat-soluble drugs
• Drug stored in:
• Fat
• Muscle
• Results in:
• Prolonged duration of action

Small Vd

• Drug largely confined to plasma
• Common with:
• Highly protein-bound drugs
• Water-soluble drugs

9. Clinical Significance of Volume of Distribution

• Determines loading dose
• Influences:
• Duration of action
• Half-life
• Important in:
• Obesity
• Cachexia
• Pregnancy

10. Conceptual Clarification (Exam Logic)

• Bioavailability answers:
• “How much drug gets into the circulation?”
• Volume of distribution answers:
• “Where does the drug go once it is in circulation?”

PART 5 — DRUG METABOLISM

(How the body chemically modifies drugs)

1. Purpose of Drug Metabolism

• Drug metabolism chemically alters the original drug.
• Main aims:
• Make drugs more water-soluble
• Facilitate elimination from the body
• Metabolism occurs mainly in the liver, but also in:
• Intestine
• Kidneys
• Lungs (minor role)

2. General Principles

• Many drugs are lipid soluble → cannot be excreted easily.
• Metabolism converts them into:
• More polar
• More water-soluble compounds
• These metabolites may be:
• Inactive
• Active
• Toxic

3. PHASE I METABOLISM

(Functionalization reactions)

3.1 Nature of Phase I Reactions

• Includes:
• Oxidation
• Reduction
• Hydrolysis
• Main enzyme system:
• Cytochrome P450 (CYP450) enzyme complex

3.2 Cytochrome P450 Enzyme System

• Located mainly in:
• Liver microsomes
• Responsible for metabolism of most clinically used drugs
• Activity can be:
• Induced
• Inhibited

→ leading to drug interactions

3.3 Outcomes After Phase I Metabolism

After Phase I, drugs can become:

A. Inactive metabolites

• Most common outcome
• Drug converted into biologically inert compounds

B. Active metabolites

• Occurs when the parent drug:
• Is a prodrug
• Is better delivered in inactive form
• CYP450 converts it to the active form
• Examples:
• Enalapril
• Diazepam

C. Toxic metabolites

• Occurs rarely at therapeutic doses
• More likely in overdose
• Drug is shunted into alternative red-ox pathways
• Classic example:
• Paracetamol overdose → toxic metabolites

4. PHASE II METABOLISM

(Conjugation reactions)

4.1 Purpose of Phase II

• Further increase water solubility
• Facilitate:
• Renal excretion
• Biliary excretion

4.2 Nature of Phase II Reactions

• Drug (or Phase I metabolite) is conjugated with another compound
• Produces:
• Highly polar
• Water-soluble metabolites

4.3 Common Conjugation Pathways

A. Glucuronidation

(mainly for basic drugs)

• Examples:
• Paracetamol
• Morphine

B. Acetylation

(mainly for acidic drugs)

• Examples:
• Hydralazine
• Procainamide
• Isoniazid

C. Sulphation

• Example:
• Oral contraceptives

5. Fate of Conjugated Metabolites

Once conjugated, drugs are excreted via:

5.1 Urine

• Via renal filtration from hepatic blood flow

5.2 Bile

• If molecular weight > 300 Da
• Excreted into:
• Intestine
• Faeces

5.3 Canalicular Secretion

• Canalicular membrane transporters actively secrete conjugated metabolites into bile.

6. Enterohepatic Circulation

• Some drugs are:
• Excreted into bile
• Broken down by colonic bacteria
• Reabsorbed from lower GI tract
• Leads to:
• Prolonged drug action
• Example:
• Combined oral contraceptive pill

7. Key Exam Transition Logic

• Phase I = modification
• Phase II = conjugation
• Both aim to:
• Increase water solubility
• Enable elimination
• Failure of metabolism → drug accumulation and toxicity

PART 6 — DRUG ELIMINATION

(How the drug leaves the body)

1. Definition of Drug Elimination

• Drug elimination refers to the irreversible removal of a drug from the body.
• Drugs may be eliminated:
• Unchanged
• Or as metabolites

2. Major Routes of Drug Elimination

Drugs are eliminated by three main routes:

1. Renal
2. Biliary
3. Pulmonary

3. Dependence on Water Solubility

• Renal and biliary elimination depend largely on water solubility.
• Lipid-soluble drugs:
• Tend to be reabsorbed
• Require metabolism before elimination

4. RENAL ELIMINATION

(Most important route for many drugs)

Renal elimination depends mainly on:

• Glomerular filtration rate (GFR)
• Plasma protein binding
• Tubular secretion
• Tubular reabsorption

4.1 Glomerular Filtration

• Drugs with molecular weight < 500 Da are filtered.
• Very large drugs:
• Example: heparin
• Are not renally excreted

Plasma protein binding effect

• Highly protein-bound drugs (e.g. warfarin):
• Are poorly filtered
• Reason:
• Protein carriers are negatively charged
• Repelled by the glomerular basement membrane (GBM)
• Only free (unbound) drug is filtered.

4.2 Tubular Secretion

• Occurs mainly in the proximal convoluted tubule (PCT).
• This is an active process.
• Depends on drug transporters.

Transporter specificity

Anion transporters (acidic drugs):

• Penicillins
• Cephalosporins
• Salicylates
• Frusemide

Cation transporters (basic drugs):

• Morphine
• Pethidine
• Amiloride
• Quinine

4.3 Tubular Reabsorption

• Occurs mainly by passive diffusion.
• Driven by:
• Drug concentration gradient
• Lipid solubility
• Lipid-soluble drugs:
• Can diffuse back into circulation
• Once a drug reaches the ascending limb of the loop of Henle:
• It will invariably be excreted in urine

5. BILIARY ELIMINATION

• Drugs or metabolites with:
• Molecular weight > 300 Da
• Are excreted into bile.
• Eliminated via:
• Faeces
• Active secretion via:
• Canalicular membrane transporters

6. PULMONARY ELIMINATION

• Relevant mainly for:
• Volatile substances
• Gases
• Eliminated via:
• Expired air

7. CLEARANCE (Cl)

Definition

• Clearance is the volume of plasma from which a drug is completely removed per unit time.

Formula

• Cl = Rate of elimination / Plasma concentration

Clinical importance

• Determines:
• Maintenance dosing rate
• Steady-state concentration

8. HALF-LIFE (t½)

Definition

• Time taken for plasma drug concentration to fall by 50%.

Determinants

• Volume of distribution (Vd)
• Clearance (Cl)

Formula

• t½ = 0.693 × Vd / Cl

9. Factors Influencing Half-Life

• Aging
• Obesity
• Liver failure
• Renal failure
• Cardiac failure
• CYP450 induction or inhibition

10. Clinical Significance of Half-Life

• Determines:
• Duration of drug action
• Time to reach steady state
• Predicts:
• Drug concentration–time relationship

ORDER OF PHARMACOKINETIC PROCESSES & KINETICS

(How PK processes behave over time)

1. Order of Pharmacokinetic Processes

Pharmacokinetic processes (absorption, distribution, metabolism, elimination) follow defined kinetic patterns that determine how drug concentration changes with time.

Two main kinetic patterns are described:

1. First-order kinetics
2. Zero-order kinetics

2. FIRST-ORDER KINETICS

(Most common in clinical practice)

Definition

• The rate of the process is proportional to the amount of drug available.

Key Characteristics

• A fixed fraction of drug undergoes the process per unit time.
• As drug concentration increases:
• Rate of the process increases proportionally.
• Produces a linear relationship between dose and plasma concentration.

Processes that follow first-order kinetics

• Absorption (by simple diffusion)
• Distribution
• Most drug elimination processes at therapeutic doses

Clinical implication

• Predictable dosing
• Safe dose adjustments
• Plasma concentration rises gradually with dose increase

3. ZERO-ORDER KINETICS

(High-risk, exam-important)

Definition

• The rate of the process does NOT increase with increasing drug concentration.

Mechanism

• Occurs due to saturation of a kinetic process, such as:
• Enzymatic metabolism
• Plasma protein binding
• Tubular secretion

Key Characteristics

• A fixed amount of drug is processed per unit time.
• Increasing the dose causes:
• Disproportionate rise in plasma concentration
• Results in a non-linear relationship.

Clinical danger

• Small dose increase → sharp increase in plasma drug level
• High risk of toxicity

4. Examples of Processes Showing Zero-Order Kinetics

• Enzymatic metabolism (when enzymes are saturated)
• Plasma protein binding (at high concentrations)
• Tubular secretion

5. Exam Transition Logic

• First-order kinetics → safe, predictable, linear
• Zero-order kinetics → saturation, unpredictable, dangerous

Examiners often ask:

“Why does toxicity suddenly appear despite small dose increases?”

Answer:

Zero-order kinetics due to saturation

DRUG MONITORING & SPECIAL CLINICAL SITUATIONS

(When and why drug levels must be monitored)

1. General Principle of Drug Monitoring

• The vast majority of drugs do NOT require close monitoring if:
• Recommended doses are used
• Proper dosing intervals are followed
• Certain drugs require close monitoring of plasma levels because:
• Small changes in dose can cause toxicity
• Therapeutic and toxic doses are close

2. Factors Determining the Need for Drug Monitoring

Drug monitoring is required depending on the following factors:

2.1 Narrow Therapeutic Window

• Therapeutic window = range between:
• Minimum effective concentration
• Minimum toxic concentration
• The narrower the window, the higher the risk of:
• Ineffectiveness (subtherapeutic)
• Toxicity (supratherapeutic)

Example

• Antiepileptic drugs (AEDs)
• Low levels → increased fit frequency
• High levels → toxicity

2.2 Intrinsic Toxicity of the Drug

• Drugs with serious or irreversible side effects require monitoring.

Example

• Gentamicin
• Nephrotoxicity
• Ototoxicity (vestibular component of VIII cranial nerve)
• Minor side effects are less important from a monitoring perspective.

2.3 Impaired Renal or Hepatic Function

• Renal or liver disease:
• ↓ drug clearance
• ↑ plasma drug concentration
• ↑ risk of toxicity
• Monitoring is essential in:
• Chronic kidney disease
• Chronic liver disease

2.4 Special Clinical Circumstances

Certain situations alter pharmacokinetics or increase risk of harm:

• Pregnancy
• Breastfeeding
• Extremes of age
• Paediatric patients
• Very elderly patients

These patients handle drugs differently, requiring careful dosing and monitoring.

3. Weight- and Height-Based Dosing

• Some drugs require dosing based on:
• Body weight
• Body surface area

Example

• Methotrexate

Monitoring is critical to avoid toxicity.

4. Summary Exam Anchor

Drug monitoring is required when there is:

• Narrow therapeutic index
• High intrinsic toxicity
• Impaired elimination
• Altered physiology (pregnancy, age extremes)

PART 9 — PREGNANCY & PHARMACOKINETICS

(How pregnancy alters drug handling)

1. General Principle

• In pregnancy, physiological changes are very large.
• The major effect is on drug handling (pharmacokinetics) rather than on intrinsic drug actions (pharmacodynamics).

2. Major Physiological Changes in Pregnancy Affecting PK

2.1 Circulating Volume

• Large increase in circulating blood volume (40–50%)
• increase vd
• Leads to:
• Dilution of drugs
• Lower plasma drug concentrations

2.2 Renal Blood Flow and GFR

• Marked increase in renal blood flow
• Increased glomerular filtration rate (GFR)
• Results in:
• Increased renal clearance of many drugs

2.3 Third Space Expansion

• Increased availability of:
• Amniotic fluid
• Peripheral oedema
• Acts as an additional drug distribution compartment

2.4 Body Fat Content

• Increased maternal fat stores
• Leads to:
• Increased storage of fat-soluble drugs
• Prolonged drug availability

2.5 Plasma Proteins

• Reduced albumin and other binding proteins
• Due to plasma dilution
• Results in:
• Increased free (unbound) drug fraction

2.6 Metabolic and Endocrine Changes

• Progressive insulin resistance
• Alters drug requirements, especially:
• Antidiabetic drugs

3. Effect of Pregnancy on ADME

3.1 Absorption

• Reduced gastric emptying
• Reduced intestinal motility
• Reduced gastric acid production

3.2 Distribution

• Increased total body water:
• Intravascular (IV)
• Extravascular (EV)
• Increased body fat
• Reduced albumin

3.3 Metabolism

Changes in hepatic enzymes:

• Increased activity of:
• CYP3A4
• CYP2A6
• CYP2D6
• CYP2C9

(e.g. metabolism of nifedipine, glibenclamide)

• Reduced activity of:
• CYP1A2
• CYP2C19
• Increased UGT1A4 activity
• Increased metabolism of lamotrigine
• Increased hepatic blood flow

3.4 Elimination

• Increased renal blood flow
• Increased GFR
• Increased clearance of renally eliminated drugs

Examples:

• Lithium
• Beta-lactam antibiotics
• Atenolol

4. Net Pharmacokinetic Effect in Pregnancy

• Increased clearance of most drugs
• Leads to:
• Reduced serum drug concentrations
• Reduced efficacy in some cases
• Single-dose therapy may be less effective.

5. Drugs Requiring Close Monitoring and Dose Adjustment in Pregnancy

5.1 Anticonvulsants

• Carbamazepine
• Phenytoin
• Valproate
• Lamotrigine
• Gabapentin

Reason:

• Seizure frequency closely related to serum levels

5.2 Mood Stabilisers

• Lithium
• Narrow therapeutic index
• Toxicity is significant

5.3 Endocrine Disorders

• Hypothyroidism
• Thyroxine dose must be increased to maintain euthyroidism

5.4 Diabetes Mellitus

• Progressive insulin resistance
• Requires:
• Increasing doses of insulin as pregnancy advances

6. Drugs Less Affected by Pregnancy-Related PK Changes

6.1 Highly Protein-Bound Drugs

• Reduced albumin → increased free fraction
• Net effect on active drug may be minimal

Example:

• Warfarin

6.2 Fat-Soluble Drugs

• Increased fat reservoir
• Slower release
• Prolonged availability

Example:

• Chloroquine

PART 10 — PHARMACODYNAMICS (PD)

(What the drug does to the body)

1. Definition of Pharmacodynamics

• Pharmacodynamics describes the effects of a drug on the body.
• It explains:
• How drugs produce their effects
• Where drugs act
• The relationship between drug concentration and effect

2. Nature of Drug Action

• Some drugs act by physicochemical actions outside cells.
• Others act by binding to specific biological targets.

3. Drugs with Physicochemical Action Outside Cells

These drugs do not require receptors.

Examples

• Antacids
• Osmotic diuretics
• Ion-exchange resins

4. Drug Targets

(Five major categories)

Drugs exert effects by acting on five main types of targets:

1. Receptors
2. Ion channels
3. Enzymes
4. Transporters (carrier molecules)
5. Intracellular targets

5. RECEPTORS

Definition

• Receptors are proteins that:
• Specifically bind ligands (drugs or endogenous substances)
• Produce a biological response

5.1 Types of Ligands Acting on Receptors

• Agonists
• Full agonist
• Partial agonist
• Antagonists
• Competitive
• Non-competitive
• Mixed agonist–antagonists
• Inverse agonists
• Full
• Partial

5.2 Endogenous Agonists

• Most receptors have natural (endogenous) agonists.
• Drugs mimic or block these physiological ligands.

5.3 Types of Receptors

A. Direct ligand-gated ion channel receptors

• Drug binding directly opens or closes ion channels.

B. G-protein–coupled receptors (GPCRs)

• Also called metabotropic receptors
• Indirectly linked to ion channels
• Act via G proteins
• Signal transduction occurs via second messengers

C. Receptors with enzymatic cytosolic domains

• Drug binding activates intrinsic enzyme activity
• Leads to intracellular signaling cascades

D. Intracellular receptors

• Located inside the cell
• Drug must cross the cell membrane
• Often regulate gene transcription

6. ION CHANNELS

Definition

• Ion channels are membrane proteins that:
• Allow ions to move along their electrochemical gradient

Types of Ion Channels

• Ligand-gated ion channels
• Voltage-gated ion channels
• Example: potassium (K⁺) channels

Drug Actions on Ion Channels

• Drugs may:
• Open ion channels
• Block ion channels

7. TRANSPORTERS (CARRIER MOLECULES)

Definition

• Transporters move substances across membranes.

Types of Transporters

Energy-independent transporters

• Uniport
• Symport
• Antiport

Energy-dependent pumps

• Na⁺/K⁺ ATPase
• H⁺/K⁺ ATPase

8. ENZYMES

Drug–Enzyme Interactions

• Drugs may:
• Inhibit enzymes
• Activate enzymes (less common)

Types of Enzyme Inhibition

Competitive inhibition

• Drug binds to the same site as the substrate

Non-competitive inhibition

• Drug binds elsewhere
• Inactivates the enzyme

Exam Anchor (End of Part 10)

• PD = effect
• PK = handling
• Targets explain:
• Selectivity
• Side effects
• Toxicity

DOSE–RESPONSE RELATIONSHIP, POTENCY, EFFICACY & RECEPTOR REGULATION

1. Drug–Target Binding Principles

• Drugs bind to their targets via weak, reversible bonds.
• Binding is:
• Selective
• Reversible
• Selective binding leads to specific pharmacological effects.

2. Major Drug Effects (Conceptual Framework)

Drug effects are explained using four linked concepts:

1. Fractional occupancy
2. Ligand–receptor binding
3. Dose–response relationship
4. Receptor activation

3. Dose–Response Relationship

• Describes the relationship between:
• Drug dose (or concentration)
• Magnitude of biological response
• Typically represented as a dose–response curve.

4. POTENCY

Definition

• Potency is the amount (dose) of a drug required to produce a given effect.

Expression

• Expressed as EC50:
• The concentration producing 50% of maximal effect

Interpretation

• A more potent drug:
• Requires a lower dose to produce the same effect
• Potency reflects:
• Affinity of the drug for the receptor

5. EFFICACY

Definition

• Efficacy is the maximum response a drug can produce, regardless of dose.

Expression

• Expressed as Emax

Interpretation

• A drug with:
• High efficacy → produces large maximal effect
• Low efficacy → produces limited maximal effect
• Efficacy reflects:
• Ability to activate intracellular response after binding

6. Distinction Between Potency and Efficacy (Exam Classic)

• Potency:
• “How much drug is needed?”
• Efficacy:
• “How big is the effect?”

A drug may be:

• Highly potent but low efficacy
• Less potent but high efficacy******

7. Receptor Conformational States

• Receptors exist in two conformations:
• Inactive state
• Active state
• Drugs shift equilibrium between these states:
• Agonists → favor active state
• Antagonists → block activation
• Inverse agonists → favor inactive state

8. Regulation of Receptor Expression

8.1 Receptor Sequestration

• Receptors may be:
• Internalised into endosomes
• Later recycled back to the membrane

8.2 Receptor Up-Regulation

• Increase in receptor number
• Occurs when receptors are chronically blocked

8.3 Receptor Down-Regulation

• Decrease in receptor number
• Occurs with chronic agonist exposure

9. TOLERANCE

Definition

• Tolerance is a diminishing response to a drug after repeated or prolonged use.

Mechanisms of Tolerance

1. Receptor desensitisation
• Reduced receptor responsiveness
2. Receptor down-regulation
• Fewer receptors available
3. Reduced signal transduction
• Impaired intracellular response
4. Compensatory physiological mechanisms
• Body counteracts drug effect

10. Exam Transition Anchor

• Tolerance explains:
• Loss of drug effect over time
• Need for increasing doses
• Central to understanding:
• Opioids
• Benzodiazepines
• Nitrates

DRUG INTERACTIONS

(Mechanisms by which one drug alters another)

1. Definition of Drug Interaction

• A drug interaction occurs when one drug alters the pharmacokinetics and/or pharmacodynamics of another drug taken at the same time.
• The more drugs a person takes, the higher the likelihood of interactions.

2. Mechanisms of Drug Interactions

Drug interactions occur mainly by:

1. Enzyme induction
2. Enzyme inhibition
3. Individual (specific) effects

3. ENZYME INDUCTION

Definition

• Enzyme induction occurs when a drug increases the activity of hepatic metabolic enzymes, mainly the cytochrome P450 enzyme complex.

Consequences

• ↑ Metabolism of affected drugs
• ↓ Plasma drug levels
• ↓ Drug efficacy

Key Example

• Phenytoin
• Potent inducer of CYP450
• Leads to reduced levels of:
• Combined oral contraceptive pill (COCP)
• Warfarin

Other Enzyme Inducers

• Carbamazepine
• Phenobarbitone
• Rifampicin
• Griseofulvin
• Spironolactone
• Ethanol (chronic use)

4. ENZYME INHIBITION

Definition

• Enzyme inhibition occurs when a drug reduces or blocks hepatic enzyme activity, slowing drug metabolism.

Consequences

• ↓ Drug metabolism
• ↑ Plasma drug levels
• ↑ Risk of toxicity and side effects

Key Example

• Sulphonamides
• Inhibit hepatic metabolism
• Increase plasma levels of:
• Phenytoin

Other Enzyme Inhibitors

• Ethanol (acute use)
• Cimetidine
• Amiodarone
• Ketoconazole
• Fluconazole
• Metronidazole
• Ciprofloxacin
• Erythromycin

5. INDIVIDUAL (SPECIFIC) DRUG EFFECTS

Definition

• Interactions that occur via unique mechanisms not directly related to enzyme induction or inhibition.

Key Example

• Ampicillin
• Alters gut bacterial flora
• ↓ Enterohepatic recirculation of oestrogens
• ↓ Efficacy of COCP

6. Populations at Higher Risk of Drug Interactions

Interactions are more pronounced in:

• Very young patients
• Very elderly patients
• Patients with:
• Renal impairment
• Hepatic impairment

7. Exam Anchor

• Enzyme induction → ↓ levels → treatment failure
• Enzyme inhibition → ↑ levels → toxicity
• Individual effects → mechanism-specific

ADVERSE & TOXIC EFFECTS OF DRUGS

(Undesirable effects of drug therapy)

1. Definitions

1.1 Adverse Drug Effect

• An adverse effect is an undesirable effect produced by a drug at intended therapeutic doses.

1.2 Toxic Effect

• A toxic effect is an undesirable effect produced when a drug is taken at supratherapeutic (toxic) doses.

2. Types of Adverse Drug Effects

Adverse effects are broadly classified into two types:

2.1 Predictable Adverse Effects

• Directly related to the known pharmacodynamic action of the drug.
• Dose dependent
• More common

Example

• Hypoglycaemia with insulin
• Exaggeration of intended glucose-lowering effect

2.2 Unpredictable Adverse Effects

• Not related to the known pharmacodynamic action of the drug.
• Not dose dependent
• Occur in susceptible individuals

3. Mechanisms of Adverse and Toxic Effects

Adverse and toxic effects occur due to several mechanisms:

3.1 Exaggeration of Intended Mechanism

• Excessive action at the intended target
• Dose related

3.2 Intended Mechanism Acting in Unintended Organs

• Drug acts on the correct receptor
• But in a different tissue, producing side effects

3.3 Unintended Mechanisms (Off-Target Effects)

• Drug interacts with unexpected targets
• Leads to side effects unrelated to therapeutic action

3.4 Immune-Mediated Reactions

Includes:

• Hypersensitivity reactions
• Autoimmune reactions

3.5 Toxic Metabolites

• Drug metabolized into harmful compounds
• Risk increased in:
• Overdose
• Enzyme pathway saturation

4. Predisposing Factors for Adverse Effects

Certain factors increase susceptibility to adverse or toxic effects:

4.1 Extremes of Age

• Neonates
• Elderly

4.2 Co-morbidities

• Renal disease
• Liver disease
• Cardiac disease

4.3 Multiple Drug Therapy

• Polypharmacy increases:
• Drug–drug interactions
• Adverse effect risk

4.4 Genetic Factors

• Differences in:
• Drug-metabolizing enzymes
• Receptor sensitivity

5. Exam Transition Anchor

• Adverse effect ≠ toxicity
• Predictable effects → dose related
• Unpredictable effects → patient related

THERAPEUTIC INDEX & THERAPEUTIC WINDOW

(Safety margins of drugs)

1. Therapeutic Index (TI)

Definition

• Therapeutic Index is an indicator of the safety of a drug.
• It compares the dose that produces toxicity with the dose that produces therapeutic effect.

Formula

• TI = TD50 / ED50

Where:

• TD50 = dose causing toxicity in 50% of the population
• ED50 = dose causing therapeutic effect in 50% of the population

2. Interpretation of Therapeutic Index

• High TI
• Large safety margin
• Drug is relatively safe
• Low TI
• Narrow margin between efficacy and toxicity
• High risk of adverse effects
• Requires close monitoring

3. Therapeutic Window

Definition

• The therapeutic window is the range of doses or plasma concentrations between:
• The minimum effective dose
• The minimum toxic dose

Key Concepts

• Below the therapeutic window:
• Drug is ineffective
• Above the therapeutic window:
• Drug causes toxicity or significant side effects

4. Clinical Importance of Therapeutic Window

• Most drugs have a wide therapeutic window.
• Some drugs have a narrow therapeutic window, making dosing critical.

Examples of Narrow Therapeutic Window Drugs

• Gentamicin
• Cyclosporin

These drugs:

• Require close plasma level monitoring
• Have high toxicity risk with small dose changes

5. Exam Anchor (Final Conceptual Lock)

• Therapeutic Index = population safety measure
• Therapeutic Window = individual clinical dosing range
• Narrow window → monitoring essential

Concept recall

DRUG INTERACTIONS, PHARMACOKINETICS & PHARMACODYNAMICS — COMPLETE CONCEPT MAP

PART 1 — DRUG INTERACTIONS (BIG PICTURE)

1. Definition of Drug Interaction

• A drug interaction occurs when one drug alters the pharmacological effect of another drug used at the same time.
• The alteration may involve:
• Pharmacokinetics (PK)
• Pharmacodynamics (PD)
• Or occur before PK or PD (pharmaceutical level).

Exam lock:

Interaction ≠ adverse effect.

Interaction = two drugs interacting.

2. Levels of Drug Interactions (Core Classifier)

Drug interactions occur at three levels, defined by WHERE the change happens:

1. Pharmaceutical interactions
2. Pharmacokinetic (PK) interactions
3. Pharmacodynamic (PD) interactions

Exam decision question:

“At what level did the interaction occur?”

PART 2 — PHARMACEUTICAL INTERACTIONS

(Before absorption / at administration level)

3. Definition

• Pharmaceutical interaction occurs when the activity of the object drug is altered at formulation or administration level.
• Occurs outside the body or immediately at administration.

3.1 Direct Pharmaceutical Interactions

(Effect-combination patterns)

1. Antagonism
• One drug reduces or blocks the effect of another.
2. Summation (Additive)
• Combined effect = sum of individual effects.
3. Synergism
• Combined effect greater than the sum.
4. Potentiation
• One drug with little/no effect alone enhances another drug’s effect.

3.2 Indirect Pharmaceutical Interactions

• One drug alters a precursor or intermediate, leading to a downstream effect.
• Drugs do not act on the same receptor, but share a pathway.

3.3 Physicochemical Pharmaceutical Interactions

• Occur when IV drugs are mixed.
• Results in:
• Precipitation
• Inactivation
• Loss of efficacy
• Pure chemical incompatibility, not biological.

4. Transition Anchor

• Pharmaceutical → before absorption
• PK → during ADME
• PD → at receptor/target level

PART 3 — PHARMACOKINETICS (PK)

(What the body does to the drug)

5. Definition

• Pharmacokinetics describes what happens to the drug after administration.
• Explains:
• Entry into body
• Movement
• Modification
• Removal

6. Components of PK (ADME)

1. Absorption
2. Distribution
3. Metabolism
4. Elimination

These determine:

• Onset
• Intensity
• Duration
• Toxicity risk

PART 4 — ABSORPTION

7. Definition

• Movement of drug from site of administration into systemic circulation.

7.1 Mechanisms of Transport

1. Passive diffusion
2. Carrier-mediated transport
3. SLC transporters (Solute carrier family)
4. ABC transporters (efflux) Antibody binging cassette
5. Pinocytosis

7.2 Passive Diffusion

• Most common
• High → low concentration
• Requires:
• Lipid solubility
• Un-ionized form

7.3 pH–pKa Concept

• Most drugs are weak acids or bases.
• Ionization depends on pH and pKa.

Rules:

• Weak acids → ionized in basic medium
• Weak bases → ionized in acidic medium
• Un-ionized = better absorption

7.4 Lipid vs Water Solubility

• Lipid-soluble:
• Cross membranes easily
• Absorbed well
• Water-soluble:
• Require carriers
• Poor passive diffusion

PART 5 — DISTRIBUTION

8. Definition

• Reversible transfer of drug from blood to tissues.

8.1 Compartments

• Central: blood/plasma
• Peripheral: interstitial + intracellular

8.2 Determinants

• Lipid solubility
• Capillary permeability
• Organ perfusion
• Biological barriers (BBB, placenta)
• Efflux transporters (P-glycoprotein)
• Plasma protein binding
• Tissue binding

Key rule:

Only free (unbound) drug is active, crosses membranes, and is eliminated.

PART 6 — BIOAVAILABILITY & VOLUME OF DISTRIBUTION

9. Bioavailability (F)

• Fraction of administered dose reaching systemic circulation unchanged.
• Determined by:
• Extent of absorption
• First-pass metabolism

IV drugs: F = 100%

10. Volume of Distribution (Vd)

• Theoretical volume needed to contain total drug at plasma concentration.

Conceptual formula:

Vd = Dose / Plasma concentration

• Large Vd → extensive tissue distribution
• Small Vd → confined to plasma

PART 7 — DRUG METABOLISM

11. Purpose

• Convert lipid-soluble drugs into water-soluble compounds for elimination.

11.1 Phase I Metabolism

• Oxidation, reduction, hydrolysis
• Enzyme system: CYP450
• Produces:
• Inactive metabolites
• Active metabolites (prodrugs)
• Toxic metabolites (overdose)

11.2 Phase II Metabolism

• Conjugation reactions
• Major pathways:
• Glucuronidation
• Acetylation
• Sulphation

11.3 Enterohepatic Circulation

• Biliary excretion → gut bacteria → reabsorption
• Prolongs drug action

PART 8 — DRUG ELIMINATION

12. Definition

• Irreversible removal of drug (unchanged or metabolized).

12.1 Routes

1. Renal
2. Biliary
3. Pulmonary

12.2 Renal Elimination

• Filtration (free drug only)
• Tubular secretion (PCT transporters)
• Tubular reabsorption (passive diffusion)

12.3 Clearance (Cl)

• Volume of plasma cleared per unit time.
• Determines maintenance dosing.

12.4 Half-Life (t½)

• Time for plasma concentration to fall by 50%.
• Depends on Vd and Cl.

PART 9 — PHARMACOKINETIC KINETICS

13. First-Order Kinetics

• Fixed fraction eliminated per time
• Linear, predictable

14. Zero-Order Kinetics

• Fixed amount eliminated per time
• Saturation
• High toxicity risk

PART 10 — PHARMACODYNAMICS (PD)

(What the drug does to the body)

15. Definition

• Describes drug effects, targets, and concentration–effect relationship.

15.1 Drug Targets

1. Receptors
2. Ion channels
3. Enzymes
4. Transporters
5. Intracellular targets

15.2 Receptor Concepts

• Agonists
• Partial agonists
• Antagonists
• Inverse agonists

PART 11 — DOSE–RESPONSE, POTENCY & EFFICACY

16. Dose–Response Relationship

• Links drug dose/concentration to magnitude of effect.

17. Potency

• Dose required to produce a given effect (EC50).

18. Efficacy

• Maximum effect a drug can produce (Emax).

ED 50= dose of a drug that produces 50% of its maximum therapeutic effect in a population.

TD=Dose that produces toxic effects in 50% of a population

Exam contrast

• ED₅₀: Effect (benefit)
• TD₅₀ / LD₅₀: Toxic / lethal effect
• Therapeutic Index (TI): TD₅₀ ÷ ED₅₀ (safety margin)

PART 12 — THERAPEUTIC INDEX & THERAPEUTIC WINDOW

(CORRECT POSITION)

19. Therapeutic Index (TI)

• Indicator of drug safety.
• Population-based measure.

Concept:

TI = TD50 / ED50

• High TI → safer drug
• Low TI → narrow safety margin

20. Therapeutic Window

• Individual-level safe concentration range.
• Between minimum effective and minimum toxic concentrations.

Exam classic:

TI = population safety

Window = individual dosing

Why this is exam-classic

• Digoxin has a narrow therapeutic window
• Small dose changes → toxicity
• Requires plasma level monitoring
• Dose must be individualized (renal function, age, interactions)

PART 13 — DRUG MONITORING

21. Why Monitoring Is Needed

• Narrow therapeutic window
• High intrinsic toxicity
• Impaired renal/hepatic function
• Pregnancy, paediatrics, elderly
• Weight/BSA-based dosing

PART 14 — SPECIAL STATES (PREGNANCY)

22. Pregnancy & PK Changes

• ↑ blood volume → ↑ Vd
• ↑ GFR → ↑ clearance
• ↓ albumin → ↑ free fraction
• ↑ fat & third spaces
• Altered enzyme activity

Net effect:

Reduced plasma drug concentrations for many drugs.

PART 15 — PK & PD DRUG INTERACTIONS

23. PK Interactions

1️⃣ Enzyme induction → ↓ drug levels

• Rifampicin induces CYP450 → ↓ oral contraceptive levels → contraceptive failure
• Phenytoin / Carbamazepine induce enzymes → ↓ warfarin effect
• Chronic alcohol use → enzyme induction → ↓ drug efficacy

Exam lock: Inducers = treatment failure.

2️⃣ Enzyme inhibition → ↑ drug levels

• Erythromycin / Clarithromycin inhibit CYP450 → ↑ warfarin → bleeding
• Cimetidine inhibits enzymes → ↑ theophylline / phenytoin
• Azole antifungals → ↑ statins → myopathy

Exam lock: Inhibitors = toxicity.

3️⃣ Altered absorption

• Tetracycline + antacids (Ca²⁺/Mg²⁺) → chelation → ↓ absorption
• Iron + levothyroxine → ↓ thyroid hormone absorption

Exam lock: Chelation = ↓ absorption.

4️⃣ Altered protein binding

• Aspirin displaces warfarin from albumin → ↑ free warfarin → bleeding

Exam lock: Highly protein-bound drugs compete.

5️⃣ Altered clearance (renal)

• Probenecid ↓ renal secretion of penicillin → ↑ penicillin levels
• NSAIDs ↓ lithium clearance → lithium toxicity

Exam lock: ↓ clearance = ↑ plasma level.

One-line exam summary

PK interactions change drug concentration by affecting absorption, metabolism, protein binding, or excretion — leading to treatment failure or toxicity.

24. PD Interactions

• Additive
• Synergistic
• Antagonistic
• Occur at same concentration

FINAL EXAM MASTER LOCK

• Pharmaceutical → before absorption
• PK → changes drug concentration
• PD → changes drug effect
• Therapeutic Index → defines safety
• Narrow TI → monitoring required
• Interactions matter most when TI is low