Pharmacology Basics

Compartmental Distribution

• The interstitial compartment holds 12-14 liters of fluid.
• The plasma compartment holds 4 liters of fluid.
• The volume of distribution (Vd) is the apparent volume of fluid required to distribute a drug evenly throughout the body.
• Phenytoin has a Vd of 3-4 liters.
• Aspirin has a Vd of 4 liters.

Selective Distribution

• Iodide is selectively distributed in the thyroid gland.
• Tetracycline is selectively distributed in bone and teeth.
• Calcium is selectively distributed in bones.
• Aminoglycosides (e.g., streptomycin) are selectively distributed in the kidney and vestibular system.

Clinical Importance of Vd

• Vd indicates whether a drug is concentrated intra-vascularly or extra-vascularly.
• Vd is constant for each drug and changes in Vd can indicate disease states (e.g., liver cirrhosis or edematous conditions).
• Dialysis is not useful for drugs with high Vd (extensive tissue distribution).
• Vd helps in estimating the total amount of drug in the body at any time.
• Vd is important for determining the loading dose.

Protein Binding

• There are two forms of a drug: bound and free.
• The bound form is inert, non-diffusible, and not available for metabolism or excretion.
• The free form is active, diffusible, and available for biotransformation and excretion.
• Significance of protein binding:
  • Affects drug interactions.
  • Hypoalbuminemia (e.g., in starvation and malnutrition) can lead to increased free drug concentration.
  • Drugs with high binding capacity persist in the body longer and are less available for dialysis.
  • The rate of injection of a highly bound drug affects the concentration of the free form.

Biotransformation

• Phases of biotransformation:
  • Phase I (non-synthetic) reactions: oxidation, reduction, and hydrolysis.
  • Phase II (synthetic) reactions: conjugation with glucuronic acid, glutathione, glycine, sulfate, and acetic acid.
• Phase I reactions result in:
  • Drug inactivation.
  • Inactive to active metabolite.
  • Active to active metabolite.
  • Toxic metabolite.
• Phase II reactions result in:
  • Inactivation (with few exceptions).
• Most drugs pass through both phase I and phase II reactions.

Sites of Biotransformation

• Microsomal enzymes: responsible for most oxidative reactions, affected by age, and inducible by drugs.
• Non-microsomal enzymes: present in liver, kidney, plasma, skin, and GIT, and are not inducible by drugs.

Factors Affecting Drug Metabolism

• Drugs:
  • Induction: increases enzyme synthesis.
  • Inhibition: decreases enzyme activity.
• Genetics:
  • Genetically determined polymorphisms affect enzyme activity.
• Nutritional state:
  • Conjugating agents (e.g., sulphate, glycine) are affected by body nutrient level.
• Age:
  • Drug metabolism is reduced in extremes of age.
• Gender:
  • Metabolism is faster in men for certain drugs (e.g., diazepam, caffeine) and faster in women for certain drugs (e.g., propranolol, lidocaine).
• Disease state:
  • Liver disease: reduces drug metabolism.
  • Heart failure: reduces hepatic flow and affects rapidly metabolized drugs.
  • Kidney disease: affects the excretion of drugs.

Renal Excretion

• Factors affecting renal excretion:
  • Glomerular filtration rate.
  • Change in urinary pH: affects the excretion of weak acid and weak base drugs.

Other Routes of Excretion

• Bile: eliminates certain drugs (e.g., ampicillin, rifampicin) through enterohepatic circulation.
• Sweat: eliminates certain drugs (e.g., rifampicin, vitamin B1).
• Lungs: eliminates gases and volatile anesthetics.
• Milk: eliminates certain drugs (e.g., morphine, amphetamine, chloramphenicol, oral anticoagulants).

Pharmacodynamics

• What the drug does to the body:
  • Physical action: e.g., kaolin adsorbs toxins.
  • Chemical action: e.g., HCl + NaHCO3.
  • Cytotoxic action: e.g., anticancer drugs.
  • Interference with selective passage of ions: e.g., local anesthetics.
  • Interference with normal metabolic pathway: e.g., sulphonamides.
  • Action on specific receptors: e.g., hormone, neurotransmitter.

Affinity and Potency

• Affinity: the tendency of a drug to bind to receptors.
• Potency: the amount of ligand required to elicit a response.### Classification of Cephalosporins
• First generation:
  • Oral: cephalexin, cephradine, cefadroxil
  • IV/IM: cefazolin, cephlothin, cephaporin
  • Activity: Gram +ve cocci (pneumococci, streptococci, staphylococci) and Gram -ve (Proteus, E. coli, Klebsiella)
  • Not effective against CSF
• Second generation:
  • Oral: cefaclor, cefuroxime
  • IV: cephmandole, cefoxitin, cefoncid
  • Activity: As 1st generation + H. influenzae, Neisseria
  • Not effective against CSF
• Third generation:
  • Oral: cefixime, cefpodoxime
  • IV: cefoperazone, cefotaxime, moxalactam, ceftriaxone
  • Activity: Less effect on Gram +ve cocci, more active on Gram -ve bacilli
  • Effective against CSF (except cefoperazone)
• Fourth generation:
  • IV: cefipime
  • Activity: As 3rd generation, more resistant to beta-lactamase
  • Effective against CSF

Kinetics of Cephalosporins

• Absorption and passage to CSF related to generation
• Pass placenta
• Excreted by kidney (except cefoperazone and ceftriaxone, which are excreted in bile)

Uses of Cephalosporins

• Infections by Klebsiella, Enterobacter, Hemophilus
• Gonorrhea (ceftriaxone)
• Meningitis (3rd and 4th generation)
• Anaerobic infection (cefoxitin)
• Typhoid fever

Toxicity of Cephalosporins

• Allergy, cross allergy
• Nephrotoxicity (cephaloridine) especially with loop diuretics and aminoglycosides
• Thrombophlebitis (IV)
• Pain (IM)
• Anti-vitamin K effect (cefamandole, cefoperazone, moxalactam)
• Disulfram-like action (moxalactam)

Mechanism of Action of Cephalosporins

• Bactericidal, binds to 30S subunit of microbial 70S ribosome, misses mRNA message, and produces non-functional protein

Aminoglycosides

• Mechanism of action: Irreversible binding to 30S subunit of microbial 70S ribosome, misses mRNA message, and produces non-functional protein
• Poorly absorbed orally, do not penetrate CSF, more active in alkaline medium
• Include: Streptomycin, Neumycin, Kanamycin, Tobramycin, Amikacin, Paromamycin
• General adverse effects: Ototoxic, Nephrotoxic, Neuromuscular blocking effects

Tetracycline

• Mechanism of action: Bacteriostatic, binds to 30S subunit of bacterial ribosome, inhibits protein synthesis
• Spectrum: +ve, -ve bacteria, Rickettsia, Chlamydia
• Kinetics: Incomplete oral absorption, absorption decreased with food, excreted in bile and urine
• Uses: Gonorrhea, Syphilis, Bacillary dysentery, Cholera, Mycoplasma, Acne, Eye infection, Amoebiasis
• Toxicity: GIT upset, Chelation with Ca in bone and teeth, Teratogenic, Photosensitivity, Hepatic toxicity, IM injection pain, IV injection thrombosis

Erythromycin

• Mechanism of action: Irreversible binding to 50S subunit of bacterial ribosome, inhibits protein synthesis
• Activity: Bacteriostatic in low concentration, bactericidal in high concentration, affects Gram +ve as (Pneumococci, Streptococci, Staphylococci, Diphtheria, Corynebacterium) and Gram -ve (H. influenzae, Legionella) and Mycoplasma, Chlamydia, Treponema palladium
• Kinetics: Given orally in enteric coated form, destroyed by HCl, activity increased in alkaline medium, distributed to all tissues except CSF, metabolized in liver, excreted in urine and bile
• Uses: Diphtheria, Pneumonia, UTI with Chlamydia during pregnancy, Penicillin allergic patients
• Adverse effects: GIT upset, Cholestatic jaundice, Fever, Rash, Eosinophilia
• Interaction: Decrease cytochrome P450, increase warfarin

Quinolones

• Mechanism of action: Bactericidal, interferes with DNA gyrase enzyme, inhibits replication of bacterial DNA
• Activity: Mainly Gram -ve, less effect on Gram +ve
• Kinetics: Absorbed orally or injection, fluorinated form distributed to all tissues, metabolized in liver, excreted in urine, milk, and bile
• Uses: UTI, Infectious diarrhea, Soft tissue, Bone, and Joint infection, Respiratory infection, Resistant TB
• Adverse effects: Allergy, Photosensitivity, CNS: Headache, Dizziness, Confusion, Avoid driving, Seizures, Chondrolytic effect, Avoid in pregnancy, lactation, and children up to 18 years
• Contraindication: Pregnancy, patients below 18 years of age

Sulphonamides

• Mechanism of action: Bacteriostatic, competes with PABA, inhibits folic acid synthesis
• Spectrum: Gram +ve, Gram -ve (E. coli, H. influenzae) and Chlamydia
• Kinetics: Given orally, bound to plasma protein, metabolized by acetylation, excreted in urine
• Classification:
  • Rapidly absorbed and excreted (e.g. sulphadiazine, sulphaisoxazole, sulphamethoxydiazine)
  • Rapidly absorbed, slowly excreted (e.g. sulphamethoxazole)
  • Poorly absorbed (e.g. sulphaguanidine, sulphasalazine)
  • Topical use (e.g. sulphacetamide, mefenide)
• Uses: Coccal meningitis, UTI, Bacillary dysentery, Ulcerative colitis, Eye infection, Wound and burn, Prophylaxis of coccal meningitis, Prophylaxis of rheumatic fever
• Toxicity: Crystalluria, Allergic reaction, Blood dyscrasias, Diarrhea, Hepatic injury, Kernicterus
• Interaction: Potentiates sulphonylurea and oral anticoagulants### Pharmacology

Efficacy and Agonists

• Efficacy: biological response to a drug
• Agonists: bind to receptors, stimulate response, and initiate changes
• Characteristics of agonists:
  • Affinity: binding to receptors
  • Efficacy: ability to stimulate response
  • Rapid dissociation rate

Partial Agonists

• Stimulate and block receptors
• Characteristics of partial agonists:
  • Affinity: binding to receptors
  • Efficacy: less than full agonists
  • Moderate dissociation rate

Plasma Half-Life

• Definition: time required for the concentration of a drug to decrease by half
• Formula: t½ = 4 hours
• Importance: determines drug elimination and steady state

Clinical Significance of Plasma Half-Life

• Measure of drug elimination
• Indicates time required to attain steady state
• Depends on drug clearance

Types of Drug Elimination Kinetics

First Order Kinetics

• Constant proportion of drug is absorbed, metabolized, or eliminated depending on concentration
• Characteristics:
  • Rate of process is directly proportional to dose
  • t½ is constant
  • Linear disappearance curve if log dose is used

Zero Order Kinetics

• Constant number of moles are absorbed or eliminated regardless of total amount present
• Characteristics:
  • Rate of process is not related to dose
  • t½ increases with dose
  • Non-linear disappearance curve if log dose is used

Factors Affecting Drug Response

Age

• Newborn infants are more susceptible to drugs due to:
  • Underdevelopment of microsomal enzymes
  • Low plasma protein and low binding capacity
  • Reduced excretory function
  • Immaturity of blood-brain barrier

Body Weight and Surface Area

• Larger body weight requires larger dose
• Surface area is a more accurate parameter for dose calculation
• In obese patients:
  • Dose of fat-soluble drugs should be increased
  • Dose of water-soluble drugs should be based on surface area

Sex

• Women may need smaller doses due to:
  • Fat content
  • Enzyme-inhibiting effect of female sex hormones
  • Enzyme-inducing effect of male sex hormones

Route of Administration

• Affects dose and action:
  • I.V dose is less than oral dose
  • I.V administration is faster than other routes
  • Examples of route-dependent effects:
    • Magnesium sulphate: orally is a purgative, rectally is a dehydrating agent, I.V. is an anticonvulsant

Pharmacological Concepts

Drug Intolerance

• Exaggerated response to a normal dose of a drug
• Causes: decreased clearance of drug or upregulation of receptors

Tolerance

• Failure of response to a usual dose of a drug
• Types:
  • Congenital
  • Acquired
• Examples:
  • Morphine, ethyl alcohol, nitrates, ephedrine

Hypersensitivity (Allergic) Reaction

• Immune response to a drug
• Characteristics:
  • Does not occur on first exposure
  • Not dependent on dose
  • Can occur on reuse of the drug
  • Can be cross-reactive between related drugs

Idiosyncrasy (Pharmacogenetics)

• Abnormal reaction to a drug due to genetic or enzyme defects
• Examples:
  • Succinylcholine apnea
  • Malignant hyperthermia with succinylcholine or halothane
  • Anaemia and methemoglobinemia with G-6-PD deficiency

Drug Dependence

• Habituation: emotional or psychological dependence on the drug
• Addiction: physical dependence on the drug

Pathological State

• Effect of a drug on a specific disease state
• Example: aspirin lowering fever temperature to normal

Cumulation

• Rate of drug administration is greater than elimination
• Examples: digitalis and guanethidine

Emotional State (Placebo Effect)

• Psychological response to an inert substance
• Used in testing new drugs

Drug Combinations

• Types:
  • Addition or summation
  • Synergism
  • Potentiation
  • Antagonism

Adverse Drug Effects

Unpredictable Adverse Effects

• Allergy (hypersensitivity reaction)
• Idiosyncrasy (pharmacogenetics)

Predictable Adverse Effects

• Overdose toxicity
• Teratogenic effects
• Iatrogenic effects
• Long-acting sulphonamides can produce jaundice in premature babies
• Blood dyscrasias by chloramphenicol
• Carcinogenic effects
• Hepatic toxicity
• Nephrotoxicity
• Nerve damage
• Secondary effects

Types of Adverse Drug Reactions

Type A

• Predictable undesirable adverse effects
• Related to the normal pharmacological actions of the drug
• Examples:
  • Side effects
  • Supersensitivity (intolerance)
  • Overdose
  • Secondary effects
  • Cytotoxic effects

Type B

• Unpredictable adverse effects
• Examples:
  • Allergy (hypersensitivity reaction)
  • Idiosyncrasy (pharmacogenetics)

Type C

• Chronic effects
• Examples:
  • Tolerance
  • Drug dependence
  • Iatrogenic disease

Type D

• Delayed effects
• Examples:
  • Teratogenicity
  • Mutagenicity and carcinogenicity

Type E

• End of use effects
• Examples:
  • Abstinence syndromes
  • Worsening of existing disease

Type F

• Failure of therapy
• Examples:
  • Primary failure
  • Secondary failure