Pharmacokinetics

Question 1

State the main routes of drug administration into the body

Answer 1

• Enteral - delivery into internal environment of body - GI tract
  
  • Oral, sublingual (under tongue), rectal
  • Through the GI tract, first pass metabolism (hepatic metabolism) and then into extracellular fluids
• Parenteral - delivery via all other routes that are not the GI tract
  
  • Intravenous, subcutaneous (applied under skin), intramuscular
    
    • Avoids first pass metabolism

Question 2

Define bioavailability and give its equation

Answer 2

• Fraction of a dose which finds its way into a body compartment, usually the circulation
• For an IV bolus, bioavailability = 100%
• For other routes, compare amount reaching the body compartment by that route with IV bioavailability
• F = amount reaching systemic circulation / total drug given IV
• F(oral) = AUC (oral) / AUC (IV)

Question 3

What are factors affecting bioavailability

Answer 3

• Absorption
  
  • Drug formulation - drugs with modified release are desirable as plasma concentration constantly within therapeutic window
    
    • Long acting drugs require less intake than short acting drugs
  • Age
  • Food - lipid soluble > water soluble
  • Vomiting/malabsorption
• First pass metabolism - any metabolism occurring before the drug enters the systemic circulation
  
  • Gut lumen - gastric acid, proteolytic enzymes, grapefruit juice
  • Gut wall - P-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen
    - Liver

Question 4

Define distribution

Answer 4

• Distribution of a drug refers to its ability to dissolve in the body
• Depends on protein binding and volume of distribution

Question 5

Describe the significance of protein binding in drug distribution

Answer 5

• In the systemic circulation, many drugs are bound to circulating proteins
• Eg. Albumin, globulins, lipoproteins, acid glycoproteins
• Most drugs must be unbound to have a pharmacological effect
  
  • Only the fraction of the drug that is unbound can bind to cellular receptors, pass across tissue membranes and gain access to cellular enzymes
    
    • Bounds drugs are not metabolised or excreted

Question 6

What are factors affecting protein binding

Answer 6

• Hypoalbuminaemia
• Pregnancy - change in fluid balance
• Renal failure
• Displacement by other drugs
  
  • If another drug takes protein binding sites of the free drug, then concentration of free drug will increase, leading to a greater therapeutic action

Question 7

Define volume of distribution and give its equation

Answer 7

• Measure of how widely a drug is distributed in body tissues
• Vd ~ Dose/[Drug]t=0
  
  • Eg. 100mg gentamicin dose, peak plasma concentration 5mg/L, then Vd will be 20 liters

Question 8

Describe the relationship between volume of distribution and half life

Answer 8

• Half life is proportional to Vd (and clearance)

- Drugs with a low volume of distribution work quicker and are eliminated quicker

Question 9

List factors affecting distribution

Answer 9

• Protein binding
• Volume of distribution
• Specific receptor sites in tissues
• Regional blood flow
• Lipid solubility
• Active transport
• Disease states
• Drug interactions

Question 10

Describe phase I and phase II metabolism in the liver

Answer 10

• Phase I
  - Oxidation and reduction due to cytochrome P450 family of enzymes
  - Activates pro-drugs or increases activation of drugs
• Phase II
  
  • Conjugation reactions that increase water solubility of drug by making it more polar
    
    • Attaches charged species to drugs
  • This inactivates the drugs and aids rapid elimination out of the body

Question 11

List the factors affecting drug metabolism

Answer 11

• Drug-drug interactions - such as charcoal grill 1A+, grapefruit juice 3A- affecting CYP450
• Race
• Age - reduced in aged patients and children
• Sex - women slower ethanol metabolizers
• Liver disease
• Hepatic blood flow
• Smoking, alcohol

Question 12

Define clearance and its equation

Answer 12

• Ability of body to excrete drug through liver and kidney
• Half life is inversely proportional to clearance
• Clearance ~ GFR

Question 13

Define half life and give its equation

Answer 13

• Drug half life is the amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it had when it was first measured
• Dependent on clearance and volume of distribution
• T(1/2) = 0.693xVd/CL

Question 14

Describe linear kinetics

Answer 14

• Linear kinetics (1st order kinetics) - rate of metabolism or excretion is proportional to concentration of drug
• Assumes there are plenty of phase I/II enzyme sites and plenty of OAT/OCT transporter
• Log [plasma] vs time is linear

Question 15

Describe non-linear kinetics

Answer 15

• Non-linear kinetics (zero order) is when rate of elimination is constant
• Occurs when elimination processes become saturated
  
  • Saturation occurs if not enough enzymes for the drug concentration
• [plasma] vs time is linear
• Most drugs exhibit zero order kinetics at higher doses

Question 16

Describe the clinical significance of zero order kinetics

Answer 16

• Zero order clinically important as more likely to result in adverse drug reaction (ADR) or toxicity
• Fixed rate of elimination per unit of time
• Therefore small dose changes can produce large increments in plasma [drug] and lead to toxicity
• Narrows therapeutic window
  - Therapeutic window - plasma concentration of which you will get a safe therapeutic effect

Question 17

Define steady state (CpSS) and when it is achieved

Answer 17

• Steady state (CpSS) is defined as when the rate of drug input is equal to the rate of drug elimination
  
  • Steady state is significant when multiple dosing is required as treatment
• The time to reach steady state is normally achieved after 4-5 half lives
  - From CpSS, it also takes 4-5 half lives to eliminate most of the drug

Question 18

Describe how steady state is achieved and maintained for drugs with long half lives

Answer 18

• Drugs with long half lives can take over a week to achieve 5 half lives
• Loading doses (higher concentration dose) given to achieve a rapid therapeutic effect
  
  • However do not need to give many doses if immediate effect not required
  • Can be given in patients with renal failure unless very severe
• Maintenance doses (lower concentration doses) are given to maintain the steady state