CPT3&4 - Clinical Pharmacokinetics & Pharmacodynamics

Question 1

5 features of drug bioavailability (F)

Definition/Formula
Factors Affecting Bioavailability  x5
Plasma Conc-Time Graphs
Modified Release Preparation
Co-Administration

Answer 1

1. ) Definition - % of dose of drug that reaches circulation unchanged. It is a measure of drug absorption
   - F = [circulation]/dose
2. ) Factors affecting Bioavailability
   - formulation (IV has 100% bioavailability)
   - age: luminal changes in intestines
   - food: chelation and gastric emptying
   - malabsorption: e.g. Crohn’s
   - first pass metabolism: gut lumen, gut wall, liver
3. ) Plasma Conc-Time Graphs - distinct phases
   - absorption (increase), distribution (sharp decline) and elimination phase (steady decline)
4. ) Modified Release Preparation - drug has slower elimination so stays in therapeutic window for longer
   - increases adherence as less doses needed
   - however, it is a lot more expensive
5. ) Co-Administration - to increase bioavailability
   - e.g anaesthetic + vasoconstrictor (e.g. adrenaline) as reduced blood flow leads to increased absorption

Question 2

4 features of drug distribution

Volume of Distribution
Order of Distribution
Factors Affecting Distribution x4
Multiple Compartment Model

Answer 2

1. ) Volume of Distribution - how well a drug is distributed out of blood plasma (circulation)
   - Vd = dose/[drug in plasma], L/kg
   - the larger the weight, the larger the Vd because the molecule can distribute even further so less in plasma
2. ) Order of Distribution
   - plasma –> interstitium –> cells –> tissues (fat)
   - Vd of around 5L suggests mosts of the drug stays in circulation (blood volume is roughly 5L)

3.) Factors affecting Distribution - blood flow, capillary structure, lipophilicity, protein binding

4. ) Multiple Compartment Model - rate of distribution and equilibration from IV follows this model
   - the more compartments, the slower the distribution

Question 3

3 features of drug metabolism

Cytochrome P450 Enzymes
Effect on Drugs x3
Factors Affecting Metabolism x9

Answer 3

1. ) Cytochrome P450 Enzymes - phase I metabolism (OILRIG)
   - converts drugs into lipophilic metabolites
   - can be induced or inhibited by other compounds e.g. grapefruit juice inhibits CYPs that metabolises statins
2. ) Effect on Drugs
   - active –> inactive: most drugs
   - inactive –> active: e.g. ACEi, aspirin (prodrugs)
   - active –> active: e.g. codeine –> morphine
3. ) Factors Affecting Metabolism
   - size, lipophilicity, hydrophilicity, structural complexity
   - age, liver failure, blood flow, alcohol, smoking

Question 4

3 routes of drug elimination

Renal
Hepatic
Other Routes x3

Answer 4

1. ) Renal Elimination - main route of elimination
   - mainly remove low molecular weight polar metabolites
   - affected by: GFR, pH, lipophilicity, protein binding, competition for transporters
2. ) Hepatic Elimination - removes high molecular weight metabolites conjugated w/ glucuronic acid
   - uses enterohepatic circulation to eliminate in faeces or reabsorption
3. ) Other Routes - fluids, solids, gases
   - fluids: sweat, tears, saliva, lactation, genital secretions
   - solids: faeces, hair
   - gases: volatile compounds

Question 5

4 features of elimination rate and clearance

Order Kinetics
Clearance
Half-Life Equation
Amiodarone Elimination

Answer 5

1. ) Order Kinetics - 0 order= linear, 1st = exponential
   - half-life used for 1st order kinetics
   - most drugs exhibit 1st order at therapeutic doses
   - high doses, alcohol, salicylic acid and phenytoin are all zero order so half-life not calculable
2. ) Clearance - volume of blood cleared per unit time
   - CL = elimination rate/[drug in plasma], ml/min
   - elimination rate = [drug]/time, mg/min
3. ) Half-Life Equation - t1/2 = 0.693 x (Vd/CL)
   - higher Vd = longer half-life = worse elimination
4. ) Amiodarone Elimination - used to treat SVTs
   - very high Vd (66L/kg) so long half-life (50-60days) so takes a very long time to eliminate
   - can increase [plasma] of other cardiac drugs
   - can easily lead to medication errors

Question 6

5 features of steady state concentration (Css)

Definition
Reaching Css
Css Equation
Oral Administration Rate
Loading Dose

Answer 6

1. ) Definition - stable concentration the drug reaches after giving repeated doses of the drug
   - therapeutic benefit optimal at steady state
2. ) Reaching Css - takes 5 half-lives
   - also takes 5 half-lives to eliminate the drug from Css
   - at steady state, rate of infusion = rate of elimination
3. ) Css Equation
   - CL = infusion rate(elimination rate)/Css([drug])
   - therefore: Css = infusion rate/CL
4. ) Oral Administration Rate = (D/t) x F (amount/time x bioavailability), oral equivalent of infusion rate
   - at steady state, administration rate = elimination rate
   - (DxF)/t = CL x Css, therefore, Css = (DxF)/(txCL)
   - D is the maintenance dose and t is the interval between doses
5. ) Loading Dose - single dose to achieve desired conc in apparent volume of distribution, Vd
   - Dose = Vd x [drug in plasma]
   - Loading Dose = Vd x Css

Question 7

8 Important Equations

Bioavailability
Volume of Distribution
Clearance 
Half-Life
IV Css
Oral Css
Loading Dose
Therapeutic Index

Answer 7

1. ) Bioavailability (%) = [circulation]/dose,
2. ) Volume of Distribution (L/kg) = dose/[drug in plasma]
3. ) Clearance (ml/min) - elimination rate/[drug in plasma]
4. ) Half-Life (hours) - 0.693 x (Vd/CL)
5. ) IV Css (mg/L) - infusion rate/CL
6. ) Oral Css (mg/L) - (DxF)/(txCL)
   - Css is increased by increasing the maintenance dose or decreasing the time interval

7.) Loading Dose (mg/kg) - Vd x Css

8. ) Therapeutic Index - ratio
   - max therapeutic dose/minimum therapeutic dose