Medicine SC065: Clinical Pharmacokinetics Flashcards
Pharmacokinetics
Describe what body does on drug:
Absorption —> Distribution —> Metabolism —> Excretion
Route of administration:
- IV, IN —> go into systemic circulation directly
- PO, IM, SC —> need to go into other compartments first before entering systemic circulation
PO:
- Goes into portal circulation —> Liver (1st pass effect —> Reduce bioavailability of the medication) —> Systemic circulation
Metabolism + Excretion:
- Liver (Biotransformation + Enterohepatic circulation (if drug has affinity to bile —> reabsorbed in gut through bile —> systemic circulation again —> prolonged t1/2 + increase bioavailability))
—> Kidney (Excretion)
Absorption
Depends on:
1. Route of administration
- Absorption environment (drugs are weak acid / base)
- unionised form —> freely absorbed through cell membrane
- ionic form —> stay in compartment - Dosage form (modified release, extended release (rely on coating of medication, ∴ cannot be crushed) —> lower peak plasma concentration —> reduce ADR)
- Physiological property
- underlying medical conditions affect pre-existing environment (e.g. gastrectomy —> affect absorption of weak acid drug)
Distribution
Transport method:
Extracellular to Intracellular:
1. Diffusion
2. Through Pore
3. Vesicular transport (Endocytosis)
4. Receptor-mediated active transport (most important factor limiting rate of absorption)
Intracellular to Extracellular:
1. ***P-glycoproteins (important for transport from intracellular to extracellular space —> anything inhibit Pgp will extend + enhance drug efficacy / toxicity)
Both ways:
1. Transcellular
Considerations:
1. Binding to plasma protein
- only unbound drug can enter interstitial fluid
- protein-bound drug are inactive (e.g. in nephrotic syndrome, chronic liver disease —> increase level of free active drug in plasma —> require dose reduction)
- Physiological volume
- in CHF —> interstitial edema —> trap drug in this compartment —> reduce efficacy of drug - Membrane permeability
- Preferential tissue perfusion
- Normalised blood flow (Blood flow per organ mass)
—> kidneys largest normalised blood flow
- Minimal drug exposure in those organs with small normalised blood flow (e.g. adipose tissue)
—> however given time drug can accumulate in respective preferential tissue
—> e.g. Diazepam can accumulate in adipose tissue
—> once adipose tissue is saturated
—> change in plasma concentration
Preferential tissue:
- Small water soluble molecules (ethanol) —> Total body water
- Large water soluble molecules (mannitol) —> Extracellular water
- High plasma protein bound molecules, Very large molecules, Highly charged molecules (heparin) —> Blood plasma
- Highly lipid soluble molecules (diazepam) —> Adipose tissue
- Certain ions (fluoride, strontium) —> Bone and teeth
Metabolism
- Activate pro-drug / de-activate active drug
- Mostly occurs in the ***liver by Phase 1 / 2 reactions (make it more soluble —> excreted by kidney)
- Dependent on circulation, organ function, genetic variability, drug-drug interaction
Lipophilic / Xenobiotic
—(Phase 1)—> Enzymes introduce reactive / polar groups into xenobiotics, then conjugated to polar compounds
—> Soluble metabolites
—(Phase 2)—>
—> Highly soluble metabolites
—(Phase 3)—> Conjugated xenobiotics are excreted
—> Secreted metabolites
Phase 1 metabolism (***Cytochrome P450 —> put on more charge —> more water-soluble)
1. Oxidation
2. Reduction
3. Hydrolysis
Phase 2 metabolism (***Transferase reaction —> put on more group —> more water-soluble)
1. Glucuronidation
2. Acetylation
3. Methylation
4. Glycine conjugates
5. Glutathione conjugates
6. Sulphate conjugates
Factors affecting metabolism:
1. Pharmacogenomics
2. Race and ethnicity
3. Age and gender
4. Diet (e.g. grapefruit juice)
5. Metabolic drug interaction (e.g. Pgp inhibitors, P450 enzyme inducers / inhibitors)
6. Disease condition (e.g. affect organ function)
7. Drug-drug interaction
Excretion
- Urinary
- Biliary (Enterohepatic circulation)
- Fecal (not a lot)
- Others (e.g. Breast milk)
Concentration time curve
Absorption phase (Absorption > Excretion)
—> Minimum effective concentration (MEC) (Onset of action)
—> Peak plasma concentration (Highest intensity of action, Absorption rate = Elimination rate)
—> Maximum safe concentration (MSC) (Above which toxic effect occur)
—> Post absorption phase (Excretion > Absorption)
Therapeutic range:
- MEC to MSC
T1/2:
- after ***5 t1/2 —> 3.12% drug remaining (<5%) —> cut off for adequate wash out of drug
(But also depends whether there is preferential tissue perfusion, enterohepatic circulation etc.)
1st order kinetics:
- drug concentration drop exponentially
- t1/2 remain unchanged irrespective of drug concentration
- rate of elimination proportional to plasma concentration (YouTube)
- clearance remains constant (YouTube)
0 order kinetics:
- t1/2 depend on drug concentration —> larger concentration —> longer t1/2
- only when saturation occurs would non-linear behaviour become evident
- rate of elimination fixed (YouTube)
- clearance not constant (YouTube)
Route of administration:
IV dosing:
- Rapid increase in plasma concentration + Higher peak plasma concentration
—> May need to change dosing frequency + dosage to prevent toxic concentration (esp. for drugs with narrow therapeutic index e.g. Phenytoin)
SC/IM/PO dosing:
- Slower + Lower peak plasma concentration
AUC should be the same for all routes (assume no loss of drug through metabolism)
Pharmacokinetics parameters
- Cmax (maximum concentration)
- Tmax (time to achieve Cmax)
- AUC
- F (bioavailability)
- Vd (volume of distribution)
- CL (clearance)
- t1/2 (elimination half life)
Area under curve (AUC)
- Reflects actual body exposure to drug after administration
- Dependent on rate of elimination of drug + dose administered
- Directly proportional to the dose when drug follows linear kinetics
- NB: Double dose —> NOT double peak concentration (Cmax) —> but double AUC!
Bioavailability (F)
- Fraction of dose available to systemic circulation
Factors influencing bioavailability:
1. Absorption environment (health of GI tract, pH, food effect, trapping of drug in different compartments)
2. First pass effect (genetic, drug-drug interaction)
50% Bioavailability —> 50% AUC (NOT 50% Cmax)
F = (AUCpo X Doseiv) / (AUCiv X Dosepo)
Clearance (CL)
- Limits the time course of action of the drug at its molecular, cellular and organ targets
- CL = [Metabolism + Excretion] / Plasma drug concentration
- Factors influencing clearance
1. Metabolism
2. Excretion
Lower CL —> Higher AUC + Higher Cmax (Post-absorption phase affected as well as Absorption phase since metabolism + excretion occurs already at Absorption phase)
(NB plasma protein binding won’t affect AUC since we are measuring the total drug concentration not just free drug)
CL = Dose(iv) / AUC or F x Dose(po)/AUC
Therapeutic dosing + frequency
Dose depends on:
1. Potency (e.g. different steroid: 4mg hydrocortisone = 1mg prednisolone)
2. Bioavailability
3. Volume of distribution (surrogate marker to determine how much drug will remain in systemic circulation, higher Vd —> lower amount of drug in systemic circulation)
Frequency depends on:
1. Elimination rate
Target:
- Maintain peak plasma concentration within therapeutic range
If a second dose of drug were given after the first dose was completely eliminated (i.e. 5 t1/2) —> dosage regimen will not result in any drug accumulation in the body
Steady state:
- Defined as dosing interval in which the AUC for that interval is equal to single-dose AUC
- Loading dose = Cpmax x Vd
- Achieved after 5 t1/2 (since after 5 t1/2 —> amount of dose given = amount of dose eliminated)
- Optimal dosing regimens typically maintain the steady state plasma drug concentration within the therapeutic window
- Csteady state = (F x dose) / (interval x CL)
Rationale of giving loading dose:
- Drug does not show therapeutic effect unless reaches desired steady state
- If drug has long t1/2 —> will take too long to reach steady state
- Plateau can be reached immediately by administering a dose that gives the desired steady state instantaneously before the start of maintenance dose
Linear vs Non-linear pharmacokinetics
Linear PK:
- Pharmacokinetic parameters are **NOT expected to change when different doses are administered / when the
drug is administered via different routes as a single dose or multiple doses
- The kinetics is characterised by the FIRST ORDER KINETICS
- Plasma concentration at a given time at steady state and AUC will both be **proportional to the dose administered
- First order kinetics greatly simplifies dosage design, bioavailability, dose-response relationship, prediction of drug distribution and disposition
- First-order elimination applies only to compounds that are eliminated exclusively by mechanisms ***not involving enzymatic or active transport processes
- At clinical dosages, the majority of drugs do ***not reach saturation concentrations at the reaction sites
Non-linear PK:
- Pharmacokinetic parameters may **vary depending on administered dose
- Other kinetic may be involved e.g. ZERO ORDER KINETICS
- Plasma concentration at a given time at steady state and AUC will **NOT be proportional to the dose administered
Processes leading to nonlinear pharmacokinetics
Absorption:
- Extent of absorption of amoxicillin ***decreases with an increase in dose
Distribution:
- Plasma protein binding of disopyramide is ***saturable at the therapeutic concentration, resulting in an increase in the volume of distribution with an increase in dose of the drug
Metabolism:
- Both phenytoin and ethanol have **saturable metabolism, which means that an increase in dose results in a **decrease in hepatic clearance and a ***more than proportional increase in AUC
Excretion:
- Dicloxacillin has **saturable active secretion in the kidneys, resulting in a **decrease in renal clearance as dose is increased
Therapeutic drug monitoring
- Clinical practice of measuring a specific drug at designated intervals to maintain a constant concentration
- Involves not only measuring drug concentrations, but also the clinical interpretation of the result
- Aims at optimising an individual’s dosage regimen
Indications:
1. Monitor drug compliance
2. Maintain drug efficacy esp. for conditions with poorly defined clinical endpoints
3. Suspected toxicity
4. Monitor and detect drug interaction
Which drugs require monitoring?
1. Narrow therapeutic range
2. Established target concentration range
3. Significant intra-/ inter-subject variability
4. Significant dose response relationship
5. Nonlinear pharmacokinetic profile
6. Availability of cost effective drug assay
Drugs:
1. Digoxin
2. Lithium
3. Phenytoin
4. Cyclosporin
5. Tacrolimus
6. Sirolimus
Which drugs NOT require monitoring?
1. Clinical outcome is unrelated either to dose or plasma concentration
2. Dosage need not be individualised
3. The pharmacological effects can be clinically quantified
4. Wide therapeutic index
