Pharmacokinetics (PK) is a fundamental branch of
pharmacology that describes what the body does
to a drug after administration. It focuses on
the movement of drugs within the body, tracking how a drug is absorbed,
distributed, metabolized, and excreted commonly known as
the ADME process.
Understanding pharmacokinetics is essential for
determining appropriate dosing, frequency, and duration of therapy to
achieve optimal therapeutic effects while minimizing toxicity.
Definition
Pharmacokinetics refers to the quantitative study of the time course of drugs within the body. It involves mathematical models to describe the rates at which a drug
moves between compartments in the body and is eventually eliminated.
Pharmacokinetics = What the body does to the drug
Pharmacokinetic Processes (ADME)
The four primary processes of pharmacokinetics are:
1. Absorption
2. Distribution
3. Metabolism (Biotransformation)
4. Excretion
Pharmacokinetic Processes (ADME)
The four primary processes of pharmacokinetics are:
1. Absorption
2. Distribution
3. Metabolism (Biotransformation)
4. Excretion
1. Absorption
Definition:
Absorption is the process by which a drug moves from its site of administration into the systemic circulation (bloodstream).
Key Routes of Administration:
· Oral (PO) – most common
· Intravenous (IV) – direct into the bloodstream
· Intramuscular (IM)
· Subcutaneous (SC)
· Sublingual
· Rectal
· Transdermal
· Inhalational
Factors Affecting Absorption:
· Drug solubility and formulation
· pH and pKa of the drug
· Gastrointestinal (GI) motility
· Presence of food in the stomach
· Blood flow to absorption site
· Surface area of absorption
Bioavailability (F):
· It is the fraction of an administered dose that reaches
systemic circulation in its active form.
· For IV administration, bioavailability is 100%.
· Oral administration often results in reduced bioavailability due to first-pass metabolism.
2. Distribution
Definition:
Distribution is the process by which the drug is dispersed throughout the body fluids and tissues after entering the bloodstream.
Key Determinants of Distribution:
· Blood flow to tissues
· Plasma protein binding (e.g., albumin)
· Lipid solubility of the drug
· Capillary permeability
· Tissue binding
Volume of Distribution (Vd):
· A theoretical volume that relates the amount of drug in the body to the plasma concentration.
· Higher Vd indicates greater distribution into tissues.
Vd=Total amount of drug in the bodyPlasma drug concentrationVd
= \frac{\text{Total amount of drug in the body}}{\text{Plasma drug
concentration}}Vd=Plasma drug concentration
Total amount of drug in the body
3. Metabolism
(Biotransformation)
Definition:
Metabolism refers to the chemical
alteration of the drug in the body, mainly by liver
enzymes, converting it into more water-soluble metabolites for easier
excretion.
Phases of Metabolism:
· Phase I: Modification reactions (oxidation, reduction,
hydrolysis)
o Mainly via the Cytochrome P450 (CYP450) enzyme system
o Results in activation, inactivation, or conversion to toxic metabolites
· Phase II: Conjugation reactions (glucuronidation,
sulfation, acetylation)
o Makes metabolites more water-soluble
First-Pass Effect:
· Drugs absorbed via the GI tract first pass through the liver via the portal vein, where they may
be metabolized before reaching systemic circulation.
· This reduces the effective concentration of the drug.
4. Excretion
Definition:
Excretion is the process of removing drugs and
their metabolites from the body.
Primary Routes of Excretion:
· Renal (urine) – major route
· Biliary (feces)
· Lungs (volatile substances)
· Sweat, saliva, breast milk
Renal Excretion Processes:
1. Glomerular Filtration
2. Tubular Secretion
3. Tubular Reabsorption
Clearance (Cl):
· The volume of plasma from which a drug is completely removed per unit time.
Cl=Rate of eliminationPlasma drug concentrationCl
= \frac{\text{Rate of elimination}}{\text{Plasma drug
concentration}}Cl=Plasma drug concentration Rate of elimination
Pharmacokinetic Parameters
1. Half-life (t1/2):
o Time required for the plasma concentration of a drug to reduce by half.
o Indicates how long a drug stays in the body.
2. Area Under the Curve (AUC):
o Represents the total drug exposure over time.
3. Cmax and Tmax:
o Cmax: Maximum plasma concentration achieved.
o Tmax: Time taken to reach Cmax.
4. Bioavailability (F):
o Percentage of the administered drug reaching systemic circulation.
5. Steady-State Concentration (Css):
o Achieved when the rate of drug administration equals the rate of
elimination.
6. Therapeutic Window:
o The concentration range where the drug is effective without being toxic.
Factors Influencing Pharmacokinetics
1. Age
o Neonates and elderly may have reduced metabolism and excretion.
2. Genetics
o Variations in metabolic enzymes (pharmacogenomics)
3. Body Composition
o Fat content, body water affect distribution.
4. Disease States
o Liver and kidney dysfunction impact metabolism and excretion.
5. Drug Interactions
o Some drugs induce or inhibit enzymes affecting metabolism.
6. Diet and Lifestyle
o Food, alcohol, smoking can influence drug metabolism.
Clinical Significance of Pharmacokinetics
· Dose Calculation: Determines correct dose and interval.
· Therapeutic Drug Monitoring: Ensures
plasma levels stay within therapeutic range.
· Understanding Drug Interactions: Predicts
effects when combining drugs.
· Individualized Therapy: Adjust dosing in
liver/kidney impairment.
· Bioequivalence Studies: For generic drug approval.
⧪Dose Calculation: Dose calculation is essential to ensure that patients receive the correct amount of medication based on their condition, body parameters, and route of administration. Administering the wrong dose can lead to ineffectiveness or toxicity.
￫ Common Methods of Dose Calculation
- Standard
Dose Calculation
- Based
on recommended doses in mg, g, mcg as per adult standards.
- Example:
Paracetamol 500 mg every 6 hours.
- Weight-Based
Dose Calculation
- Formula:
Dose = Weight (kg) × Dose per
kg
- Example:
If the dose is 10 mg/kg for a 20 kg child:
Dose = 20 kg × 10 mg = 200 mg
- Body
Surface Area (BSA) Based Calculation
- Common
for chemotherapy or critical care drugs.
- BSA
(m²) is calculated via:
BSA = √[(Height(cm) ×
Weight(kg))/3600]
- Then:
Dose = BSA (m²) × Dose per m²
- Age-Based
Calculation
- Pediatric
doses can sometimes be derived using age:
- Young's Rule:
Dose = (Age / (Age + 12)) ×
Adult dose
- Clark's Rule:
Dose = (Weight (lb) / 150) ×
Adult dose
- Dose
Calculation for IV Infusion (Drip Rate)
- Formula:
Flow rate
(ml/hr) = (Volume to be infused × Drop factor) / Time (minutes)
ml/hr =
Total volume (ml) / Total time (hr)
- Dilution
Calculations
- Using
the Formula of Concentration:
C1 × V1 = C2 × V2
Where:
- C1 = Initial concentration
- V1 = Initial volume
- C2 = Final concentration
- V2 = Final volume
🔹 Example Calculations
- Paracetamol
for a Child
- Dose:
15 mg/kg
- Weight:
25 kg
Dose = 25 kg × 15 mg = 375 mg
- Chemotherapy
Example
- Drug
dose: 100 mg/m²
- Patient's
BSA: 1.5 m²
Dose = 100 mg/m² × 1.5 m² = 150
mg
- IV Drip
Rate
- 1000
ml over 8 hours
Rate = 1000 ml / 8 hr = 125
ml/hr
🔹 Key Points
- Always
check drug references for standard doses.
- Consider
patient-specific factors: age, weight, renal/liver function.
- Always
use appropriate formulas to minimize dosing errors.
- Double-check
your calculations before administration.
⧪Definition
Therapeutic Drug Monitoring (TDM) is a clinical practice
of measuring specific drug concentrations in a patient's bloodstream to ensure
that the dosage remains within a targeted therapeutic range. The aim is to
optimize the drug’s effectiveness while minimizing potential toxicity or side
effects.
Importance of TDM
Some drugs have:
- A narrow
therapeutic index (small difference between effective and toxic
doses).
- Significant
variability in how patients absorb, distribute, metabolize, and eliminate
drugs.
- High
risk of toxicity or subtherapeutic levels if not properly
monitored.
Objectives of TDM
- Optimize
Drug Dosage — Ensure the drug concentration is effective but
not toxic.
- Improve
Clinical Outcomes — Achieve better disease
control and symptom relief.
- Avoid
Adverse Effects — Reduce the risk of drug toxicity.
- Assess
Patient Compliance — Detect non-adherence
to prescribed medication.
- Monitor
Drug Interactions — Adjust doses in polypharmacy
scenarios.
Drugs Commonly Monitored via TDM
- Antiepileptics:
Phenytoin, Carbamazepine, Valproic acid
- Immunosuppressants:
Cyclosporine, Tacrolimus
- Antibiotics:
Vancomycin, Gentamicin
- Psychotropic
Drugs: Lithium, Clozapine
- Cardiac
Drugs: Digoxin, Theophylline
Phases of TDM Process
- Patient
Evaluation
- Assess
age, weight, organ function (kidney, liver), and comorbidities.
- Understand
patient compliance and medication history.
- Sample
Collection
- Correct
timing is crucial:
- Trough levels:
Just before the next dose.
- Peak levels: After the drug has
been administered (when absorption is complete).
- Standardized
methods to ensure accurate sampling.
- Laboratory
Analysis
- Use of
analytical techniques:
- Immunoassays
- Chromatography methods (HPLC, LC-MS/MS)
- Ensures
precise measurement of drug levels.
- Interpretation
of Results
- Compare
measured levels to established therapeutic ranges.
- Factor
in patient-specific parameters like age, organ function, and drug
interactions.
- Clinical
Decision and Dose Adjustment
- Modify
the dose, frequency, or form of the drug.
- Re-monitor
as necessary.
- Documentation
and Follow-Up
- Keep
records of drug levels, dose changes, and patient responses.
- Continuous
monitoring in long-term therapies.
Factors Affecting Drug Levels
- Age
(elderly, pediatric)
- Body
weight and fat composition
- Renal
and liver function
- Drug
interactions
- Genetic
factors affecting metabolism (Pharmacogenomics)
- Patient
compliance
- Disease
conditions
Advantages of TDM
- Ensures
personalized treatment.
- Prevents under dosing and overdosing.
- Improves
medication adherence.
- Prevents
drug toxicity.
- Enhances
therapeutic success.
Limitations of TDM
- Not
suitable for all drugs (only drugs with narrow therapeutic windows or
variable pharmacokinetics).
- Requires
specialized laboratory facilities.
- Interpretation
requires clinical expertise.
- Sample collection errors can affect accuracy.
