Table Of Contents
Overview
Pharmacokinetics (PK) is the study of what the body does to a drug over time.
Four major processes.
| Letter | Process | Definition |
|---|---|---|
| A | Absorption | Entry of drug into bloodstream |
| D | Distribution | Spread of the drug through the body compartments |
| M | Metabolism | Chemical alteration of drug |
| E | Excretion | Removal of the drug from the body |
Pharmacokinetics vs pharmacodynamics
| Pharmacokinetics | Pharmacodynamics |
|---|---|
| What the body does to the drug | What the drug does to the body |
| Drug movement | Drug effect |
| ADME | Mechanism of action |
| Concentration changes | Receptor interaction |
Some factors affecting pharmacokinetics
| Factor | Effect |
|---|---|
| Elderly patients | Reduced excretion, increased sensitivity, and polypharmacy risk |
| Neonates | Reduced excretion and metabolism, and altered protein binding |
| Liver disease | Reduced metabolism → increased bioavailability → increased toxicity risk |
| Renal failure | Reduced clearance and longer half-life. Dose reduction is required. |
| Pregnancy | Increased Vd |
| Obesity | Alters lipophilic drug distribution |
| Hypoalbuminemia | Increased free drug |
Summary table
| Parameter | Main Concept |
|---|---|
| Absorption | Drug enters blood |
| Bioavailability | Fraction reaching circulation |
| Distribution | Drug spreads through body |
| Vd | Extent of tissue distribution |
| Protein binding | Only free drug active |
| Metabolism | Drug chemical alteration |
| CYP450 | Major metabolism system |
| Excretion | Drug removal |
| Clearance | Drug removal efficiency |
| Half-life | Time for 50% decrease |
| First-order kinetics | Constant fraction eliminated |
| Zero-order kinetics | Constant amount eliminated |
- Why is it important to determine the pharmacokinetic properties of a drug?
- Understanding pharmacokinetics helps doctors to:
- Choose the correct dose
- Choose the route of administration
- Predict the onset/duration of action
- Avoid toxicity
- Adjust doses in liver/kidney disease
- Design loading and maintenance doses
- Understand drug interactions
- Understanding pharmacokinetics helps doctors to:
Absorption
Absorption is the movement of a drug from its site of administration into systemic circulation
Routes of administration
| Route | Features |
|---|---|
| Intravenous (IV) | Immediate absorption; 100% bioavailability |
| Oral | Convenient but subject to first-pass metabolism |
| Intramuscular (IM) | Slower, sustained absorption |
| Subcutaneous (SC) | Slow absorption |
| Sublingual/Buccal | Rapid; bypasses first-pass metabolism |
| Rectal | Partial avoidance of first-pass metabolism |
| Inhalational | Rapid absorption via lungs |
| Transdermal | Slow sustained release |
| Intrathecal | Direct delivery into CSF |
Transport mechanisms that facilitate the absorption of a drug
| Mechanism | Description |
|---|---|
| Passive diffusion | Occurs if the drug is present in the GIT in a greater concentration than it is in the bloodstream |
| Carrier-mediated transport | Involves the use of specific membrane transport proteins. It is specific, saturable, and inhibitable. It includes facilitated diffusion and active transport. |
| Facilitated diffusion | Depends on the concentration gradient, without use of energy |
| Active transport | Occurs gainst a concentration gradient. Uses energy in the form of ATP |
| Others | Pinocytosis and phagocytosis |
- Factors that affect gastrointestinal absorption
- Drug factors
- Lipid solubility
- Molecular size
- Ionization
- Formulation
- Stability in gastric acid
- Patient factors
- Gastric emptying
- Gastrointestinal motility
- Blood flow
- Food intake
- pH
- Disease states
- Drug factors
- Liberation
- Before absorption, many oral drugs are first released from their dosage form in a process called liberation.
- An example is when tablets dissolve in the stomach or intestines before they are absorbed.
- Delayed liberation delays the onset of action
- Bioavailability (F)
- Bioavailability (F) is the fraction of the administered drug that reaches systemic circulation unchanged
- It is a key factor for the onset of action of the drug
- It is 1 (100%) for drugs administered intravenously since they enter circulation directly
- F = amount reaching circulation/amount administered
- Oral drugs and first-pass metabolism
- Oral drugs undergo the following steps before reaching circulation:
- Gastric degradation
- Intestinal metabolism
- Hepatic first-pass metabolism
- First-pass metabolism is the initial metabolism of orally administered drugs by the gut wall and liver before reaching systemic circulation
- Drugs with extensive first-pass metabolism require higher oral doses and may need non-oral administration
- Glyceryl trinitrate is completely inactivated by first-pass metabolism. This can be avoided by administering it intradermally
- Other drugs with extensive first-pass metabolism include lidocaine and propranolol
- Morphine also has reduced oral bioavailability (<40%) due to significant first-pass metabolism
- Oral drugs undergo the following steps before reaching circulation:
- Area under the curve (AUC)
- The AUC represents the total drug exposure over time
- A larger AUC = greater bioavailability
- Implications of pH on absorption
- Acidic drugs are largely unionized and absorbed in the stomach
- Basic drugs are absorbed faster in the intestines
Distribution
Distribution describes how drugs move from the blood into tissues and body compartments. Its goal is to achieve effective concentration at the receptor sites.
- Factors that affect drug distribution
- Drug factors
- Lipid solubility
- Molecular size
- Ionization
- Protein binding
- Patient factors
- Blood flow
- Capillary permeability
- Body fat
- Hydration
- Plasma proteins
- Plasma barrier
- Blood- brain barrier
- Storage sites
- Bone and teeth accumulate tetracyclines
- Anticoagulants are stored in fat tissue
- Drug factors
- Volume of distribution (Vd)
- This is the theoretical volume that would accommodate all the drug amount at the same concentration as the plasma
- Vd = dose administered (mg)/ concentration in plasma (mg/L)
- Low Vd = drug stays in plasma
- Large protein-bound drugs (heparin, cetorelix, aspirin, and furosemide) remain intravascular
- High Vd = drug enters the tissues extensively
- Lipophilic drugs such as chloroquine and digoxin are extensively distributed in tissues
- Antibiotics such as ampicillin and cephalexin are also extensively distributed
- Loading dose
- Vd is used to calculate the loading dose to rapidly achieve therapeutic concentrations
- Examples of drugs with loading doses include vancomycin, digoxin, and phenytoin
- Loading dose = (Vd x desired plasma concentration)/bioavailability
- Protein binding
- Drugs can circulate bound to protein or free (active)
- Albumin binds acidic drugs
- Alpha-1 acid glycoprotein binds basic drugs
- Only the free drugs cross membranes, bind receptors, and are metabolized/excreted
- Reduced protein binding increases the free drug concentration and increases the risk of toxicity
- Renal failure → uremia reduces diazepam binding → respiratory depression risk
- Tolbutamide displaces warfarin → increasing the risk of hemorrhage
- Salicylates can displace tolbutamide →increasing the risk of hypoglycemia
- Drugs can circulate bound to protein or free (active)
Metabolism (Biotransformation)
Metabolism is the enzymatic conversion of drugs into metabolites, which are more polar an dless lipid-solubel for excretion through the kidneys. It usually occurs in the liver.
Phases of metabolism
| Phase | Description | Processes |
|---|---|---|
| Phase I reaction | Produce slightly polar metabolites (active or inactive) via the CYP450 enzymes | Oxidation, reduction, and hydrolysis |
| Phase II reactions | Conjugation reactions to produce very polar metabolites (inactive) before excretion. | Glucuronidation, sulfation, methylation, and acetylation. |
- Sites of metabolism
- Liver
- Gut wall
- Plasma
- Kidneys
- Lungs
- Skin
- Placenta
- Factors that affect drug metabolism
- Genetic differences
- Age of the patient
- Disease process
- Concurrent use of drugs (inhibitors or inducers)
- Prodrugs
- These are inactive drugs requiring metabolism for activation
- Examples
- Codeine → morphine
- Pharmacogenetics
- This is the genetic basis for differences in individual responses to drugs regarding metabolism and transport in the body
- Examples:
- Acetylation of isoniazid: people can either be fast or slow acetylators
- CYP2D6 polymorphism: At least 17 variant alleles have been identified
- CYP2C9 polymorphism and warfarin therapy: Affected individuals require lower doses of warfarin for anticoagulation, which are 10-25% of those required by normal individuals
- Tolerance
- When some drugs are given repeatedly, their metabolism becomes more effective due to enzyme induction
- Therefore, larger doses of the same drug are needed to produce the same effect
Excretion
Excretion is the removal of a drug from the body. It mainly occurs through the kidneys.
Drug kinetics
| Feature | First-Order Kinetics | Zero-Order Kinetics |
|---|---|---|
| Elimination | Constant fraction eliminated per unit time | A constant amount is eliminated per unit time |
| Depends on plasma concentration | Yes | No |
| Half-life | Constant | Variable |
| Saturation | No | Yes |
| Examples | Most medications, morphine, penicillin | Ethanol, phenytoin, and high-dose aspirin |
- Sites of drug excretion
- Renal excretion
- Glomerule filtration
- Tubular secretion
- Tubular reabsorption
- Pulmonary excretion for volatile substances (ethanol)
- Sweat and saliva
- Biliary system
- Feces
- Intestines
- Breast milk
- Basic compounds such as morphine and codeine are concentrated in milk, which is more acidic than plasma (pH 6.5)
- Renal excretion
- Clearance (Cl)
- Clearance is the volume of plasma cleared of a drug per unit time
- Clearance = rate of elimination/plasma concentration
- Maintenance dose
- Clearance is used to calculate the maintenance dose
- Maintenance dose = (clearance x desired plasma concentration)/bioavailability
- Clearance is used to calculate the maintenance dose
- Half-life (t 1/2)
- Half-life is the time required for plasma drug concentration fo fall by 50%
- Half-life increases with increased Vd
- Half-life increases with reduced clearance
- It is used to determine:
- Dosing interval
- Duration of action
- Time to steady state
- Time to elimination
- Half-life is the time required for plasma drug concentration fo fall by 50%
- Steady state
- Steady state occurs when the drug administration rate = elimination rate
- It is usually achieved after 4 – 5 half-lives
- Most drugs are effectively eliminated after 4 – 5 half-lives
- Therapeutic drug monitoring
- Drug concentrations are monitored when the drug has a narrow therapeutic index or significant toxicity
- Examples include:
- Gentamicin
- Vancomycin
- Lithium
- Digoxin
- Phenytoin
- Implications of pH on excretion
- Acidic drugs are excreted faster in alkaline urine
- Basic drugs are excreted faster in acidic urine.