Pharmacokinetics Flashcards
What is the equation for total plasma concentration of drugs (C)?
C = Cfree + Cbound
Cfree = Free drugs in plasma
Cbound = Drugs bound to plasma proteins
What is the most abundant drug binding plasma protein?
Albumin
What factors determine total amount of drugs in the body?
- Absorption
- Distribution
- Elimination
What are the different routes of drug administration?
- Intravenous (infusion/injection)
- Intramuscular/subcutaneous injection
- Transdermal absorption
- Inhalation
- Sublingual/buccal absorption
- Rectal absorption
- Oral administration
What are the numbers of barriers that need to be crossed by drug in order to reach blood for each route of administration?
- Intravenous (infusion/injection) - 0
- Intramuscular/subcutaneous injection - 1 (endothelium)
- Transdermal absorption - 2 (skin epithelium, endothelium)
- Inhalation - 2 (lung epithelium, endothelium)
- Sublingual/buccal administration - 2 (mucosal epithelium, endothelium)
- Rectal administration - 2 (mucosal epithelium, endothelium)
- Oral administration - 2 (gut epithelium, endothelium)
What are the advantages of intravenous injections/infusions?
- Quick absorption and minimum delay for effect
- Control: Can be immediately stopped and started when required.
- Accuracy: Rate of administration directly relates to plasma concentration (due to 100% bioavailability)
What are the disadvantages of IV administration?
- Irreversible
- Great skill for administration
- Infusion requires special equipment
- Inconvenient
- Risk of infection
- High initial concentration straight after injection
What factors affect rate of absorption from intramuscular/subcutaneous injection?
- Concentration of drug at site of injection:
- Amount of drug injected
- Water solubility of drug (if drug precipitates, concentration remains constant as long as precipitate remains)
- Rate of absorption - Blood flow:
- Type of tissue (muscle > skin)
- Physiological state (temperature, exercise…) - Lipid solubility of drug
What are the advantages of IM/SC injection?
- Absorption is slow and prolonged
- Large amounts can be administered with less fear of overdose
What are the disadvantages of IM/SC injection?
- Inconsistent, unpredictable rate of injection
- Painful
- Risk of infection
- Absoprtion can be very slow (if drug precipitates)
What factors determine rate of transdermal absorption?
- Lipid solubility of drug
- Blood flow to skin
What are the advantages of transdermal absorption?
- Slow and prolonged absorption
- Avoids first pass metabolism in liver
What are the disadvantages of transdermal absorption?
- Very slow
- Highly variable rate of absorption
What factors determine rate of inhalation absorption?
- Lipid solubility of drug
- Concentration of drug
What are the advantages of sublingual/buccal absorption?
- Rapid onset
- Avoids first pass metabolism
What are the disadvantages of sublingual/buccal absorption?
- Bad taste
- Small surface area of absorption
- Washing away by saliva
What are the advantages of rectal absorption (suppositories)?
- Avoids first pass metabolism
- Can be used in patients who are persistently vomiting
What are the disadvantages of rectal absoprtion?
- Slow
- Variable rate of absorption
What are the factors influencing rate of absorption by oral administration?
- Availability of drug
- Rate of dissolution
> Dosage form (tablet or sugar syrup)
> Particle size
- Food in gut
- Pathological state (e.g. diarrhoea, vomiting)
2. Permeability of drug - Ionisation
> Gut pH
> Drug pKa
- Lipid solubility of drug
- Size of water-soluble drug particles
3. Surface area of gut epithelium (small intestines have the greatest SA)
How does the pH of environment and pKa of drug affect rate of absorption?
- Drugs that are weaks acids absorb well in acidic environments (stomach, pH = 1)
- Drugs that are weak bases absorb well in neutral environments and basic environments
- Small intestines absorb all types of drugs well due to high SA
What is an important class of drugs absorbed from the stomach?
Tetracyclines
How can the stomach secrete drugs?
Weak base drugs diffuse into gastic fluid from blood and become protonated and trapped.
What is bioavailability?
The fraction of dose given that is absorbed and reaches systemic circulation
What factors influence oral bioavailability?
- Inability to cross gut epithelium
- Active transport out of gut epithelial cells
- Metabolism of drug in gut epithelium
- First pass metabolism
What factors affect volume of distribution (Vd)?
- Plasma protein binding: Decreases Vd below ECF
- Sequestration in tissue (e.g. fat): Increases Vd above ECF
How can drugs be sequestered into tissue?
- Partition (e.g. fat)
- Adsorption (e.g. bone, muscle)
What factors affect the distribution of drugs?
- Binding to plasma protein: Restricts drugs to plasma compartment
- Sequestration into tissues: Removes drug from plasma and prevents action
- Tissue perfusion: Better perfused tissues contain more drugs
- Barriers to movement: Restricts drugs to certain compartments in body
- Disease states
What affects presence barriers of movement in distribution of drug?
- Physical barrier surrounding a tissue
- Lipid solubility of drug
- Presence of transporters for drug
What are the ways in which drug action can be terminated?
- Redistribution
- Metabolism
- Elimination
What are the common routes of excretion?
- Liver → Bile
- Kidneys → Urine
- Lungs → Lungs
Why are drugs more commonly metabolised first before being excreted?
Most drugs are too lipophilic to be excreted directly from kidneys. Metabolism converts drug into more hydrophilic form.
What are the 2 phases of drug metabolism?
- Phase 1 (Functionisation): Creation of reactive group in preparation for conjugation
- Phase 2 (Conjugation): Attachment of chemical group to drug to make it more polar
What types of reactions occur during phase 1 metabolism?
- Oxidation
- Reduction
- Hydrolysis
What groups are attached to drug molecules in conjugation reactions?
- Glucuronyl
- Sulfate
- Methyl
- Acetyl
- Glycine
- Glutathione
Which group of enzymes are responsible for metabolism of majority of drugs?
Cytochrome P450 enzymes (in liver)
What are the common features of CYP enzymes?
- Contains haem group
- Has peak absorbance at 450nm when bound to carbon monoxide in reduced form
- Found on smooth ER and so only act intracellularly on lipophilic drugs
Which phase of drug metabolism is the rate-limiting phase and why?
- Phase 2
- Conjugating groups are not widely available in body
What types of proteins mediate secretion of drugs from the liver?
P-glycoproteins
What are the factors that create individual variation in drug metabolism?
- Age (reduced in neonates and elderly)
- Sex
- Pathology (mainly liver, e.g. hepatitis)
- Genetics
- Drug interactions
What is induction of metabolism?
- Repeated administration of drugs causes increased expression of CYP enzymes mediating their activation
- Increases rate of metabolism and elimination to cause tolerance
How can drugs inhibit CYP enzymes?
Complexing with heme group (e.g. imidazole-containing drugs (azole antifungals) or erythromycin)
What criteria must drug satisfy for induction/inhibition to be significant?
- Concentration must be therapeutically critical
- Induction/inhibition must change clearance substantially
What are the variables that affect rate of renal secretion?
- Rate of filtration
- Rate of reabsorption
- Rate of secretion
What is the equation for rate of renal filtration for drugs that are freely filtered?
Rate of filtration = GFR x [Drug]Plasma
What drugs are freely secreted from the kidneys?
Aminoglycoside antibiotics
How can rate of renal tubular reabsorption be decreased?
- Making drug molecule more polar
- Changing urine pH to promote formation of ionised form of drug
Why are most drugs not efficiently excreted from the kidneys?
- Low rate of filtration due to plasma protein binding
- High rate of reabsorption due to being lipophilic
What is the equation for rate of excretion for drug that is freely filtered, not reabsorbed and not secreted?
Rate of excretion = GFR x [Drug]Plasma
What is the equation for rate of excretion for drug that is may be reabsorbed, secreted and not freely filtered?
Rate of excretion = Urine flow rate x [Drug]Urine
What are the types of drug elimination kinetics?
- Zero-order: Rate of elimination is independent of [Drug]Plasma
- First-order: Elimination is directly proportional to [Drug]Plasma
When is zero-order elimination observed?
When drug elimination requires enzyme (metabolism) and enzyme is saturated.
When is first-order elimination observed?
- When drug is eliminated via non-saturable route (e.g. kidneys)
- When drug is eliminated by enzyme, but enzyme is not saturated (Km of enzyme >> [Drug]Plasma)
