Pharmacokinetics - Sinal 2 Flashcards
Pharmacokinetics
Quantitative study and characterization of the time course of drug concentrations in the body
Can predict concentration of drug in blood and magnitude of effect hours later, absorption, distribution and elimination
Utilizes simplified mathematical representations to model physiological processes
Pharmacokinetic differences
Major determinant of patient response to drugs
Differences between how they absorb drugs, metabolize, receptors
Routes for drug administration
- Enteral
- Parenteral
- Topical
Enteral drug administration
Desired effect is systemic (given via digestive tract)
Oral is most common and convenient route (but subject to first pass effect)
Not suitable for drugs that are rapidly metabolized, acid labile or known to cause GI irrigation
Gastric feeding tube or rectal
First pass effect
Drug metabolism by intestine and liver enzymes
Reduces amount of drug that ultimately reaches the systemic circulation: reduces bioavailability
Parenteral
Desired drug effect is systemic
Route other than digestive tract
Injection, transdermal, transmucousal
Injection
Rapid delivery
100% bioavailability
Topical
Local effect
Epicutaneous, inhalation, eye drops, ear drops, intranasal, vaginal
Physical factors that affect oral drug absorption
Concentration differences across membrane, size, polarity, ionization
Passive drug absorption of the small intestine
Majority of drug absorption
Large surface area, brush border, extremely high bloodflow
Physiological factors that affect oral drug absorption
- Gastrointestinal motility
- Metabolism
- Changes in pH of gastrointestinal tract (affects ionization)
Drug distribution
Process in which a drug reversibly leaves the blood and is distributed throughout the tissues of the body
Extent is dependent on blood flow, ability of drug to transverse cell membranes, and degree of binding to blood proteins
Distribution of a drug to target organ is critical requirement for achieving therapeutic benefit
Vd
Volume of distribution= total amount of drug in body/initial plasma concentration
Apparent volume of fluid which an administered drug is dispersed in
Assumes equal partitioning throughout the body
Determined from measurement of initial plasma drug level after IV bolus injection
Small Vd
Infers retention within the plasma volume
Large Vd
Infers retention in volumes outside of plasma
Factors causing high Vd
- High lipophilicity
- Low polarity
- Low ionization
- Low molecular weight
* Increased ability to traverse biological membranes of cells
Factors causing low Vd
- Low lipophilicity
- High polarity
- High ionization
- High molecular weight
- Binding to blood proteins, ie. Albumin
Albumin
Binds many drugs
Bound drug is therapeutically inactive
Binding is reversible, but can cause potentially dangerous increase in blood concentration of free drug (great concern for high bound >90% drugs with narrow therapeutic window)
Elimination
Major: urine, bile
Minor: saliva, sweat, milk, other body fluids, exhalation
Drug metabolism
Biotransformation
Metabolism increases polarity, ionization and water solubility
Metabolites often are deactivated, prodrugs have more active or toxic metabolites
Liver is major site of metabolism of drugs
Lipophilic drugs are poorly excreted by the kidney and the liver
Phase 1 metabolism
Creation or unmasking of small polar or reactive functional groups
Usually rate limiting
Phase 2 metabolism
Addition of large polar groups to small, reactive functional groups
Cytochrome P450
Most important contributor to metabolism of most drugs
Extremely broad substrate range
Expression levels very among individuals
Enzymatic activity can be inhibited by drugs and diet components: decreases rate of metabolism of co-administered drugs
Expression levels can be induced by drugs and diet components
Inhibitors of CYP3A4
Antifungals (ketoconazole), antibiotics (erythromycin), diet (grapefruit juice)
Inducers of CYP3A4
Anticonvulsants (phenobarbital), steroids (dexamethasone), HIV protease inhibitors (saquinavir), antibiotics (rifampicin)
CYP3A4
Most relevant enzyme to human drug metabolism: must abundant CYP in intestine and liver, very broad substrate specificity, metabolizes 50-70% of drugs
Felodipine and CYP3A4
CYP3A4 makes felodipine an inactive metabolite M3
Dihyropyridine calcium channel antagonist (relaxes smooth muscle) for treatment of hypertension
Poor bioavailability: extensive first-pass metabolism
Coadministration with CYP3A4 inhibitors/substrates causes plasma concentration of felodipine to increase and cause excessive hypotension, cardiac side effects
Terfenadine and CYP3A4
Terfenadine is metabolized by CYP3A4 to active Fexofenadine
Terfenadine is toxic: inhibition of K channel, life-threatening cardiac arrhythmias
CYP3A4 inhibitors increase likelihood of cardiac toxicity
Withdrawn from market
Cyclosporine and Rifampicin
Rifampicin induces expression of CYP3A4
Co-administration of the two reduces plasma levels of cyclosporine and can cause acute rejection episodes
Increases cyclosporine dose requirement by 3-fold
Inter individual differences in drug metabolism
- Diet, environment
- Age
- Disease
- Genetic factors
CYP2D6
Metabolizes ~15% of drugs
Highly polymorphic
4 genotypic groups:
1. Poor metabolizers
2. Intermediate metabolizers
3. Extensive metabolizers (most common in all ethnic groups)
4. Ultrarapid metabolizers (increased risk of respiratory depression)
Kidney drug excretion
Most important route for parent drug and metabolites
Excretion in urine
Promoted by drug metabolism
Organic cation transporters and organic anion transporters
Most polar and ionized compounds are not reabsorbed efficiency by passive diffusion and are excreted in urine
Liver drug excretion
Important for a number of drugs
Excretion in bile
Promoted by drug metabolism
Organic cation transporters
OCT, MATEs (multidrug and toxin extrusion proteins) and Pgp (P-glycoproteins)
In kidney proximal tubules
Organic anion transporters
OATs, MRPs (multidrug resistance proteins)
Initial drug concentration
Co= Q/Vd
Plasma concentration
C=Co e^(-kel t)
Kel
Elimination rate constant
Half-life
t1/2= 0.693/kel
Clearance
Volume of plasma from which drug is removed per unit of time
Reflects elimination of drug through metabolism and various routes of excretion
Cl=rate of elimination/C
Cl=kelQ/Co
Cl=kel Vd
Cl= 0.693Vd/(t1/2)
Continuous IV infusion
To maintain drug levels in blood
Plasma concentration will rise fast at first, then more slowly and reach a plateau where rate of administration = rate of elimination = Css
Css
Steady state blood concentration
If time to achieve Css is too long, an initial higher dose is used with subsequent doses being smaller maintenance doses
Usually takes 3 half-lives
Multiple doses
Can be used to achieve steady state
Steady state blood concentration that oscillates between Cmax and Cmin
Target concentration strategy
Assumes that for most drugs, magnitude of therapeutic effect and risk for adverse reactions is predictable given target concentration in the blood
Dose required to achieve TC will vary between individuals
Pharmacokinetic models and parameters can be used to reliably predict the dose required to achieve TC and therapeutic benefit
