Pharmacokinetics Flashcards
Draw the flow chart outlining the relationship between pharmacokinetics and pharmacodynamics.
Pharmacokinetics
Routes for drug administration
- systemic (parenteral and enteral)
- local (topical)
Enteral drug administration
- substance given via the digestive tract
- oral is most common and convenient route
- others are gastric feeding tube, rectal
First pass effect
- metabolism by intestine and liver enzymes
- reduces amount of drug that ultimately reaches the systemic circulation (bioavailability)
Oral administration is not suitable for drugs that are…
- rapidly metabolized
- acid labile- would be broken down in high acidity of the stomach
- known to cause GI tract irritation
Parenteral drug administration
- drug is given by route other than digestive tract
- injection
- transdermal (nicotine patches)
- transmucosal (buccal, insufflation, inhalational)
Drug administration by injection
- intravenous, intramuscular, subcutaneous
- intravenous gives 100% bioavailability
- bypasses first pass effect
- suitable for acid labile drugs
Cons of drug administration by injection (3)
- may require professional admin
- costs assoc w/ injection materials and disposal
- requires sterile prep
Topical drug administration
- local effect
- substance is applied directly where its action is desired
Oral Drug Absorption
- the process by which a drug moves from the site of admin (GI tract) to the site of measurement (blood)
- requires passage across membranes of cells (enterocytes) that comprise the intestine wall
- mostly occurs by passive diffusion across membranes
Physiochemical Factors that affect oral drug absorption (4) and explain.
- concentration difference across membrane
- size
- polarity
- ionization
Why does the majority of absorption for most drugs occur in the small intestine?
- extremely large SA
- 250m2
- 1000x > stomach
- villi, microvilli - extremely high blood flow
Physiological factors that affect oral drug absorption (3)? Explain
- gastrointestinal motility
- metabolism
- changes in pH of GI tract
Drug Distribution
Process by which a drug reversibly leaves the blood and is distributed throughout the tissues of the body
-distribution to target organ is critical for achieving therapeutic benefit
The extent of drug distribution is dependent upon what factors? (4)
- blood flow
- ability of drug to traverse cell membranes
- degree of binding to blood proteins (albumin)
- unique properties of drug/tissue
Volume of distribution (Vd)
The apparent volume of fluid into which an administered drug is dispersed
- determined from measurement of initial plasma drug level after IV bolus injection
- apparent b/c assumes that the conc measured in the plasma accurately reflects the conc in the interstitial and intracell vol => every drug should have a Vd of 42L
A small Vd infers?
A large Vd infers?
small=retention in the plasma
large=retention in volumes outside of plasma
As Vd increases, dose required to achieve a particular initial plasma conc ?
Increases
What are 2 factors that contribute to high Vd?
- physiochemical properties of drug
2. physiological properties of tissues
What physiochemical properties of drug favour a high Vd?
-high lipophilicity
-low polarity
-low ionization
-low molecular weight
=>increased ability to traverse biological membranes of cells
What are 2 factors that contribute to low Vd?
- physiochemical properties of drug
2. binding to blood proteins (blood serum albumin)-explain
? and ? are the major determinants of a drugs duration in the body
-metabolism and excretion
The goal of metabolism is to increase ?, ? and ? of drugs.
- polarity
- ionization
- solubility
Bioavailability
The amount of administered drug that reaches the systemic circulation in unchanged form following administration by any route
Phase I Metabolism
Creation or unmasking of small polar or reactive functional groups
-usually rate limiting step
eg hydroxylation
Phase II Metabolism
Addition (conjugation) of large polar groups to small reactive functional groups
eg glucuronidation
The cytochrome P450 gene superfamily
- 57 individual genes
- families 1, 2, 3 are most relevant to drug metabolism -Phase I
T or F: CYP3A4 has very broad substrate specificity
True
What are 3 inhibitors of CYP3A4?
- antifungals (ketoconazole)
- antibiotics (erythromycin)
- diet (grapefruit juice)
What are 4 inducers of CYP3A4?
- Anticonvuslants (phenobarbital)
- Steroids(dexamethasone)
- HIV protease inhibitors (saquinavir)
- Antibiotics (rifampicin)
CYP3A4 is most abundant in ? and ?
intestine and liver
Explain the interaction of felodipine with CYP3A4
- dihydropyridine Ca channel antagonist for the treatment of hypertension
- poor oral bioavailability b/c deactivated by CYP3A4
- coadministration w/ grapefruit juice or other CYP3A4 substrates/inhibitors increase bioavailability and plasma conc up to 5 fold, increases risk for hypotension and cardiac side effects (HR increase)
Explain the interaction of Terfenadine (marketed as seldane) with CYP3A4.
- non sedating antihistamine
- prodrug
- extensively metabolized by CYP3A4 to fexofenadine (allegra)
- serious cardiac side effects at high concentrations of terfenadine (inhibition of K channels, life threatening arrhythmias)
- CYP3A4 inhibitors increase likelihood of cardiac toxicity
- withdrawn from market in Canada in 1999
CYP3A5 Induction caused by cyclosporine and rifampicin
cyclosporine-immunosupressant drug used to prevent rejection of transplanted organs
-metabolized to inactive metabolite by CYP3A4
Rifampicin
-antibiotic used to treat a variety of bacterial infections
-induces expression of CYP3A4
Coadministration of cyclosporin and rifampicin
-reduces plasma levels of cyclosporin
-can result in acute rejection episodes
-increases dose requirement by 3 fold
What are 4 inter individual differences in drug metabolism?
- Diet and environment (smoking, occupational exposure)
- age (children exhibit differences from adults, drug metabolism reduced in elderly)
- disease (drug metabolism reduced with disease)
- genetic factors (polymorphisms in genes, affects expression level, inherent enzyme activity and response to inducers)
Cytochrome P450 2D6
- metabolizes 15% of drugs
- highly polymorphic
What are 4 CYP2D6 phenotypic groups?
- poor metabolizers (caucasians)
- intermediate metabolizers (east asia and subsaharan africa)
- extensive metabolizers (normal, most common phenotype)
- Ultrarapid metabolizers (elevated expression and activity, Middle east, north africa, oceania)
Codeine
- narcotic analgesic prescribed after surgery
- often combined w/ acetaminophen
- analgesic effect is due to morphine metabolites generated by CYP2D6 metabolism
How do CYP2D6 polymorphisms affect codeine analgesia?
Poor metabolizers may experience reduced analgesia (pain relief) from a normal dose of codeine due to reduced levels of morphine metabolites
- Mistaken for drug-seeking behaviour?
Ultrarapid metabolizers may experience adverse effects (e.g. respiratory depression) as a consequence of a rapid accumulation of morphine metabolites
What is the role of the kidney in drug excretion?
- Quantitatively, most important route for parent drug and metabolites
- Excretion in urine
- Promoted by drug metabolism
What is the role of the liver in drug excretion?
- excretion in bile
- Promoted by drug metabolism
What are other structures impt for drug excretion (other than liver and kidney)
- sweat, tears, repro fluids, milk, lung
- may be influenced by drug metabolism
How does metabolism promote renal drug excretion
-by producing metabolites with greater polarity, ionizability and reduced lipophilicity (organic anions and cations)
What are the 2 major classes of transport proteins involved in renal drug secretion?
- Organic cation transporters (OCTs, MATEs, P-gp)
- organic anion transporters (OATs, MRPs)
- present on faces of nephron tubule epithelial cells, most abundant is proximal tubule
