Lecture 66 Flashcards
Absorption, Bioavailability, Distribution
pharmacokinetics: ADME
- absorption, distribution, metabolism, elimination
- after absorption → free drug is distributed in systemic circulation to receptors, tissue reservoirs,or become protein-bound
- after distribution → they are metabolized and the metabolites they secrete are excreted
- sometimes free drug can be directly excreted
pg 1688
absorption
- irreversible transfer of a xenobiotic from its site of administration to the systemic circulation (blood)
- a drug administered via IV = immediate and complete (100%) absorption (but really bypasses absorption), then distributed to other body compartments and eliminated by 1st-order kinetics
- a drug administered extravascularly must pass through physiological barriers to the blood to be effective (barriers → skin, mucous membranes, GIT, BBB, placenta…)
pg 1689
routes of administration
based on the mechanism of drug absorption (transport)
pg 1690
oral administration (enteral route)
- easily and conveniently self-administered
- shows the weaknesses in human barrier defenses
- exposes the drug to harsh acidic (stomach) and basic (intestine) environments → limits absorption and drug must be stable
pg 1690
first-pass metabolism
- drug moves to the liver via portal system for detoxification before entering the blood; inactivates a fraction of the drug
- drugs exhibiting significant first-pass metabolism must be administered in sufficient doses to ensure therapeutic drug concentrations in the blood (or change the route)
- oral is most convenient, but may have a significant first-pass effect (5 to < 100% bioavailability); rectal has less of a first-pass effect than oral (30 to < 100%)
pg 1691
factors affecting GI absorption
Drug Factors (properties):
- size (molecular size and type of dosage form)
- lipid solubility (hydrophobicity vs hydrophilicity)
- ionization (strong bases and acids are poorly absorbed)
small size, hydrophobic and neutral drugs cross cell membranes»_space;> large size, hydrophilic or charged drugs, unless they are carried by transporters
Physiological Factors:
- gut content
- GIT pH
- motility
- generally, little absorption in stomach until drug reaches small intestine (exceptions: buccal, sublingual, or rectal dosage forms)
pg 1692
parenteral route of drug administration
- a drug is introduced directly into the systemic circulation
- rapid onset of action > oral
- irreversible toxicity when administered too rapidly or in incorrect doses
Examples:
- subcutaneous (SC) → into poorly vascularized adipose tissue (slow onset, oil-based drugs, small volumes)
- intramuscular (IM) → well vascularized IM space (immediate onset, oil-based, can affect lab tests)
- intravenous (IV) → rapid onset, controlled drug delivery
- intra-arterial (IA)
- intrathecal (IT) → into cerebrospinal fluid (bybasses BBB)
pg 1693
mucous membrane route of drug administration
- highly vascular
- rapid absorption and onset
- low incidence of infection
- convenience of administration
Examples:
- sublingual → rapidly dissolving tablets
- ocular and nasal → liquid drops
- pulmonary → aerosols, gaseous drugs, avoid 1st pass effect, rapid absorption and onset due to high SA (bioavailability 5 to < 100%)
- rectal → suppositories, decreased 1st pass effect, good for unconscious patients, infants, or in vomiting
- reproductive tract → suppositories, creams
pg 1694
transdermal route of drug administration
- simple and convenient
- no risk of infection
- ideal for drugs slowly absorbed and continuously administered
- for lipophilic drugs
- bioavailability between 80 and 100%
- enables passive diffusion across the skin
- Examples: nicotine, estrogen, scopolamine patches
pg 1695
Absorption is the reversible transfer of a xenobiotic from its site of administration to the systemic circulation.
A. True
B. False
B. False
pg 1696
A 29-year-old woman is prescribed carbamazepine for trigeminal neuralgia. She has a strong family history of osteoporosis. As a result, the physician also advises her to increase her intake of vitamin D. The most likely reason for this recommendation is that carbamazepine may affect which of the following pharmacokinetic processes?
A. absorption
B. distribution
C. excretion
D. metabolism
E. protein binding
D. Metabolism
pg 1697
local factors that affect absorption
- large or rapidly administered dose → high local concentration of a drug vs the surrounding tissue → high concentration gradient ΔC
- high ΔC → drives the distribution of the drug into the nearby tissue and/or vasculature
- factors decrease ΔC → reduce drug distribution → reduce drug absorption
pg 1698
regional factors that affect absorption
- highly perfused region → high absorption and rapid clearance → maintains the drug concentration at a low level (sink condition) in the compartment → maintains ΔC → driving force for absorption
- ex: volatile general anesthetics (inhalation)
- lungs are highly perfused, anesthetic is cleared rapidly into the systemic circulation → no dose accumulation in and a ΔC promoting diffusion of anesthetic into the blood is maintained
- individual with greater body mass → large SA for absorption → large Vd → remove a drug from the site of administration faster → increase the rate and extent of drug absorption
KNOW SINK CONDITION
pg 1699
other factors that affect absorption
Chemical Properties of Drug:
- water/lipid solubility
- ionization of drug
Physical Properties:
- particle size
- disintegration time (breakdown of the tablet)
- dissolution time of drug
pg 1700
mechanism of absorption
- passive diffusion (non-carrier mediated)
- facilitated diffusion (carrier mediated)
- active transport (carrier mediated → against the gradient)
pg 1701
passive diffusion
- described mathematically by Fick’s 1st Law
- rate of diffusion across a membrane (dC/dt) is proportional to the difference in concentration (Ce - Ci)
- molecules transported across a cell membrane (from a region of higher conc to one of lower conc) → NO energy is consumed
- used by most relatively small lipophilic molecules and drugs
dC/dt = DA/h × (Ce - Ci)
A = surface area
C-C = concentration gradient
Ce = extracellular gradient
Ci = intracellular gradient
h = thickness of membrane
D = diffusion coefficient of drug across GI membrane
pg 1702
Which of the following is correct regarding the process of passive diffusion?
A. It requires a carrier protein molecule.
B. It requires a concentration gradient.
C. It is a saturable process.
B. It requires a concentration gradient
pg 1703
facilitated diffusion
- NO energy is required
- higher conc saturates the carrier mechanism → increasing drug does NOT increase the rate of absorption → constant rate of absorption
- competition between 2 similar molecules for same transfer mechanism inhibits the absorption of one or both molecules
- plays a very minor role in drug absorption
pg 1704
active transport
- molecules transported against the concentration gradient across a cell membrane (from a region of lower conc to one of higher conc)
- requires ATP
- ex in SI: peptide, nucleoside, sugar, bile acid, amino acid, and ions
pg 1705
bioavailability (F)
- F = rate and extent to which drug is absorbed from a dosage form and becomes available in the blood (at the site of action)
- F = fraction of drug that reaches the systemic circulation
- certain drugs are influenced by the presence of food, which can reduce the absorption rate and the max conc (and vice versa)
- many orally administered drugs undergo first-pass metabolism in the liver
- drugs with 100% bioavailability → 100% of drug reaches the blood → same for all routes of drug administration
- if the drug has less than 100% bioavailability, the dose should be increased (to a safe dosage)
- drugs with similar bioavailability have similar AUC (plasma drug concentration vs time → total amount of drug reaching systemic circulation)
- rate of absorption = ΔC/Δt
pg 1707-1708
Which one of the following routes of administration does not have an absorption phase?
A. subcutaneous
B. intramuscular
C. intravenous
D. sublingual
E. inhalation
C. intravenous
pg 1709
factors affecting bioavailability
bioavailability (F) = quantity of drug reaching systemic circulation ÷ quantity of drug administered (F = mg absorbed/mg dose)
- chemical-physical properties of the drug
- route of administration
- patient-specific factors like transporters and enzymes
pg 1710
calculating the oral dose and bioavailability
- bioavailabilityoral = doseIV × bioavailabilityIV ÷ doseoral
- doseoral = (doseIV × FIV) ÷ Foral
pg 1711
A 52-year-old man present to the office for routine follow-up. Currently, he is under treatment for HTN and congestive heart failure with intravenous Vasotec (1.25 mg) and a diuretic. The physician decided to prescribe an oral dose of the same drug, bioavailability = 60%. What will be the value of the oral dose?
A. 2.083
B. 2.58
C. 2.83
D. 3.83
E. 0.83
doseoral = doseIV × bioavailabilityIV ÷ bioavailabilityoral
dose = 1.25 mg × (100/100) ÷ (60/100) = 2.083 (A)
pg 1712-1713
half-life (t1/2)
- time required for the drug concentration in the plasma to decrease to 1/2 of its original value
- used to estimate the frequency of dosing required to maintain the plasma concentration of the drug in the therapeutic range
- because most drugs are eliminated by first-order kinetics, the body is considered as a single compartment with a volume of distribution = Vd
- concentration at steady state is target for therapeutic window (based on drug dosing and dosing frequency) → take dose so many times at drug t1/2 to reach steady state
- t1/2 = 0.693/Kel… Kel = K elimination
pg 1714
Csteady state
- (bioavailability × dose) ÷ (intervaldosing × clearance)
- t1/2 = (0.693 × Vd) ÷ Cl
- a decrease in clearance or increase in Vd = prolonged t1/2 and enhances the effect of the drug on the target
pg 1715
factors altering half-life
- physiologic and pathologic changes in Vd and Cl
- some P450 enzymes are induced by some drugs (carbamazepine and phenytoin) and inhibited by (cimetidine and ciprofloxacin)
- effects on Vd: aging, obesity, pathologic fluid
- effects on clearance: cytochrome P450 induction, cytochrome P450 inhibition, cardiac failure, hepatic failure, renal failure
pg 1716
A 35-year-old male presents to the clinic for the treatment of an infection. His physician prescribes amoxicillin, which has a volume of distribution of 21 L. If the patient weighs 85 kg and the clearance of the drug is 25 L/hr, what is the elimination half life of the drug?
A. 0.707 hr
B. 0.85 hr
C. 0.58 hr
D. 1.25 hr
E. 0.37 hr
Vd = 21 L for ideal body weight (70 kg)
for pt BW of 85 → Vd = 25.5 L
t1/2 = (0.693 × 25.5 L) ÷ (25 L/hr) = 0.707 (A)
pg 1717-1718
volume of distribution
usually given in reference to someone of ideal body weight (70 kilograms for male)
A 39-year-old man comes to the clinic with NYHA class IV congestive heart failure. He states that he is currently taking 250 μg/day of digoxin. The Vd of digoxin is 7.3 L/kg, based on ideal body weight. The patient’s weight is 68 kg. The average half-life is 40 h. The average bioavailability of digoxin is 70%. What is the steady-state concentration of digoxin?
A. 0.848 μg/L
B. 0.814 μg/L
C. 1.848 μg/L
D. 0.085 μg/L
Csteady state = [(0.7)(250 μg)]/[(24 h)(Cl)]
Cl = (Vd)(Kel) = (7.3)(68)(Kel)
Kel = 0.693/t1/2 = 0.693/40 h = 0.0173 h-1
Cl = (7.3 L/kg)(68 kg)(0.0173 h-1) = 8.6 L/h
Csteady state = [(0.7)(250 μg)]/[(24 h)(8.6 L/h)] = 0.848 (A)
pg 1719-1720
