Pharmokinetics chapter 1 Flashcards
pharmokinetics
what the body does to a drug
four pharmokinetic properties
absorption, distribution, metabolism, elimiation
oral administration
absorption is variable,
advantages: safest, convenient, economical
disadvantages: limited absorption of some drugs, food, patient compliance necessary, drugs metabolized sometimes
IV admin.
absorption not required
advantages: immediate effect, ideal for large volumes, suitable for irritating substance, emergencies, titration possible, good for high MW proteins
disadvantages: oily substances not good, bolus may be bad, most must be slowly injected, strict aseptics
subcutaneous admin.
absorption depends on drug diluents. aqueous is prompt and depot is slow
advantages: suitable for slow release and for poorly soluble suspensions
disadvantages: pain or necrosis, has to be in small volumes
intramuscular admin
absorption same as subcutaneous
advantages: suitable for moderate drug vol., oily and irritating substances, and for self administering patients
disadvantages: affects creatine kinase test, painful, and can cause intramuscular hemorrhage
transdermal admin. (patch)
absorption is slow and sustained
advantages: bypasses first pass metab., convenient, painless, ideal for lipophilic , drugs w/ poor bioavailability, and drugs that are quickly eliminated
disadvantages: allergies, drug must be highly lipophilic, delay of delivery, limited to drugs taken in small doses
rectal admin
absorption is erratic and variable
advantages: partially bypasses first pass effect, and stomach
disadvantges: irritation of rectum
inhalation admin.
systemic absorption may occur and is not always desirable
adavntages: rapid, titration possible, fewer systemic side effects, good for respiratory problems
disadvantages: addictive, regulation is difficult
sublingual admin.
absorption depends on drug
advantages: bypasses first pass, stomach acid destruction,stability maintained because of pH of saliva, immediate effect
disadvantage: limted to certain drug type and small doses,, may lose part of drug if swallowed
Weak acid and. Weak base uncharged form
HA B
PKa
Measure of strength of interaction between a compound with a proton. Lower pKa means more acidic and vice versa
Distribution equilibrium
Permeable form of drug achieve equal concentration in all body water spaces
Why intestine absorption is favored over stomach
Blood flow, surface area, p glycoproteins (high amounts equal slow absorption), contact time, pH
Bioavailability
Rate and extent which drug reaches systemic circulation. IV is 100%. AUC measures extent of absorption
Factors that influence bioavailability
First pass hepatic metabolism, solubility of drug (largely lip ophicleide but soluble in aqueous solution is best), chemical instability in certain pH or enzymes, nature of drug formulation
Bioequivalence
Two drugs are bio equivalent if same bioavailability and similar times to achieve peak blood conc.
Therapeutic equivalence
Two drugs that have same dosage form, active ingredient, same route of admin., similar clinical and safety profile
Drug distribution
Reversible leaves blood to interstitial, depends on CO,BF,cap. Perm., tissue vol., binding of drug, and lipophilicity of drug
Cap perm.
Dependent slit junctions between endothelial cells. Liver has a lot. Brain has none
Binding of drugs to plasma and tissue proteins
Binding to plasma proteins makes it non diffusable and slows rate of transfer out of vasculature. Conversely binding to tissue proteins may cause toxicity or prolong actions .
Volume of distribution
Vd=amount of drug in body/C0 (concentration at time zero) fluid volume that is required to contain the entire drug in the body at the same concentration measured in plasma. Vd=dose/C0
Plasma compartment
High MW or protein bound. Low VD
Extra cellular fluid
Low MW but hydrophilic can pass through slit junction to interstitial fluid but can’t pass through cell membrane.
Total body water
Low MW and lipophilic. Can go anywhere
Effect of Vd on half life
Increases in Vd increases half life because they are unavailable to excretory organs
Half life
Time it takes to reduce the plasma drug conc to half. .693 Vd/CL
Three major routes of elimination
Urinary,biliary,hepatic
Clearance
CL=.693 x (Vd/t1/2)
First order kinetics
Rate of dug metabolism and elimination is directly proportional to concentration of free drug. Constant fraction of drug is metabolized over time. v=(Vmax [C])/Km
Zero order kinetics
v=Vmax concentration is higher than michaelis constant so does not depend on concentration. Constant amount is metabolized over time
Kidney metabolism
Cannot efficiently eliminate lipophilic drugs that readily cross cell membranes back to distal convoluted tubules so they are metabolized into hydrophilic substance in the liver via phase 1 and 2
Phase 1
Convert lipophilic drugs into more polar molecules by introducing or unmasking polar functional group such as OH or NH2. Mostly catalyze do by cytochrome P450 in the liver and GI tract
C P450 isoforms all CYP family and contributions to drug bio transformation
3A4/5,2A6,2B6,2E1,2C19,1A2(11%),
2C8/9(16%)2D6(19%)
Phase 2
If a drug is still too lipophilic to be excreted than it enters phase 2 and a subsequent conjugation occurs.
CLtotal =
CL hepatic, CL lungs, CL renal, CL other
Increase in drug half life Is caused by
Diminished renal or hepatic BF, decreased ability to extract drug from plasma, decreased metabolism
Steady state concentration
Reached when rate of drug elimination is equal to to drug administration rate. Steady state plasma concentration is proportional to infusion rate. If infusion rate is doubled than steady state concentration is doubled. Time needed to achieve steady state does not change.
Time required to reach steady state concentration
Rate constant to reach steady state is same as elimination. Thus 50% at t1/2. 75 at 2 half life. 87.5 at 3 half life. 90 at 3.3 half lives. So drug reaches steady state in about four to five half lives. Half life is sole determinant of rate drug reaches steady state and is only affected by factors that affect half life. When infusion stops concentration washes out at same rate to zero
Dosing rate
(Target C plasma)(CL)/F
Loading dose
VDx(desired steady state plasma concentration)/F(absorbed bioavailability) in IV infusion it is 100 so it is ignored. Loading dose is useful for drugs with long half lives
four mechanisms of drug absorption
passive diffusion, facilitated diffusion, active transport, endocytosis and exocytosis (for large molecules)
factors influencing absorption
pH,
