Pharm 2 Lecture Flashcards
Bioavailability
the fraction of an administered drug that reaches the systemic circulation
What bioavailability do IV drugs have?
100%
What factors affect bioavailability?
First pass (hepatic) elimination Solubility characteristics of the drug Chemical Stability in the GI tract Drug formulation (ex. extended release)
First pass (hepatic) elimination
Via the portal circulation
The liver can metabolize or excrete (via bile) drugs such as nitro and thus limiting their bioavailability
Drugs with high first-pass metabolism must be given in higher doses (orally) or parentally
Solubility characteristics of the drug
Too lipophilic and the drugs may be poorly absorbed; too hydrophilic and the drugs have difficulty passing through lipid cell membranes
(this is why commonly administered drugs are either weakly alkaline or weakly acidic)
What drug is unstable in stomach acid?
Penicillin-G
Biggest determinant of sieving coefficient
Degree of protein binding (NOT well correlated with molecular weight)
Volume of Distribution
volume of fluid that is required to contain an entire drug in the critter’s body at the same concentration measured in a given “compartment” such as plasma, for example.
Vd = Drug in body (dose)/ Concentration at time zero in given compartment
Drugs confined to the intravascular space have a ________ volume of distribution.
smaller
Drugs that have extensive distribution outside the plasma appear to have a ______volume of distribution.
large
What drugs have a large volume of distribution?
Ex. Digoxin, diltiazem, labetalol, meperidine, or nortriptyline
Main ways to eliminate drugs
urine, bile, hepatic metabolism, lung/oxygenator expiration, artificial filtration (hemoconcentrator)
Half-Life
time required for the concentration or amount of drug in a critter’s body to be reduced by 1/2; goes in both directions
(Assumes first order kinetics)
First-Order Kinetics
The rate of drug metabolism and elimination is directly proportional to the concentration of free drug; proportion of the drug is metabolized per unit time
Formula for 1/2 Life
F = A(1/2) ^ (t/h)
90% of the steady-state drug concentration is achieved in how many 1/2 lives
3.3 half lives
Clearance Equation
Cl = (0.693 x Vd) / (Half-life)
Zestil (Lisinopril)
commonly used angiotension-converting enzyme inhibitor; first-order elimination
Half-life: 12 hours
Distribution appears to be limited to the intravascular space
Zero-Order Kinetics
they are eliminated by a constant amount over time because they’ve overwhelmed clearance mechanisms
Target Concentration
The drug concentration that will produce the desired therapeutic effect
Loading Doses
particularly important with drugs that have long half-lives
Loading dose = Vd x Target plasma concentration/ Bioavailability %
Maintenance dose equation
Maintenance dose = dosing rate x dosing interval
Maintenance dosing rate Equation
(CI x Target Plasma Concentration)/ Bioavailability %
What does Biotransformation accomplish?
Lipophilic drugs tightly protein-bound and thus unavailable for excretion by the kidneys
shorten drug’s 1/2 life
Convert into active form
Reduce activity
What happens if you biotransform a drug into a more polar molecule?
Greatly decreases its activity
Less protein bound –> more readily filtered
Decreases half-life
Where does biotransformation occur?
Liver, Intestine, Lungs, Skin
Two Main Biotransformations
Phase I
Phase II
Phase I Biotransformation
Metabolize the drug into a more polar form
Phase II Biotransformation
Conjugates the drug with another chemical (such as acetylation)
How does the liver (and GI) biotransform drugs?
Cytochrome P450 Complexes
Cytochrome P450 Complex
A large family of heme-containing enzymes with enormous genetic variation
Induction
Drugs/chemicals make the Cytochrome P450 systems more active by increasing rate of synthesis or decreasing rate of degradation
Induced P450 Enzymes
Metabolize drugs faster
Inhibited P450 Enzymes
Metabolize drugs slower
How much of US health care dollars go toward drugs?
1/8
How much did drug companies spend in lobbying dollars in 2013?
A quarter of a billion lobbying dollars
What are the stages of drug development?
In vitro studies (2 years)
Animal testing (2 years)
Clinical testing (4-5 years)
marketing (11 years)
After how many years does a patent expire after filing of application?
20 years
After how many years of making a drug does the generic become available?
20 years
Phase I Clinical Trials
20-100 Subjects
Is it safe? Pharmacokinetics?
Phase 2 Clinical Trials
100-200 Subjects
Does it work in patients?
Phase 3 Clinical Trials
1000-6000
Does it work? Double clind
Phase 4 (Marketing)
Postmarketing surveillance
After how many years of making a drug is the point of having an “investigational new drug”
4 years
When is the NDA (new drug application)?
8-9 years
Who oversees drug trials?
FDA
