Quiz 1- Pharmocokinetics, Pharmocodynamics Flashcards
What is pharmacokinetics all about?
- Absorption
- Distribution
- Metabolism
- Excretion
What is bioavailability?
The percent of medication that reaches systemic circulation.
What affects the bioavailability?
ABSORPTION
- Dissolution and absorption characteristics
- Route
- Stability in GI tract
- Metabolism prior to blood stream
Example: Redosing synthroid IV to PO because bioavailibility of IV= 100%
need to increase dose
What consideration should be made about oral administration?
- Gastric pH and contents
- Surface area
- Blood flow
- GI Motility
- Complete GI tract
- Flora
What considerations should be made about sublingual/buccal administration of drugs?
- Drains to vena cava (no 1st pass)
- Very rapid
- Must be HIGHLY lipid soluble and potent
What happens to drugs taken orally?
1st Pass Metabolism:
-90% percent of oral medication is metabolized and destroyed by the liver before it gets to the heart
some meds wouldn’t make it past this
Topical administration into the eye should have special consideration because?
The medication could become systemic due to the nasolacrimal canal
What should be consider for inhalation of drugs?
- Rapid due to large surface area
- Avoid first pass-Local site of action
- Difficult to control
What is volume of distribution?
Size of compartment necessary to account for the total amount of drug in the boy if it were present throughout the body at the same concentration found in the plasma.
What is the volume of distribution in an average adult’s plasma?
3 Liters
What is the volume of distribution for total body water?
0.65 L/kg
What is the formula for loading dose?
Volume of distribution x Desired concentration = Loading dose
What is involved in two compartment model?
- redistribution before elimination
- Slow rate of administration for secondary redistribution
- Target organ may be in the initial or secondary “compartment”
What should be known about protein binding drugs?
- Unbound/free drug = active
- acidic drugs: albumin
- Basic drugs: alpha 1 acidic glycoprotein
- Generally reversible
- Saturable
- Non-linear
- Competitive
What should be known about tissue binding?
- Fat: Reservoir for lipid soluble drugs
- Bone: Tetracyclines
- Heart muscle: Digoxin
What is membrane permeability?
Drugs ability to permeate all membranes that separate the organ from the site of drug administration.
Are benzodiazepines membrane permeable and how does it work?
The are very lipophilic and cross the gut wall, capillary wall and blood brain barrier. Great for treating anxiety and seizures.
What are the point for placental transfer?
- fetal plasma is more acidic:ion trapping of basic drugs occurs
- P-glycoproteins limit transport in
- Fetus is exposed to nearly all medication a mother takes
What are P-glycoproteins?
- Family of transporter proteins
- Found all over, including the blood brain barrier (kidney, colon, jejunum, liver, pancreas)
- Important for medication interactions and drug resistance
- Requires ATP
What are the mechanisms for drug transport across membranes?
- Passive diffusion
- Facilitated diffusion
- Aqueous channels
- Active transport
Does passive diffusion require energy and a carrier?
Energy: No
Carrier: No
Note: Rapid for lipophilic, nonionic, small molecules
Does facilitated diffusion require energy and a carrier?
Energy: No
Carrier: Yes
Notes: Drugs bind to carrier by noncovalent mechs. Chemically similar drugs compete for channel.
Does aqueous channels require energy and a carrier?
Energy: No
Carrier: No
Notes: Small, hydrophilic drugs diffuse along concentration gradient by passing thru aqueous channels/pores.
Does active transport require energy and a carrier?
Energy: Yes
Carrier: Yes
Notes: Identical to facilitated diffusion except that ATP powers drug transport against concentration gradient.
What occurs during phase 1 metabolism?
- induce or expose a functional group on the parent compound (by oxidation, reduction, hydrolysis)
- Then often hydrolyzed or ester linked for rapid elimination thru the kidneys
What occurs during phase 2 metabolism?
- Conjugation reactions
- Links parent compound OR phase 1 metabolite with a functional group via covalent linkage
MOST reactions are ______ driven
Enzyme
What is inhibition?
Will keep the enzyme from working properly.
Inhibitors have the potential to interact with each other
What is induction?
Will enhance the capability of the enzyme.
What is Cytochrome P450?
- Terminal oxidase in a multicomponent electron transfer chain (mixed fx oxidase system).
- Is the largest family of enzymes responsible for breaking down 75% drugs
What factors affect metabolism of a drug?
- genetics
- environmental (diet)
- Disease factors (liver, kidney)
- Age: peds/geriatrics
What are the routes of elimination?
- Renal #1
- Biliary
- Fecal
- Sweat
- Saliva
- Tears
- Lungs
What is the equation for Ideal Body weight of a male?
IBW = 50 + (2.3 x inches > 5 feet)
What is the equation for ideal body weight of a female?
IBW = 45.5 + (2.3 x inches > 5 feet)
What are the modifications needed for the creatinine clearance equation?
(formula will be provided on test)
CrCl = (IBW) x (140 - age) x 0.85 (female)
————————
Cr x 72
-* if patient >65, round Cr up to 1 if <
- *use the LOWER body weight (of IBW vs ABW- actual body weight)
How many doses does it take to achieve a steady state??
5 half lives
- because we can’t change the rate out, only the rate in (so loading dose/ increased frequency wont help to reach SS faster)
Why do you check a trough level?
Checking efficacy
Why do you check a peak?
Checking for toxicity
What are the GENERAL receptors found on a cell?
Proteins or glycoproteins
What happens after receptor saturation occurs?
Receptor mediated responses plateau
What happens after a drug is bound to a receptor?
3 common actions:
- An ion channel is opened or closed
- Biochemical messengers (second messengers) are activated.
- Biochemical messengers initiate a series of chemical reactions within the cell, and transduce the signal stimulated by the drug - A normal cellular function is physically inhibited or initiated.
?What are the three points to Stephenson’s modified theory of 1956?
- Modified dose-response theory
- Drug response depends on both the affinity and efficacy.
- Describe “spare receptors”. This suggests that a maximal response can be achieved even if a fraction of receptors “spare receptors” are unoccupied.
What is affinity?
Strength of binding between a drug and its receptor.
What is dissociation Constant (Kp)?
The measure of a drug’s affinity for a given receptor.
The concentration of drug required in solution to achieve 50% occupancy of its receptors.
What does agonist mean?
drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors
What is a strong agonist?
Agonist which causes maximal effects even though it may only occupy a small fraction of receptors on a cell
What is a weak agonist?
Agonist which must be bound to many more receptors than a strong agonist to produce the same effect
What is an antagonist?
Inhibit or block actions caused by agonist
What is a competitive antagonist?
- Competes with agonist for receptors
- Can be overcome by high doses of agonists
What is a noncompetitive antagonist?*
Binds to a siteother than the agonist-binding domain. Induces a conformational change in the receptor such that the agonist no longer “recognizes” the agonist-binding domain.
What does surmountable
and insurmountable mean?
Surmountable: Antagonism being overcome by high doses of agonists.
Insurmountable: even at high doses of agonist, they can not overcome the antagonism
What does efficacy mean?
Degree to which a drug is able to cause maximal effects
What does potency mean?
Amount of drug required to produce 50% of the maximal response that the drug is capable of causing
What does effective concentration 50% (EC50%) mean?
Concentration of drug which induces a specified clinical effect in 50 % of the subjects to which the drug is administered.
What does lethal dose 50 % mean?
Concentration of drug which induces death in 50% of the subjects to which the drug is administered
What is the therapeutic index?
Measure of the safety of a drug
Calculated by dividing the LD50 by ED50
What is margin of safety?
Margin between therapeutic and lethal doses of a drug
What does addition mean in drug interaction?
the response elicited by combined drugs is EQUAL to the combined responses of the individual drugs
What does synergism mean in drug interaction?
The response elicited by combined drugs is GREATER THAN the combined responses of the individual drugs
What does potentiation mean in drug interaction?
Drug which has no effect enhancing the effect of a second drug
What does antagonism of drug interaction mean?
Drug inhibits the effect of another drug, usually the antagonist has no inherent activity
CYP substrate + CYP inducer = _______ amount of substrate due to ______
reduced
increased metabolism
CYP substrate + CYP inhibitor = _______ amount of substrate due to ______
increased
reduced metabolism
What is steady state?
rate in= rate out
amount of a drug administered over time= amount of drug eliminated during the same time
What is context sensitive half time?
For continuous infusion medication- the time until medication plasma levels reduce by 50% after stopping a continuous infusion
What are some age related PK changes for the elderly?
- Reduced absorption via carrier proteins
- Reduced first pass metabolism
- Higher body fat: water ratio*
- Possible reduced albumin concentration and/or increased alpha-1 acid glycoprotein**
- Reduced phase 1 metabolism
- Reduced kidney fx
- Disease states, thinning BBB*, GI tract changes
What are some age related PK changes for neonates and infants?
- Higher gastric pH, longer emptying time
- Higher body water: fat ratio* (opposite peds)
- Reduced/immature CYP450 enzymes**
- Reduced protein binding
- Reduced renal clearance
Dialysis provides an average CrCl ~___mL/min
30mL/min
What will be removed in dialysis?
- Unbound volume < 3.5L/kg
- Dosing interval longer than 1/2 life
- Molecular weight <1000 daltons
(unbound, small, more ionic)
What is a Partial Agonist?
A drug which fails to produce maximal effects, even when all receptors are occupied
What is an Inverse Agonist?
Binds to receptor site and causes the opposite effect of an agonist (doesn’t block anything)
Pregnancy Catergories
A- adequate well-controlled studies, no risk
B- Animal studies- no SE, no human studied
C- potential benefits may warrant use of the drug in pregnant women despite potential risks
D- +evidence of human fetal risk, but potential benefits may warrant use
X- animals/humans have + fetal abnormalities
