W7: Pharmalcology Flashcards
Large/narrow therapeutic index (TI) is safe (what is TI?)
Large (big gap between effectiveness and toxicity)
TI is ratio: TD50/ED50
Define pharmacokinetics and name what ADME stands for.
what body does to drug;
ADME – absorption, distribution, metabolism, excretion
What is quantal dose-response (d-r) curve? Describe its components:
X and Y axis
ED50
TD50
LD50
graph used to quantify quantal response to a drug (quantal - all or none; yes or no)
X - dosage each person took
Y - % of people who responded to the drug
Median effective dose (ED50) - dosage at which 50% responded favorably
Median toxic dose (TD50) - toxic dosage for 50% of participants
Median lethal dose (LD50) - dosage at which 50% found lethal
What is graded dose-response (d-r) curve ?
X and Y axis?
What are 2 important information you can get?
D-R curve is a graphical representation between quantity of drug and a graded biological effect
X - drug concentration
Y - % maximal response
efficacy and potency
Magnitude of a response is called __.
Efficacy
EC50 is used to compare the potency/efficacy of two drugs.
Potency
Therapeutic window is utilized in quantal/graded dose-response to gauge the effective plasma drug concentration range.
graded
competitive/non-competitive antagonist reduces the EC50 (efficacy/potency) of the original drug.
competitive, potency
Non-competitive antagonists reduces the efficacy/potency of the original drug which can/cannot be overcome with increased [original drug].
efficacy, cannot
Define concept of spare receptors. How was this discovered?
Idea that when maximal response is reached, not all receptors are activated
Experiment: When agonist + irreversible antagonist are added, maximal response was still achieved.
Conclusion: Max response can be achieved with less than 100% of receptors (because spare receptors are present)
difference between EC50 and Kd?
EC50 describes potency of the drug action.
Kd describes the binding affinity of drug/ligand to receptor.
What is the difference between occupancy theory and the two state receptor model?
occupancy: one ligand, one receptor (receptor inactive if no ligand)
two state: presence of constitutively active receptor and inactive receptor that needs to be bound to a ligand (receptor can be spontaneously active in absence of ligand)
Draw a dose x drug activity graph indicating the terms below:
constitutive activity full agonist partial agonist antagonist inverse agonist
constitutive activity - activity (y axis) > 0 (all graphs start here)
full agonist - sigmoidal, max activity
partial agonist - sigmoidal, less than max activity
*antagonist = constitutive
(two state receptor model)
inverse agonist - decrease to zero from constitutive
3 targets of drug
- receptor (potency, efficacy)
- enzyme (affinity, efficacy)
- transporters (blockers)
Two factors that influence absorption of drug into plasma are __ and __, which both determine the __ of drug.
route of administration, membrane penetration;
bioavailability
Differentiate therapeutic index and therapeutic window and their parameters (X vs. Y).
TI: range of safe dose for general population
(X - dose; Y - % of people who responded to the drug)
TW: - range of doses that produce a therapeutic response without unacceptable side effects
(X - time; Y - PLASMA drug concentration)
Calculation for oral bioavailability (%)
AUC (area under the curve)
iv does is 100% bioavailability (plasma absorption)
oral dose AUC/ iv dose AUC
Enteral/Parenteral administration of drug means via the GI tract.
Enteral
__ is the disadvantage of oral administration of drug, subjecting drug to degradation/alteration in __ and __ prior to reaching the systemic circulation (blood).
First Pass Effect;
liver and intestine
Trajectory: oral –> GI –> vasculature –> portal vein –> liver (metabolism) –> hepatic vein –> systemic circulation (absorption)
3 ways drug enters cell/tissue (distribution)
- Diffusion (partition coefficient)
- Carrier-mediated transport
- Endocytosis
What determines the diffusion of drug into cell/tissue?
Jx = Px A (Co – Ci)
Px - partition coefficient
A - area of membrane
(Co – Ci) - concentration gradient
__ is measure of solubility of drug in lipid.
Partition coefficient
[Drug] lipid phase / [Drug] aqueous phase
Drug distribution to tissue is influenced by 3 factors (list them), determining the __.
ion trapping, protein binding, tissue barrier;
volume of distribution
Drug-protein binding in the plasma functions as a
__ of drugs in the circulation. The fraction of bound (drug-protein complex) to total drugs in plasma remains constant.
reservoir
Treatment for Aspirin toxicity is __ by administering __ intravenously.
basifying (alkalinization) of urine, bicarbonate
Describe the mechanism of detoxification of aspirin in the context of ion trapping.
When urine is alkalinized, aspirin (weak acid) in urine (basic environment) becomes charged (cation). A significant amount of drug (cation) is now trapped in urine for excretion.
Drug distribution to target tissue will be most ideal for a weak acid drug in an acidic/basic environment.
acidic (weak acid becomes more neutral)
basic environment for weak base drug (conjugate acid)
Drugs first end up in location with highest/lowest blood flow (2 organs in the body)
highest; kidney and liver
Functional outcome of metabolism (actions of phase I and II)
make metabolites more H2O soluble
Phase I - functionalization
Phase II - conjugation reaction
Sites of metabolism (2)
GI tract (intestine) and liver
What is CYP450 system and where does it occur?
CYP450 system facilitates (the most common) Phase I of drug metabolism. CYP450 proteins are mostly found in the liver.
Components of CYP450 and how they work
Flavoprotein (P450 reductase) Heme protein (CYP450)
Oxidation of drug: flavoprotein takes e- from NADPH, transfers to CYP450, add -OH to H (oxidizes the drug)
4 different mechanisms of phase I
Monooxygenase (oxidation by CYP450)
Monoamine Oxidase (non-P450 oxidation)
Alcohol Metabolism (CYP and non-CYP)
Esterase (hydrolysis)
List 4 major P450 CYP enzymes.
CYP3A4/5
CYP2E1 (minor metabolism of ethanol)
CYP2D6
CYP2C19
Major pathway for ethanol metabolism:
enzymes and their products
ADH (alcohold DH)
ALDH (aldehyde DH)
ethanol –ADH–> aldehyde –ALDH–> acetate
Esterase is part of Phase __ activity, found in __.
I; plasma and other tissues
Monoamine oxidase (located in __ of cell) is part of Phase __ activity, converting __ to __.
mitochondria; I; amine to aldehyde
Describe the main types of end-products of phase 1 metabolism (3).
aliphatic hydroxylation
aromatic hydroxylation
N-dealkylation
Describe the main types of end-products of phase 2 metabolism (5).
glucuronidation (add sugar) acylation (add R-C=O) glycine conjugation sulfate conjugation glutathione conjugation
Most phase II metabolites are active/inactive (except __)
inactive; morphine
Prodrugs become active upon __.
metabolism
What does induction of CYP450 mean and what is the result?
Enhancing synthesis and activity of CYP450 that results in reduced availability, hence reduced effect of drug
What does inhibition of CYP450 result in?
Decreases ability of CYP450 to metabolize more drug, resulting enhanced effect of drug
To increase drug effect, you __ (induction/inhibition of CYP450)
add drug that acts as a CYP450 inhibitor (inhibition)
CYP450 inhibition leads to increased/decreased drug effect.
increased
CYP450 induction leads to increased/decreased drug effect.
decreased
To decrease drug effect, you __ (induction/inhibition of CYP450)
add inducing agent of CYP450 (increase expression) (induction)
Phase I and II application:
Acetaminophen (Tylenol) toxicity can be reversed by administration of __ (mechanism?)
NAC (N-acetylcysteine)
mechanism: NAC + glutamine–> glutathione in liver (avoid toxic pathway)
__ can result in difference in ability to metabolize xenobiotics in the body (extensive vs. poor metabolizers)
SNP (single nucleotide polymorphism)
Enzyme polymorphism: give examples of how polymorphism of each enzyme can have adverse effect.
ADH -
ALDH -
ADH - alcohol dehydrogenase high activity (and relatively low activity of following ALDH) leads to build-up of acetaldehyde.
ALDH - aldehyde dehydrogenase
many Asians produce inactive ALDH, leading to acetaldehyde build-up
Build-up of __ leads to histamine release from __ cells
acetaldehyde; mast cells
