PK/PD/etc! Flashcards
Hydrogen Bond
H atoms bound to Nitrogen or O2 become more + polarized, allowing them to bond to more (-) polarized atoms such as O2, Nitrogen or Sulfer. Strength: Second Weakest
Covalent Bond
Two bonding atoms share electrons - Strongest bond - often irreversible
Example: ASA
Ionic Bond
Atoms with an excess of electrons (imparting overall (-) charge on the atom) are attracted to atoms with a deficiency of electrons (imparting an overall (+) charge on the atom. Third strongest bond.
Van der wals
Shifting electron density in areas of a molecule, or in a molecule as a whole, results in the generation of transient (+) or (-) charges - these areas interact with transient areas of opposite charge on another molecules
Define PD
what the drug does to the body
Define PK
What the body does to the drug
Efficacy vs. potency
Potency: Strength (amt of drug needed to achieve intended effect.
Efficacy: ability of drug to produce same response:
NOTE: Drugs can have the same efficacy but different potency (i.e. statins).
Characteristics of HYDOPHILIC
Water loving
Polar, usually ionized
Renal excretion
Requires transport mech to x cell membranes and BBB
Forms H= bonds (ionized = (-) charge somewhere)
Can penetrate CNS via active transport, facilitated transport, intrathecal admin.
Characteristics of HYDOPHOBIC
Think Oil/Vinegar LIPOphilic Fat Loving/water insoluble Passively diffuses across cell membranes and BBB (d/t lipid bilayer so fat soluble will go through) Non-polar, usually NOT-ionized
Core of a cell is what: hydrophilic or phobic?
Hydrophobic lipid core
Membrane of a cell is what: hydrophilic or phobic?
Hydrophilic
“D+R DR DR* “ means what?
Empty drug + empty rc (does nothing)
DR = drug bound to rc
DR* activated drug/rc (activity taking place).
Agonists : Full
Elicit max. result
Stabilize DR*
Think “Full faucet”
i.e. ACH binds to nicotinic rc and induces conformational change from nonconducting to fully conducting state.
Partial Agonist
Activates rc w/o max efficacy
Stabilizes DR and DR*
i.e. Beta Blockers
Typically this is an intended design ie. CNS meds when you do not want full firing or full activity.
Inverse agonists
Inactivates free active rc’s (which is active at BSL)
Stabilizes DR in the case of R* (which is the natural state of the enzyme).
Example: inactivate an overactive enzyme in CA pt.
Example: Diphenhydramine: inverse agonist when need histamine to be turned OFF.
Competitive Antagonists
Reversible binding blocks agonist at ACTIVE SITE
Stabilizes DR, PREVENTS DR*
Agonist can bump antagonist off which would lead to DR* therefore, need more agonist on board to out compete the antagonist.
Noncompetitive Antagonist
Irreversible binding
Blocks agonist at Active or Allosteric site
Can reach plateau b/c agonist is taken out of play or antag prevents it from doing anything.
TI: What and how calculated
TI = TD50/ED50
Want higher TI for low toxicity and high efficacy; high TD and low ED
High TI: wide therapeutic window with TD much > ED
pKa and why do we care?
pH at which 50% of drug is ionized, ph at which 50% of a drug can passively diffuse across membranes. Want to know if a drug can cross membrane or not and NOT GET TRAPPED as it needs to be WITHOUT a charge to passively diffuse.
What is the MOST desirable PD for a medication:
a. Low LD50
b. Low TI
c. High TI
d. Low TD50
C: high efficacy and low toxicity
Absorption: where
GI tract, parenteral, Skin/Membranes
Absorption and drug tx affected by:
Absorption: concentration, circulation at the site, drug solubility, surface area.
Transfer: concentration, circulation, drug solubility, surface area
Distribution: where
Blood, target tissue
By what is volume of distribution affected?
Age (body composition changes); Volume status; protein binding, high tissue binding
Metabolism: where?
Liver, tissue, blood, CYP450 enzymes
By what is metabolism affected?
Inhibition, induction, race/ethnicity, age, gender, diet, disease.
Excretion: where?
Kidney, lungs, fecal
Low Vd vs. High Vd?
Vd: volume of fluid required to contain the total amt of drug absorbed in the body at uniform concentrations = to that in plasma steady state.
Low: distribution retained in the plasma and not distributed well.
High: high distributed into non-vascular component.
**SLOW in, SLOW out and vice versa*
T/F: nonionized lipophilic drugs favored for oral absorption.
True (small and passive)
T/F: Weak acids are best absorbed in the stomach
T
T/F: Rectal administration of drug provides for inconsistent and unregulated absorption
T
T/F: weak bases are best absorbed in the small intesting
T (will get absorbed from mucosa there)
T/F: Drugs with a low Vd may be highly protein bound and more likely to remain the plasma compartment
True.
CYP450 enzymes: Induction: what does that mean?
- Inc. transcription or translation
- Dec. degradation
- Induction by another drug or autoinduction
(note: a drug that is an inducer increases metabolism of a drug that is ALSO metabolized by that same enzyme)
CYP450 enzymes: Inhibition: what does that mean?
Incidental or deliberate
Competitive inhibition
Irreversible inhibition
Drug toxicities: On-target A/E
Intended tissue, intended rc OR
Unintended tissue, intended rc
Drug toxicities: Off-target A/E
Intended tissue, unintended rc OR
Unintended tissue, unintended rc
EXAMPLE from async: metoprolol given for HR control, causes bronchoconstriction in respiratory tract. Unintended rc (B2) in unintended tissue (lungs, not heart).
What are the 3 types of transmembrane channels:
- Ion channel
- G coupled protein (indirect)
- Enzyme within cytosolic domain (direct_
Drug will either open and allow influx OR close channel and PREVENT influx into the cell.
How does intracellular interaction work?
Drug x’s membrane and works inside the cell itself. Drug NEEDS to be hydrophobic (where in transmembrane that is irrelevant).
What is the difference b/w allosteric and irreversible NONCOMPETITIVE antagonists:
Irreversible; compete in a way that is irreversible (covalent). When bind to same site, agonist being added will NOT reverse no matter how much you give).
Allosteric: binds to alternate side which prevents the agonist from binding OR prevents DR* when it does bind.
Distribution: Initial phase
initial phase reflects regional blood flow.
Delivery of drug is slower to muscle, most viscera, skin, and fat
Distribution: Second phase
Distribution to tissues
Rapid distribution to interstitial compartment d/t highly permeable nature of capillary endothelial membranes
Restricted distribution: a) lipid insoluble that permeate membranes poorly; b) drug binding plasma proteins
Drug metabolism: 5 things metabolism does
active drug -> inactive drug active drug -> active metabolite active drug -> toxic metabolite prodrug -> active drug Unexcretable drug -> excretable metabolite
what is a prodrug?
in parent form it has no activity; needs metabolite in order to do its job
why is first pass significant?
determines bioavailability of a drug
Can a drug that is protein bound be metabolized?
No
Phase 1 metabolism: CYP450 3A4, 2D6, 2C9, 2E1, 1A2
enzyme family-subfamily-specific enzyme
substrate specificity
MAO: oxidizes amines
Phase II Metab
substrates include drugs or drug metabolites
Results in large polar conjugates (allow urine and fecal excretion)
Active metabolite possible (i.e. active conjugate of morphine is a more potent analgesic with phase II making it more active).
What is a substrate?
breaks something down
what is an inducer?
increases activity from the enzyme to break down
what is the inhibition?
slow down activity
What are some factors affecting metabolism?
- genetics: slow-acetylator phenotype
- race and ethnicity (cyp450 2D6 is nonfunctional in 8% of caucasians
- Age and Gender (lack of UDPGT in neonates)
- Diet (grapefruit juice)
- Disease States (liver disease, cardiac disease)
Three most important parameters to clinical PK:
- Clearance
- Volume of distribution
- Bioavailability
Therapeutic doses goals
Maintain Cmax below toxic concentration
Maintain Cmax above minimum effective concentration
Maintain Cxx w/in therapeutic window
Want to steady state concentration
Dose timing based upon half life (dose does not change based on half life)
