PK/PD/etc!

Question 1

Hydrogen Bond

Answer 1

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

Question 2

Covalent Bond

Answer 2

Two bonding atoms share electrons - Strongest bond - often irreversible
Example: ASA

Question 3

Ionic Bond

Answer 3

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.

Question 4

Van der wals

Answer 4

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

Question 5

Define PD

Answer 5

what the drug does to the body

Question 6

Define PK

Answer 6

What the body does to the drug

Question 7

Efficacy vs. potency

Answer 7

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).

Question 8

Characteristics of HYDOPHILIC

Answer 8

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.

Question 9

Characteristics of HYDOPHOBIC

Answer 9

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

Question 10

Core of a cell is what: hydrophilic or phobic?

Answer 10

Hydrophobic lipid core

Question 11

Membrane of a cell is what: hydrophilic or phobic?

Answer 11

Hydrophilic

Question 12

“D+R DR DR* “ means what?

Answer 12

Empty drug + empty rc (does nothing)
DR = drug bound to rc
DR* activated drug/rc (activity taking place).

Question 13

Agonists : Full

Answer 13

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.

Question 14

Partial Agonist

Answer 14

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.

Question 15

Inverse agonists

Answer 15

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.

Question 16

Competitive Antagonists

Answer 16

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.

Question 17

Noncompetitive Antagonist

Answer 17

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.

Question 18

TI: What and how calculated

Answer 18

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

Question 19

pKa and why do we care?

Answer 19

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.

Question 20

What is the MOST desirable PD for a medication:

a. Low LD50
b. Low TI
c. High TI
d. Low TD50

Answer 20

C: high efficacy and low toxicity

Question 21

Absorption: where

Answer 21

GI tract, parenteral, Skin/Membranes

Question 22

Absorption and drug tx affected by:

Answer 22

Absorption: concentration, circulation at the site, drug solubility, surface area.
Transfer: concentration, circulation, drug solubility, surface area

Question 23

Distribution: where

Answer 23

Blood, target tissue

Question 24

By what is volume of distribution affected?

Answer 24

Age (body composition changes); Volume status; protein binding, high tissue binding

Question 25

Metabolism: where?

Answer 25

Liver, tissue, blood, CYP450 enzymes

Question 26

By what is metabolism affected?

Answer 26

Inhibition, induction, race/ethnicity, age, gender, diet, disease.

Question 27

Excretion: where?

Answer 27

Kidney, lungs, fecal

Question 28

Low Vd vs. High Vd?

Answer 28

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*

Question 29

T/F: nonionized lipophilic drugs favored for oral absorption.

Answer 29

True (small and passive)

Question 30

T/F: Weak acids are best absorbed in the stomach

Answer 30

T

Question 31

T/F: Rectal administration of drug provides for inconsistent and unregulated absorption

Answer 31

T

Question 32

T/F: weak bases are best absorbed in the small intesting

Answer 32

T (will get absorbed from mucosa there)

Question 33

T/F: Drugs with a low Vd may be highly protein bound and more likely to remain the plasma compartment

Answer 33

True.

Question 34

CYP450 enzymes: Induction: what does that mean?

Answer 34

* 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)

Question 35

CYP450 enzymes: Inhibition: what does that mean?

Answer 35

Incidental or deliberate Competitive inhibition Irreversible inhibition

Question 36

Drug toxicities: On-target A/E

Answer 36

Intended tissue, intended rc OR | Unintended tissue, intended rc

Question 37

Drug toxicities: Off-target A/E

Answer 37

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).

Question 38

What are the 3 types of transmembrane channels:

Answer 38

1. Ion channel 2. G coupled protein (indirect) 3. Enzyme within cytosolic domain (direct_ Drug will either open and allow influx OR close channel and PREVENT influx into the cell.

Question 39

How does intracellular interaction work?

Answer 39

Drug x's membrane and works inside the cell itself. Drug NEEDS to be hydrophobic (where in transmembrane that is irrelevant).

Question 40

What is the difference b/w allosteric and irreversible NONCOMPETITIVE antagonists:

Answer 40

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.

Question 41

Distribution: Initial phase

Answer 41

initial phase reflects regional blood flow. | Delivery of drug is slower to muscle, most viscera, skin, and fat

Question 42

Distribution: Second phase

Answer 42

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

Question 43

Drug metabolism: 5 things metabolism does

Answer 43

``` active drug -> inactive drug active drug -> active metabolite active drug -> toxic metabolite prodrug -> active drug Unexcretable drug -> excretable metabolite ```

Question 44

what is a prodrug?

Answer 44

in parent form it has no activity; needs metabolite in order to do its job

Question 45

why is first pass significant?

Answer 45

determines bioavailability of a drug

Question 46

Can a drug that is protein bound be metabolized?

Answer 46

No

Question 47

Phase 1 metabolism: CYP450 3A4, 2D6, 2C9, 2E1, 1A2

Answer 47

enzyme family-subfamily-specific enzyme substrate specificity MAO: oxidizes amines

Question 48

Phase II Metab

Answer 48

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).

Question 49

What is a substrate?

Answer 49

breaks something down

Question 50

what is an inducer?

Answer 50

increases activity from the enzyme to break down

Question 51

what is the inhibition?

Answer 51

slow down activity

Question 52

What are some factors affecting metabolism?

Answer 52

1. genetics: slow-acetylator phenotype 2. race and ethnicity (cyp450 2D6 is nonfunctional in 8% of caucasians 3. Age and Gender (lack of UDPGT in neonates) 4. Diet (grapefruit juice) 5. Disease States (liver disease, cardiac disease)

Question 53

Three most important parameters to clinical PK:

Answer 53

1. Clearance 2. Volume of distribution 3. Bioavailability

Question 54

Therapeutic doses goals

Answer 54

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)