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Pharmacology > ADRs, DDIs and pharmacogenetics > Flashcards

ADRs, DDIs and pharmacogenetics Flashcards

0
Q

Phase I drug metabolism

A

modification of functional groups in order to increase clearance of the drug

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1
Q

Drug metabolism function and location

A

F(x): detox for xenobiotics and metabolism of endogenous cmpds
Locations:
liver and GI tract, also: kidneys, lungs, skin, brain

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2
Q

Phase II drug metabolism

A

addition of molecules to a (pro-)drug –> increase polarity in order to increase excretion of the drug conjugate

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3
Q

fate for drugs that increase QTc interval

A

never go to market!

= dangerous, esp. with P450 inhibition, so not approved by FDA

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4
Q

Mechanisms for DDIs that alter absorption

A
  1. alter gastric pH
  2. Chelating agents
  3. alter gastric motility
  4. alter GI flora
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5
Q

consequences of altering gastric pH (DDI)

A

some drugs require low pH for activation,
so = inhibited by drugs that increase gastric pH

antacids, H2 blockers –l aspirin, azoles/antifungals (need low pH)

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6
Q

chelating agent DDIs

A

chelating agents IRReversibly bind antibiotics/resins to antacids,
inactivate both.

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7
Q

example of DDI that alters gastric motility

A

L-DOPA increases motility, so increases emptying rate & excretion rate
–> other drugs taken = less effective at normal dose

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8
Q

Mech. of DDI altering GI flora

A

steroid conjugates hydrolyzed by flora, so decrease activation if decrease flora activity.
ie:
antibiotics kill flora –> (may) decrease f(x) of some birth controls

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9
Q

mech. for DDIs that alter drug metabolism

A

some P450 polymorphisms increase OR decrease metabolism
–> increase risk of therapeutic failure (esp. –> slow metabolizers)
ie: CYP2D6 – CNS/CV drugs
CYP2C19 – PPIs
CYP2C9 – Warfarin
CYP3A4 – MANY drugs!

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10
Q

P450 inhibition “Perpetrator”

A

a drug which causes inhibition of a P450 subtype

does not necessarily affect it’s own metabolism

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11
Q

P450 inhibition “Victim”

A

a drug whose metabolism is blocked bc another drug inhibits it’s specific P450 subtype

  • danger from inhibition depends on the victim drug’s toxic potential and therapeutic index
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12
Q

Cimetadine (aka tagamet)

A

blocks MANY CYPs –> slows metabolism

* can be helpful for decreasing size of therapeutic dose*

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13
Q

Cause of increased QTc

A

Efflux of K+ from myocytes bc pump = inhibited,

–> delays repolarization and causes arrhythmia (!)

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14
Q

P450 Induction (DDI)

A

Inducing cmpd binds to nuclear Rs and increases DNA transcription –> increase P450 synthesis and activity
=> increase clearance, so decrease drug effect,
OR Liver damage (if metabolite = toxic)

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15
Q

P450 inducing compounds

A
  1. Rifampin
  2. Dexamethasone
  3. phenobarbital
  4. St. John’s wort
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16
Q

Requirements for successful P450 induction

A
  1. inducer present for long enough duration
  2. inducer binds to correct spot on DNA
  3. P450 turnover rate is ideal (not too fast or too slow)
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17
Q

Drug Distribution (as DDI)

A

Blocking P-gp pump –> increase CNS penetration and GI absorption; (via mdri gene)
counteract by: decrease bioavailability of drug
Ex: less anti-histamine across BBB –> “Non-drowsy”

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18
Q

Renal F(x) DDIs

A
  1. block/reduce P-gp pump activity
  2. decreased Renal Tubular Secretion (ie: saturated transporters)
    Ex:
    amoxicillin –> methotrexate transport
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19
Q

P-gp Pump

A

protein efflux pump in epithelial tissues (ie: brain BBB, renal tubules, etc.)
= protective mechanism for body

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20
Q

drugs/compounds that Inhibit CYP3A4 activity

A
  1. cyclosporine —> increases [statins] in plasma
  2. Grapefruit juice
    Also: HIV meds, Beta blockers, Ca2+ blockers, statins, etc.
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21
Q

Common differences in Women (special pop.)

pharmaokinetics

A 
Absorption: low. 
- low gastric empty rate, high gastric pH
- low alcohol dehydrogenase, low CYP3A4
Distribution: high. 
- high % body fat, low muscle mass
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22
Q

common diff. in Women (special pop.)

pharmacoDynamics

A
  • higher risk for “torsades de pointes” (heart problem)
    (bc avg QTc 20ms greater than men)
  • on average have MORE ADRs
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23
Q

DDIs specific to Women

A

(some) antibiotics –l oral contraceptives

also: higher use of dietary supplements –> unknown DDIs

24
Q

Common diff. in Maternal-Fetal Unit (special pop.)

* in general*

A

HUGE lack of controlled studies (unethical)

–> pregnant women usually go untreated or take standard adult dose

25
Q

Common diff. in Maternal-Fetal Unit (special pop.)

pharmacoKinetics

A

Absorption: low.
- low gastric empty rate, slow GI transit time
Distribution: high.
- high plasma volume, high CO/HR/SV
Metabolism: change/low.
- low P450 activity (varies by person and CYP)
- low [albumin]p, high serum pH (minimal change [active]serum)
Clearance: altered.
- high renal and blood flow –> high GFR; BUT low hepatic BF

26
Q

Rules for placental transfer

A

Best transfer if:
low molec. weight, high lipid solubility, non-ionized.

placental perfusion LEAST during contractions

27
Q

teratogen

A

a chemical that induces fetal malformations
severity depends on:
- stage of dvpt @ time of exposure
- mom & baby genotypes

28
Q

“critical tissue [ ]” (for teratogens)

A

insult to fetal development does not occur until reach specific [ ] in tissue.
==> sharp “dose-effect relationship” (small difference in amt of exposure btwn no effect and horrible effects)

29
Q

FDA testing Grades for maternal-fetal drugs/dosing

A

(A, B, C, D, X)
A = safe, well-studied
C = safe in studies on non-pregnant ppl
X = proven UNsafe

30
Q

common diff. in Pediatrics/Infants (special pop.)

pharmacoKinetics

A

Absorption: low.
- low pH, low GI motility
Distribution: high Vd.
* high free fraction ( [active] in plasma)
Metabolism and excretion: both Low.
* canNOT glucouronidate –> morphine = toxic!*

31
Q

what measurement used to determine dosage in pediatrics?

A

use (total) Body Surface Area (aka: BSA).

–> Under-dose if use weight

32
Q

Special conditions in infants that change rapidly with age

ie: days-weeks

A
  • pH: start ~neutral, get more acidic
  • GFR: increases. kids have HIGH clearance relative to size
    (Bc increase drug clearance –> need to increase dose)
  • hepatic dvpt: increase CYP3A4 w/ maturity (and other CYPs)
    • no CYP1A2 (for caffeine) until 2 months old!
33
Q

Common diff. in Elderly (special pop.)

pharmacoKinetics

A

Distribution: High for lipophilic, Low for hydrophilic.
Metabolism: Low (esp. low CYP3A)
Clearance: Low (esp. renal)

  • No change in absorption or phase II rxns*
34
Q

Specific DDIs especially common in Eldery

A

none specifically,
but VERY high risk bc avg. # chronic meds = very high.

Elderly ADRs = 2.5 x # adult ADRs (!)

35
Q

Mechanisms of toxicity (7)

A
  1. Reversible binding
  2. Covalent binding
  3. Free Radical Generation
  4. Heavy Metals
  5. Xenobiotic Metabolism (into toxins)
  6. Chemical mixtures
  7. Idiosyncrasy
36
Q

Reversible binding toxicity

A

Dose-related exaggeration OR unrelated to therapeutic effect
(binds to same or different R as therapy target)
Antidote: R antagonist

Ex: CO binds to Hemoglobin (treat w/ pure O2)

37
Q

Covalent Binding toxicity

A

= electrophilic attack –> inhibits normal f(x).
Antidote: depends on substance.

Ex: Acetominophen into toxic intermediate… (highly reactive)
if overdose/deficient GSH enzyme –> build up and damage
Treat: N-acetylcysteine (GSH substitute)

38
Q

Free Radical toxicity

A 
metabolic activation (or natural cause) --> high amt reactive species ==> damage tissue. 
Treat: free radical scavengers
39
Q

Causes of Free radical toxicity

A

Drugs: paraquat, Fe (Fenton rxn)

natural: aging, caner, neurodegeneration, coronary artery disease

40
Q

Heavy metals that cause toxicity

A
  • Arsenic
  • Lead
  • Mercury
  • Digoxin
41
Q

Lead poisoning

A

from: air/pollutants, paints
Dx: accumulates in bones (“lead line” on x-ray), blood test
Sx: anemia, colic, renal injury, HTNN, cognitive impairment (in children)
Treat: chelation, remove source of exposure

42
Q

Arsenic Poisoning

A

From: groundwater
Mech: inhibits synth of Acetyl CoA/glutathione, replaces PO4-
Sx: keratosis (benign), malignant skin lesions/lung carcinomas, peripheral neuropathy, GI effects, anemia
(multiple targets across body)
Treat: chelation

43
Q

Mercury poisoning

A

(“mad hatters”)
Sx: behavioral/cognitive deficits, renal toxicity (if exposed to salt form)
Treat: chelation

44
Q

Digoxin poisoning

A

Sx: heart arrhythmias
Treat: digoxin antibody
whole Ab is too big to be excreted, so gets cleaved…
Fab w/ bound digoxin = excreted

45
Q

Chelation

A

process of surrounding heavy metal (reactive) with cmpd in order to minimize damage to tissues
Use: EDTA, BAL, or Succimer

46
Q

Xenobiotic metabolism

A

Metabolic activation of a cmpd into toxin/carcinogen
Treat: enzymes to inhibit metabolic transformation into toxin
ex:
1. Aflatoxin (from grain/peanut molds) –> liver cancer
Also: Methanol and EtOH

47
Q

Metabolism of methanol into toxin

A

Methanol –(alcohol dehydrog.)–>formaldehyde–> formic acid
* formic acid = toxic! (acidosis, blindness, coma)

Treat: give EtOh or fomepizole (both inhibit Alcohol Dehydrog.)

48
Q

Treating alcoholism

A

EtOH –(alc.deh.)–> Acetaldehyde –(ALD) –> acetate
* ALD = aldehyde Dehydrogenage*

Acetaldehyde = toxic, so use Disulfram to inhibit ALD…
build up acetaldehyde –> induce sickness when drink alcohol

49
Q

Idiosyncratic toxicities

A

= uncommon effects when given standard dose (usually tolerated)
can be: allergies, tissue sensitivities, metabolism polymorphisms.
** always involve adduct formation (bind to something extra)**
ex:
slow/fast metabolizers of Warfarin, not therapeutically effective
(should inhibit Vit K activation -X-> coagulation)

50
Q

Warfarin:

Polymorphisms affecting metabolism

A

= anticoagulant, blocks Vit K activation.

  1. Cyp2C9: slow elimination
  2. VKORC: multiple polymorphisms @1 locus –> low/med/high dose variants
51
Q

Dapsone:

polymorphisms affecting treatment

A

= topical acne med.

G6PD: if deficient –> FATAL hemolytic anemia
* also w/ fava beans

52
Q

Maraviroc:

genetic variation affecting treatment

A

aka “Selzentry”
= anti-retroviral for a SPECIFIC HIV trope.

ONLY effective for CCR5-tropic HIV,
– must test virus type 1st, but very effective if IS that variant –

53
Q

Irinotecan:

genetic variants affecting treatment

A

aka “camptostar”
= anti-neoplastic injection for metastatic colon/rectal carcinomas –> topoisomerase inhibitor.

UGT1A1: if deficient –> neutropenia
(decreased clearance -> increased [ ]plasma)

54
Q

6-Mercaptopurine:

genetic variants affecting treatment

A

aka “purinethiol”
= purine analog for Acute Lymphatic Leukemia.

TPMT enzyme (ThioPurine S-Methyl Transferase): 
	if low, drug = toxic! 
-- Test blood for polymorphism before use --
55
Q

Trastuzamab:

genetic variation affecting treatment

A

aka “Herceptin”
= HER2 antagonist for Her2 over-expressing breast cancer.

No benefit if NOT Her2 over-expressing.
– test biopsy cells to check –

56
Q

Imatinib:

genetic variation affecting treatment

A

aka “gleevac,”
treats Philadelphia-chrom. + (cancer-causing) CML.

ONLY works if have Philadelphia chromosome translocation.

57
Q

Tamoxifen:

genetic variants affecting treatment

A

aka “Nolvadex
= Estrogen R antagonist (anti-cancer med)

  1. ONLY works if cancer is Estrogen R +.
  2. Cyp2D6 polymorphism: if deficient, higher recurrence rate

Pharmacology (8 decks)

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