Lecture 23 Flashcards
Mechanisms of Toxicity
1
Q
ADR
A
Adverse drug reactions
2
Q
Why are there so many ADRs?
A
- 2/3 of patient visits end with Rx
- 3 billion outpatient Rx are written per year
- Specialists give 2.3 Rx per visit
- Medicare patients - take LOTS of medicine from lots of doctors (and sometimes from out of the country)
- ADR increases exponentially with 4 or more Rx
3
Q
Toxicity Spectrum
A
- On-target - same receptor, wrong tissue (mechanism based, dose dependence is clear)
- Off-target - hERG channel effects (dose dependence is clear)
- Bioactivation to reactive intermediates - acetaminophen
- Hypersensitivity & immunologic reactions - penicillins (dose-dependence not clear)
- Idiosyncratic toxicities - rare events that don’t fit into the other categories (dose-dependence not clear)
Becomes more complex as list descends
4
Q
Classifications
A
-Lots of them
-Focus on A & B
A - augmented pharmacologic effects, dose-dependent and predictable, intolerance, side effects, drug interactions
B - Bizarre (idiosyncratic) effects, dose independent and unpredictable
5
Q
Type A ADRs
A
- ~80% of ADRs
- Dose-dependent and predictable
- Often due to excessive pharmacologic effects (EX: Opiates and respiratory depression causing death)
- Often drug-drug interactions
- Often reproduced in animals
- Mediated through receptor-interaction of drug/metabolite (wrong dose, receptor, or tissues)
6
Q
Type A ADRs + Absorption
A
- Change in drug ionization - altering of stomach pH for example and causing weak acids/bases to not absorb
- Drug sequestration by other drugs - bile acid sequestrants (ionic and hydrophobic interactions between polymer and bile acid present in intestine reabsorption)
- Others: chelation - tetracycline and Ca^(2+), no absorption of complex and not a real toxicity event
7
Q
Type A ADRs + Distribution
A
- Drugs often bind to plasma proteins if has high log(P)
- If binding sites are limited, give a second drug with higher affinity for plasma protein and reduced affinity for target to displace drug and encourage target binding
- RARELY a problem
- Drug-drug interactions are rare and binding site requirements are usually not met with albumin
8
Q
Type A ADRs + Metabolism
A
- Often done by P450s that cause an inactive metabolite or active prodrug to be formed
- Know how inhibition/induction/polymorphisms of this enzyme affect the drugs
9
Q
Type A ADRs + Elimination
A
- Underdosing due to increased elimination
- Hydrophobic, weak acids having increased excretion in bile/feces
- Increased pH causing weak acids to be more polar and more easily eliminated renally
10
Q
Transporters
A
- Tons of them can control drug levels and effects
- Can be inhibited or up regulated by other drugs to cause more drug-drug interactions
- Still basic handles on this concept
11
Q
DD Interactions
A
- Very common, mechanisms and targets are well understood so these interactions are as well
- Potentiation: antihistamine and alcohol
- Antagonists - Vitamin K and warfarin
12
Q
Do more Rx increase the risk of DDI?
A
Yes. More likely to affect the ADMET of another Rx, usually well understood and managed though.
13
Q
iv NAC
A
- works best if given within 8 hours of oral APAP OD
- Absorption of AP is slow (>8 hours to Cmax) so NAC is ready and in place to defend
- The absorption of iv NAC is slow, so needs to be given soon after to be absorbed enough
- APAP metabolism to NAPQI is only relatively slow, after 8 hours enough damage has already occurred to potentially be a problem
14
Q
Why is the liver vulnerable to toxicities?
A
- The liver is intrinsically susceptible as its GSH levels are lower than other tissues.
- The livers position roughly in the center of the body leaves it vulnerable to attack from many angles
- Since the toxicity is caused by reactive metabolites, they will most react where they were formed in the first place
15
Q
Type B ADRs
A
- ~20% of ADR
- Rare, unpredictable, highly host dependent
- Mechanisms usually unknown but some are allergic/pseudoallergic reactions, decreases in protective factors, or polymorphisms
- RARELY reproduced in animals - only crop up in trials or post-approvals if the reaction is rare
