Lecture 23

Question 1

ADR

Answer 1

Adverse drug reactions

Question 2

Why are there so many ADRs?

Answer 2

• 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

Question 3

Toxicity Spectrum

Answer 3

1. On-target - same receptor, wrong tissue (mechanism based, dose dependence is clear)
2. Off-target - hERG channel effects (dose dependence is clear)
3. Bioactivation to reactive intermediates - acetaminophen
4. Hypersensitivity & immunologic reactions - penicillins (dose-dependence not clear)
5. Idiosyncratic toxicities - rare events that don’t fit into the other categories (dose-dependence not clear)

Becomes more complex as list descends

Question 4

Classifications

Answer 4

-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

Question 5

Type A ADRs

Answer 5

• ~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)

Question 6

Type A ADRs + Absorption

Answer 6

1. Change in drug ionization - altering of stomach pH for example and causing weak acids/bases to not absorb
2. Drug sequestration by other drugs - bile acid sequestrants (ionic and hydrophobic interactions between polymer and bile acid present in intestine reabsorption)
3. Others: chelation - tetracycline and Ca^(2+), no absorption of complex and not a real toxicity event

Question 7

Type A ADRs + Distribution

Answer 7

• 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

Question 8

Type A ADRs + Metabolism

Answer 8

• 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

Question 9

Type A ADRs + Elimination

Answer 9

• 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

Question 10

Transporters

Answer 10

• 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

Question 11

DD Interactions

Answer 11

• Very common, mechanisms and targets are well understood so these interactions are as well
• Potentiation: antihistamine and alcohol
• Antagonists - Vitamin K and warfarin

Question 12

Do more Rx increase the risk of DDI?

Answer 12

Yes. More likely to affect the ADMET of another Rx, usually well understood and managed though.

Question 13

iv NAC

Answer 13

• 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

Question 14

Why is the liver vulnerable to toxicities?

Answer 14

• 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

Question 15

Type B ADRs

Answer 15

• ~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

Question 16

Haptens

Answer 16

• Common
• Drug connects to part of protein and goes on to react with B/T-cells
• B/T-cells chew up the protein and express the peptides that then react and causes immune response and toxicity
• Some drugs react with protein directly like intrinsically reactive drugs, intrinsically inert drugs, or ones that need metabolic activation to create reactive metabolites

Question 17

Reactive Groups

Answer 17

• Lots of groups require activation (ex: inhaled anesthetic, hepatitis)
• Try to avoid reactive groups on drugs
• Also avoid drugs with the potential to be metabolized into reactive groups
• Companies screen drugs at earlier stages not, may lose leads and some money but avoid massive costs