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D&T 4, Exam 3 (Liver) > Valentovic - Drug Interactions > Flashcards

Valentovic - Drug Interactions Flashcards

1
Q

Facts:

  • Interactions lead to adverse reactions
  • Over 2 MILLION serious drug interactions/year
  • 2.8% of hospital admissions
  • 100,000 DEATHS annually
  • $136 BILLION annually
  • Theoretical vs. clinical impact
A
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2
Q

The following are risk factors, predisposing patients to _______.

– Multiple medications
– Female gender –> oral contraceptives + Rifampin, antibiotics or St. John’s wort

– Extremes of age (babies - lower protein binding to drugs)
– Major organ dysfunction
– Genetic polymorphisms

– Metabolic and endocrine dysfunction (altered metabolic rates!)
– Other medical issues

A

Drug Interactions

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3
Q

What term?

– “what the body does to the drug”
– follows “ADME” model

  • Change in absorption, distribution, metabolism, excretion
  • Affecting its delivery to the site
A

Pharmacokinetic

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4
Q

What term?

– “what the drug does to the body”

– Additive/antagonistic/synergistic

  • Affecting its Mechanism of action

– Can occur at receptor or during signal transduction

– Precipitant/causing drug (Drug A) modifies the object drug (Drug B) even at normal drug concentrations (alcohol & APAP or benzodiazepines)

Drug A: Alcohol —–> Drug B: Acetaminophen (tylenol)

A

Pharmacodynamics

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5
Q

What is the pharmacodynamic effect seen with alcohol and benzodiazepines?

A

Additive effect

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6
Q

What is the pharmacodynamic effect seen with diazepam (BZD) and flumazenil?

i.e. Naloxone and Oxycodone - competing at the receptor

A

Antagonistic effect

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7
Q

What drug worsens respiratory depression in surgery with anesthesia?

  • Have nondepolarizing neuromuscular activity (presynaptic ↓Ach & ↓ postsynaptic activation of receptor) = lower respiration
  • Respiratory paralysis can happen alone
  • Drug interaction with *Succinylcholine increases risk of respiratory depression (magnifies its effect)
  • Reverse with Neostigmine**
A

Aminoglycosides (especially Tobramycin), possibly taking for infection

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8
Q

What are the 4 Pharmacokinetic mechanisms of drug interactions?

A

Absorption, Distribution, Metabolism, Elimination

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9
Q

Pharmokinetic Mechanism

Absorption mechanism:

  • Drug-drug, drug-food interactions can cause a change in _____, ______, _____ or _______.
  • Complexes with other drugs
  • binds drugs in stomach
  • prevents either drug from being absorbed
A
  • pH
  • Transport (p-glycoprotein - grapefruit blocks efflux in the GI tract)
  • Chelation (calcium and tetracycline - binds it and lowers levels)
  • Metabolism
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10
Q

How can you overcome the problem of drug interactions with absorption?

A

Stagger the doses of the two drugs!

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11
Q

Problems with absorption:

  • Antacids of calcium, magnesium, or aluminum (precipitant drugs - form complexes) can interact with what drug?
    • What antifungal agents need an acid environment?
  • Cholestyramine (resin binds acidic drugs) can interact with what drug(s)?
  • > What should you do to solve this problem?
  • Ferrous sulfate, calcium, magnesium, or aluminum can interact with what immunosuppressive agent diminsing immune suppression?

*All prevent absorption!

A
  • Tetracycline
    • Ketoconazoles
  • Digoxin, Warfarin
    • stagger the drugs
  • Mycophenolate mofetil (inhibitor of Inosine monophosphate dehydrogenase - IMPDH)
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12
Q

Changes in GI motility may change the ______ of absorption, but not the _______ of absorption!

  • Shift in the peak time, but not in the bioavailability!
  • Decreased gastric motility - examples?
  • > Dec rate of absorption
  • > No change in extent of absorption (Bioavailability)
  • Increased gastric motility - example?
  • >shorter peak time; greater peak effect
  • ->no net change in absorption (bioavailability)
A

Rate

Total Extent

Amitriptyline (Anticholinergic effects), Morphine

Metoclopramide

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13
Q

Some drugs require acidic environment of the stomach to be absorbed - pH may change!

  • H2 agonists (cimetidine, ranitidine) decrease absorption of ____ and _____
  • PPI (omeprazole) decrease absorption of _____, ___ and ______

*** Increased pH, more ionized drug, less drug absorption aka lower blood levels –> Therapeutic failure more likely!

A
  • Ketoconazole, Intraconazole
  • Atazanavir (HIV protease inhibitor), Ketoconazole, Intraconazole
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14
Q

What is the ATP-dependent molecular transport that protects the body from harmful substances?

  • “Gatekeepers” of metabolism
  • Transport lipophilic molecules
  • Apical membrane of enterocytes of small intestine epithelium
  • exporting
  • Helps facilitate excretion of drugs into gut lumen, bile, urine, out of brain
A

P-glycoprotein (PGP)

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15
Q

What are some inhibitors of P-glycoprotein?

So, p-glycoprotein inhibitors result in more bioavailability bc you have blocked the export in the small intestine.

***Some inhibitors of CYP3A4 also inhibit P-glycoprotein

A

Inhibitors: ketoconazole/itraconazole, erythromycin, grapefruit juice, clarithromycin

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16
Q

Drug transporters:

  • ______ and _______ are inhibited by Ketoconazole and itraconazole
  • Therefore, the efflux transporters are BLOCKED resulting in more absorption! what happens to the half life of drugs?
A
  • CYP3A4, P-glycoprotein
  • Half life is increased! Increased bioavailability
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17
Q

What is the relationship between oral contraceptives and antibiotics?

– Enterohepatic circulation

– Estrogen hydrolysis

A

greater therapeutic failure if OC’s taken with antibiotics (erythromycin)

18
Q

What pharmacokinetic interaction?

  • Involves protein binding sites - mostly binding displacement
    – Drug must be >90% bound******** (10% free fraction)

– Increased free serum drug concentration - distributes in the tissues

– Not always clinically significant

* Drugs that have limited distribution
* More likely with drugs with **narrow therapeutic window** – **Warfarin 99% bound, 1% Free Fraction** (unbound drug distributes in to tissue)

– Sulfamethoxazole-trimethoprim (Abx) increase INR >6

A

Distribution

19
Q

What metabolic component?

  • Present in the endoplasmic reticulum
  • Primarily Phase 1 metabolism (biotransformations)
A

Cytochrome P450 system

20
Q

What type of CYP450 interaction?

– Increased concentration of object drug (Inc. t1/2 of the drug)

– Known examples:
*****Ketoconazole, cimetidine, erythromycin, grapefruit juice (furanocoumarins & naringin), clarithromycin

A

Inhibition

21
Q

What are some inhibitors of CYP450? ****

A

Ketoconazole, cimetidine, erythromycin, grapefruit juice (furanocoumarins & naringin), clarithromycin

22
Q

What type of CYP450 interaction?

– Decreased concentration of object drug (blood level goes down bc increased clearance)

– Known examples: phenytoin, rifampin, carbamazepine, St. john’s Wort

23
Q

What are some inducers of CYP450?

A

phenytoin, rifampin, carbamazepine, St. john’s Wort

24
Q

What CYP isoenzyme?

Substrate: Theophylline

Inhibitor: Amiodarone

Inducer: Phenobarbitol

25
Q

What CYP isoenzyme?

Substrate: S-Warfarin

Inhibitor: Fluconazole

Inducer: Rifampin

26
Q

What CYP isoenzyme?

Substrate: Diazepam

Inhibitor: Omeprazole

Inducer: Rifampin

27
Q

What CYP isoenzyme?

Substrate: Atomoxetine

Inhibitor: Ritonavir

Inducer: Not known

28
Q

What CYP isoenzyme?

Substrate: Atorvastatin, Indinavir, Cyclosporine, Warfarin

Inhibitor: Erythromycin, Ketoconazole, Verapamil, Nicardipine

Inducer: Phenytoin, Dexamethasone, Carbamazapine, Rifampin

29
Q

What genetic polymorphism?

– 7.5% Caucasians & slightly higher in African Americans

– 1% Asians

– Tamoxifen substrate less formation of active metabolite/less therapeutic effect in slow metabolizers

A

CYP2D6 low activity

30
Q

What genetic polymorphism?

  • 20% Asians low or deficient
  • 3-5% Caucasians in US

(Clopidogrel prodrug less effective in slow metabolizers bc don’t convert prodrug to its active metabolite)

31
Q

What route of elimination?

– Drug competes for the same transport – Can be both beneficial and harmful

  • Probenecid (competes with transporter) and penicillins (levels go up)
  • Sulfamethoxazole & Methotrexate causes higher methotrexate blood levels and toxicity high dose MTX
A

Renal Tubular Secretion

32
Q

What route of elimination?

Trimethoprim inhibits sodium channel in distal tubule resulting in increased potassium reabsorption (pts with Pneumocysitis pneumonia-HIV taking higher doses of drug possibly resulting in hyperkalemia)

Lithium and diuretics/NSAIDs: decreased Lithium clearance

A

Altered tubular reabsorption

33
Q

What is also a prominent player in renal tubule for elimination?

Digoxin and quinidine (precipitant drug) via P- glycoprotein inhibitor get less digoxin renal excretion –> higher levels and half-life –> toxicity from Digoxin

Digoxin has narrow therapeutic window and entirely excreted by the kidney.

A

P-glycoprotein

34
Q

Renal elimination:

  • __________ drugs are reabsorbed
  • High pH causes _____ drug to be unionized
  • Low pH causes _____ drug to be unionized
A
  • Non-ionized drugs
  • Basic drugs
  • Acidic drugs
35
Q

Acetazolamide (high altitude sickness), quinidine, amphetamines

  • How do these affect urine and blood pH?
  • leads to higher unionized quinidine, amphetamine
  • leads to higher reabsorption and blood levels
A

Increase urine pH

Decrease blood pH

36
Q

When ASA and acetazolamide (precipitant drug) are taken together,

  • how is the elimination of ASA affected?
A
  • Metabolic acidosis ↑unionized ASA entry into brain
  • ↑unionized ASA filtered and reabsorbed by kidney
  • ↑ASA toxicity

​Acetazolamine decreases blood pH resulting in more unionized ASA.

37
Q

Summary Table: Not always a class effect…

38
Q

Remember:

Take a good medication history

  • Remember high risk patients
  • Look for “red-flag” drugs (warfarin - 1% free form, ketoconazole - CYP3A4 inhibitor, etc.)
  • Interactions do not necessarily happen in every patient
39
Q

Street Drug Use of CYP450 Metabolism.

Decreased clearance of Oxycodone & Fentanyl resulting in longer half-time when combined with what antibiotics?

A

Erythromycin and Clarithromycin - inhibitors of CYP3A4

40
Q

What drugs inhibits all of the Isoenzyme CYPs?

A

Cimetidine

D&T 4, Exam 3 (Liver) (19 decks)

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