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[Ther 201] 1st Exam Transes > Drug Action and Fate during Special Conditions (Jody Vergiere Dalmacion, MD) > Flashcards

Drug Action and Fate during Special Conditions (Jody Vergiere Dalmacion, MD) Flashcards

1
Q

T/F: Impaired renal function is a major risk factor predisposing patients to drug toxicity

A

True

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2
Q

How does the proximal tubule handle drugs?

A
  1. Filtration
  2. Active Secretion
  3. Active Reabsorption
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3
Q

What type of drug is filtered by the proximal tubule?

A

Unbound drug only

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4
Q

Give examples of acidic drugs that are actively secreted

A

Penicillin, probenecid and frusemide

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5
Q

Give examples of basic drugs that are actively secreted

A

Cimatidine, amiloride and metformin

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6
Q

What drugs are actively reabsorbed?

A

Nephrotoxic drugs such as aminoglycosides

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7
Q

How does the distal tubule handle drugs?

A

Passive reabsorption

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8
Q

What drugs are passively reabsorbed by the distal tubule?

A
  1. Salicylic acid
  2. Phenobarbital
  3. Theophylline
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9
Q

What is the most widely used test of renal function?

A

Creatinine clearance, which approximates GFR

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10
Q

How do you assess renal function?

A

Measure hourly urine output and amount of circulating urea and nitrogen concentrations

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11
Q

What are the reasons why creatinine clearance is a good approximation of GFR?

A
  1. Eliminated only by kidneys
  2. Freely filtered
  3. Not secreted or reabsorbed
  4. Easily and accurately measured
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12
Q

What is the normal value for creating clearance?

A

120 ml/min

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13
Q

Give the formula for creatinine clearance

A

ClCr = (urine concentration x volume)/(plasma concentration x collection time)

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14
Q

When can serum creatinine be used as a substitute for endogenous creatinine?

A
  1. Age-dependent reduction in renal function
  2. Sex and body weight of patient

WARNING: It depends on muscle bulk, so it’s not a reliable measure.

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15
Q

What is the normal value for serum creatinine?

A

0.06 - 0.13 mmol/L

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16
Q

What is the formula for conversion o serum creatinine levels to creatinine clearance?

A

ClCr = [(140 - age) x weight x 0.85 (women)]/[48,869 x serum creatinine]

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17
Q

What is the formula for dose adjustment factor?

A

DAF = 1/(F(kf - 1) + 1)

F = fraction of drug excreted unchanged
kf = ClCr/120
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18
Q

Define: Dosage Adjustment Factor (DAF)

A

It is the ratio of the half-life of the drug in a ureic patient to the half-life in a normal person.

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19
Q

In what ways can you use the DAF to make adjustments?

A
  1. Change dose (divide)
  2. Change interval (multiply)

Change only one!

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20
Q

When is the use of DAF valid?

A
  1. One compartment model
  2. Non-toxic metabolites of a drug
  3. No difference in ADME of normal and ureic patients
  4. Stable kidney function
  5. No alteration of sensitivity in uremic patients
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21
Q

What are the factors in considering dose alteration?

A
  1. Therapeutic index of the drug
  2. Renal clearance proportion of total clearance
  3. Severity of renal impairment
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22
Q

What is an alternative method for calculating dose adjustment?

A

Cl = [(clearance in normal) x (1 - fraction excretion)] + (fraction of excreted unchanged x ClCr)]

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23
Q

What is the formula for average steady state plasma concentration?

A

Cssav = F x D/Cl x T

T = dosage interval

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24
Q

What is the formula for maintenance dose?

A

MD = Css x Cl x T/F

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25
Q

What does the dosage modification process involve?

A
  1. Lengthening the dosage interval

2. Reducing the dose size

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26
Q

What does lowering the dose do?

A

It lowers the peak plasma concentration.

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27
Q

T/F: Prolonging the interval reduces the trough concentration in plasma.

A

True

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28
Q

When is a combination of lengthening the interval and reducing the dose preferred?

A

When either method produces sub therapeutic troughs or toxic peaks.

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29
Q

What is the preferred dose adjustment method for digoxin and anti-arrythmic drugs?

A

Dose lowering to prevent toxic doses

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30
Q

What is the preferred dose adjustment method for antibiotics?

A

Changing dose interval

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31
Q

T/F: Acidic drugs that bind to albumin show increased binding in uremic patient serum.

A

False

Decreased binding!

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32
Q

What are the reasons for decreased acidic drug binding to albumin in uremic patients?

A
  1. Hypoalbuminemia

2. Endogenous displacers

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33
Q

Enumerate the extent of binding for different acidic drugs in patients with poor renal function (TABLE 3)

A

Slight decrease - Amoxicillin

Decreased - Bilirubin, cefazolin, cefoxitin, clofibrate, diazoxide, furosemide, phenobarbital, phenytoin, salicylate, theophylline, sulfonamide, and naproxen

Normal - Indomethacin

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34
Q

Describe: Pethidine

A
  1. Given as an active metabolite to pregnant women
  2. Given right before delivering the baby

Unlike pethidine, enalapril is useless when not metabolised.

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35
Q

Enumerate the active metabolite, action of metabolite and management of PETHIDINE.

A

Active metabolite - norethidine
Action - CNS stimulation and seizures
Management - avoid prolonged treatment

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36
Q

Enumerate the active metabolite, action of metabolite and management of PROPOXYPHENE ALLOPURINOL.

A

Active metabolite - thiocyanate N-Acetyle procainamide
Action - metabolic acidosis; encephalopathy.
Management - shorten duration of treatment & reduce dose

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37
Q

Enumerate the active metabolite, action of metabolite and management of QUINIDINE.

A

Active metabolite - 3-hydroxyquinidine
Action - same as parent
Management - reduce dose 25 - 50% in severe renal failure

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38
Q

Enumerate the active metabolite, action of metabolite and management of CLOFIBRATE

A

Active metabolite - clofibric acid
Action - muscle damage
Management - avoid

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39
Q

What does clofibrate do?

A

Lowers cholesterol

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40
Q

What condition can statins cause?

A

Rhabdomyolysis

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41
Q

Uremic patients have increased sensitivity to what drugs?

A
  1. Anticholinergics
  2. CNS depressants
  3. Narcotic analgesics
  4. Sedatives
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42
Q

What is the effect of hyperkalemia on the heart?

A

Arrythmia

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43
Q

T/F: Antibiotics have a large therapeutic martin

A

True

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44
Q

What method is used to determine free levels of highly bound acidic drugs?

A

Therapeutic drug monitoring

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45
Q

What urinary tract antibacterial agents experience an altered response in renal disease?

A

Nalidixic acid and nitrofurantoin

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46
Q

What diuretics are potent enough to achieve diuresis in renal disease?

A

Loop diuretics

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47
Q

What ACE inhibitors carry the risk of reduced renal function, neutropenia and rash?

A

Captopril/enalapril

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48
Q

Among ibuprofen, mefenamic acid and sulindamycin, which is least nephrotoxic?

A

Sulindamycin

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49
Q

What substances may produce decreased GFR, fluid and sodium retention and cause edema?

A

NSAIDs

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50
Q

What type of drugs does the liver metabolise that the kidney can’t?

A

Lipophilic drugs

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51
Q

What is the most important metabolic pathway of detoxification in the liver?

A

Conjugation

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52
Q

Why do Filipinos have rapid acetylator toxicity?

A

This is due to IMA.

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53
Q

T/F: Profile of Filipinos is peripheral neuropathy rather than liver toxicity.

A

False

It’s the other way around!

54
Q

What should be added to prevent peripheral neuropathy?

A

Vitamin B6 (Pyridoxine)

55
Q

What are the factors for determining drug metabolism?

A
  1. Metabolizing enzyme

2. First pass metabolism

56
Q

Metabolism of what drug is adversely effective if there is liver dysfunction?

A

Propanolol

57
Q

What are the reasons for reduced drug metabolism in people with liver disease?

A
  1. Decreased enzyme metabolising capacity
  2. Decreased liver blood flow
  3. Intra- or extrahepatic shunting
58
Q

How many % of drugs in plasma does the liver clear?

59
Q

Define: Hepatic Extraction Ratio

A

The extent to which a drug is cleared in one passage through the liver

60
Q

T/F: Extraction of the liver is highly dependent on blood flow.

61
Q

What happens when the unbound fraction of propanolol increases?

A

It distributes to other tissues, giving rise to an increase in Vd and half-life.

62
Q

What happens if there is an increase in the unbound fraction of phenytoin and warfarin?

A

Increased hepatic extraction and reduced half-life

63
Q

What drugs have an unchanged half-life in a person with parenchymal liver disease?

A 
Ampicillin
Chloropromazine
Cotrimoxazole
Colchicine
Digoxin
Lorazepam
Paraaminosalicylic Acid (PAS)
Salicylic
64
Q

What drugs can have either a prolonged or unchanged half-life in a person with parenchymal liver disease?

A

Equivocal Drugs

Pentobarbital
Phenytoin
Prednisone
Tolbutamine

65
Q

What drugs have a prolonged half-life in a person with parenchymal liver disease?

A 
Acetaminophen
Carbenicillin
Chloramphenicol
Clindamycin
Rifampicin
Isoniazid
Lidocaine
Meperdine
Phenobarbital
Diazepam
Theophylline
66
Q

Define: Idiosyncratic Drug Response

A
  1. Infrequently observed in most patients
  2. Caused by genetic differences in metabolism of the drug
  3. Hyporeactive vs. hyperreactive
67
Q

T/F: Allergic reaction to hepatotoxic drugs occurs at low dosage.

68
Q

What are the basic mechanisms for converting hepatotoxic drugs into stable drugs?

A
  1. Alkylating
  2. Arylating
  3. Acylating
69
Q

What are the effects of furosemide and thiazide diuretic on patients with liver disease?

A

Potassium loss, metabolic alkalosis and hepatic encephalopathy

70
Q

What is the effect of morphine and analgesic, sedatives and tranquillisers on patients with liver disease?

A

Hepatic encephatopathy

71
Q

What is the effect of hypoglycaemia agents on patients with liver disease?

A

Possible hypoglycemia coma

72
Q

What is the effect of anticoagulants on patients with liver disease?

A

Exaggerated effect (i.e. bleeding); vitamin K deficiency may also contribute

73
Q

T/F: Dosage interval should be prolonged in patients with liver disease.

74
Q

Which drugs should be avoided in patients with liver disease?

A

Barbiturates, cyclophosphamide, decarbazine, thiotepa and l’asparaginase

75
Q

What are the factors affecting drug effects on the fetus?

A

Maternal: pharmacokinetic changes during pregnancy
Fetus: age
Drug: related drug characteristics/factors

76
Q

T/F: An older fetus will experience a more adverse reaction to drugs.

A

False

Younger fetuses will.

77
Q

When are maternal physiological changes most pronounced?

A

Third trimester

78
Q

How much does plasma volume in the mother increased by during pregnancy?

A

40 - 50% (affects drugs with low Vd)

79
Q

What proteins decrease during pregnancy?

A
  1. Albumin
  2. Alpha-1 glycoproteins
  3. Lipoproteins
80
Q

Is GFR increased or decreased in pregnant women?

81
Q

What type of drugs primarily bind to albumin?

A

Acidic and neutral drugs

82
Q

Where do basic drugs bind?

A

Alpha-1 acid glycoprotein

83
Q

If albumin becomes saturated, where will the drugs bind to?

A

Lipoprotein

84
Q

What is the effect of progesterone on motility and gastric emptying time?

85
Q

Should you prescribe iron during the first trimester?

A

Absolutely not

86
Q

What should you recommend an anaemic pregnant patient?

A

Eat iron-rich food

87
Q

What is the only vitamin indicated during the first trimester of pregnancy?

A

Folic acid (prevents spina bifida and neural tube defect)

88
Q

How much folic acid should be given per dose?

89
Q

What happens to acid secretion during the different trimesters of pregnancy?

A

Decreased during first and second trimesters

Increased during third trimester

90
Q

Why is epidural the anaesthesia of choice for women giving birth?

A

So that they can swallow what they vomit out

91
Q

Estrogens and progesterone change the metabolism of what drugs?

A
  1. Anti-infectives
  2. Anti-depressants
  3. Anti-epileptic drugs
92
Q

T/F: All anticonvulsants are teratogenic.

A

True

Go with mono therapy!

93
Q

What causes lung function reduction in the fetus and small birth weight?

A

Polymorphism in CYP1A1

94
Q

How many % of all pregnancies are aborted or miscarried?

95
Q

When is the “all-or-nothing” effect applicable?

A

Before the 20th day

96
Q

Is it possible for the fetes to survive unharmed if exposed to drugs before the 20th day?

A

Yes, because this precedes organogenesis.

97
Q

What agents can cause congenital defects?

A

Radiation and chemotherapeutic agents

98
Q

When does organogenesis occur?

A

3rd - 8th week

99
Q

What are the possible outcomes of drug use during the stage of organogenesis?

A
  1. No effect
  2. Abortion
  3. Sub-lethal gross anatomic defect
  4. Covert embryopathy
100
Q

What are the two organs that continue to grow even after birth?

A 
Brain (7th to 9th year of life)
Reproductive organs (most vulnerable organ)
101
Q

What anti-depressant causes twice the risk of congenital malformation compared with others?

102
Q

Should pregnant women be included in clinical testing?

103
Q

What is thalidomide?

A

It is an anti-emetic (alpha-phthalimido-glutarimide)

104
Q

What is the most prominent manifestation of thalidomide babies?

A

Phocomelia

105
Q

What is the critical stage in thalidomide exposure in babies?

A

Neuromuscular defect

106
Q

What is the relation between drug exposure and fetal toxicity?

A

The higher the exposure, the greater the toxicity

107
Q

When pregnant, what should be given instead of warfarin or coumadin?

A

Heparin (because of high molecular weight)

108
Q

Above what size is a molecule incompletely transferred across the placenta?

109
Q

T/F: Lipophilic opioids and antibiotics do not readily cross the placenta.

A

False

They do.

110
Q

What are the properties that determine the passive rate of diffusion?

A
  1. Molecular weight
  2. Lipid solubility
  3. Protein binding
  4. pKa
111
Q

What is the closest animal model for placenta and drug metabolism?

A

Sheep placenta

112
Q

Do oxidation and conjugation take place in the placenta?

113
Q

How does the placenta express CYPs?

A

In mRNA form

114
Q

How does recirculation of the drug occur in the fetus?

A

It is trapped in the amniotic fluid.

115
Q

In what condition will low ratio of fetal to maternal total drug concentration still result to higher exposure?

A

Fetal lactic acidosis

116
Q

T/F: Sulfonamide, barbiturates and phenytoin may cross the placental barrier.

117
Q

T/F: Ampicillin has a faster action compared to amoxicillin.

118
Q

What are the four drugs contraindicated during pregnancy?

A
  1. Kanamycin (neuro & nephro toxic)
  2. Tetracycline (muscle and teeth formation)
  3. Streptomycin (vestibular effects)
  4. Sulfonamides
119
Q

What factors can lead to uteroplacental hypo perfusion?

A

Uterine contraction
Cord compression
Supine positioning

120
Q

Mice deficient in what protein are more susceptible to cleft palate development?

A

P-glycoprotein

121
Q

Define: P-glycoprotein

A

Efflux pump that transports substrates from intracellular to extracellular compartment

122
Q

Define: Gabapentin

A

Anti-convulsant used to control neurologic pain

NOTE: It may be a substrate for certain amino acid transporters.

123
Q

What gene encodes the P-glycoprotein?

124
Q

Why is there an increased risk of vertical HIV infection from mommy to fetus?

A

Viral protease inhibitors are substrates of P-glycoprotein

125
Q

What are the drug categories in pregnancy according to the FDA?

A 
Category A (no increased risk)
Category B (no risk to fetus)
Category C (adequate studies)
Category D (benefits may outweigh risks)
Category X (positive evidence of risk)
126
Q

What are examples of category C drugs?

A

Omeprazole

Domperidone

127
Q

What are examples of category D drugs?

A

Etoposide
Bleomycin
Aspirin

128
Q

What are examples of category X drugs?

A

Enalapril
ACE inhibitors
Chemotherapeutic agents

129
Q

What is an example of a category A drug?

A

Folic acid

130
Q

What are examples of category B drugs?

A

H2 receptor antagonist
Ranitidine
Metochlopramide

[Ther 201] 1st Exam Transes (11 decks)

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