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
2
Q
How does the proximal tubule handle drugs?
A
- Filtration
- Active Secretion
- Active Reabsorption
3
Q
What type of drug is filtered by the proximal tubule?
A
Unbound drug only
4
Q
Give examples of acidic drugs that are actively secreted
A
Penicillin, probenecid and frusemide
5
Q
Give examples of basic drugs that are actively secreted
A
Cimatidine, amiloride and metformin
6
Q
What drugs are actively reabsorbed?
A
Nephrotoxic drugs such as aminoglycosides
7
Q
How does the distal tubule handle drugs?
A
Passive reabsorption
8
Q
What drugs are passively reabsorbed by the distal tubule?
A
- Salicylic acid
- Phenobarbital
- Theophylline
9
Q
What is the most widely used test of renal function?
A
Creatinine clearance, which approximates GFR
10
Q
How do you assess renal function?
A
Measure hourly urine output and amount of circulating urea and nitrogen concentrations
11
Q
What are the reasons why creatinine clearance is a good approximation of GFR?
A
- Eliminated only by kidneys
- Freely filtered
- Not secreted or reabsorbed
- Easily and accurately measured
12
Q
What is the normal value for creating clearance?
A
120 ml/min
13
Q
Give the formula for creatinine clearance
A
ClCr = (urine concentration x volume)/(plasma concentration x collection time)
14
Q
When can serum creatinine be used as a substitute for endogenous creatinine?
A
- Age-dependent reduction in renal function
- Sex and body weight of patient
WARNING: It depends on muscle bulk, so it’s not a reliable measure.
15
Q
What is the normal value for serum creatinine?
A
0.06 - 0.13 mmol/L
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]
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
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.
19
Q
In what ways can you use the DAF to make adjustments?
A
- Change dose (divide)
- Change interval (multiply)
Change only one!
20
Q
When is the use of DAF valid?
A
- One compartment model
- Non-toxic metabolites of a drug
- No difference in ADME of normal and ureic patients
- Stable kidney function
- No alteration of sensitivity in uremic patients
21
Q
What are the factors in considering dose alteration?
A
- Therapeutic index of the drug
- Renal clearance proportion of total clearance
- Severity of renal impairment
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)]
23
Q
What is the formula for average steady state plasma concentration?
A
Cssav = F x D/Cl x T
T = dosage interval
24
Q
What is the formula for maintenance dose?
A
MD = Css x Cl x T/F
25
What does the dosage modification process involve?
1. Lengthening the dosage interval
| 2. Reducing the dose size
26
What does lowering the dose do?
It lowers the peak plasma concentration.
27
T/F: Prolonging the interval reduces the trough concentration in plasma.
True
28
When is a combination of lengthening the interval and reducing the dose preferred?
When either method produces sub therapeutic troughs or toxic peaks.
29
What is the preferred dose adjustment method for digoxin and anti-arrythmic drugs?
Dose lowering to prevent toxic doses
30
What is the preferred dose adjustment method for antibiotics?
Changing dose interval
31
T/F: Acidic drugs that bind to albumin show increased binding in uremic patient serum.
False
Decreased binding!
32
What are the reasons for decreased acidic drug binding to albumin in uremic patients?
1. Hypoalbuminemia
| 2. Endogenous displacers
33
Enumerate the extent of binding for different acidic drugs in patients with poor renal function (TABLE 3)
Slight decrease - Amoxicillin
Decreased - Bilirubin, cefazolin, cefoxitin, clofibrate, diazoxide, furosemide, phenobarbital, phenytoin, salicylate, theophylline, sulfonamide, and naproxen
Normal - Indomethacin
34
Describe: Pethidine
1. Given as an active metabolite to pregnant women
2. Given right before delivering the baby
Unlike pethidine, enalapril is useless when not metabolised.
35
Enumerate the active metabolite, action of metabolite and management of PETHIDINE.
Active metabolite - norethidine
Action - CNS stimulation and seizures
Management - avoid prolonged treatment
36
Enumerate the active metabolite, action of metabolite and management of PROPOXYPHENE ALLOPURINOL.
Active metabolite - thiocyanate N-Acetyle procainamide
Action - metabolic acidosis; encephalopathy.
Management - shorten duration of treatment & reduce dose
37
Enumerate the active metabolite, action of metabolite and management of QUINIDINE.
Active metabolite - 3-hydroxyquinidine
Action - same as parent
Management - reduce dose 25 - 50% in severe renal failure
38
Enumerate the active metabolite, action of metabolite and management of CLOFIBRATE
Active metabolite - clofibric acid
Action - muscle damage
Management - avoid
39
What does clofibrate do?
Lowers cholesterol
40
What condition can statins cause?
Rhabdomyolysis
41
Uremic patients have increased sensitivity to what drugs?
1. Anticholinergics
2. CNS depressants
3. Narcotic analgesics
4. Sedatives
42
What is the effect of hyperkalemia on the heart?
Arrythmia
43
T/F: Antibiotics have a large therapeutic martin
True
44
What method is used to determine free levels of highly bound acidic drugs?
Therapeutic drug monitoring
45
What urinary tract antibacterial agents experience an altered response in renal disease?
Nalidixic acid and nitrofurantoin
46
What diuretics are potent enough to achieve diuresis in renal disease?
Loop diuretics
47
What ACE inhibitors carry the risk of reduced renal function, neutropenia and rash?
Captopril/enalapril
48
Among ibuprofen, mefenamic acid and sulindamycin, which is least nephrotoxic?
Sulindamycin
49
What substances may produce decreased GFR, fluid and sodium retention and cause edema?
NSAIDs
50
What type of drugs does the liver metabolise that the kidney can't?
Lipophilic drugs
51
What is the most important metabolic pathway of detoxification in the liver?
Conjugation
52
Why do Filipinos have rapid acetylator toxicity?
This is due to IMA.
53
T/F: Profile of Filipinos is peripheral neuropathy rather than liver toxicity.
False
It's the other way around!
54
What should be added to prevent peripheral neuropathy?
Vitamin B6 (Pyridoxine)
55
What are the factors for determining drug metabolism?
1. Metabolizing enzyme
| 2. First pass metabolism
56
Metabolism of what drug is adversely effective if there is liver dysfunction?
Propanolol
57
What are the reasons for reduced drug metabolism in people with liver disease?
1. Decreased enzyme metabolising capacity
2. Decreased liver blood flow
3. Intra- or extrahepatic shunting
58
How many % of drugs in plasma does the liver clear?
90%
59
Define: Hepatic Extraction Ratio
The extent to which a drug is cleared in one passage through the liver
60
T/F: Extraction of the liver is highly dependent on blood flow.
True
61
What happens when the unbound fraction of propanolol increases?
It distributes to other tissues, giving rise to an increase in Vd and half-life.
62
What happens if there is an increase in the unbound fraction of phenytoin and warfarin?
Increased hepatic extraction and reduced half-life
63
What drugs have an unchanged half-life in a person with parenchymal liver disease?
```
Ampicillin
Chloropromazine
Cotrimoxazole
Colchicine
Digoxin
Lorazepam
Paraaminosalicylic Acid (PAS)
Salicylic
```
64
What drugs can have either a prolonged or unchanged half-life in a person with parenchymal liver disease?
Equivocal Drugs
Pentobarbital
Phenytoin
Prednisone
Tolbutamine
65
What drugs have a prolonged half-life in a person with parenchymal liver disease?
```
Acetaminophen
Carbenicillin
Chloramphenicol
Clindamycin
Rifampicin
Isoniazid
Lidocaine
Meperdine
Phenobarbital
Diazepam
Theophylline
```
66
Define: Idiosyncratic Drug Response
1. Infrequently observed in most patients
2. Caused by genetic differences in metabolism of the drug
3. Hyporeactive vs. hyperreactive
67
T/F: Allergic reaction to hepatotoxic drugs occurs at low dosage.
True
68
What are the basic mechanisms for converting hepatotoxic drugs into stable drugs?
1. Alkylating
2. Arylating
3. Acylating
69
What are the effects of furosemide and thiazide diuretic on patients with liver disease?
Potassium loss, metabolic alkalosis and hepatic encephalopathy
70
What is the effect of morphine and analgesic, sedatives and tranquillisers on patients with liver disease?
Hepatic encephatopathy
71
What is the effect of hypoglycaemia agents on patients with liver disease?
Possible hypoglycemia coma
72
What is the effect of anticoagulants on patients with liver disease?
Exaggerated effect (i.e. bleeding); vitamin K deficiency may also contribute
73
T/F: Dosage interval should be prolonged in patients with liver disease.
True
74
Which drugs should be avoided in patients with liver disease?
Barbiturates, cyclophosphamide, decarbazine, thiotepa and l'asparaginase
75
What are the factors affecting drug effects on the fetus?
Maternal: pharmacokinetic changes during pregnancy
Fetus: age
Drug: related drug characteristics/factors
76
T/F: An older fetus will experience a more adverse reaction to drugs.
False
Younger fetuses will.
77
When are maternal physiological changes most pronounced?
Third trimester
78
How much does plasma volume in the mother increased by during pregnancy?
40 - 50% (affects drugs with low Vd)
79
What proteins decrease during pregnancy?
1. Albumin
2. Alpha-1 glycoproteins
3. Lipoproteins
80
Is GFR increased or decreased in pregnant women?
Increased
81
What type of drugs primarily bind to albumin?
Acidic and neutral drugs
82
Where do basic drugs bind?
Alpha-1 acid glycoprotein
83
If albumin becomes saturated, where will the drugs bind to?
Lipoprotein
84
What is the effect of progesterone on motility and gastric emptying time?
Delays
85
Should you prescribe iron during the first trimester?
Absolutely not
86
What should you recommend an anaemic pregnant patient?
Eat iron-rich food
87
What is the only vitamin indicated during the first trimester of pregnancy?
Folic acid (prevents spina bifida and neural tube defect)
88
How much folic acid should be given per dose?
400 mcg
89
What happens to acid secretion during the different trimesters of pregnancy?
Decreased during first and second trimesters
| Increased during third trimester
90
Why is epidural the anaesthesia of choice for women giving birth?
So that they can swallow what they vomit out
91
Estrogens and progesterone change the metabolism of what drugs?
1. Anti-infectives
2. Anti-depressants
3. Anti-epileptic drugs
92
T/F: All anticonvulsants are teratogenic.
True
Go with mono therapy!
93
What causes lung function reduction in the fetus and small birth weight?
Polymorphism in CYP1A1
94
How many % of all pregnancies are aborted or miscarried?
40%
95
When is the "all-or-nothing" effect applicable?
Before the 20th day
96
Is it possible for the fetes to survive unharmed if exposed to drugs before the 20th day?
Yes, because this precedes organogenesis.
97
What agents can cause congenital defects?
Radiation and chemotherapeutic agents
98
When does organogenesis occur?
3rd - 8th week
99
What are the possible outcomes of drug use during the stage of organogenesis?
1. No effect
2. Abortion
3. Sub-lethal gross anatomic defect
4. Covert embryopathy
100
What are the two organs that continue to grow even after birth?
```
Brain (7th to 9th year of life)
Reproductive organs (most vulnerable organ)
```
101
What anti-depressant causes twice the risk of congenital malformation compared with others?
Paxil
102
Should pregnant women be included in clinical testing?
Sometimes
103
What is thalidomide?
It is an anti-emetic (alpha-phthalimido-glutarimide)
104
What is the most prominent manifestation of thalidomide babies?
Phocomelia
105
What is the critical stage in thalidomide exposure in babies?
Neuromuscular defect
106
What is the relation between drug exposure and fetal toxicity?
The higher the exposure, the greater the toxicity
107
When pregnant, what should be given instead of warfarin or coumadin?
Heparin (because of high molecular weight)
108
Above what size is a molecule incompletely transferred across the placenta?
500 D
109
T/F: Lipophilic opioids and antibiotics do not readily cross the placenta.
False
They do.
110
What are the properties that determine the passive rate of diffusion?
1. Molecular weight
2. Lipid solubility
3. Protein binding
4. pKa
111
What is the closest animal model for placenta and drug metabolism?
Sheep placenta
112
Do oxidation and conjugation take place in the placenta?
No
113
How does the placenta express CYPs?
In mRNA form
114
How does recirculation of the drug occur in the fetus?
It is trapped in the amniotic fluid.
115
In what condition will low ratio of fetal to maternal total drug concentration still result to higher exposure?
Fetal lactic acidosis
116
T/F: Sulfonamide, barbiturates and phenytoin may cross the placental barrier.
True
117
T/F: Ampicillin has a faster action compared to amoxicillin.
True
118
What are the four drugs contraindicated during pregnancy?
1. Kanamycin (neuro & nephro toxic)
2. Tetracycline (muscle and teeth formation)
3. Streptomycin (vestibular effects)
4. Sulfonamides
119
What factors can lead to uteroplacental hypo perfusion?
Uterine contraction
Cord compression
Supine positioning
120
Mice deficient in what protein are more susceptible to cleft palate development?
P-glycoprotein
121
Define: P-glycoprotein
Efflux pump that transports substrates from intracellular to extracellular compartment
122
Define: Gabapentin
Anti-convulsant used to control neurologic pain
NOTE: It may be a substrate for certain amino acid transporters.
123
What gene encodes the P-glycoprotein?
MDR1
124
Why is there an increased risk of vertical HIV infection from mommy to fetus?
Viral protease inhibitors are substrates of P-glycoprotein
125
What are the drug categories in pregnancy according to the FDA?
```
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
What are examples of category C drugs?
Omeprazole
| Domperidone
127
What are examples of category D drugs?
Etoposide
Bleomycin
Aspirin
128
What are examples of category X drugs?
Enalapril
ACE inhibitors
Chemotherapeutic agents
129
What is an example of a category A drug?
Folic acid
130
What are examples of category B drugs?
H2 receptor antagonist
Ranitidine
Metochlopramide
