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2nd term test Flashcards

1
Q

What is first order elimination VS zero order elimination?
How will the slope of each looks like in a graph?

A

Zero order: constant amount of drug being removed through time, independent from drug conc’n, rate= k
ie: 2.5mg of clearance at any time any concentration
First prder: Most cases. Constant porpotion is eliminated per unit time. clerance depends on the concentration of the drug
rate= k[drug], rate increase when conc’n increase
ie: 5 mg, 2.5 mg, 1.25 mg

First order: straight line
Zero order: Curve line

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2
Q

What is drug clearance? What is the units?

A

Measurment that describes the RATE of drug removal, ie a theoretical volume of biological fluid (blood) from which a drug is completely cleared
Drug clearance does NOT indicate the actual amount of drug being removed, as the actual amount depends on the plasma conc’n
UNIT: volume/time

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3
Q

What is TBC?

A

Total body clearance.
Different body organs can remove drugs, and the sum of all clearnace from different organs = TBC
It’s the measuremnt of total overall rate of removing drug from the whole body

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4
Q

What are the two processes of drug removal?

A

Excretion: drug discharges from body, most commonly through urine
Biotransformation (metabolism): Chemical transformation of drug within body (p450)

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5
Q

What is the excretion of water VS lipid soluble drug?

A

Water soluble: Excrete in urines, by kidneys. Happen imeediately and drug is unchanged
Lipid soluble: drug being biotrabsformed to water soluble, then get excreted

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6
Q

Why should we only have 1 alcohol drink per hour?

A

Alcohol (ethanol) is zero order elimination, therefore, only a constant amount of alcohol can be eliminated. Drinking too much can easily lead to OD, as only 1 drink can be eliminated per hour

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7
Q

what is half life, Half life formula:
k formula when slope is given:

A

Half life= time to halve the drug plasma conc’n
0.693/k, where k= elimination rate constant (per hour), o.693= ln(2)

k= -slope x 2.3, where 2.3= conversion factor

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8
Q

What is CLTB? formula?

A

CLTB = total body clearance
CLTB= k Vd
CLTB= Dose/ AUC, which AUC is area under cuvre, measuring the bioavailability

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9
Q

What happen when dosing rate = elimination rate
Dosing rate formula? What happen when drug is administered orally?

A

When dosing rate= intake rate, stady state drug concentration is maintained, Css
dosing rate= CLTB x Css
When oral, devide by bioavailability (F), so dosing rate is (Css x CLTB)/F

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10
Q

What does Q stand for? What is rate of elimination formula?
What is E?
What is formula for CLorgan? What does it depends on?

A

Q=blood flow/ perfusion rate, dep
Rate of
elimination = Q (Cin - Cout)
E is extraction ratio, E= (Cin- Cout)/Cin
CLorgan= QE= Q(Cin-Cout)/Cin
It depends on blood flow to the organ (Q), and the ability of the organ to extract drugs (E)

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11
Q

What is hepatic clearance? What is it via?
What is intrinsic hepatic clearance?

A

It’s the major clearance for non-polar drugs, involving liver
It is via haptatic metabolism and biliary excretion
Intrinsic hepatic clearance is the max ability of liver to eliminate drug from blood, without the aids of other cofactors such as protein binding/ blood flow, indicating how efficiently liver enzymes can metabolize a drug.

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12
Q

How does blood flow, protein binding and changes in enzyme function affect CLheptatic of high extraction drugs? What about low extraction drugs?

A

For high:
1) CLh depends on blood flow (sensitive to hemodynamic changes)
1) Protein binding does NOT limit CLh
3) Enzyme function doesn’t really affect CLh

For low:
1) Blood flow doesn’t really affect CLh
2) Protein binding lower/ limit CLh
3) CLh is sensitive to enzyme function changes

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13
Q

What is first pass effect? What does it depends on? What is the fraction of drug available after first pass?

A

For orally administered drug, before drug reaching the general circulation, some of the drugs may be metabolized in liver, reducing the drug bioavailability.
It depends on the extraction ratio of the drug, and F= 1-E

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14
Q

What is biliary excretion?
What is the formula for biliary clearance?
What is this significant for?

A

Bile is producted by hepatocytes, and drug can be secreted into bile
CLb= (bile flow x Cb)/Cp
This is significant for drugs that are concentrated in bile, relative to plasma

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15
Q

What is the 3 net processes of elimination through renal clearance?
What is the drug filtration rate? What if drug is only filtered?

A

Renal excretion= Filtration- reabsorption + secretion
Rate= GFR x Cunbound, Cunbound= Funbound x Cp
when only filtered= GFR x Funbound

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16
Q

What does it mean when CLr is smaller than calculated filtration of compound? What if it’s larger

A

When CLr is smaller, reabsorption has took place
When CLr is larger, drug is filtered and secreted

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17
Q

What is the CLr formula?

A

CLr = rate of excretion / Cin = (urine floe x Curine)/ Cin

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18
Q

What happen to drug clearance of acidic/ basic drug in acidic/ basic urine?

A

Acidic drug has low clearance ratio in acidic urine, while basic drug has low clearance ration in alkaline urine
This is due to the fact that less ionization occur to the drugs in corresponding pH, making them less polar–> less clearance (more reabsorbance as they are non-polar)

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19
Q

What is dose, dosing interval and dosage?

A

Dose= amount of drug, eg 5mg
Dosing interval: How often to take the drug, eg every 5 hours
Dosage: Amount of drug to be administered in a time interval, eg 5mg every 5 hours

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20
Q

How many half life does it take for most drug to be removed from body?
eg when half life is 5 hours, how long does it take to be removed?

A

Rule of thumb, 5 half lives
Therefore for a drug with 5 hours half life, it takes 25 hours

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21
Q

What are the two significants of rule of thumb of half life?

A

5 half lives= 96.9% drug to be romved, it also = drug dosing regimen to achieve 96.9% of Css (take 5 half lives to achieve a steady state)

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22
Q

What is toxicology?

A

Studies of adverse effect of chemicals/ physical agents, like the harmful effects of drugs, contaminants, or naturally occurring substances

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23
Q

What do toxicologist do?

A

Assess and and study harmful effect of chemicals, and the probability of the harm

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24
Q

What is the difference between pharmacology VS toxicology

A

Pharmacology: focus on therapeutic effect of therapeutic products
Toxicology: focus on adverse effect of essentially everything

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25
What is toxin? What about toxicants?
Toxin: toxic substances that are produced naturally by biological system (plants/ fungi/ etc) Toxicants: produced by human activities
26
What are the two hemlock plants?
1: Poison Hemlock Contain coniine 2: Water Hemlock Contain cicutoxin The two hemlocks contain different toxin, and different mechanism of action
27
What is the toxicology risk assessment?
1: Hazard identification, associated harm 2: Dose-response assessment, attempt to quantify 3: Exposure assessment, considering the route of exposure 4: Risk characterization
28
What are the two mechanisms of toxicity?
1: A molecule bind reversibly to a cellular receptor 2: A non-toxic chemical got bioactivated to a reactive metabolites that irreversibly bind to cell macromolecules, such as protein/ DNA
29
What are the four common routes of exposure?
Oral Injection Inhalation Transdermal
30
What are the four duration and frequency of exposure to toxicity?
Acute: expose to chemical for <24 hrs, usually single administration Subacute: repeated expose for less than a month Subchronic: repeated expose for 1-3 months Chronic: repeated expose for > 3 months
31
What is graded VS quantal dose response curves?
Graded: relate the does to the intensity of the effect, the efficacy regarding to concentration Quantal: relate the dose to the frequency of the effect, the all or none effect that occur in the population regarding to concentration
32
What is LD/TD, what does LD50 represent?
Lethal does/ toxic dose, which LD50 means lethal dose in 50% of the population (eg 50% cell death)
33
What is the formula of TI
TI= LD50/ ED50 which LD50 is lethal dose in 50% of the population, and ED50 is the effective dose in 50% of the population
34
What is Certain safety factor?
CSF= LD1/ ED99
35
What is perinatal, prenatal/antenatal, and postnatal/postpartum
Perinatal: time period around birth Prenatal: before birth Postnatal: after birth
36
What is LMP? What is T1, T2 and T3?
LMP= last menstrual period T1= fertilization and major organ development T2= rapid growth and development T3= organ maturation
37
What is the affect of maternal effects of pregnancy toward drug therapy?
Body may handle drug differently, as changes occur during pregnancy, so changes need to be made to current drug therapy, or new drug therapy needs to be initiated due to physiological changes in pregnant woman
38
What are the factors that affect maternal drug absorption?
1: Vomit happen more likely 2:Increased gastric pH 3: Decreased gastric emptying intestinal mobility 4: Increased cardiac output and tidal volume
38
For pregnant women, what enzymes are induced?
Cyp3A4, 2D6, 2C9, 2A6 and UGT phenytoin, warfarin or nicotine are metabolized rapidly
39
What happened to pregnant woman, that would affect drug distribution?
1: Increased body weight and TBW, dilute drug concentration 2: Increased plasma volume 3; Change in regional blood flow 4: Decreased in plasma protein binding, more free drug for albumin binding drug
40
What enzymes are inhibited for pregnant women?
Cyp1A2 and 2C19 caffeine is cleared slower
41
What factors affect maternal drug excretion?
1: increased renal blood flow 2: increased glomerular filtration rate 3: increased drug secretion rate
42
How does fetal toxicity occur during prenatal period?
It can be result from maternal drug transfer, as the mother can takes drug that target the baby
42
So in general, would a pregant woman need a lower/ normal/ higher dose? Why?
Higher dose in general, as Vd, renal blood flow, CL are increased, while Cmax and half life is decreased
43
What is minor anomalies?
Problems arise when the child is growing up, such as learning issue
44
What's teratogen?
Agent/ factor that the preganant mother was exposed to, that cause malformation/ abnormal physiological function/ mental development of the fetus, or in the child after birth
45
What's chemical teratogenesis?
Birth defects that's caused by exposure to chemicals, such as drugs and xenobiotics
46
What is Thalidomide drug? What is Thalidomide teratogenicity? When does the teratogenesis occur?
Thalidomide is a tranquilizer/ anti-emetic drug during pregnancy, and it's popular due to it's absence of actue toxicity and adverse effect during preclinical rodent studies. It causes limb reduction defect ( poor development), facial hemangioma, small ears, eye abnormalities, kidney malfunctions and congenital heart disease It's critical period of exposure for birth defects is 20-36 days post fertilization, as this is the limbs development state
47
What are the critical periods?
1: All or nothing period, which is first 2 weeks post conception embryo won't survive if too many cells are damaged/ killed 2: organogenesis week 3-8 post conception, which has the greatest sensitivity to chemical insult
48
How does drug disposition occur in the maternal-placental-fetal unit
Fetal circulation is slightly more acidic than maternal, so when a basic drug enter maternal, it is non polar and pass into fetal unit. In fetal, drug will be ionized due to the lower pH, and getting trapped in fetal
49
What are the two direct effects of drugs on fetus?
1: receptor-mediated toxicity 2: Reactive-intermediate mediated toxicity, which proteratogens are biotransformed to electrophile/ free radicals, targeting DNA/protein/ lipids (irreversible)
50
What is the anticancer agents that is teratogens, and what does it cause?
Cyclophosphamide, which kill rapidly divide cells, including fetus and cancer Cause CND malformation and cancer
51
What is the anticoagulant teratogens? What is the effect
Warfarin, which cause growth retardation, chondrodysplasia, hypolastic nasal bridge, CNS malformation and congenital heart defects
52
What drugs cause fetal hydantoin syndrome? What are the symptoms?
Antiseizure agents, including phenytoin, carbamazepine and valproic acid Phenytoin cause cleft lip/palate, growth retardation, CNS deficit Carbamazepine and valproic acid cause neural tube defect
53
What is diethylstilbestrol?
Synthetic estrogen that is a teratogen
54
What is retinoids/ isotretinoin?
Vitamin A derivative used to treat acne, that is a teratogen, causing CNS craniofacial, cardiovascular malformations
55
What are the effects of fetal alcohol syndrome?
Growth retardation, microcephaly (small brain), mental retardation, neurobehavioural deficits and facial dysmorphology thin upper lips
56
What is the effect of maternal smoking?
It is not associated with major malformations, but are associated with spontaneous abortion and low birth weight
57
What is neonatal withdrawal/ neonatal abstinence syndrome?
It usually occur within days of delivery, and has similar feature regardless of the drug It involves irritability, high pitched cry. tremor, rapid breathing and increased mucle tone and seizures
58
What are two types of drug that cause neonatal withdrawal?
Opioids and antidepressant
59
How does drug get transferred to breast milk?
Milk is mostly lipid, contains proteins, and has a lower pH So drug that are lipophilic, has low molecular weight and are protein binding can be trapped in milk. The low pH also causes ion trapping of basic drug
60
What is the infant dose formula?
Concentration of drug in breast milk times 150ml/kg/day
61
What happen to the response to antibiotics, when an individual has inflamed meninges.
The individual's meningesn get more fluidity, so drug can access the brain, which lead to a higher chance of OD. Therefore, they will have increased response toward the drug.
62
What are the four main factors affecting the drug response variability?
1: Compliance, did patient take drug as instructed 2: bioavailability, did the drug make it to the circulation 3: PK, did the drug reach the target at its Cther, and have a proper duration of action 4: PD, did the target tissue respond as expected to the drug
63
How does age relate to patients compliance?
Age itself is not a significant factor, but it can be associated to other factors that are, such as polypharmacy, isolation, physical/cognitive limitations (forgetting to take drug, etc)
64
What are four predictive patient factors related to patient compliance?
Psychological problem Cognitive impairment Social isolation Perception of illness, treatment efficacy and ADR
65
What are some disease related factors affecting compliance
Low compliance with no/mild symptoms, chronic disease, delayed repercussions or preventative treatment
66
How does treatment-related factors affect patient compliance?
-complexity of the dosing regimen -number of drugs -unwanted effects -container/ packaging design -palatability
67
What dose would a obese individual need, in term of lipid/water soluble drugs?
Obese individual need lower dose of water soluble drug, and higher dose of lipid soluble drug
68
What drugs affect metabolism of terfenadine, what is the consequence?
Drug such as ketoconazole or erythromycin will inhibit cyp3A4 activity, so terfenadine cannot be metabolized into fexofenadine. Terfenadine will cause arrythmia
69
What is polymorphism?
Common gene variation that occur frequently in the population
70
How is the polymorphism of CYP2D6 dicovered?
Variable in drug responses is shown in debrisoquine and sparteine drugs
71
What is the most common metabolizer form CYP2D6
Extensive metabolizers are more common than poor and ultra rapid metabolizers
72
What is poor metabolizers?
They have defective gene alleles
73
Name 3 drugs that are affected by CYP2D6 polymorphism
Codeine, dextromethorphan and Tamoxifen
74
How does cyp2D6 affect codeine?
Codeine needed to be activated into morphine by Cyp2D6 Cyp2D6 poor metabolizers show poor analgesia effect from codeine
75
How is CYP2D6 activity tested/ predicted?
Using Dextromethorphan, which is a safe probe used to test Cyp2D6 activity
76
How does Cyp2D6 metabolizer phenotype increase breast cancer survival rate?
Breast cancer is treated by tamoxifen Tamoxifen will be metabolized by cyp2D6 into endoxifen active metabolite Extensive metabolizer has high cyp2D6 activity, produce more endoxifen, so they have highest survival rate
77
How is warfarin metabolized?
Cyp2C9
78
What happen to cyp2c9 deficit patient who are on warfarin treatment
Internal bleeding might occur, so dose reduction may be needed
79
How is omeprazole metabolized? What metabolizer is favored?
Omeprazole, which reduce stomach acid, is metabolized by Cyp2C19 Poor metabolizer is favored, as more drug are kept in the gastric, maintaining the gastric pH for longer, and better reduction of stomach acidity
80
How is 6MP metabolized?
6MP need to be partially metabolized by TPMT, making the drug inactive and safe Unmetabolized 6MP will be converted to TGN which is highly cytotoxic and narrow therapeutic index, which can kill cancer, but also wipe out bone marrow
81
What happen to leukemia patient who are poor metabolizer
PM with low TPMT activity cannot detoxify 6MP, causing high toxicity, and higher chance of death
82
What is the effect of genetic variation at amino acid 16?
It alters the B2-adrenergic receptor response to slbutamol
83
How does Trastuzumab work?
It is an antibody that direct against HER2, which is a growth factor receptor in some breast tumor This treatment is only effective in patient who have overexpression of HER2
84
What can be the reasons of bleeding caused by warfarin, beside genetics
dietary intake of vitamin K rich food
85
What are the challenges in personalized medicine?
Polygenic inheritance Technology challenge clinical challenge
86
What is Vioxx?
Cox2 inhibitor drug intended for analgesic/ anti-inflammatory Comparing to NSAIDs, it has increased rate of myocardial infraction, so it was withdrawn
87
What are some risk factors for ADR
Polypharmacy History of ADR Impaired renal function Hepatic dysfunction Age Gender Genetic
88
What is type A ADR?
Dose related it is predictable Common, low mortality Treated/ prevented by dose adjustment
89
What is type B ADR?
Bizarre ADR unpredictable, dose unrelated Uncommon, high mortality
90
How are drug effects mediated?
Same receptor, same tissue Same receptor, different tissue Different receptor
91
What is warfarin ADR? (type of effect)
Effects on same receptor in same tissue The ADR, which is bleeding, is a result of extension of drug therapeutic action, which is anticoagulant
92
What is dioxin ADR effect?
Same receptor, different tissues Beside treating heart failure, digoxin can cause renal function impairment and disrupts electrolyte balance
93
What is Beta adrenergic drugs ADR?
Effects mediated by different receptor subtypes Some drugs have multiple affinities for different receptor subtypes
94
What is Dobutamide ADR?
It binds to B1 receptor more than B2 receptor ADR includes hypotension, cause by B2 binding
95
What is Terbutaline ADR?
It binds to B2 more than B1 ADR includes increase heart rate and chest pain, due to B1 binding
96
What are the causes of type B ADR?
Due to increased susceptibility of patient, including genetic factors or drug allergy
97
What is abacavir ADR?
Type B ADR, cause by genetically determined hypersensitivity to abacavir
98
What is Type 1 immunologic response?
Anaphylactic/ hypersensitivity Happen immediately Allergen react with IgE antibody on mast cell/ basophils, releasing histamines
99
What is type 2 immunologic response?
Cytotoxic/ complement-fixing IgG react with drug directly on cell surface, causing cell lysis
100
What is type 3 immunologic response?
Toxic-immune complex Antigen-antibody complexes (drug and antibody) formed in blood and deposit on target tissue cell, causing inflammation and tissue destruction
101
What is type 4 immunologic response?
Cell-mediated (delayed) Most severe, and take 2-3 days to occur Allergens and sensitized lymphocytes( T-cell) release cytokines, causing eczematous and contact dermatitis--> slow destructive inflammation
102
What is Stevens Johnson syndrome
severe immune ADR result of type 4/3 immunological response
103
What are C, D, E, F ADR
Chronic Delayed: delayed onset End of treatment withdrawal Failure of treatment
104
Intention to treat VS as treated
ITT= Analyze all participants based on the group they were originally assigned to, even if they didn't complete the treatment or didn't stick to the protocol. AT= Analyze participants based on what treatment they actually received, regardless of their original group assignment.
105
When is most ADR discovered?
Common ADR can be found during drug development, uncommon ADR is found during post market surveillance period
106
What is the probability of at least on event occur? In term of patients population and event rate
Larger population of people in trial has higher probability for seeing a rare event to occur
107
what is prospective cohort studies?
follow a group of people to determine the risk of ADR, collecting info on drugs, demographics, lifestyle factors and outcomes
108
What is retrospective case control study
Start with cases (people with suspected ADR) and controls (people without ADR), then look back at past relative use of suspected drug
109
Case control study VS cohort study
Case control: always retrospective, start with the outcome (ADR), compare with control (no ADR) and see if ADR is related to the drug Cohort study: can be prospective or retrospective, start with the known exposure, and follow a group of people (take/ not take drug) and see if they get ADR

Pcl201 (6 decks)

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