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Pharm 2060 > Midterm > Flashcards

Midterm Flashcards

1
Q

origin of the word pharmacology

A

greek
pharmakon = remedy
logos = study

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2
Q

what is pharmacology?

A

the study of drugs

includes how it is delivered, how it works, the therapeutic effects and adverse effects

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3
Q

classification of therapeutics

A

drugs - traditional drugs i.e. chemical agents
biologics - ie antibodies, hormones
natural health products - i.e. herbals, vitamins, minerals `

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4
Q

Describe the levels of Canadian Drug Legislation

A

Food and Drugs Act and Regulations
then Health Canada
then Health Canada Products & Food Branch
then
Therapeutic Products Directorate (traditional drugs)
Biologics and Genetic Therapies Directorate (abs, hormones)
Natural Health Products Directorate (vitamins, herbals etc)

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5
Q

3 types of drug names

A

chemical name
generic name
trade name

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6
Q

chemical name

A

describes the chemical structure of the molecule

used by chemists

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7
Q

generic name

A

a unique name that identifies a drug

most often used in pharmacology and should be used by health care professionals

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8
Q

trade name

A

assigned by a drug company
easy to remember and marketable
many companies make the same drug so there can be many trade names for the same drug

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9
Q

steps of approval of marketed drugs in Canada

A 
preclinical testing 
clinical trial application 
phase I clinical trial 
phase II clinical trial 
phase III clinical trial 
new drug submission submitted to health Canada 
phase IV clinical trial

about 15 years total, up to $800 million

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10
Q

preclinical testing

A

also called discovery
in cultured cells, living tissue or experimental animals
evaluate biological effects, pharmacokinetics and toxicity
about 6.5 years

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11
Q

clinical trial application

A

paperwork detailing all pre-clinical data must be submitted to Health Canada before any human studies
they will respond within 30 days of receipt

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12
Q

phase I clinical trial

A

20-100 HEALTHY volunteers
evaluation of pharmacokinetics and pharmacodynamics
about 1 year

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13
Q

phase II clinical trial

A

300-500 PATIENTS with the target disorder
therapeutic effectiveness, side effects, and dosing information gathered
about 2 years

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14
Q

phase III clinical trial

A

500-5000 patients with the target disorder
therapeutic effectiveness verified, long-term side effects assessed
about 4 years

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15
Q

new drug submission (NDS)

A

NDS submitted to Health Canada
a report that details therapeutic effectiveness and safety
includes results from pre-clinical and clinical studies
about 1.5 years

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16
Q

if a NDS is approved what happens?

A

Health Canada issus a Notice of Compliance (NOC) and a Drug Information Number (DIN)
both are required to market the drug

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17
Q

phase IV clinical trial

A

post-marketing surveillance

Health Canada monitors the efficacy and safety of the drug after it has been marketed (can be pulled i.e. vioxx)

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18
Q

what is pharmacokinetics?

A

study of drug movement in the body
what the body does to a drug
includes absorption, distribution, metabolism and excretion

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19
Q

when an oral drug is absorbed and goes to the liver what are the 2 options it has?

A

can enter systemic circulation and go to heart, brain, muscle, kidney etc

or

can enter the bile duct and be excreted into the intestine

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20
Q

when a drug is parenteral where does it go?

A

absorbed right into systemic circulation

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21
Q

physiological barriers to drug transport

A

intestinal villi

tight junctions between cells

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22
Q

what happens in the SER?

A

metabolizes drugs, carbs and steroids

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23
Q

what happens in the golgi?

A

processes and packages proteins and lipids

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24
Q

why is the cell membrane fluid?

A

phospholipids are flexible and undulate

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25
Q

3 ways drugs pass through cell membranes

A

direct penetration
ion channels and pores
transporters

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26
Q

what molecules go through ion channels and pores?

A

MW <200 (i.e. very small compounds)

examples: Na, K, Li

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27
Q

uptake transporters

A

move drugs from outside cell to inside cell

mediate intestinal absorption, renal excretion and reaching target sites

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28
Q

efflux tranporters

A

move drugs from inside cell to outside

protect cells

are found in the intestine, placenta, kidney and BBB

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29
Q

polar drugs

A

uneven distribution of charge but no net charge

ie kanamycin

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30
Q

ion drugs

A

total # of electrons is not equal to protons
have a net charge
ie Na+, Li+ etc

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31
Q

quaternary ammonium compounds

A

at least one N atom and always have a positive charge

cannot cross cell membranes bc of this charge

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32
Q

when can weak acids and bases cross cell membranes?

A

when un-ionized

ie weak acid in acidic environment or weak base in basic environment

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33
Q

how do drugs move out of capillaries?

A

hydrophilic drugs pass between fenestrations
lipophilic drugs either pass between fenestrations or directly through PM of endothelial cells

except in the BBB where there are no fenestrations, there are tight junction - drugs either need to be lipophilic or have a transporter to get into brain

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34
Q

absorption

A

movement of drug from site of administration into the blood
rate of it determines how quickly drug effect will occur
and the amount of it determines how intense the effect will be

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35
Q

6 factors affecting drug absorption

A 
rate of dissolution 
surface area
blood flow 
lipid solubility 
pH partitioning 
activity of transport proteins
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36
Q

how does rate of dissolution affect drug absorption?

A

drugs need to dissolve before they can be absorbed

faster dissolution = faster onset of action

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37
Q

surface area and drug absorption

A

larger surface area = faster absorption

this is why there is more absorption in the intestine than stomach (villi vs rugae)

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38
Q

blood flow and drug absorption

A

absorption is fastest in areas with high blood flow

high blood flow maintains a concentration gradient to drive absorption

exercises increases blood flow
heart failure, severe hypotension, hypothermia and circulatory shock decrease blood flow

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39
Q

lipid solubility and drug absorption

A

high lipid solubility are absorbed more rapidly

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40
Q

pH partitioning and drug absorption

A

absorption is greater when theres a difference between pH at the site of administration and the blood such that the drug is ionized in the blood

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41
Q

activity of drug transporters and absorption

A

uptake transporters increase absorption

efflux decrease it

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42
Q

major routes of drug administration

A

ENTERAL

  • oral
  • rectal

PARENTERAL

  • intravenous
  • intramuscular
  • subcutaneous

OTHER

  • sublingual
  • transdermal
  • pulmonary
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43
Q

advantages and disadvantages of oral drugs

A

safety, convenience, economical

incomplete and variable absorption

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44
Q

are weak acids absorbed better in the stomach or intestine?

A

intestine - stomach has thick layer of mucus and small surface area so even though they’d be unionized aren’t absorbed better here

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45
Q

pharmaceutical phase

A

what occurs after an oral tablet is taken

includes the disintegration phase into granules and smaller particles and the dissolution phase

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46
Q

gastric emptying and drug absorption

A

increasing gastric emptying increases drug absorption because it puts drugs into the intestine where more absorption occurs

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47
Q

increasing gastric emptying

A

taking meds on an empty stomach
taking meds with cold water
lying down on the right side
high osmolality feeding (i.e. feeding tube)
taking a pro kinetic drug (increases GI motility)

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48
Q

decreasing gastric emptying

A

high fat meal
heavy exercise
lying down on the left side
taking drug that inhibits vagus nerve (i.e. anticholinergics)

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49
Q

enteric coating

A

special coating that prevents drugs from dissolving in the acidic environment of the stomach
coating will dissolve once in the intestine

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50
Q

bioavailability

A

fraction of drug that reaches systemic circulation unchanged
influenced by drug formulation, route of administration and degree of metabolism

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51
Q

bioavailability by drug formulation, lowest to highest

A 
time release capsules
enteric coated
compressed tablets 
capsules 
granules 
chewable (no disintegration) 
suspension 
syrup (no disintegration or dissolution)
aqueous solution
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52
Q

sublingual drug delivery

A

put under tongue, dissolves and is absorbed across oral mucosa
venous drainage from oral mucosa is to the superior vena cava to heart

avoid first pass metabolism
need to be lipophilic and uncharged

is especially convenient for drugs that act on the heart

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53
Q

transdermal drug delivery

A

need to be lipophilic enough to penetrate epidermis
also need to be relatively hydrophilic to dissolve in ECF
<600 Da

usually sprays, ointments, patches etc
provide constant plasma levels (i.e. minimal troughs and peaks)

tolerance may develop unless there is a drug free period (i.e. take patch off for 6-10 hours a day)

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54
Q

what affects transdermal drug absorption

A

thickness of skin
hydration
number of hair follicles (give a way to bypass the epidermis barrier)
application area
integrity of the barrier (i.e. psoriasis, burned skin etc increases absorption)

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55
Q

rectal drug absorption

A

useful when unconscious or vomiting
approx 50% bypasses the liver

given as a suppository which dissolves, crosses the rectal mucosa into the blood

disadvantages include incomplete absorption and some drugs may irritate the rectal mucosa

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56
Q

IV drug absorption

A

directly into peripheral vein, usually back of the hand or median cubital vein at the elbow (any visible can be used though)

IV bolus or drip
if it is a drip, usually diluted in a vehicle i.e. saline

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57
Q

advantages of IV drug absorption

A

no barriers, 100% bioavailability
precise control of dosage and duration of action
can administer poorly soluble drugs that need to be diluted in a large volume
can inject drugs that are irritants slowly so they are diluted in blood

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58
Q

disadvantages of IV drug absorption

A 
expensive
invasive
inconvenient 
drug cannot be removed once injected 
risk of infection and fluid overload 
risk of injecting wrong formulation i.e. giving IM by IV
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59
Q

subcutaneous drug absorption

A

under skin into subcutaneous tissue
only barrier to absorption is the capillary wall
cannot inject irritants - will cause pain and/or tissue sloughing
primary determinants of rate of absorption are blood flow and water solubility (need to be water soluble to dissolve in ECF)

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60
Q

intramuscular drug absorption

A

injected into muscle tissue
absorption determined by ability of drug to pass through fenestrations in capillary wall
primary determinants of rate of absorption are blood flow and water solubility

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61
Q

advantages of IM

A

can be used for poorly soluble drugs

can administer depot preparations

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62
Q

disadvantages of IM

A

pain/discomfort

can cause local tissue and/or nerve damage if not done properly

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63
Q

how does blood flow affect IM drug absorption

A

deltoid > vastus lateralis > gluteal

exercises increases

heart failure, severe hypotension, hypothermia decrease

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64
Q

pulmonary drug absorption

A

gaseous and volatile drugs can be inhaled and absorbed through pulmonary epithelium

very rapid absorption bc there is a large surface area

good for pulmonary disease drugs i.e. for asthma bc they are delivered to site of action

often used for general anaesthetics

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65
Q

what drugs distribute to the interstitial space?

A

low MW, water soluble

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66
Q

what drugs distribute to the plasma?

A

strongly bound to proteins, high MW

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67
Q

what drugs distribute to adipose tissue?

A

lipid soluble

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68
Q

where else do some drug distribute?

A

muscle
bone - absorb onto the crystal surface and eventually get incorporated in, can be a reservoir for slow release of some drugs

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69
Q

what determines drug distribution? how does this affect blood concentration?

A

blood flow to tissues
ability to move out of capillaries
ability to move into cells

more distributes = less in the blood

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70
Q

blood flow and drug distribution

A

well perfused i.e. liver, kidney, brain = rapid distribution

lower blood flow i.e. skin, fat, bone = slow

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71
Q

examples of altered blood flow

A

neonates have limited blood flow
heart failure or shock
solid tumors have low regional blood flow (decreases towards middle)
abscesses have no blood supply (need to drain)

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72
Q

P-glycoprotein

A

efflux transporter
protective
facilitates drug excretion and protects body from exposure to drugs and other toxins
active (needs ATP), against concentration gradient

in heptocytes on the bile canicular membrane - excrete in bile
in enterocytes on apical side - prevent absorption into blood
in proximal tubule cells on luminal side - excretion
in neuronal cells on blood vessel side - keep drugs away from brain

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73
Q

albumin

A

high affinity for lipophilic and anionic (weak acids)

malnutrition, trauma, aging, liver and kidney disease decrease plasma albumin
this increases free drug concentration, can cause toxicity

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74
Q

alpha 1 acid glycoprotein

A

primarily binds cationic (weak bases) and hydrophilic drugs

aging, trauma, and hepatic inflammation (ie hepatitis) increase plasma alpha 1 acid glycoprotein
decreases free drug concentration, can lead to ineffective therapy

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75
Q

Vd for drugs with low, intermediate and high Vds

A

low = 0.057 L/kg
intermediate -= 0.2 L/kg
high = >0.2 L/kg

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76
Q

volume of distribution

A

apparent volume that a drug distributes into

Vd = D/C (total amount/plasma concentration)

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77
Q

plasma

A

4 L

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78
Q

interstitial fluid

A

10 L

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79
Q

intracellular fluid

A

28 L

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80
Q

drugs with small Vd

A

remain in the capillaries
highly protein bound
large molecular weight (can’t get through fenestrations)

can’t leave the plasma
Vd is about 0.057L/kg

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81
Q

drugs with intermediate Vd

A 
low molecular weight (can go through fenestrations) 
very hydrophilic (can't go through PM) 
intermediate protein binding

can leave plasma and enter interstitial fluid, but can’t go into cells

Vd is about 0.2 L/kg

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82
Q

drugs with large Vd

A

low molecular weight
lipophilic
minimal protein binding

can leave vascular space and interstitial fluid and go into fat, bone, muscle etc (i.e. into intracellular fluid)

Vd >0.2 L/kg

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83
Q

what happens if small Vd drug is displaced from proteins

A

does NOT distribute to tissue, stays in plasma so free drug concentration increases

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84
Q

what happens if large Vd drug is displaced from proteins

A

distributes into tissues, total plasma drug concentration decreases and apparent Vd increases further

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85
Q

how does body composition affect drug distribution?

A

elderly ppl have increased fat mass

  • > drugs that distribute into fat will have larger Vd in elderly or obese ppl
  • > drugs that distribute into muscle will have lower Vd in elderly (less muscle mass)
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86
Q

what is metabolism and where does it occur

A

enzyme-mediated alteration of a drug’s structure
also called biotransformation

liver- primary site 
intestine - enterocytes can metabolize drugs 
stomach - alcohol metabolism 
kidney 
intestinal bacteria
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87
Q

5 possible therapeutic consequences of drug metabolism

A

1) increase water solubility to promote excretion
2) inactivate drugs
3) increase drug effectiveness
4) activate prodrugs
5) increase drug toxicity

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88
Q

first order kinetics

A

most drugs
concentration of drug is much lower than the metabolic capacity of body (i.e. less drug than enzymes)

drug metabolism is directly proportional to the concentration of free drug

constant fraction metabolized per unit time

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89
Q

zero order kinetics

A

ie ethanol

plasma drug concentration is much higher than metabolic capacity of the body
drug metabolism is constant over time i.e. constant amount is metabolized per unit time

metabolism is independent of drug concentration

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90
Q

where can drugs taken orally undergo first pass metabolism and what is the result

A

hepatocytes in liver
enterocytes in intestine
stomach
intestinal bacteria

result is decreased parent drug in the systemic circulation

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91
Q

extraction ratio

A

depends on how much metabolism occurs on the first pass through the liver
high ER = lots of first pass metabolism

can greatly determine bioavailability

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92
Q

high ER drugs

A

low oral bioavailability (1-20%
PO doses higher than IV doses to compensate
small changes in hepatic enzyme activity produce large changes in bioavailability
very susceptible to drug-drug interactions

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93
Q

low ER drugs

A

high oral bioavailability (>80%)
PO doses similar to IV doses
small changes in hepatic enzyme have little effect on bioavailability
not very susceptible to drug-drug interactions
may pass through liver via systemic circulation multiple times before completely metabolized

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94
Q

phase I drug metabolism

A

lipophilic to more polar by introducing or unmasking polar functional groups (i.e. OH, NH2)

involved oxidation, reduction, hydrolysis

CYP enzymes, esterases and dehydrogenases

metabolites can be more active, less active or equally active as parent drug

occurs in SER

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95
Q

phase II drug metabolism

A

increase polarity of lipophilic by conjugation of large water soluble molecules to drug
ie glucuronic acid, sulphate, acetate, amino acids

metabolites are less active than the parent drug

** exception - morphine 6-glucuronide is more potent analgesic than morphine**

occurs in cytosol, except glucuronidation which is in SER

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96
Q

CYP enzymes

A

predominant phase I drug metabolizing enzymes
mostly hepatic, in SER

oxidize drugs by inserting one O atom into the drug molecule, produces water as a byproduct

12 families, 3 does most drug metabolism
(naming goes family, subfamily, isozyme)

malnutrition can decrease CYP activity as they requires dietary protein, iron, folic acid and zinc

CYP3A4 metabolizes 50% of currently marketed drugs

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97
Q

5 types of phase II drug metabolizing enzymes

A 
UGTs
SULTs
GSTs 
NATs
TPMT
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98
Q

UGTs

A

UDP-glucuronosyltransferases
only phase II found in SER
catalyze transfer of a glucuronic acid to a drug
once glucuronidated = more polar for easier excretion

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99
Q

SULTs

A 
sulfotransferases
phase II
cytosolic 
transfer sulfate to hydroxyl of a drug 
more polar, easier excretion
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100
Q

GSTs

A

glutathione S transferases
phase II
cytosolic
transfer glutathione to drug (glutathione is an intracellular anti-oxidant)
putting glutathione onto a reactive drug renders the metabolite less toxic

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101
Q

NATs

A 
N-acetyltransferases 
phase II 
cytosolic 
transfer acetyl from acetyl CoA to drug 
subject to polymorphisms which causes large variability in drug response
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102
Q

TPMT

A

thiopurine methyltransferase
phase II
cytosolic
transfer methyl from S-adenosylmethionine to a drug
subject to SNPs, rare but have dramatic effect

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103
Q

4 factors that affect drug metabolism

A

age
drug interactions i.e. enzyme inducers and inhibitors
disease state
SNPs

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104
Q

age and drug metabolism

A

infants have almost no CYP activity
1 year until reasonable, 2 until adult levels

elderly also have decreased levels

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105
Q

diseases that decrease CYP activity

A

liver disease
kidney disease
inflammatory diseases
infection

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106
Q

CYP2C9

A

metabolizes anticoagulant warfarin
SNPs can decrease activity
patients require lower dose of warfarin , if not get extensive bleeding

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107
Q

CYP2D6

A 
metabolizes codeine to morphine = more potent analgesic 
SNPs give 4 phenotypes 
ultra-rapid metabolizer (multiple copies) 
extensive metabolizer (normal)
intermediate metabolizer 
poor metabolizer (almost no metabolic activity)
108
Q

UGT1A1

A

glucuronidates SN-38 (anti-cancer drug, active metabolite of irinotecan)
SNPs decrease its activity
increased risk of diarrhea and dose limiting bone marrow suppression (potentially fatal)

109
Q

NAT2

A 
acetylates isoniazid (tuberculosis drug), caffeine and various cancer causing chemicals 
either rapid or slow acetylator

slow are more susceptible to isoniazid toxicity (neuropathy, hepatotoxicity) than rapid acetylators are
also have higher risk of developing some cancers

110
Q

methotrexate side effects

A 
azotemia 
infection 
inflammation of gums
anemia (decreased platelets) 
prone to infections 
fever 
loss of appetite
111
Q

mercaptopurine side effects

A

vomiting
diarrhea
loss of appetite
easy bruising and bleeding

112
Q

methotrexate pharmacokinetics

A 
hepatic and intracellular metabolism
poorly crosses placenta and BBB bc its ionized 
~50% protein bound 
orally readily absorbed 
high bioavailability 
long 1/2 life
113
Q

mercaptopurine pharmacokinetics

A 
incompletely absorbed when oral 
metabolized in liver 
excreted in urine 
pro-drug - active form is thioguanine nucleotides 
inactivated by TPMT
114
Q

what happens if you have a TPMT SNP and take mercaptopurine?

A

decreased activity of TPMT, get build up of toxic metabolites

115
Q

how to diagnose TPMT SNPs and what to do to mercaptopurine doses

A

genotype or phenotype
hetero = 50% reduction in dose
homo = 90% reduction

116
Q

sites of drug excretion

A

kidney
bile
lung
breast milk

117
Q

what happens if your kidneys aren’t functioning properly

A

get prolonged action and intensity of drug effects

118
Q

what does the nephron control

A

water, electrolyte and drug excretion

blood volume, blood pressure, blood pH and solute excretion

119
Q

factors affecting renal drug excretion

A

glomerular filtration
tubular secretion
tubular reabsorption

120
Q

what percentage of renal plasma flow is GFR?

A

~20%

121
Q

do lipid solubility and pH affect glomerular filtration of drugs?

A

no

122
Q

what drugs are filtered at the glomerulus?

A

only free (i.e. not protein-bound)

123
Q

tubular secretion

A

drugs can be secreted from the blood into the tubule in the proximal tubule

there are 2 systems, one for weak acids, one for weak bases

124
Q

tubular reabsorption

A

water is reabsorbed in loop of henle so drugs become more concentrated

in distal tubule drug concentration often exceeds that of the blood surrounding

if uncharged or lipid soluble can be reabsorbed

125
Q

age and renal function

A

decreases as we age

126
Q

characteristics of drugs eliminated in bile

A

MW > 300 Da
amphipathic (ie lipophilic and polar groups)
glucuronidated

127
Q

biliary drug excretion

A

transporters on canalicular membrane of hepatocytes transport drugs and metabolites into the bile

P-gp transports amphipathic ones and MRP2 does glucuronidated metabolites

get released into intestine during digestion then excreted in fees or recycled

128
Q

enterohepatic recycling

A

intestinal bacteria can cleave conjugate metabolites leaving the original drug

can then be reabsorbed through the intestine

drugs that do this persist in the body for substantially longer periods

129
Q

pulmonary drug excretion

A

gaseous or highly volatile i.e. general anesthetics

not heavily reliant on drug metabolism

affected by: rate of respiration, cardiac output, solubility of drug in blood
i.e. high blood solubility = low pulmonary excretion

130
Q

drug excretion in breast milk

A

> 90% of women take a drug in the first week postpartum

low protein binding
low molecular weight
high lipophilicity

transported by breast cancer resistance protein (BCRP)

breast milk has a lower pH and higher lipid content than plasma

so lipophilic will go in
substrates for BCRP will go in
weak base unionized will go in and then become ionized and trapped

131
Q

name 3 lesser routes of drug excretion

A

hair - drugs can be excreted into hair follicles, can use to determine how long a person has been exposed (hair grows 1 cm/month)

saliva - usually if excreted in saliva swallowed and then either get intestinal absorption or fecal excretion

sweat - mostly washed away, some dermal reabsorption can occur

132
Q

clinical pharmacokinetics

A

want a quantitative relationship between drug dose and effect and a framework to interpret measures of drug concentrations in biological fluids to benefit patient in drug therapy

133
Q

clearance

A

efficiency of irreversible drug elimination from the body
ml/min or L/hr
can be by route of elimination or total
can be used to determine the dosage rate required to maintain a certain plasma concentration

dosing rate = plasma concentration * clearance

134
Q

elimination half life

A

measure of the rate of removal of the drug from the body

T1/2 = 0.693*Vd/Cl

so larger Vd gives longer half life

135
Q

why are drugs measured in plasma usually?

A

relatively non-invasive

most drugs have good correlation between plasma concentration and therapeutic and toxic effects

note: measure total plasma [ ] not just free (still a good measure though)

136
Q

oral drug concentration time curve

A

at first absorption is greater than elimination so plasma concentrations increase

there is a peak called Cmax where the absorption and elimination are equal

then elimination rate is greater than absorption so plasma concentrations decrease

137
Q

MEC

A

minimum effective concentration ie minimum concentration needed for therapeutic effect

138
Q

duration

A

length of time [drug] is above MEC

139
Q

therapeutic range

A

above MEC but below toxic

width is an index for the safety of the drug

narrow therapeutic range = therapeutic drug monitoring, usually trough sampling

140
Q

onset of action

A

oral drugs usually have a lag period
rate and extent of absorption affect it
onset of action determines how soon a drug’s effect will occur

141
Q

continuous IV infusion

A

constant rate of drug entry
no absorption bc it goes directly into systemic circulation
plasma concentration rises until infusion equals elimination then have steady state until infusion is stopped
then plasma concentrations decrease

142
Q

IV bolus

A

drug is rapidly injected into the blood, quickly distributes and then is eliminated over time

usually first order kinetics for elimination i.e. rate of elimination is dependent on the blood concentration

143
Q

repeated dosing

A

accumulation occurs until a plateau is reached - steady state
want steady state to be within therapeutic range (concentration fluctuates for oral or IV bolus drugs)

144
Q

steady state

A

when the peak and trough concentrations are the same between doses

if the same dose is given it takes about 5 half lives to get to steady state

if the dose of the drug is constant the time to reach steady state is independent of the size of the dose

145
Q

how can you reduce fluctuations in plasma drug concentration?

A

continuous IV infusion
depot preparations
change the dosing interval i.e. multiple smaller doses

146
Q

loading dose

A

drugs with long half life will take a while to get to steady state so can give a large loading dose first and then smaller maintenance doses

loading dose = target [plasma]*Vd

(assuming 100% bioavailability)

147
Q

declining from steady state

A

depends on the drug’s half life

time is independent of the dose

5 half lives for most (97%)
9 half lives for every molecule

148
Q

pharacodynamics

A

what the drug does to the body i.e. biochemical and physiological effects of drugs

149
Q

dose response curve

A

increasing dose increases response
monotonic
not linear, usually use semi-logarithmic plot

150
Q

phases of semi-logarithmic dose response curve

A

phase 1 = doses are too low to elicit a clinically relevant response
phase 2 = response is graded and nearly linear
phase 3 = larger doses do not lead to greater response (may cause toxicity) i.e. has plateaued

151
Q

efficacy

A

how effective a drug is at a given dose

max efficacy is the top of dose response curve

152
Q

potency

A

amount of drug required to elicit a pharmacological response

can’t compare unless the drugs have the same therapeutic effect

ED50 used to assess (the dose required to produce a half-maximal response)
low ED50 = more potent

153
Q

ED50

A

dose required to produce a half maximal response
OR
dose that elicits response in 50% of patients

154
Q

give an example of a drug that doesn’t act on a cellular target

A

antacids - neutralize stomach acid

155
Q

what is a receptor and what are the 4 most important types?

A

a protein that a drug binds to and produces a measurable response

ligand gated channels
g protein coupled receptors
enzyme linked receptors
intracellular receptors

156
Q

ligand gated channels

A

ligands control the opening and closing of ion channels

duration of milliseconds

many neurotransmitters bind these channels
ie GABA binds to GABA receptor and causes channel to open allowing Cl- to flow into the cell
benzodiazepene drugs also bind to GABA receptors
activation of this receptor causes sedation and muscle relaxation

157
Q

GPCRs

A

norepinephrine, serotonin and histamine all mediate their effects through GPCRs

response lasts from seconds to minutes

158
Q

enzyme-linked receptors

A

response are within seconds

ie insulin receptor, get phosphorylation then activation of intracellular effector which then causes translocation of GLUT to cell membrane

get increased cellular glucose uptake and utilization

159
Q

intracellular receptors

A

transcription factors
ligands diffused or are transported across membrane, bind and then the complex goes into the nucleus and binds DNA

response is hours to days

ligands are usually highly lipid soluble

160
Q

drug receptor selectivity

A

lock and key hypothesis
lock is receptor, drug is key, needs to be the right size and shape

selective drugs will only bind to one receptor and will be less likely to produce side effects

side effects can still occur if only binding to one receptor though because that receptor may be located in multiple tissues even though you only want to target one

161
Q

simple occupancy theory

A

intensity of drug’s response is proportional to # of receptors occupied
maximal response occurs when all receptors are occupied

implies that 2 drugs on the same receptor should have the same effect (obviously not true)

162
Q

modified occupancy theory

A

intensity of response is proportional to # of receptors occupied
2 drugs occupying the same receptor can have different binding strengths (affinities)
2 drugs occupying the same receptor can have different intrinsic activities

163
Q

what is the primary determinant of a drug’s potency?

A

its affinity for the receptor

164
Q

what helps determine a drugs efficacy?

A

intrinsic activity

165
Q

agonists

A

have both affinity and intrinsic activity
agonists can cause increased or decreased physiological response
some can bind to different receptors depending on the dose

166
Q

dopamine and dose

A

low dose = dopamine receptors, causes renal artery vasodilation, increased renal blood flow and urine output

intermediate dose = B1 adrenergic receptors, increased cardiac output

high dose = alpha adrenergic receptors, renal artery vasoconstriction, decreased renal blood flow and urine output

167
Q

antagonists

A

have affinity but no intrinsic activity

pharmacological effet is dependent on the presence of an agonist

168
Q

beta blockers

A

block binding of endogenous epinephrine to beta 1 receptors in the heart

slows beating of the heart

169
Q

antihistamines

A

block histamine binding to H1 histamine receptors in the nasal mucosa

prevents symptoms of allergy

170
Q

gastric acid reducers

A

block histamine binding to H2 histamine receptors in the gut

decreases gastric acid secretion

171
Q

opioid receptor blockers

A

block opioids binding to opiate receptors

useful for overdose

172
Q

competitive antagonists

A

same site as agonist, reversible

if antagonist and agonist have equal affinities, higher concentration wins

173
Q

irreversible antagonists

A

same site, irreversible
decreases maximal response the agonist may have
effects last until the receptor is replaced

174
Q

allosteric antagonists

A

different site
reversible, but not competitive
decrease maximal response

175
Q

partial agonist

A

act as agonists with minimal or partial activity or as antagonists

176
Q

3 types of drug tolerance

A

desensitization
metabolic tolerance
tachyphylaxis

177
Q

desensitization

A

receptors are internalized or destroyed

decreased receptors on cell surface, decreased effects of drug

178
Q

metabolic tolerance

A

induction of drug metabolizing enzymes

can cause decrease in plasma [ ] of drug

179
Q

tachyphylaxis

A

rapid decrease in response to a drug

may need drug free periods to prevent (i.e. for transdermal routes especially)

180
Q

receptor upregulation

A

continuous exposure to an antagonist has opposite effect to tolerance
cell becomes hypersensitive or supersensitive
synthesizes more receptors and puts them on the surface
increased response

181
Q

what influences a patients response to medication?

A

genetics, environment and disease state

182
Q

what phase of clinical trials establish dose response information over a range of doses?

A

phase II
can evaluate the number of ppl who experience an endpoint at each dose
ED50 = average effective dose i.e. dose required to produce response in 50% of the population

183
Q

TD50

A

average toxic dose

dose in which 50% of animals experience drug toxicity

184
Q

LD50

A

average lethal dose

dose in which 50% of animals die

185
Q

what are LD50 and TD50 expressed in?

A

mg drug/kg body weight

186
Q

therapeutic index

A

indicator of a drug’s safety
is the TD50/ED50 or LD50/ED50
high TI = safe

187
Q

body weight and composition and intermittent variation in response

A

adjust dose to body weight of patient to compensate for size differences
also adjust drugs by body surface area bc fat distribution can change drug distribution

188
Q

normal body surface area for an adult

A

1.73m^2

189
Q

known differences in drug metabolism between genders

A

alcohol metabolism is slower in females
certain opioids are more effective in women
certain drugs for irregular heart beat prolong the QT interval of women

190
Q

why is the effect of gender on a lot of drugs not known?

A

because until 1997 health canada and the US FDA didn’t put pressure on drug companies to include women in trials of new drugs

191
Q

give an example of race known to effect drug metabolism

A

rosuvastatin a cholesterol lowering drug has 2-3 times higher concentrations in asian patients compared to caucasians

192
Q

how does kidney disease affect drug metabolism?

A

drug excretion is decreased, which causes the half life of renally excreted drugs to increase

hepatic and intestinal drug metabolism are also decreased

net effect is increased oral bioavailability and decreased excretion

193
Q

how does liver disease affect drug metabolism?

A

decreased hepatic metabolism in diseases such as cirrhosis and hepatitis

drugs that are extensively metabolized can have significantly increased half lives

194
Q

examples of environmental exposures that affect drug metabolism

A

cigarette smoke induces some drug metabolizing enzymes
alcohol can exacerbate toxicity of some other drugs (i.e. in liver)
exercise improves the actions of insulin
some pesticides can induce CYPs

195
Q

adverse drug reactions

A

unintended and undesired responses from drugs

7.5% of hospital admissions in canada a year

196
Q

7 types of adverse drug reactions

A 
side effects 
drug toxicity 
allergic reaction 
idiosyncratic reaction 
carcinogenic effects 
mutagenic effects 
teratogenic effects
197
Q

side effects

A

are expected
occur at normal therapeutic doses and are unavoidable
often due to poor selectivity

198
Q

example of side effects

A

antihistamines block H1 receptors to prevent allergy symptoms, but they also cause drowsiness, dry mouth and urinary retention because they bind OTHER receptors in the brain

199
Q

drug toxicity and an example

A

any severe adverse drug event
often due to overdose
often extensions of the therapeutic effect

i.e. take too much insulin, become hypoglycemic

200
Q

allergic reactions

A

mediated by immune system and require prior sensitization
mast cells release chemicals such as histamine
can vary from itching and rash to life threatening anaphylaxis (bronchospasm, edam and severe hypotension)
intensity is independent of dosage
10% of ADRs are due to allergic reaction
trunk is most common area, then arms and legs and neck, then feet and hands and face is last

201
Q

examples of drugs that commonly cause allergic reactions

A

pencillins
sulfonamides (antibiotic)
NSAIDs

202
Q

idiosyncratic reactions

A

occur rarely and unpredictably in the population

SNPs in metabolizing enzymes and transport proteins probably account for most

203
Q

what are some examples of idiosyncratic reactions that can be tested for

A

warfarin and 6-mercaptopurine

CYP2C9 and TPMT respectively

204
Q

OATP1B1 SNP

A

uptake transporter in the liver
15% of asian and caucasian patients have SNP that decreases function leading to increased plasma drug concentrations
implicated in myopathy (muscle toxicity) in patients taking statins

205
Q

carcinogenic effects example

A 
cause cancer 
ie DES (diethylstilbestrol) used to be used to prevent spontaneous abortion but was found to cause vaginal or uterine cancer in female babies later in life
206
Q

mutagenic effects

A

change DNA
can be mutagenic but not carcinogenic or teratogenic
tested as mutagens using the Ames test, which evaluates the ability of the compound to cause a mutation in specialized strains of bacteria

207
Q

teratogenic effects

A

produce birth defects or impair fertility
can be physical, behavioural or metabolic
less than 1% are caused by drugs
sensitivity to teratogens changes during development

gross malformations are usually during 1st trimester
2nd and 3rd usually affect function

CNS highly sensitive throughout most of pregnancy, most other systems are only highly sensitive during the 1st trimester

208
Q

when is transfer of drugs across the placenta greatest?

A

3rd trimester because SA has increased and the placental-fetal barrier is thinner

209
Q

who classified teratogens?

A

US FDA

210
Q

class A pregnancy risk

A

well controlled human studies have failed to show risk to fetus during 1st trimester
no evidence of harm later in pregnancy

211
Q

class B pregnancy risk

A

animal reproduction studies have failed to show harm to the fetus and there are no well controlled studies in humans
OR
animal studies have shown an adverse effect but well controlled studies in humans have fail to show any harm

212
Q

class C pregnancy risk

A

animal studies have shown harm to fetus but there are no well-controlled studies in humans
potential benefits outweigh the potential risk

213
Q

class D pregnancy risk

A

clear risk to fetus from studies in humans

potential benefits outweigh potential risk

214
Q

class X pregnancy risk

A

studies in animals and humans clearly demonstrate risk to the fetus
risk using clearly outweighs the benefits
should never be used in pregnancy women
i.e. known teratogen

215
Q

where does organ-specific toxicity occur? where is it most common?

A

kidney, lung, heart, liver, muscle, inner ear

most common are liver and heart

216
Q

hepatotoxicity

A

most common reason drugs are removed from the market
some drugs once metabolized in the liver, metabolites can cause liver injury
signs are jaundice, dark urine, light-coloured stool, nausea and vomiting
AST and ALT are increased in the blood when liver is damaged

drugs known to be hepatic should be used with caution in patients at high risk for hepatic disease i.e. alcoholics, ppl with hepatic disease already and ppl taking other medications that cause hepatotoxicity

217
Q

QT interval prolongation

A

major risk factor for development of tornadoes de points, a life threatening form of ventricular arrhythmia (ventricles contract and then take a while to relax and fill with blood)

more than 100 drugs known to cause it have been removed from the market

drugs that prolong QT interval should be used with caution in patients that are predisposed to arrhythmias

218
Q

who is predisposed to QT prolongation

A 
elderly
ppl with bradycardia 
heart failure 
low potassium 
congenital QT prolongation 
women (their normal one is longer)
219
Q

P wave

A

atrial depolarization

220
Q

QRS complex

A

rapid depolarization of right and left ventricles

221
Q

U wave

A

not always seen

222
Q

T wave

A

repolarization of the ventricles

223
Q

QT interval

A

time required for the ventricles to repolarize

224
Q

opiate withdrawal

A

normally used for analgesia

anorexia
irritability 
nausea 
vomiting 
weakness
muscle spasm
225
Q

benzodiazepene withdrawal

A

anxiety med

anxiety 
insomnia 
sweating 
tremors 
panic 
delirium 
paranoia 
convulsions
226
Q

beta blocker withdrawal

A

med for hypertension, decrease heart rate

rebound hypertension
chest pain
MI
arrhythmia

227
Q

most common cause of adverse drug reactions

A

medication errors

228
Q

iatrogenic error

A

caused by a health care professional

229
Q

5 categories of medication errors

A

prescribing - prescribe the wrong drug, dose or route

dispensing - pharmacist screws up

administration - health care professional administers wrong dose, drug or route

patient education - patient doesn’t understand instructions

patient - understands instructions but doesn’t follow i.e. misses a dose

230
Q

what causes drug naming errors?

A

poor handwriting, illiteracy, strong accents

~15% of all medication errors

231
Q

IU abbreviation

A

means international unit, ppl might think it says IV or 10

say units instead

232
Q

q.d abbreviation

A

everyday

233
Q

q.o.d abbreviation

A

every other day

234
Q

trailing 0 after decimal point i.e. 1.0 mg

A

might think its 10 so write 1 mg

235
Q

leading zero missing i.e. .5

A

might think its 5 so write 0.5 mg

236
Q

MgSO4 abbreviation

A

magnesium sulfate, might think its morphine sulphate so write the name

237
Q

MS or MSO4 abbreviations

A

morphine sulfate, might think its magnesium sulphate so write the whole name

238
Q

what are the most common drug-drug interactions?

A

pharmacokinetic ones (ADME)

239
Q

when drugs interact what are the possible consequences?

A

increased effects
decreased effects
new effect

240
Q

4 types of drug interactions

A 
direct physical interaction 
pharmacokinetic interaction (ADME)
pharmacodynamic interaction (receptor binding) 
combined toxicity (ie toxic to same organ)
241
Q

direct physical interaction of drugs

A

most commonly when two or more IV solutions are mixed together and form a precipitate

diazepam (benzodiazepine) should never be mixed with anything else

can occur outside or inside the patient
i.e. if you give sodium bicarbonate and then calcium gluconate a precipitate can form in the blood

242
Q

how do drug interactions alter absorption?

A 
altered pH 
chelation/binding
altered blood flow
gut motility 
vomiting 
drugs that kill intestinal bacteria
243
Q

explain how drugs that alter pH can cause drug interactions that have to do with absorption

A

antacids increase gastric pH, which increases absorption of weak bases and decreases absorption of weak acids

also can cause enteric coated drugs to dissolve in the stomach - can cause stomach issues or destroy the drug

244
Q

explain how chelation/bind can affect drug absorption (interaction)

A

some drugs will bind to each other in the intestine and form insoluble complexes that can’t be absorbed

ie bile acid sequestrates are supposed to bind cholestyramine and this complex will bind the drug digoxin, which decreases its absorption

245
Q

how do drugs that alter blood flow affect absorption (interaction)

A

drugs that decrease blood flow decrease absorption of drugs

246
Q

how do drugs that alter gut motility affect absorption (interaction)

A

laxatives increase gut motility which decreases drug absorption because the drug is in contact with the microvilli for less time

opiates decrease gut motility which increases drug absorption

247
Q

how do drugs that induce vomiting affect the absorption of other drugs?

A

they will decrease the absorption of other drugs
if vomiting occurs 20-30 minutes after taking medication it is likely that absorption is incomplete
need to determine if another dose should be given

if drug has already entered the intestine when vomiting occurs, giving more could cause toxicity

248
Q

describe how drugs that kill intestinal bacteria affect the absorption of other drugs

A

intestinal bacteria deconjugate phase II drug metabolites so if they are killed there is less absorption during enterohepatic recycling
results in decreased plasma concentration

an example is oral contraceptives

249
Q

how do drug interactions alter distribution?

A

altering pH

protein binding

250
Q

describe how drugs that alter pH can alter drug distribution (interaction)

A

a drug that changes extracellular pH can influence ionization of other drugs
sodium bicarbonate increases extracellular pH, ammonium chloride decreases it

i.e. if someone overdoses on aspirin, a weak acid, you can increase the extracellular pH with sodium bicarbonate which will draw aspirin outside the cell and trap it there (can then be excreted in urine)

251
Q

describe how drugs that alter protein binding can alter drug distribution (interaction)

A

if 2 drugs bind to the same site of plasma proteins, co-administration will lead to competition
lower affinity drug will become free
can cause increased therapeutic effect, toxicity or excretion

252
Q

where do most metabolism-involved drug interactions occur?

A

in the liver or intestine

253
Q

examples of CYP inducers

A

cigarette/ marijuana smoke (1 joint = 5-10 cigarettes)
rifampin and St John’s Wart - CYP34A
phenobarbital - many CYPs
barbecued food - CYP1A2
alcohol - CYP2E1 (severe alcoholism causing cirrhosis decreases CYP activity though)

254
Q

examples of CYP inhibitors

A

many antibiotics and antifungals, HIV protease, grapefruit juice - CYP3A4
fluvoxamine - CYP1A2
selective serotonin reuptake inhibitors - CYP2D6

255
Q

how do drug interactions alter excretion?

A

altered blood flow
altered pH
tubular secretion

256
Q

how do drugs that alter blood flow alter excretion (interaction)

A

drugs that decrease renal blood flow, decrease glomerular filtration
this gives decreased renal excretion and increased plasma concentrations

NSAIDs cause renal vasoconstriction (decrease blood flow)
beta blockers decrease CO, which indirectly decreases renal blood flow also

257
Q

how do drugs that alter pH alter excretion (interaction)

A

drugs that change the pH of renal tubular filtrate can alter excretion
ie overdose on amphetamines, a weak base, can acidify filtrate with ammonium chloride to trap in tubule and prevent reabsorption (i.e. increase excretion)

258
Q

how do drugs that alter tubular secretion alter excretion (interaction)

A

if one drug blocks a transporter that secretes drugs into the tubule lumen then a drug that uses that transporter will have increased plasma concentration (and decreased renal excretion)

ie probenecid (for gout) blocks the transporter that secretes penicillin 
get increased penicillin in the blood
259
Q

two main types of pharmacodynamic drug interactions

A

same receptor

separate sites

260
Q

drug interactions at the same receptor

A

usually antagonist blocking agonist
can cause decreased therapeutic action or can decrease toxicity in overdose situations

ie morphine overdose, give naloxone and compete out morphine to reverse symptoms

261
Q

drug interactions at different receptors

A

drugs with different mechanisms can produce an interaction if they produce the same physiological response

ie diazepam (anxiolytic drug) and morphine are both CNS depressants, but bind to different receptors (morphine on opiod, diazepam on benzodiazepine) 
take together, get enhanced CNS depression
262
Q

combined toxicity

A

ie acetaminophen and alcohol, both are hepatoxic

same with isoniazid and rifampin, which are used to treat tuberculosis
need to take both though, so have to monitor liver function

263
Q

examples of food drug interactions

A

grapefruit juice inhibits CYP3A4

monoamine oxidase inhibitors (depression) inhibit the breakdown of tyramine
tyramine is found in aged cheese, yeast, red wine, sauerkraut and cured meat
need to avoid while taking MAO inhibitors
tyramine causes increased release of NE from peripheral nerves and results in a potentially fatal hypertensive crisis

264
Q

symptoms of hypertensive crisis

A 
tachycardia
sever hypertension 
headache 
nausea 
vomiting
265
Q

St John’s Wart

A

treatment for depression
can interact with tacrolimus because it induces CYP3A4 and P-glycoprotein
induces CYP3A4 through pregnant X receptor (transcription factor)
this leads to metabolism of tacrolimus and therefore decreased concentrations of it (no longer effective)

Pharm 2060 (2 decks)

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