week 5

Question 1

Interpatient Variability in Response

Answer 1

 In an ideal world the response to medications would be the same for every patient.

 Unfortunately in reality, response to medications is quite variable between patients.

 Because response to medications is variable, every patient’s response must be evaluated to ensure an adequate therapeutic response.

 The response to medication is influenced by genetics, disease state, and the environment.

Question 2

Determining Interpatient Variability

Answer 2

Clinical trials are an important first step in determining interpatient variability to drug response

To determine interpatient variability in response to medications, we first set an endpoint. For example, if we were talking about an analgesic drug, the
endpoint would be pain relief.

From phase II clinical trial data we can evaluate the number of patients that experience pain relief from each dose of the drug.

 This data is plotted on a frequency distribution curve.
 The average effective dose (ED50) is at the peak of
the frequency distribution curve. The ED50 is the
dose required to produce a response in 50% of the
population.
 The ED50 is often used as the initial dose for therapy

Question 3

clinical trials phase I

Answer 3

• 20-100 healthy volunteers
• evaluation of pharmacokinetics and pharmacodynamics
• animal studies guide dosing

Question 4

clinical trials phase II

Answer 4

• 300-500 patients w disorder
• short term trial to determine efficacy and side effects
• dose-response is determined
• Phase II clinical trials establish dose response information over a range of doses.

Question 5

clinical trails phase III

Answer 5

• 500 - 5000 patients w target disorder

- efficacy verified and long term side effects evaluated

Question 6

clinical trials phase IV

Answer 6

• post-marketing surveillance

Question 7

dosing implications

Answer 7

If all patients are given the ED50 as a starting dose, some patients will have more drug than they need and others will not have enough as seen in the graph below.

 The initial dose of a drug is a starting point, however many patients will require dose adjustments to optimize efficacy and minimize adverse events.

Most importantly, responses to medication can be quite variable. It is more important to adjust dosing based on the patient’s response rather than simply using a dosing reference.

Question 8

When is it okay to use the

ED50 as a starting dose?

Answer 8

When the drug has a wide therapeutic range. If the

drug has a wide therapeutic range there will be a decreased risk of adverse events.

Question 9

How do we dose drugs
that have a narrow
therapeutic range?

Answer 9

Drugs with a narrow therapeutic range should have their dose titrated (start low and increase slowly until the desired response is achieved)

Question 10

toxic and lethal doses

Answer 10

Up until now we have always looked at a response as a measure of efficacy (i.e. pain relief).

 Responses can also include toxicity or even death due to drug treatment.

 We obviously do not want to test for toxic or lethal responses in humans. For this reason, these tests are carried out in experimental animals.

 Acute (short term) and chronic (6 month – 2 year) animal testing is carried out to determine the doses that produce toxicity or death in multiple animal species.

 The average toxic dose (TD50) is the dose in which 50% of animals experience drug toxicity.

 The average lethal dose (LD50) is the dose in which 50% of animals die.

 TD50 and LD50 are typically expressed in mg drug/kg body weight.

Question 11

therapeutic index

Answer 11

Therapeutic index is an indicator of a drug’s safety.

 The therapeutic index is calculated by determining the ratio of the TD50 or LD50 to the ED50.
TI = TD50/ED50
or
TI = LD50/ED50

 Drugs with a high therapeutic index are considered safe whereas those with a low therapeutic index are
considered unsafe.

 Drugs that are safe have a large space in between the dose that produces a therapeutic response and the
dose that produces a toxic or lethal response.

Question 12

Factors Affecting Interpatient Variation in Response

Answer 12

1. Body Weight and Composition
2. Genetics
3. Gender
4. Race
5. Kidney Disease
6. Liver Disease
7. Environment

Question 13

Body Weight and Composition

Answer 13

 We know that the response to medications is largely determined by the concentration of the drug in the body, with the higher concentrations giving a
greater response.

 For many drugs, the dose is adjusted for the body weight of the patient (i.e. mg drug/kg body weight) in order to compensate for differences in size.

Normal BSA for an adult is 1.73m2 so some drugs are dosed as mg/1.73m2.

Question 14

Although body weight helps to normalize dose, what happens when two people have the same body weight but different body composition?

Answer 14

Percentage body fat can change the distribution of the
drug so obese patients may respond differently.
Clinicians often adjust the dose of drugs by body surface area (BSA) because this partially accounts for body composition as well.

Question 15

genetics

Answer 15

Pharmacogenetics is the study of the effect of DNA sequence variation to the clinical response of drugs.

 Single Nucleotide Polymorphism (SNP, pronounced “SNIP”) is a change in DNA sequence that involves a single nucleotide (A,T,C or G).

 SNPs can exist in genes that regulate drug metabolism, drug transport or drug receptors, as you have already seen in Module 4.

 Genetic variation such as SNPs can explain some of the intersubject variation in drug response.

Doses of some drugs are adjusted based on a patient’s genotype (genetic makeup).

Question 16

gender

Answer 16

This may seem like an obvious statement but
women and men are different. This is may be
true in terms of drug effects as well.

 A drug may be more effective in women than a
man or vice versa

Question 17

For many drugs the effect of gender is unknown. Why?

Answer 17

Until relatively recently, the majority of drug research was conducted in men.

 In 1997 drug regulatory bodies (Health Canada and the US FDA) put pressure on drug companies to include women in trials of new drugs.

Question 18

A few differences between women and men that
we know of in terms of variation in drug
response are:

Answer 18

o Alcohol metabolism is slower in females.

o Certain opioids are more effective in women, therefore they require lower doses.

o Certain drugs used to treat irregular heart beat cause prolongation of the QT interval on the electrocardiogram of women. This means it is more likely for women to have a fatal cardiac dysrhythmia.

Question 19

race

Answer 19

The effect of race or ethnicity is difficult to relate to variability of drug response.

 One reason is that race is difficult to define.
 Many people in our society are from an ethnically heterogeneous background so they cannot simply be categorized by a single race.

 There are some instances where generalizations are made by race because of convincing data. For example, concentrations of the cholesterol lowering drug rosuvastatin are 2-3 times higher in Asian compared to Caucasian patients. This can (and has) led to drastic side effects and even death. Therefore doses of rosuvastatin should be decreased in Asian patients.

Question 20

kidney disease

Answer 20

The kidney is the primary organ responsible for drug elimination.

 In patients with kidney disease, drug excretion is significantly decreased.

 Decreased drug excretion causes an increase in the half life for drugs that are renally excreted.

 Recent evidence also suggests that hepatic and intestinal drug metabolism is also decreased in renal failure.

 The net effect of renal failure is increased oral bioavailability and decreased excretion.

 Therefore, the dosage of many drugs must be decreased in patients with kidney disease.

Question 21

liver disease

Answer 21

cirrhotic liver

The liver is the primary organ responsible for drug metabolism.

 Patients with liver diseases such as cirrhosis or hepatitis exhibit decreased hepatic drug metabolism.

 For drugs that are extensively metabolized, half life
may be significantly increased in patients with liver
disease.

Question 22

environment

Answer 22

Environmental exposures can significantly change the way patients respond to drugs.

 Environmental exposure can be voluntary (smoking, alcohol, diet, exercise) or involuntary (environmental pesticides).

Question 23

e.g, of environment

Answer 23

1. Cigarette smoke induces some drug metabolizing enzymes and can make some drugs less effective.
2. Alcohol can exacerbate the toxicity of some other drugs.
3. Exercise improves the actions of insulin.
4. Some commonly used pesticides can induce CYPs and therefore decrease the response to drugs that are metabolized by CYP enzymes.

Question 24

adverse drug reactions

Answer 24

Adverse drug reactions (ADRs) are the unintended and undesired responses from drugs.

 Adverse drug reactions are an enormous societal health problem.

 Canadian research suggests that 7.5% of hospital admissions in Canada are attributed to adverse
drug reactions. This represents 185,000 people per year!

Question 25

Adverse drug reactions can include:

Answer 25

1. Side effects
2. Drug toxicity
3. Allergic Reaction
4. Idiosyncratic Reaction
5. Carcinogenic Effects
6. Mutagenic Effects
7. Teratogenic Effects

Question 26

side effects

Answer 26

Side effects are secondary to the main therapeutic effect of the drug and are expected.

 Side effects occur at normal therapeutic doses and are often unavoidable.

 Side effects are often due to poor specificity or selectivity of the drug.

Question 27

side effects example

Answer 27

antihistamines act by blocking H1 histamine receptors to prevent the symptoms of allergy (i.e. runny nose, watery eyes).

Side effects include drowsiness, dry mouth and urinary
retention.

In the figure you can see that histamine binding to the histamine receptor in sinuses causes vasodilation which results in runny nose and watery eyes.

Antihistamines act by blocking the effect of histamine. Side effects occur when antihistamines bind to either histamine receptors or other receptors in the brain. This produces sedation, dry mouth and urinary
retention. These are side effects of antihistamines.

Question 28

drug toxicity

Answer 28

 Drug toxicity can be considered as any severe adverse drug event.

 Drug toxicity is often mediated by overdose where
patients unintentionally or intentionally take too much
medication.

 These types of reactions are often extensions of the
therapeutic effect.

 For example, a patient who takes too much insulin will experience hypoglycemia (low blood glucose).

Question 29

allergic reaction

Answer 29

Allergic reactions are mediated by the immune system.

 Allergy requires a prior sensitization where a patient is exposed to the allergen (i.e. drug).

 Upon subsequent exposure to the drug an allergic reaction will occur. During allergic reactions, mast cells
release chemical mediators such as histamine.

 Allergic reactions can vary from itching and rash, to life threatening anaphylaxis (bronchospasm, edema
and severe hypotension).

 The intensity of allergic reactions are independent of dosage size. Therefore small doses can produce severe allergy.

 ~ 10% of all ADRs are related to drug allergy.

 Very few drugs cause allergic reactions. The most common drug class to cause drug allergy are the penicillins. Sulfonamides (an antibiotic) and nonsteroidal anti-inflammatory drugs (NSAID) are also known to cause drug allergy.

Question 30

Idiosyncratic Reaction

Answer 30

 These are reactions that occur rarely and unpredictably in the population.

 Recent evidence suggests that genetic polymorphisms account for the majority of idiosyncratic reactions.

 The majority of polymorphisms causing idiosyncratic reactions occur in drug metabolizing enzymes and drug transport proteins.

 It is hoped that one day, routine blood test will be able to determine people at risk for idiosyncratic reactions due to genetic polymorphisms. This already occurs in some centres for the drugs warfarin and 6-mercaptopurine which are metabolized by CYP2C9 and
thiopurine methyltransferase (TPMT) respectively

Question 31

Example of genetic polymorphisms that cause idiosyncratic reactions:

CYP2C9

Answer 31

– Approximately 15% of Caucasians have a polymorphism that decreases metabolism

Question 32

Example of genetic polymorphisms that cause idiosyncratic reactions:

CYP2D6

Answer 32

10% of Caucasian and African Americans are poor metabolizers. These patients do not
experience pain relief when they take codeine. Codeine is a prodrug that is metabolized by
CYP2D6 to morphine.

Question 33

Example of genetic polymorphisms that cause idiosyncratic reactions:

Thiopurine methyltransferase (TPMT)

Answer 33

– Approximately 10% of patients have decreased activity and 0.3% have no activity.

Treatment with thiopurine drugs in patients with low or absent TPMT can result in life threatening bone marrow suppression

Question 34

Example of genetic polymorphisms that cause idiosyncratic reactions:

OATP1B1

Answer 34

– An uptake drug transporter in the liver. 15% of Asian and Caucasian patients have a polymorphism that decreases function.
This leads to an increase in plasma drug concentrations.
This polymorphism has been implicated in causing myopathy (muscle toxicity) in patients taking statin drugs

Question 35

Example of genetic polymorphisms that cause idiosyncratic reactions:

Glucose 6-Phosphate dehydrogenase deficiency (G6PDH)

Answer 35

– An enzyme important in red blood
cell metabolism.

Deficiency is common in people of African and Middle Eastern descent.

Patients with deficiency may have red blood cell hemolysis following treatment with certain
analgesics (i.e. Aspirin) or anti-malarial drugs.

Question 36

Carcinogenic Effects

Answer 36

 Carcinogenic means the ability of a drug to cause cancer.

 Relatively few drugs are carcinogenic.

 Determining whether a drug is carcinogenic is difficult because it normally takes years after the initial dose to appear.

 The drug diethylstilbestrol (DES) used to be prescribed to prevent spontaneous abortion in high risk pregnancies. Years later it was determined that the female offspring developed vaginal or uterine cancer.

Question 37

Mutagenic Effects

Answer 37

 If a drug is mutagenic it is able to change DNA.

 Often when a drug is mutagenic it is also carcinogenic or teratogenic.

 Sometimes drugs that are mutagenic are not carcinogenic or teratogenic. These drugs may receive approval for use from regulatory agencies if there is sufficient evidence of safety from preclinical studies.

 Drugs are tested for their potential as mutagens by the Ames test.

 The Ames test evaluates the ability of the test compound (i.e. a drug) to cause a mutation in specialized strains of bacteria.

Question 38

Teratogenic Effects

Answer 38

 Compounds that are teratogens are known to produce birth defects or impair fertility.

 Typically we think of birth defects as major physical malformations, but birth defects also include behavioural and metabolic defects.

 Less than 1% of all birth defects are caused by drugs.

 Sensitivity to teratogens changes during development.

 The United States Food and Drug Administration has categorized drugs according to their risk. In Canada we use the American table as a guideline.

Question 39

exposure to tertogen during diff pregnancy stages

Answer 39

 Gross malformations typically occur when exposure to a teratogen is in the 1st trimester.

 Teratogen exposure during the second and third trimesters usually disrupts function as opposed to gross anatomy.

 Transfer of drugs across the placenta is thought to be greatest in the third trimester because as the placenta develops, the surface area for transfer between maternal and fetal circulation increases. In addition, the placental-fetal barrier becomes progressively thinner.

Question 40

pregnancy risk categories - A

Answer 40

well controlled human studies have failed to show risk to fetus in 1st trimester

no evidence of harm later in pregnancy

Question 41

pregnancy risk categories - B

Answer 41

animal reproduction studies have failed to show harm to the fetus and there are no well controlled studies in preg women

OR

animals studies have shown an adverse effect but well controlled studies in preg women fail to how any harm

Question 42

pregnancy risk categories - C

Answer 42

animal studies have shown harm to the fetus but there are no well-controlled studies in preg women

potential benefits of the drug outweigh the potential risk

Question 43

pregnancy risk categories - D

Answer 43

clear evidence of risk to the fetus from studies in humans

potential benefits of drug outweigh the potential risk

Question 44

pregnancy risk categories - X

Answer 44

studies in animals and humans clearly demonstrate risk to the fetus

risks of using the drug clearly outweigh the benefits

these drugs should never be used in preg women

Question 45

Organ Specific Toxicity

Answer 45

 Many drugs exhibit toxicity to a specific organ.

 Organ specific toxicity can occur to the kidney, lung,
heart, liver, muscle and inner ear amongst others.

 The most common and important organ specific
toxicity is observed in the liver and heart.

Question 46

Hepatotoxicity

Answer 46

 Hepatotoxicity is the most common reason for an approved drug to be removed from the market.

Question 47

why are drugs taken off market for hepatotoxicity

Answer 47

Remember the liver is the primary site of drug

metabolism. Some drugs are metabolized to toxic metabolites which can then cause liver injury

Question 48

hepatotoxicity and patients

Answer 48

Several drugs known to be hepatotoxic are
administered to patients.

 All patients taking hepatotoxic drugs should be educated to look for signs of liver toxicity which include: jaundice (yellow skin), dark urine, light coloured stool, nausea and vomiting

 Drugs known to be hepatotoxic should be used with caution in patients at high risk for hepatic disease (alcoholics), patients with hepatic disease, and patients taking other medications with known hepatotoxicity.

Question 49

AST and ALT

Answer 49

In addition, liver function tests should be performed by measuring blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT).

 AST and ALT are liver enzymes that normally have a low concentration in the blood. When the liver is damaged, blood concentration of these enzymes increases

Question 50

QT Interval Prolongation

Answer 50

 The electrocardiogram (ECG or EKG) shows the electrical activity of the heart.

An ECG is obtained by placing electrodes on the skin and measuring the electrical activity that occurs with each heartbeat.

 Each “bump” in the ECG represents a different event in the heart beat

Question 51

P-Wave:

Answer 51

normal atrial depolarization.

Question 52

QRS complex:

Answer 52

rapid depolarization of the left and right ventricles

Question 53

T-Wave:

Answer 53

repolarization of the ventricles.

Question 54

U Wave:

Answer 54

not always seen on an ECG.

Question 55

QT Interval:

Answer 55

Represents the time required for the ventricles to
repolarize.

A prolongation of the QT interval is a major risk factor for the development of torsades de pointes, a life threatening form of ventricular arrhythmia.

More than 100 drugs are known to prolong the QT interval and many have been removed from the market.

 Drugs that prolong the QT interval should be used with caution in patients predisposed to arrhythmias such as the elderly, and patients who have bradycardia (slowed heart beat), heart failure, low potassium or congenital QT prolongation.

 Women are at higher risk than men because their normal QT interval is longer.

Question 56

drug withdrawal

Answer 56

Some medications must be withdrawn slowly to prevent adverse reactions.

 An important part of patient education is to
make sure that patients understand that they cannot simply stop taking a medication because they feel better. In some cases this can have drastic consequences.

Question 57

opiates consequences

Answer 57

therapeutic use - analgesia (pain relief)

consequence of rapid withdrawal

• anorexia
• irritability
• nausea
• vomitting
• weakness
• muscle spasms

Question 58

benzodiazepines consequences

Answer 58

therapeutic use - anxiety

consquence of rapid withdrawal

• anxiety
• insomnia
• sweating
• tremors
• panic
• delirium
• paranoia
• convulsions

Question 59

beta blockers consequences

Answer 59

therapeutic uses - hypertension, decrease heart rate

consequences of rapid withdrawal

• rebound hypertension
• chest pain
• myocardial infarction
• arrhythmia

Question 60

Medication Errors

Answer 60

 Medication errors are the most common cause of adverse drug reactions.

 If a medication error is caused by a health care professional it is called an iatrogenic error.

Question 61

Medication errors can be broken up into 5 main categories:

Answer 61

1. Prescribing – Health care professional prescribes the wrong drug, wrong dose or wrong route.
2. Dispensing – The prescription is correct but the pharmacist dispenses the wrong drug.
3. Administration – The health care professional administers the incorrect dose and/or drug. Note,
   a patient can also make this error.
4. Patient education – Illiteracy or language barriers may cause the patient to not comprehend the
   instructions. The health care professional (doctor, nurse and pharmacist) must work together to
   ensure all patients understand information about drugs.
5. Patient – The patient understands the instructions but doesn’t follow them (i.e. misses doses,
   takes more medication than prescribed).

Question 62

drug naming

Answer 62

Unfortunately the naming of many drugs are similar.

 Medication errors are likely to occur when drug names look and/or sound the same.

 Confusion over drug names represents ~ 15% of all medication errors.

 Poor handwriting, illiteracy and strong accents (english as a second language) increase the chance of this type of medication error.

 The diagram shows some common drug naming errors.

Question 63

abbreviations

Answer 63

 Abbreviations can be dangerous sources of errors.

Question 64

abbreviations - IU

Answer 64

International unit

read as - IV or 10

write “units”

Question 65

abbreviations - q.d

Answer 65

every day

read as - qid -> tail of q and dot read as i

write “every day”

Question 66

abbreviations - q.o.d

Answer 66

every other day

read as qid or q.d

write “every other day”

Question 67

abbreviations - trailing 0 after decimal point - 1.0

Answer 67

1 mg

read as 10 mg is decimal missed

dont use trailing 0s if not needed

Question 68

abbreviations - missing the leading 0 - 0.5

Answer 68

0.5mg

read as 5mg if miss the decimal

use 0 before decimal

Question 69

abbreviations - MgSO4

Answer 69

magnesium sulfate

read as morphine sulfate

write out “magnesium sulfate”

Question 70

abbreviations - MS, MSO4

Answer 70

morphine sulfate

read as magnesium sulfate

write out “morphine sulfate”

Question 71

drug interactions

Answer 71

Drugs can interact with each other or components in our diet to produce complicated responses.

 Drug-drug interactions may occur whenever a patient takes two or more drugs.

 Drug-food interactions may occur even if a patient is only taking one drug.

 The risk of drug interactions increases (almost linearly) with the number of medications a patient
takes.

The most common type of drug-drug interaction are those affecting pharmacokinetics (ADME).

Question 72

Drug interactions are especially

important in the elderly. Why?

Answer 72

The average 65 year old takes 7 medications, significantly more than the average 20 year old.

Question 73

When two drug or more drugs interact there are 3 possible outcomes:

Answer 73

1. Increased effects:
   𝐷𝑟𝑢𝑔 + 𝐷𝑟𝑢𝑔 → 𝐼𝑛𝑐𝑟𝑒𝑎𝑠𝑒𝑑 𝐸𝑓𝑓𝑒𝑐𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔
2. Decreased effects:
   𝐷𝑟𝑢𝑔 + 𝐷𝑟𝑢𝑔 → 𝐷𝑒𝑐𝑟𝑒𝑎𝑠𝑒𝑑 𝐸𝑓𝑓𝑒𝑐𝑡 𝑜𝑓 𝐷𝑟𝑢𝑔
3. Generation of a new effect:
   𝐷𝑟𝑢𝑔 + 𝐷𝑟𝑢𝑔 → 𝑁𝑒𝑤 𝐸𝑓𝑓𝑒ct

Question 74

increased effects

Answer 74

Drug interactions can increase drug effects by either an increase in the therapeutic effect or an increased adverse effect.

Question 75

Increased Therapeutic Effects

ampicillin, sulbactam

Answer 75

 Ampicillin is an antibiotic that is rapidly inactivated by bacterial enzymes.

 Sulbactam is an inhibitor of the bacterial enzyme that inactivates ampicillin.

Ampicillin → Rapid Inactivation, poor therapeutic response

Ampicillin + Sulbactam → Increased therapeutic activity of ampicillin

Question 76

Increased Adverse Effects

warfarin, aspirin

Answer 76

 Warfarin is an anticoagulant used to thin the blood.

 Aspirin is an analgesic that also thins the blood.

Warfarin → Effective blood thinner

Warfarin + Aspirin → Bleeding (potentially life threatening side effect)

Question 77

Decreased effects:

Answer 77

 Drug interactions can reduce drug effects by either reducing therapeutic effects or reduced
adverse effects

Question 78

Reduced Therapeutic Effects

Answer 78

 Clopidogrel is an anticoagulant. It is a pro-drug that requires metabolic activation by CYP2C19.

Omeprazole (a drug used to treat stomach ulcers) inhibits CYP2C19.

 When given together, the active metabolite of clopidogrel is not formed, therefore insufficient anticoagulation occurs.

Question 79

Reduced Adverse Effects

Answer 79

 Morphine is an analgesic used to treat pain.

 Morphine overdose can produce coma, respiratory depression and even death.

 To treat morphine overdose the competitive antagonist naloxone can be administered.

Question 80

Generation of a new effect:

Answer 80

 Although drug interactions usually either increase or decrease drug effects, there are a few interactions that produce a unique response.

 Disulfiram is a drug used to help treat chronic alcoholism.

 Alcohol is normally metabolized to acetaldehyde and then further to acetic acid.

 It is the acetaldehyde that makes you feel hungover (headache, nausea, vomiting, visual disturbance etc.).

 Disulfiram inhibits the metabolism of acetaldehyde. Use of this drug causes acetaldehyde levels to increase and patients have very severe hangover like symptoms. This occurs within as little as 10 minutes after alcohol intake.

Question 81

types of drug interactions

Answer 81

1) Direct Physical Interaction
 Direct chemical or physical interaction of two or more drugs.

2. Pharmacokinetic Interaction
    Interactions affecting absorption, distribution, metabolism or excretion (ADME).
3. Pharmacodynamic Interaction
    Interactions affecting receptor binding.
4. Combined Toxicity
    Two or more drugs exhibit toxicity to the same organ (i.e. hepatotoxicity or QT interval prolongation)

Question 82

direct physical interaction

Answer 82

The most common direct interaction occurs when two or more IV solutions are mixed together.

 Often mixing IV solutions together can cause a precipitate to form.

 If a precipitate is formed the mixture should be discarded and NOT administered to a patient. “When in
doubt, throw it out”

Question 83

direct physical interaction

- mixing drug solutions

Answer 83

Drug solutions should never be mixed together without consulting a compatibility chart.

 The benzodiazepine drug diazepam is particularly problematic and should never be mixed with another drug.

 Although direct drug interactions are more common when mixing medication, they also may occur following administration.

 For example, if a patient is given sodium bicarbonate followed by calcium gluconate, a precipitate may form in the blood

Question 84

Pharmacokinetic Interaction

Answer 84

 Pharmacokinetic drug interactions are by far the most common type of drug interaction experienced in patients.

 In these types of interactions, taking two or more drugs may change the absorption, distribution, metabolism and/or excretion of one or more drugs

Question 85

The following are ways in which drug interactions can alter pharmacokinetics:

ABSORPTION

Answer 85

altered pH
Chelation/ binding
altered blood flow
gut motility
vomiting
drugs that kill intestinal bacteria

Question 86

The following are ways in which drug interactions can alter pharmacokinetics:

DISTRIBUTION

Answer 86

altering pH

protein binding

Question 87

The following are ways in which drug interactions can alter pharmacokinetics:

METABOLISM

Answer 87

CYP induction

CYP inhibition

Question 88

The following are ways in which drug interactions can alter pharmacokinetics:

EXCRETION

Answer 88

altered blood flow
altered pH
tubular secretion

Question 89

altered pH - absorption

Answer 89

Drugs that effect gastric or intestinal pH can alter drug absorption.
 The most common drug interaction with respect to alteration of pH occurs with antacids.
 Antacids increase gastric pH and therefore increase the absorption of drugs that are weak bases and decrease the absorption of drugs that are weak acids.
 Antacids can also dramatically affect the absorption of enteric coated drugs.
 Enteric coated drugs are designed to pass through the acidic stomach without dissolution.
Once they reach the more alkaline intestine dissolution begins.
 When an antacid is taken, it increases the pH of the stomach and therefore promotes
premature dissolution of enteric coated drugs.

Question 90

what are the consequences of premature dissolution of enteric coated drugs?

Answer 90

enteric coated drug
- passes through stomach, dissolution in small intestine

enteric coated drug + antacid

• antacid increases stomach pH
• enteric coating dissolves in stomach

Question 91

chelation/ binding - absorption

Answer 91

Some drugs are known to bind other drugs within the intestine.

 In many cases this binding causes the formation of insoluble complexes that can’t be absorbed.

Question 92

chelation/ binding - bile acid sequestrants

Answer 92

 The best example of this type of interaction occurs with drugs known as bile acid sequestrants

 Bile acid sequestrants are designed to bind intestinal bile acids and prevent their absorption from the intestine. The cholestyramine-bile acid complex is
excreted in the feces.

 In the figure the bile acid sequestrant
cholestyramine binds to digoxin in the intestine and decreases its absorption. Notice how
only the free digoxin is absorbed into the blood.

Question 93

altered blood flow pH

Answer 93

Drugs that decrease blood flow decrease the absorption of drugs.

 One example is the use of epinephrine with a local anesthetic.

 If a local anesthetic is administered alone, it may diffuse into the blood away from the injection site.

 If epinephrine is injected with a local anesthetic, it causes vasoconstriction and decreases the absorption of the local anesthetic. This allows the local anesthetic to stay at the injection site where it is required to prevent pain sensation.

Question 94

gut mobility - absorption

Answer 94

Some drugs affect intestinal motility.

 Drugs can either cause an increase or a decrease in intestinal motility.

 Laxatives used to treat constipation cause increased gut motility.

 Increased gut motility results in decreased drug absorption.

 Opiate drugs used to treat pain, such as morphine, decrease gut motility and therefore
increase drug absorption.

Question 95

vomiting - absorption

Answer 95

Drugs that induce vomiting will decrease the absorption of other drugs.

 Patients taking drugs known to have nausea and vomiting as a side effect should be monitored carefully.

 If vomiting occurs within 20 – 30 minutes after taking one or more medications it is likely that absorption is incomplete.

 Health care practitioners must determine whether another dose should be administered.
 If the drug(s) entered the intestine before the patient vomited, giving another dose may
produce toxicity.

Question 96

Drugs that Kill Intestinal Bacteria

- absorption

Answer 96

 Intestinal bacteria play an important role in the metabolism of some drugs.

 Their primary metabolic activity is deconjugating phase II drug metabolites as part of enterohepatic recycling.

 Antibiotic drugs that kill intestinal bacteria can cause decreased deconjugation and therefore decreased absorption during enterohepatic recycling.

 The end result is decreased plasma drug concentration.

Question 97

altering pH - distribution

Answer 97

A drug that can change extracellular pH can influence the ionization of other drugs.
 Ionization is a major determinant of drug distribution.
 The drug sodium bicarbonate increases the extracellular pH whereas ammonium chloride
decreases extracellular pH.
 Due to pH partitioning, changing the extracellular pH can draw a drug from inside the cell to
outside by changing its ionization.
 For example, during an overdose of aspirin, increasing the extracellular pH with sodium
bicarbonate will draw aspirin (a weak acid) outside the cell and cause it to become ionized.
Once “trapped” in the extracellular fluid aspirin may be eliminated in the urine.

Question 98

protein binding - distribution

Answer 98

If two drugs are bound to the same site on plasma proteins, co-administration will result in competition for binding.
 The drug with the lower affinity for the protein will become free.
 This may result in increased therapeutic effect, increased toxicity and/or increased
excretion.
 In the example below we can see that addition of the green drug causes displacement of the yellow drug from the plasma protein. This causes the free concentration of the yellow drug to increase.

Question 99

metabolism

Answer 99

Altered drug metabolism is one of the most important and common types of drug interaction.

 Some drugs increase the metabolism of other drugs by inducing drug metabolizing enzymes (CYPs).

 Other drugs inhibit the metabolism of drugs by inhibiting CYPs.

 Most of these types of drug interaction occur in the liver and/or intestine.

Question 100

CYP induction

Answer 100

 Some drugs increase the synthesis of CYP enzymes, a process known as induction.

 The result of induction is increased drug metabolism.

 Induction is delayed, therefore it may take 2-10 days following exposure to the enzyme inducer before the induction occurs.

 Once the inducer is stopped it takes 7 – 10 days before the CYP enzyme levels return to
normal.

Question 101

eg of CYP inducers

Answer 101

Cigarette/marijuana smoke (one joint has the same effect on induction as 5-10 cigarettes).

• Rifampin – induces CYP3A4
• Phenobarbital – induces many CYPs.
• BBQ’d food – Induces CYP1A2
• Alcohol – Induces CYP2E1 (but severe alcoholism causing cirrhosis decreases CYP activity

Question 102

CYP inhibition

Answer 102

Some drugs can inhibit CYP enzymes in the intestine or liver.

 Enzyme inhibition results in decreased metabolism of other drugs metabolized by the same enzyme.

 Typically enzyme inhibition results in increased plasma concentration of the parent drug.

 If a pro-drug is given when CYP enzymes are inhibited, there will be decreased metabolic
activation.

Question 103

e.g. CYP inhibitors

Answer 103

Many antibiotics and antifungals inhibit CYP3A4.

• HIV protease inhibitors also inhibit CYP3A4.
• Omeprazole inhibits CYP2C19.
• Selective serotonin reuptake inhibitors (SSRIs) – inhibit CYP2D6.
• Fluvoxamine – Inhibits CYP1A2
• Grapefruit juice – Inhibits CYP3A4

Question 104

altered blood flow - excretion

Answer 104

Drugs that decrease renal blood flow cause a decrease in glomerular filtration.

 Decreased glomerular filtration causes decreased renal excretion which will cause increased plasma drug
concentrations.

 Non-steroidal anti-inflammatory drugs (NSAIDS) used as analgesics cause renal vasoconstriction and therefore decrease renal blood flow.

 Beta blockers act on the heart to decrease cardiac output. Decreased cardiac output indirectly decreases renal bloodflow.

Question 105

altered pH - excretion

Answer 105

Drugs that change the pH of the renal tubular filtrate can alter drug excretion.

 This is due to pH partitioning and ion trapping.

 Altering the renal tubular filtrate can be a useful drug interaction in terms of the treatment of drug overdose.

 If a patient overdoses on amphetamine (a weak base), the filtrate may be acidified with ammonium chloride.

 This causes the amphetamine to be ionized and therefore trapped in the renal tubules and prevents reabsorption into the blood.

 The net result is increased renal excretion of the amphetamine.

Question 106

tubular secretion

Answer 106

Tubular secretion is mediated by transporters at the proximal tubule.
 If one drug blocks the transporter, it may block another drug from being secreted into the tubule lumen.
 This will ultimately result in decreased renal excretion and increased plasma concentration.
 The best example of a drug interaction involving secretion involves the antibiotic penicillin
and the drug probenecid (used to treat gout).
 When administered together, probenecid inhibits the transporter responsible for moving
penicillin from the blood into the tubule lumen.
 This causes renal penicillin excretion to decrease and blood penicillin concentration to rise.
 This interaction was intentionally used during times of war when penicillin supplies were
low.

Question 107

two main types of pharmacodynamic drug interactions:

Answer 107

1. Interactions that occur at the same receptor.

2. Interactions that occur at separate sites.

Question 108

Interactions that occur at the same receptor.

Answer 108

 Usually drug interactions that occur at the same receptor are the result of an antagonist
blocking the action of an agonist (i.e. inhibitory).

 Drug interactions at the same receptor site can cause decreased therapeutic action.

 They can also decrease toxicity in overdose situations. This is a beneficial interaction.

 For example, when a patient overdoses on morphine they have the symptoms of respiratory
depression and coma.

 In this situation naloxone, a competitive antagonist can be administered to reverse the
symptoms.

Question 109

2. Interactions that occur at separate sites.

Answer 109

 Two drugs that have completely different mechanisms can produce a drug interaction if
they produce the same physiological response.

 For example, the analgesic morphine and the anxiolytic drug diazepam are both central
nervous system depressants.

 Although they both act in the brain they bind to completely different receptors to produce
their effects.

 Morphine acts on brain opioid receptors whereas diazepam acts on the benzodiazepine
receptor.

 When these drugs are taken together, the result is enhanced CNS depression.

Question 110

combined toxicity

Answer 110

If you know one drug may cause hepatotoxicity,
would you give a patient another drug that may
also cause hepatotoxicity? This would almost
certainly produce a drug interaction known as
combined toxicity.

 Examples of combined toxicity include the use of
acetaminophen and alcohol. Both are
hepatotoxic and when used together can
increase the amount of liver damage.

 Isoniazid and rifampin are both used to treat
tuberculosis and are both hepatotoxic.
Unfortunately effective treatment of
tuberculosis requires both drugs. In a situation
like this liver function tests must be performed
to monitor the degree of hepatotoxicity.

Question 111

food-drug interactions

Answer 111

Another important food drug interaction exists
with monoamine oxidase (MAO) inhibitors, a
class of drug used to treat depression.

 Patients taking these drugs must avoid foods
containing tyramine including aged cheese,
yeast, red wine, sauerkraut, cured meat (i.e.
pepperoni) and soy sauce.

 MAO inhibitors inhibit the breakdown of
tyramine.

 Tyramine causes increased release of
norepinephrine from peripheral nerve
terminals resulting in a potentially fatal
hypertensive crisis.

 Symptoms of hypertensive crisis include
tachycardia (increased heart rate), severe
hypertension, headache, nausea and vomiting.

 MAO inhibitors should not be used in patients not capable of adhering to strict dietary
restrictions.