Module 1 Section 4 (Adverse Drug Reactions)

Question 1

How is drug toxicity assessed? How is it calculated?

Answer 1

It is assessed by using a measure called the therapeutic index, which is calculated by the formula
Therapeutic Index = TD50 / ED50

• TD50 = the toxic dose 50 (the dose that is toxic to 50% of a population).
• ED50 = the effective dose 50 (he dose of drug that is effective in 50% of a population).

Question 2

What does the therapeutic index do?

Answer 2

The therapeutic index tells you how safe the drug is.

It relates the dose of the drug required to produce a beneficial effect to the dose required to produce an undesirable or adverse effect.

The higher the therapeutic index, the safer the drug. When a drug has a low therapeutic index, it is more likely that toxicities will be observed.

Question 3

If you know that the ED50 for seizure control is 4 mg and the TD50 for sedation is 50 mg, what is the TI? What does it tell us about the drug toxicity?

Answer 3

Therapeutic Index = TD50 / ED50

50 mg / 4 mg = 12.5 mg

This means that there is a 12.5-fold difference between the beneficial dose and the toxic dose, which tells us that if the drug is taken correctly, it is improbable that adverse effects will occur.

Question 4

What does a TI of 2 tell us about the drug toxicity?

Answer 4

Since there is only a 2-times difference between the beneficial dose and the toxic dose, it is much more probable that adverse effects will occur with the use of this drug.

Question 5

What is an adverse drug reacion?

Answer 5

An adverse drug reaction is defined as any effect produced by the drug in a patient that is not the intended effect.

Question 6

What are the several types of adverse drug reactions?

Answer 6

1) Extension of therapeutic effect
2) Effects in non-target tissues or organs
3) Unrelated to the main drug action
4) Drug idiosyncrasy
5) Allergic reactions
6) Adverse biotransformation reactions
7) Drug dependence and addiction
8) Teratogenesis (birth defects)

Question 7

What adverse effect is extension of therapeutic effect? Provide an example. How can it be stopped?

Answer 7

It occurs when too much of the drug is in the blood. This is what commonly happens in drug overdose.

Ex: a benzodiazepine is taken for its sedative effects; an overdose will produce over-sedation.

Ex: Similarly, an anticoagulant is used to prevent clot formation; an overdose will cause bleeding.

In order to stop this adverse reaction, you can reduce the dose of the drug

Question 8

What adverse effect are effects in non-target tissues or organs? Provide an example. How can it be stopped?

Answer 8

When receptors for the drug exist in more areas than the target tissues, you can observe effects in these non-target tissues or organs.

Ex: Morphine produces its analgesic effect by acting on opioid receptors in the CNS, but morphine also causes constipation by acting on opioid receptors in the gastrointestinal tract.

Usually, reducing the dose will alleviate the adverse effect

Question 9

What adverse effect is unrelated to main drug action? Provide an example.

Answer 9

This type of adverse reaction includes effects that are unexpected and unrelated to the intended pharmacological action of the drug.

Ex: the heart drug Digitalis, sometimes used to treat heart failure, causes nausea, vomiting, and abnormal colour vision, which are unrelated to the main therapeutic action on the heart.

This adverse effect is observed from activating different receptors than the ones involved in the therapeutic effect. Usually nothing is done unless the adverse drug reaction is severe.

Question 10

What adverse effect is drug idiosyncrasy? Provide an example.

Answer 10

It’s genetic. It refers to an unusual response to a drug that is only observed in a small number of people.

Example: Succinylcholine is used to produce muscle relaxation. Approximately 1 in 3,000 pts lack the enzyme that normally inactivates the drug, resulting in the drug acting for excessively long periods of time in these patients.

Question 11

What adverse effect is allergic reactions? Provide an example.

Answer 11

Allergic reactions are mediated by the immune system. An antigen-antibody combination provokes an adverse reaction in the patient. The reaction may be very mild (e.g. skin rash) or very severe (e.g. anaphylaxis). Susceptibility to allergic drug reactions may have a genetic component.

Ex: most of the adverse reactions observed with penicillin are allergic in nature.

Question 12

What adverse effect is adverse biotransformation reactions? Provide an example.

Answer 12

They occur when a drug is converted into a chemically reactive metabolite that can bind to tissue components and cause tissue or organ damage.

Ex: at recommended doses, acetaminophen is converted to harmless metabolites and excreted. However, overdose of acetaminophen leads to the production of a chemically reactive metabolite that binds to tissue components and causes liver injury. To avoid these kinds of reactions, drugs should always be taken at the recommended doses.

Question 13

What adverse effect is drug dependence and addiction? Provide an example.

Answer 13

They are unwanted physiological and psychological effects of the drug.

Ex: Morphine will cause both dependence and addiction. Drug dependence and addiction can be avoided by taking the drug at the recommended dose for the recommended amount of time.
- If an individual has become dependent or addicted to a drug, gradual withdrawal from the drug will alleviate these adverse effect

Question 14

What adverse effect are teratogenesis (birth defect? Provide an example.

Answer 14

Teratogenesis is multifactorial and depends on the drug. Overall, it refers to drug-induced defects in the developing fetus.

Ex: babies exposed to the sedative drug thalidomide during pregnancy were born with deformed arms and legs.

Question 15

A patient has just come out of surgery and is on morphine to alleviate the post-surgical pain. You realize that the patient’s breathing seems to be laboured. The patient is not on any other drugs. What could potentially be occurring?

Answer 15

The patient is likely experiencing an adverse effect to the morphine, s pecifically an effect in a non-target tissue is occurring. Morphine binds to opioid receptors in the brain, relieving pain.

Opioid receptors are also found in the respiratory center of the brain, and activation of these opioid receptors will depress breathing. If the dose of morphine is lowered, the patient’s breathing should normalize.

Question 16

Why is drug toxicity difficult to predict? (4)

Answer 16

1) The adverse event may be a rare event.
- These adverse events are only detected once the drug is widely used.
- Ex: the antibiotic chloramphenicol was used for several years before it was recognized that in 1 in 40,000 patients, the drug caused fatal bone marrow damage.

2) The toxic reaction only appears after prolonged use of the drug.
- Some adverse events only appear after long term use of the drug (i.e. months to years).
- Ex: streptomycin, an antibiotic used to treat tuberculosis, causes deafness after long term use.

3) The toxic effect is not detectable in animals.
- Adverse effects such as headache, nausea, or mental disturbances are difficult to detect in animal tests. Therefore, these adverse effects are only detected once the drug is administered to humans.

4) The adverse effect is unique to a particular period or circumstance.
- Until it was demonstrated that thalidomide produced abnormal limb growth in the fetus, it was not realized that it was necessary to test drugs in pregnant animals.
- Results in pregnant animals doesn’t necessarily reflect what will happen w/ humans.

Question 17

Who’s at risk for an adverse reaction?

Answer 17

1) Age: Newborns and individuals >60 years of age are more likely to experience an adverse drug reaction than middle-aged individuals. This is due to immature or damaged organs (e.g. liver and kidneys), that make the individual more sensitive to drugs.

2) Multiple diseases in the same patient: this can increase the chance of an adverse drug reaction occurring.
- Ex: in the presence of kidney disease, drugs used to treat other diseases may be removed from the body more slowly than expected, causing a higher than normal concentration in the blood, increasing the risk of an adverse drug reaction.

• Genetics: Enzymes that biotransform and inactivate drugs (e.g. CYPs) can exist in different forms based on the genes that code for the enzymes, resulting in slow, normal, and fast metabolizers for some drugs.
• At the usual dose, the slow metabolizer will have a high blood concentration of the drug and be at increased risk of an adverse drug reaction.

Question 18

What are drug-drug interactions? What may they cause?

Answer 18

It’s the modification of the pharmacological effect of one drug by the presence of another drug in the body.

Drug interactions can lead to altered absorption, distribution, biotransformation, and/or excretion of drugs, which can lead to an altered response to the drug.

• Can be beneficial = increasing the effectiveness of the drug OR decreasing the toxicity of a drug
• Can be detrimental= decreasing effectiveness of drug OR increasing toxicity of a drug.

Question 19

What are the 5 types of drug-drug interactions?

Answer 19

1) Additive
2) Synergistic
3) Potentiation
4) Antagonism
5) Altered physiology

Question 20

What are additive drug-drug interactions? Provide an example.

Answer 20

The combined pharmacological effect of the two drugs is the sum of the individual effects (i.e. 1 + 1 = 2).

Ex: two different drugs from the benzodiazepine class of drugs given together will produce an additive effect because the two drugs bind to the same receptor to produce sedation.

Question 21

What are synergistic drug-drug interactions? Provide an example.

Answer 21

The combined pharmacological effect of two drugs is greater than the sum of the individual effects (i.e. 1 + 1 = >2). In this case, the two drugs bind to different receptors, but produce the same overall pharmacological effect.

Ex: the excess central nervous system depression produced by a combination of two sedatives, such as alcohol and a barbiturate.

Question 22

What are potentiation drug-drug interactions? Provide an example.

Answer 22

The pharmacological effect of one drug is increased by a second drug, even though the second drug is devoid of the intended therapeutic effect.

Ex: the administration of a sedative together with a drug that inhibits the biotransformation and inactivation of the sedative, resulting in higher than expected blood levels of the sedative.

Question 23

What are antagonism drug-drug interactions? Provide an example.

Answer 23

One drug reduces the pharmacological effect of another drug by binding to and competing for the same receptor, reducing the ability of the first drug to bind to the receptor and produce a response.

Ex: the inhibition of the effects of morphine at the opioid receptor by the opioid receptor antagonist, naloxone. Naloxone is used to treat opioid-related overdoses

Question 24

What are altered physiology drug-drug interactions? Provide an example.

Answer 24

One drug may alter the normal physiology of the body so that the response to another drug is altered.

Ex: administration of the diuretic, hydrochlorothiazide, combined with the heart drug, digoxin, can increase the toxicity of digoxin. Hydrochlorothiazide increases the excretion of potassium through the kidneys, lowering the amount of potassium in the blood. Digoxin toxicity is enhanced by low potassium levels in the blood.

Question 25

How do drug-drug interactions relate to pharmacokinetics?

Answer 25

One drug alters the concentration of the other drug in the blood and at the site of action. Drug interactions can occur at all pharmacokinetic stages (ADME).

Question 26

How can drug-drug interactions occur during absorption? Provide an example.

Answer 26

One drug can interfere with the absorption of another drug from the GI tract:
- One drug may combine with a second drug in the stomach or intestine to form a complex that cannot be absorbed into the blood.
• Ex: the tetracycline group of antibiotics will combine with antacids containing calcium, magnesium, or aluminum; thus, tetracylcines should not be taken at the same time as antacids.
- Some drugs increase the rate of intestinal motility (e.g. diarrhea) to such an extent that there is insufficient time for the absorption of other drugs.
- Some drugs seriously hinder the movements of the intestine. By doing so, they prevent the mixing of the intestinal contents which normally brings a drug into contact with the absorbing surface of the intestinal wall, thereby affecting absorption.

Question 27

How can drug-drug interactions occur during distribution? Provide an example.

Answer 27

One drug may alter the distribution of a second drug.

For instance, a number of drugs use the same binding sites on proteins in the blood.
- Thus, the addition of the second drug thereby increases the amount of unbound drug in the blood.

Ex: the blood thinner warfarin is extensively bound to blood proteins. Adding a second drug that is also protein bound will displace warfarin from its binding sites, increasing the amount of unbound warfarin in the blood, resulting in the patient bleeding

Question 28

How can drug-drug interactions occur during biotransformation? Provide an example.

Answer 28

A number of drugs can affect the activity of the Cytochrome P450 (CYP) enzymes, resulting in changes in the rate at which other drugs are metabolized and inactivated.

For instance, drugs can increase the amount of CYPs in the liver. This results in an increase in the rate of biotransformation of other drugs.

Question 29

Describe the process of biotransformation in the deactivation of a drug.

Answer 29

When biotransformation results in deactivation of a drug, the increased CYPs results in a shortened half-life of the drug, decreased blood concentrations of the drug, and a blunted pharmacological effect to the drug (i.e. lower intensity and shortened duration of action than expected). In addition, the drug is removed from the body at a faster rate than anticipated.
- Ex of drugs that increase the activity of the CYPs: the barbiturates and antiepileptic drugs.

Question 30

Describe the process of biotransformation in the inhibition of the metabolism of the drug.

Answer 30

Inhibition of metabolism occurs more frequently when several drugs are given together (drugs may compete for same CYP and thereby inhibit the metabolism of the first drug). In this case, the result is an increase in the half-life of the drug, an increase in the blood levels of the drug, a decrease in the rate of removal of the drug, and as a consequence, an increase in the pharmacological effect of the drug.
- Ex: antidepressants and antipsychotics

Question 31

How can drug-drug interactions occur during elimination? Provide an example.

Answer 31

One drug may alter the rate of elimination of another drug by the kidneys.

Ex: a diuretic increases the amount of urine produced, and thus may increase the excretion of other drugs. Another drug-drug interaction can occur if two drugs are transferred into the urine by the same transport mechanism and they compete for the transporter, decreasing elimination.

Question 32

A patient comes into the clinic complaining of increased agitation, restlessness, and the feeling that their heart is racing. After talking to the patient, you discover that the patient generally drinks about 4 large cups of coffee a day and that they are currently trying to quit smoking “cold-turkey.” You remember that nicotine from cigarettes increases the biotransformation of caffeine. With this knowledge, what is your suggestion for this patient?

Answer 32

When caffeine and nicotine are consumed together, a drug-drug interaction occurs, as nicotine increases the biotransformation of caffeine, thereby increasing the deactivation and elimination of caffeine from the body.

The result is a reduced pharmacological effect to caffeine when nicotine is also consumed. When the patient stopped smoking, the biotransformation of caffeine returned to normal. As a result, the caffeine is producing a greater pharmacological effect than the patient expects, causing the patient’s symptoms. The patient should be advised to decrease their caffeine intake to help alleviate the symptoms.

Question 33

What are the risk factors for drug-drug interactions? (4)

Answer 33

1) Age: as we age, our liver and kidney function decreases, affecting our ability to metabolize and eliminate drugs.
- The elderly are more susceptible to drug-drug interactions.

2) Polypharmacy (multiple drugs taken by the patient): the more drugs a person takes, the greater the chance of a drug-drug interaction happening simply by chance.

3) Genetic factors: certain genetic traits will make certain individuals more likely to have a drug-drug interaction than most of the population.
- Ex: variability in the genes coding for the CYPs will result in different rates of metabolism of certain drugs.

4) Drug properties: certain drug properties make them more likely to be involved in drug-drug interactions, such as:
- a narrow therapeutic index
- a saturated metabolism at therapeutic doses (i.e. metabolism is occurring at the maximal rate)
- extensive blood protein binding
- a small apparent volume of distribution
- requires active transport to reach the site of action or be eliminated
- eliminated by only one of biotransformation or renal excretion
- site of action is an organ with high blood flow

Question 34

What are drug-food interactions?

Answer 34

Drug-food interactions are similar to drug-drug interactions, but involve the interference of food with drugs taken concurrently. A number of foods can modify the effect of drugs.

Ex: fatty foods delay the absorption of fat soluble drugs, hence delaying their onset of action.

Question 35

Is grapefruit a drug-food interaction?

Answer 35

It appears to increase the bioavailability of drugs after the consumption of grapefruit juice.

Grapefruit juice contains compounds that inhibit CYP 3A4, one of the P450s found in the GI cells and which contributes to the first pass effect of drugs.

When grapefruit juice inhibits CYP 3A4, the first pass effect is removed and more of the administered dose reaches the systemic circulation, thereby increasing the pharmacological effect normally observed with that dose.

Some of the drugs affected are calcium channel blockers and antihistamines. It is recommended that patients taking drugs do not consume drinks or food containing grapefrui

Question 36

Is Tyramine a drug-food interaction?

Answer 36

Another well studied food-drug interaction occurs between antidepressants of the monoamine oxidase inhibitor class and any food containing tyramine, such as aged cheddar cheese.

The monoamine oxidase inhibitors prevent the inactivation of tyramine, and tyramine can cause a large increase in blood pressure, leading to a hypertensive crisis

Question 37

Penicillin has the ability to combine with proteins to form antigens, and a small percentage of the population receiving penicillin experience adverse effects. These adverse effects are properly classified as:

a) An extension of the therapeutic effect
b) An idiosyncratic reaction
c) A drug allergy
d) A drug-drug interaction

Answer 37

c) A drug allergy

Question 38

The TD50 of a drug in rats was found to be 50 mg/kg. The ED50 of the same drug in rats was 1mg/kg. From this information, one can calculate that the therapeutic index of the drug in rats is:

a) 0.02
b) 50
c) 49
d) 51

Answer 38

Therapeutic Index = TD50 / ED50

50mg/kg / 1mg/kg = 50

b) 50