Module 1 Section 4 (Adverse Drug Reactions) Flashcards
How is drug toxicity assessed? How is it calculated?
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).
What does the therapeutic index do?
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.
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?
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.
What does a TI of 2 tell us about the drug toxicity?
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.
What is an adverse drug reacion?
An adverse drug reaction is defined as any effect produced by the drug in a patient that is not the intended effect.
What are the several types of adverse drug reactions?
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)
What adverse effect is extension of therapeutic effect? Provide an example. How can it be stopped?
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
What adverse effect are effects in non-target tissues or organs? Provide an example. How can it be stopped?
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
What adverse effect is unrelated to main drug action? Provide an example.
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.
What adverse effect is drug idiosyncrasy? Provide an example.
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.
What adverse effect is allergic reactions? Provide an example.
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.
What adverse effect is adverse biotransformation reactions? Provide an example.
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.
What adverse effect is drug dependence and addiction? Provide an example.
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
What adverse effect are teratogenesis (birth defect? Provide an example.
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.
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?
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.
Why is drug toxicity difficult to predict? (4)
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.
Who’s at risk for an adverse reaction?
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.
What are drug-drug interactions? What may they cause?
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.
What are the 5 types of drug-drug interactions?
1) Additive
2) Synergistic
3) Potentiation
4) Antagonism
5) Altered physiology
What are additive drug-drug interactions? Provide an example.
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.
What are synergistic drug-drug interactions? Provide an example.
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.
What are potentiation drug-drug interactions? Provide an example.
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.
What are antagonism drug-drug interactions? Provide an example.
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
What are altered physiology drug-drug interactions? Provide an example.
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.
