Pharmacology L3: Adverse Drug Reactions Flashcards
What is the goal of drug therapy?
The goal of drug therapy is to select a dose in the therapeutic range and to avoid doses that produce toxicity.
This is not an easy process, as many factors affect how much drug reaches the site of action, such as route of _____, _____ and drug ______.
administration; absorption; metabolism
Genetics, age, gender…etc
What is the Drug Pipeline: Research and Development through to use by patients?
Even after this pipeline has been completed and the drug is being used by patients, the numbers of ADRs which occur after commercial release may be very small for an individual doctor, but when captured across a country or globally, trends may appear
What are Adverse Drug Reactions (ADR)?
“any response to a drug which is noxious (Unpleasant), unintended, and which occurs at doses normally used for therapy of disease”
Serious ADRs should be reported to a _____ to build up evidence across all users over time. (Safety concerns –> observe the effects) Drugs are withdrawn from the market each year as a result of such data. (Can change drugs) This definition does not cover drug overdose, drug abuse, or error in administration of drug.
national database
How does drug safety done?
Federal policies govern the approval and use of all drugs
All drugs must satisfy two major requirements before it can be approved in humans. What are they?
- Efficacy (effectiveness) in the disease state for which it is approved
- Safety, determined by extensive animal testing and controlled human testing.
What are the 6 various types of ADRs?
The most frequently used scheme for classifying types of ADRs is simply: ABCDEF
- Type A: Acute, predictable, related to MOA or ADME
- Type B: “Bizarre”, unpredictable, not necessarily related to MOA, but may involve patient qualities
- Type C: Chronic (continuous) effects
- Type D: Delayed effects
- Type E: End of treatment effect
- Type F: ???
What is type A (acute) for ADRs?
Dose-related toxicity
What is type A (acute) for ADRs related to?
- Related to the main pharmacological action of the drug, and often dealt with by reducing the dose
- Should be evident from clinical trials, reproducible in animals;
Type A (acute) Dose-related toxicity is generally ______ (predictable/unpredictable) and is ______ -dependent.
predicable; concentration
What are specific groups of patients that many be at risk for type A (acute) dose-related toxocity?
e.g. elderly, patients with kidney/liver damage, young children
What is phenytoin, an anticonvulsant used for epilepsy?
- drug given at different doses per individual (x-axis) blood concentrations measured
- <10 μg/ml is lower than the therapeutic range (reduced or no effectiveness)
- >15 μg/ml begin to show toxic (adverse) effects Note the large amount of individual variation shown by patients!
- A narrow therapeutic window requires careful patient monitoring as concentrations are a key determining factor. Thus, patients would have to submit to blood testing to check the concentration present.
What is the blood concentrations that is lower than the therapeutic range (reduced or no effectiveness) for phenytoin, an anticonvulsant used for epilepsy?
<10 μg/ml
What is the blood concentrations begin to show toxic (adverse) effects for phenytoin, an anticonvulsant used for epilepsy?
>15 μg/ml
What is the Therapeutic window?
range of concentrations where therapeutic effect is obtained without toxicity.
What is the Therapeutic Index?
ratio of desired vs adverse effect; the larger the better.
How is drug metabolism also a significant contributor to Type A ADRs?
- Example: An antihistamine, SeldaneR (terfenadine) was being used in the USA by prescription. It had an advantage over other antihistamines in that it did not cause drowsiness as it did not cross the blood-brain barrier. It was a prodrug, with the enzymes converting it to fexofenidine.
- Initial testing in the lab and in patients (pipeline) had no ADRs. There were no significant safety issues associated with terfenadine.
- However, it was used by 24 million patients for more than a decade – and one ADR that was detected in a few patients without any cardiovascular problems were going to hospitals with potentially fatal arrhythmias.
What is the Terfenadine’s novel MOA?
Research as to terfenadine’s effects on the heart showed that it had the ability to block specific K+ ion channels of the heart (HERG), but at concentrations higher than expected if the patient was using the antihistamine at the recommended dose.
Research as to terfenadine’s effects on the heart showed that it had the ability to block specific K+ ion channels of the heart (HERG), but at concentrations _____(higher/lower) than expected if the patient was using the antihistamine at the recommended dose.
higher
How were higher concentrations possible in Terfenadine’s novel MOA?
- Attention turned to the metabolism of terfenadine. We knew that it was metabolised by CYP3A4 in the liver.
- It was found that patients who were taking other medications at the same time as terfenadine were most likely to have issues….particularly those which also used CYP3A4! Free to travel in blood stream at higher conc. = adverse effects of K+ ion channels of heart = heart arrhythmia
What is the problem with Terfenadine?
- This discovery was not obvious during clinical trials – it was only really determined that there was an effect on the heart that was dangerous once terfenadine was used in the marketplace with millions of people, combining with other drugs.
- Terfenadine is NOT on the market any longer – instead, its metabolite (fexofenadine)and other similar drugs are – after being screened for HERG effects.
What are 2 good examples of how the actions of one drug can affect the metabolism of another?
- Competitive inhibition of P450s
- Potent inhibition of a P450 by a single drug
What is competitive inhibition of P450s of of how the actions of one drug can affect the metabolism of another?
Drug 1 is a substrate for the same P450 enzyme as Drug 2 → they competitively inhibit the metabolism of each other leading to an increase in circulating drug levels of both drugs
e. g. co-administration of nifedipine and erythromycin -
* both are metabolised by hepatic CYP3A4, and thus have to compete with each other for metabolism.
What is potent inhibition of a P450 by a single drug of of how the actions of one drug can affect the metabolism of another?
- P450 activity can be lost for an extended time (until new enzyme is synthesised)
- this leads to increases in circulating concentrations of any other drug that is metabolised by that P450
- e.g. coadministration of erythromycin (substrate for CYP3A4)
- ketoconazole (potent inhibitor of CYP3A4) = higher than expected erythromycin (cripple body’s ability to metabolise)
What might be the outcome of co-administering inducers of CYP450s and substrates?
Eg. St John’s Wort + Terfenadine = breaks down terfenadine faster = not working runny nose, itchy = adverse reaction (not getting desired effect)
What is Type B?
(Bizarre): idiosyncratic/drug hypersensitivity/ drug allergy Rarely, a patient may exhibit a severe and unpredictable ADR.
What are 3 characteristics of Type B (Bizarre): idiosyncratic/drug hypersensitivity/ drug allergy?
- For a drug allergy, the patient will have had prior exposure to either the same or a chemically related drug, with rapid development of allergic reaction after re-exposure. Symptoms may become more severe each time the drug is introduced into the body. Anaphylaxis is the most serious allergic response.
- Usually Type B ADRs are not seen in clinical trials - only when many patients are exposed do we see these rare events (~20% of ADRs reported).
- Factors contributing to these ADRs include receptor or metabolic abnormalities, pharmaceutical variation, drug allergy. Never been near a cat but is allergic –> first encounter = okay –> consecutive exposure = worsening
What does Type B (Bizarre): idiosyncratic/drug hypersensitivity/ drug allergy look like?
What is Type C ADR?
(Continuous): occurs with long term use (chronic)
When do Type C ADR occur?
these ADRs occur as a consequence of longterm chronic use.
Type C (Continuous): occurs with long term use (chronic) is often _____- dependent and ____ (predictable/unpredictable), but usually low incidence if a “safe” drug
dose; predictable
What is an example with Type C (Continuous): occurs with long term use (chronic) ADR?
is the development of movement difficulties (tardive dyskinesia) in sufferers of schizophrenia who are treated with neuroleptic drugs.`
What is Type C (Continuous): occurs with long term use (chronic) ADR?
This may be due to drug tolerance or receptor changes due to physical dependence.
What is Type D ADRs?
(Delayed) Carcinogenicity (Cause cancer), teratogenicity (Cause birth defects/Pregnant or breastfeeding)
- Understandably, these ADRs may require years before connections are made between drug and effects
What is an appearance of delayed ADRs in type D?
Appearance of delayed effects, such as irreversible infertility in young persons undergoing chemotherapy for cancer treatment.
What is type E?
End of Treatment ADRs
What are 2 characteristics of Type E: End of Treatment ADRs?
Notice how the symptoms of withdrawal are generally the opposite of the effects of the drugs. This “rebound effect” in terms of symptoms is due to the re-sensitisation and re-regulation of receptors of CNS and PNS. Cardiovascular effects are the most concerning and thus may require monitoring.
What is the classification of ADR?
What is the importance of the liver and kidneys in ADME?
- hepatocytes are a predominant site for cytochrome P450 (CYP) enzymes which metabolise drugs to reactive metabolites;
- drug metabolites may become concentrated in the kidney renal tubules, which may be toxic;
- Likely reasons for halting drug testing are excessive levels of hepatotoxicity or nephrotoxicity.
______ are a predominant site for cytochrome P450 (CYP) enzymes which metabolise drugs to reactive metabolites
Hepatocytes
Drug metabolites may become concentrated in the kidney _____, which may be toxic
renal tubules
Likely reasons for halting drug testing are excessive levels of _____ or _____.
hepatotoxicity; nephrotoxicity.
What is Hepatotoxicity?
Many drugs can cause liver damage. e.g. paracetamol
Case Study: Why does taking paracetamol the morning after excessive alcohol consumption possibly contribute to hepatotoxicity?
Alcohol induces CYP enzymes, which then convert paracetamol to the reactive metabolite NAPBQI NAPBQI then initiates the mechanisms of cell damage/death if it is not conjugated, leading to hepatotoxicity. This direction of metabolism to CYP enzymes can lead to glutathione deficiency, which is needed for Phase II reactions. Thus, toxic NAPBQI accumulates.
What are the 4 phase as Symptoms of paracetamol poisoning?
- Phase 1 (0-24h): nausea and vomiting
- Phase 2 (24-72h): right upper quadrant Pain, elevated liver enzymes
- Phase 3 (72-96h): Vomiting, symptoms of liver failure, renal failure, pancreatitis
- Phase 4 (>4 days): resolution of symptoms or progression to fatality. Cannot reverse the effect but can reduce the effect
What is phase 1 as symptoms of paracetamol poisoning?
(0-24h): nausea and vomiting
What is phase 2 as symptoms of paracetamol poisoning?
(24-72h): right upper quadrant Pain, elevated liver enzymes
What is phase 3 as symptoms of paracetamol poisoning?
(72-96h): Vomiting, symptoms of liver failure, renal failure, pancreatitis
What is phase 4 as symptoms of paracetamol poisoning?
(>4 days): resolution of symptoms or progression to fatality.
What is the Prescribing Cascade?
A prescribing cascade occurs when a new medicine is prescribed to ‘treat’ an adverse reaction to another drug in the mistaken belief that a new medical condition requiring treatment has developed.
Eg.
- Patient has infection
- Doctor A prescribed antibiotics
- Antibiotics causes nausea and diahorrea (doesn’t know the side effects)
- Goes to Doctor B with nasea and diahorrea
- Doctor B prescribes new medication
- Now on 2 medications for different things
What are 5 characteristics of preventing a prescribing cascade?
- Begin new medicines at low doses and adjust the dose to reduce the risk of adverse reactions.
- Consider the potential for any new symptoms to be caused by an adverse reaction, particularly if a medicine has been recently started or the dose changed.
- Ask patients if they have experienced any new symptoms, particularly if a medicine has been recently started or the dose changed.
- Any new medications?
- Provide patients with information about possible adverse effects of medicines and what to do when adverse drug reactions occur
- e.g. in the form of Consumer Medicines Information.
- The decision to prescribe a second medicine to counteract an adverse drug reaction from a first medicine should only occur after careful consideration, and where the benefits of continuing therapy with the first medicine outweigh the risks of additional adverse reactions from the second medicine.
What is poly-pharmacy and age?
The proportion of people using medications grows with age; most people over 44 years used only one type of medication, but by age 85 years, most are using 3 or more medications.
Taking multiple types of drugs contributes significantly to _____s.
ADR
What are 2 characteristics of ADRs?
- occur at all ages, and are twice as common in women, and a major contributor to morbidity and mortality in the elderly.
- Very little data on neonates, infants, children and teens…prescribers often estimate dosages for the young.
What is ADR?
An ADR is any noxious or unintended response to a drug that occurs at normal doses.
Many drug reactions are erroneously diagnosed as ______ or _____ responses.
hypersensitivity; allergic response
ADR’s significantly increase patient _____ and _____.
morbidity; mortality
Recognising and reporting ADR’s are a _____ priority.
high
ADR’s are classified according to their preventability: _______
ABCDE(F)
Patient _____ (age, genetics, disorder eg. Hepatic) are important for ADRs.
variation
ADR’s should be reported into the _____ to track the effects of drugs once they hit the general market.
national database
SUMMARY What are the five main classes of ADRs?
STUDY QUESTION
A: Acute predictable
B: Bizarre predictable
C: Chronic
D: Delated
E: End of treatment
How can drug metabolism impact on ADRs? Can you give 3 mechanisms? STUDY QUESTION
aaa
Drug A is known to induce CYP450 enzyme function which is used to metabolise Drug B. What would happen if Drugs A and B are taken together to the concentration of B? EXAM QUESTION
Taking drug A will increase the metabolism of drug B
- B will be metabolised faster
Drug C antagonises CYP1A2 – what will happen to the plasma concentration of Drug D uses CYP1A2 for metabolism? EXAM QUESTION
Plasma concentration increase
- Drug D can’t metabolise (decrease metabolism)
T/F Drug development tends to take 10 years for drugs to get to market.
EXAM QUESTION
True
