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Pharmacology and therapeutics > Adverse Drug Reactions > Flashcards

Adverse Drug Reactions Flashcards

1
Q

What can too much vitamin C give you

A

Kidney stones

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2
Q

What is important to remember about clinical pharmacology

A

All substances are poisons: there is none that
is not a poison. The right dose differentiates
a poison from a remedy.

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3
Q

What is meant by an adverse drug event

A

preventable or unpredicted medication event—with harm to patient

could be due to an adverse drug reaction or due to a medication error ( wrong drug or wrong dose prescribed)

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4
Q

Describe the importance of adverse drug reactions

A

They are costly and cause a lot of morbidity and mortality in patients.

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5
Q

Describe the epidemiology of ADRs

A

substantial morbidity and mortality
estimates of incidence vary with study methods, population, and ADR definition
4th to 6th leading cause of death among hospitalized patients*
6.7% incidence of serious ADRs*
0.3% to 7% of all hospital admissions
annual costs in the billions (?$120 billion in US)
30% to 60% are preventable

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6
Q

Generally, how can we classify ADRs

A

Onset
Severity
Type

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7
Q

Summarise the classification of ADRs based on onset

A

Acute - most commonly anaphylactic immune reactions
Within 1 hour

Sub-acute
1 to 24 hours

Latent
> 2 days

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8
Q

Summarise the classification of ADRs based on the severity of the reaction

A

Mild
requires no change in therapy

Moderate
requires change in therapy, additional treatment, hospitalisation

Severe
disabling or life-threatening

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9
Q

Outline the consequences of a severe ADR

A

Results in death
Life-threatening
Requires or prolongs hospitalisation (LIVER DAMAGE)
Causes disability
Causes congenital anomalies
Requires intervention to prevent permanent injury (ANTIDOTES, AVOID THE DRUG ALTOGETHER)

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10
Q

Describe type A ADRs

A

extension of pharmacologic effect
usually predictable and dose dependent
responsible for at least two-thirds of ADRs
e.g., atenolol and heart block, anticholinergics and dry mouth (also visual problems and constipation), NSAIDS and peptic ulcer

Augmented and often predictable effect of the pharmacology of the drug- but sometimes we don’t understand why the side effects are produced.

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11
Q

How can we reverse type A ADRs

A

In many instances, this type of unwanted effect is reversible, and the problem can often be dealt with by adjusting the dose to obtain a more favourable balance between efficacy and safety.
This may be problematic in patients who have developed tolerance for opiods.

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12
Q

Compare the relationship between the incidence of ADRs (y-axis) and dose (x-axis) for digoxin and paracetemol

A

§ Paracetamol has a threshold below which it has minimal side effects (and then exceeding this, side effects rapidly increase). Digoxin just has a dose-dependent line with constant increasing SEs. (linear relationship with digoxin)

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13
Q

Summarise type B ADRs

A

Examples of such ADRs, which are often immunological in nature, include drug-induced hepatic or renal damage, bone marrow suppression, carcinogenesis and disordered fetal development. Uncommon but severe unpredictable adverse effects that have been mentioned in earlier chapters include aplastic anaemia from chloramphenicol and anaphylaxis in response to penicillin. They are usually severe – otherwise they would go unrecognised – and their existence is important in establishing the safety of medicines. The unpredictable nature of such reactions means that adjustment of the recommended therapeutic regimen (e.g. using a lower dose) may not prevent them.

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14
Q

Outline the classification for type B ADRs

A 
idiosyncratic or immunologic reactions
includes  allergy and “pseudoallergy”
rare (even very rare) and unpredictable
e.g., chloramphenicol and aplastic anemia,
	ACE inhibitors and angioedema

Many serious ADRs are totally unexpected eg Herceptin
and cardiac toxicity

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15
Q

What is meant by aplastic anaemia

A

Total bone marrow failure

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16
Q

Describe angioedema

A

Similar to anaphylaxis:

Swelling of lips and tongue, heart failure, breathlesness to bronchoconstriction.

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17
Q

Nowadays, what are all anti-cancer drugs tested for

A

cardiac toxicity

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18
Q

Outline type C ADRs

A

associated with long-term use
involves dose accumulation
e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity

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19
Q

What is the key factor in type C ADRs

A

how much of the drug has accumulated over time

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20
Q

What is methotextrate used to treat

A

Immunosupressant

anti-cancer drug

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21
Q

Give an example of some antimalarial drugs

A

Chloroquinolone and hydrochloroquinolone

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22
Q

Outline the type D classification of ADRs

A 
delayed effects (sometimes dose independent)
carcinogenicity (e.g. immunosuppressants)
teratogenicity (e.g. thalidomide)
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23
Q

Outline the type E ADRs

A

End of treatment side effects. BDP = benzodiazepines.

§ Withdrawal reactions – patient cannot make endogenous supply – opiates (cold turkey reaction), corticosteroids, BDPs.

§ Rebound reactions – disease gets worse when drugs stopped – clonidine, b-blockers, corticosteroids.

§ “Adaptive” reactions – adapted body reactions to drugs – neuroleptics (tranquilisers). and anti-psychotics for schizophrenia.

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24
Q

Why is it important not to stop prescribing corticosteroids immediately to a patient who has been on them for a long period of time

A

The patient will have lost the ability to make steroids

Therefore their CVS may collapse after sudden withdrawal.

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25
Describe and explain the clonidine rebound
Clonidine is an alpha-2 agonist so it suppresses the release of noradrenaline Long-term use of clonidine leads to an upregulation in adrenergic receptors on the post-synaptic membrane If the dose of clonidine is missed once or twice, it will cause an increase in noradrenaline release, which then acts on an increased number of receptors so has a greater effect This causes a large increase in blood pressure
26
Summarise the Rawlins and Thomson classification for ADRs
``` A Augmented pharmacological effect B Bizarre C Chronic D Delayed E End-of-treatment ```
27
Essentially, what are the two types of hypersensitivity reactions
Hypersensitivity reactions of types I, II and III (Ch. 7) are antibody-mediated reactions, while type IV is cell mediated.
28
Outline the types of allergic reactions
Type I - immediate, anaphylactic (IgE) e.g., anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and hemolytic anemia Type III - serum sickness (IgG, IgM) antigen-antibody complex e.g., procainamide-induced lupus Type IV - delayed hypersensitivity (T cell) e.g., contact dermatitis
29
What is important to remember about anaphylactic reactions
They are a medical emergency and thus require treatment immediately.
30
Give examples of pseudoallergies
Aspirin/NSAIDs and bronchoconstriction • This occurs because aspirin and NSAIDs inhibit the production of prostaglandins, which are bronchodilators and pro-inflammatory -caution when given to asthmatics • They promote the production of leukotrienes, which are bronchoconstrictors ACE inhibitors and cough/angioedema • ACE inhibitors prevent the breakdown of kinins • Kinins accumulate in the sensory nerves in the lungs and trigger cough Substitute for another type of drug More common in afro-carribeans Angioedema- a milder and non-immunological version of anaphylaxis.
31
Which four classes of drug account for over 2/3rds of ADRs
Antineoplastics Cardiovascular drugs NSAIDs/analgesics CNS drugs This is because so many patients are taking these drugs- so the NUMBER is large but the INCIDENCE is small.
32
List some other drugs which commonly cause ADRs
Hypoglycemics Antihypertensives Antibiotics Antiocagulants
33
What does ADR frequency increase with
Increasing drug use
34
Describe the two ways in which we can detect ADRs
``` Subjective report patient complaint (yellow card scheme)- clinician will then determine whether this ADR is likely (based on his knowledge of the pharmacology of the drug). ``` ``` Objective report: direct observation of event abnormal findings physical examination laboratory test diagnostic procedure ```
35
Explain why rare ADRs will probably not be detected before the drug is marketed
Even is the expected incidence is 1 in 100 You will probably need to see more cases (i.e 300) to pick up one event. And 650 cases to pick up 3 events.
36
Summarise the yellow card scheme
introduced in 1964 after thalidomide run by the Medicines and Healthcare Products Regulatory Agency (MHRA) entirely voluntary can be used by doctors, dentists, nurses, coroners and pharmacists, and members of the public includes blood products, vaccines, contrast media for established drugs only report serious adverse reactions (fatal, life-threatening, needing hospital admission, disabling) for “black triangle “ drugs (newly licensed, usually <2 years) report any suspected adverse reaction
37
Outline what should happen if an ADR is suspected
Try and confirm it (to a high probability) The try and estimate the frequency Then report it to the prescribers- who should withdraw the drug overnight if it appears to be a high risk to the patient.
38
Why are drug interactions almost inevitable
Because of the issue of polypharmacy
39
Explain why the true incidence of ADRs is difficult to determine
True incidence difficult to determine Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs Lack of availability of comprehensive databases (lots of different drug combinations and lots of different patients). Difficulty in assessing OTC and herbal drug therapy use Difficulty in determining contribution of drug interaction in complicated patients Sometimes principal cause of ADRs with specific drugs eg statins
40
What is important to remember about statins
Much of the toxicity of statins is due to the combination with other drugs- by enhancing their toxicity by blocking their metabolism.
41
Outline the 3 types of drug interactions
Pharmacodynamic Related to the drug’s effects in the body Receptor site occupancy Pharmacokinetic Related to the body’s effects on the drug Absorption, distribution, metabolism, elimination Pharmaceutical - drugs interacting outside the body (mostly IV infusions)- things being added to IV. lines that shoudln't be.
42
What are the 3 types of pharmacodynamic drug interactions
Additive, synergistic, or antagonistic effects from co-administration of two or more drugs Additive- drugs result in the same result but work via different mechanisms Synergistic- one drug potentiates the effect or toxicity of another
43
Give some examples of pharmacodynamic drug interactions
· Synergistic actions of antibiotics – use of two ABs will increase the effect more than their separate contributions (i.e. 2+2=5) OR they antagonise each other. Overlapping toxicities - ethanol & benzodiazepines (additive) Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
44
Describe how pharmacodynamic drug interactions are often deliberate
B2 agonists and bronchodilators often given to asthmatics- same result- but work via different mechanisms Additive.
45
Summarise the different types of pharmacokinetic drug interactions
Alteration in absorption Protein binding effects (albumin binding) Changes in drug metabolism Alteration in elimination
46
Give an example of an alteration in drug absorption
Chelation Irreversible binding of drugs in the GI tract to form something insoluble or something that cannot be absorbed Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
47
What is meant by protein binding interactions
Competition between drugs for protein or tissue binding sites Increase in free (unbound) concentration may lead to enhanced pharmacological effect Many interactions previously thought to be PB interactions were found to be primarily metabolism interactions
48
What is a key protein binding interaction to remember
PB interactions are not usually clinically significant but a few are (mostly with warfarin) · Warfarin is 99% albumin-bound so anything to decrease that will increase the free warfarin so there is more anti-coagulative effects.
49
Describe the different paths of drugs for elimination or metabolism
Can be excreted unchanged by the kidney -- furosemide (diuretic) Can undergo phase 1 metabolism in the liver, kidney or gut and then be excreted Can undergo phase 2 metabolism in the kidney and then be excreted.
50
What different reactions can occur in phase 1 metabolism
Phase 1 metabolism = oxidation, reduction, hydrolysis.
51
What reactions occur in phase 2 metabolism and what is its purpose
§ Phase 2 metabolism = conjugation (glutathione, amino-acid), glucuronidation, sulphation, acetylation and methylation. Convert the drug into a water-soluble polar form (often mean that the drug is ionised).
52
What can drug metabolism be inhibited or enhanced by
Drug metabolism inhibited or enhanced by coadministration of other drugs CYP 450 system has been the most extensively studied CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others Phase 2 metabolic interactions (glucuronidation, etc.) occur, research in this area is increasing
53
Describe CYP450 metabolism by a single isoenzyme
Metabolism by a single isozyme (predominantly) Few examples of clinically used drugs Examples of drugs used primarily in research on drug interactions
54
Describe CYP450 metabolism by multiple isoenzymes
Most drugs metabolized by more than one isozyme Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19 If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme Imipramine is an anti-depressant
55
Which CYP450 enzymes are responsible for over half of drug metabolism
CYP2D6 CYP3A4 CYP 3A4 is the most common in humans
56
Which CYP450 is responsible for the metabolism of paracetemol
CYP1A2
57
List some CYP450 inhibitors
Cimetidine (a2 antagonist in peptic ulcers) Erythromycin and related antibiotics (macrolides) Ketoconazole etc Ciprofloxacin and related antibiotics (quinolones) Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice (furanocoumarins- CYP 3A4)
58
What are the CYP450 inducers
``` Rifampicin (nati-TB) Carbamazepine (anti-epileptic) (Phenobarbitone) (CNS suppressant) (Phenytoin) (anti-epileptic) St John’s wort (hypericin) (anti-depressant) ```
59
Compare the time course of action between CYP450 inhibitors and CYP450 inducers
Inhibitors- instantaneous and rapid effect | Inducers- slow effect- needs to alter mRNA and thus gene expression.
60
Give some examples of drug elimination interactions
Almost always in renal tubule - probenecid and penicillin (good)- prevents the elimination of penecillin- so high levels remain in the plasma - lithium and thiazides (bad)- sodium lost at expense of lithium in DCT- lithium builds up- more toxicity
61
What is lithium often prescribed for
A mood stabiliser
62
Give some examples of deliberate drug interactions
Levodopa + carbidopa can use lower doses of levodopa as carbidopa reduced peripheral metabolism. § ACEi + thiazides treat HF and HTN § Penicillin’s + gentamycin treat severe staph. Infections. § Salbutamol + ipratropium beta-agonists and anti-muscarinics used in inhalers to treat asthma.
63
What else is important to remember
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Pharmacology and therapeutics (30 decks)

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