Unit 3

Question 1

What are side-effects?

Answer 1

The use of almost all drugs is associated with side-effects

A side-effect is an unwanted action caused by a drug used at a therapeutic dose

Side-effects will be listed in the product data-sheet.

Side-effects vary in severity and may be acute or chronic

Adverse drug reaction is a term used to describe any unwanted event associated with the use of a drug at therapeutic doses. This can be referred to as drug toxicity.

Question 2

Why do side effects occur?

Answer 2

Targets may be found in many parts of the body, not just the target organ
- Targeted drug delivery can reduce off-target effects

Drugs may interact with many targets in a dose-dependent manner
- Drugs may have affinity for many targets, but different potency of effect at these targets

Disease or physiological state (PK factors) may alter the concentration/distribution of the drug in the body

Question 3

What are dose-dependent side-effects?

Answer 3

Drugs can cause unwanted effects, commonly referred to as side-effects, at therapeutic doses.

Depending on the drug, these can be mild, moderate, or severe.

Question 4

What are the severities of drug side-effects?

Answer 4

Limited significance

Debilitating

Disabling

Fatal

Question 5

What is adverse drug reaction (ADR)?

Answer 5

Adverse drug reaction, ADR, is used to describe any reaction which is harmful that occurs at a therapeutic dose

ADRs can be referred to as SADRs (suspected adverse drug reactions) initially. This is because it may be difficult to prove a direct association between administration of a drug and the unwanted effect that is observed.

Question 6

What are type A adverse drug reactions (ADRs)?

Answer 6

Type A - Augmented

Expected, but exaggerated, responses which are predictable

Usually attributable to increased drug concentrations due to defective metabolism/excretion or inappropriate dosing

The MOST COMMON type of ADR

Question 7

What are type B adverse drug reactions (ADRs)?

Answer 7

Type B - Bizarre

Unexpected or abnormal responses

Not dose-dependent and cannot be predicted.

Examples include:
- Allergic and pseudoallergic reactions
- Direct, toxic, effects on organs by an action unrelated to that responsible for the therapeutic effect
- Aberrant responses in different species

Question 8

What are pseudoallergic reactions?

Answer 8

Reactions that resemble an allergic response but do not have an immunological basis.

No prior drug exposure is required.

One example is an anaphylactoid reaction caused by morphine which is due to release of histamine (from circulating basophils and tissue mast cells).

Allergic and pseudoallergic reactions will occur most commonly when a drug is injected intravenously.

Question 9

What are type C adverse drug reactions (ADR)?

Answer 9

Type C - Chronic

Only occur after prolonged use.

E.g. induction of Cushing’s disease by long-term administration of prednisolone (iatrogenic - i.e. drug-induced)

Question 10

What are type D adverse drug reactions (ADRs)?

Answer 10

Type D - Delayed

Occur at a time remote from drug treatment

E.g. Second cancers or thalidomide-induced phocomelia

Question 11

What are type E adverse drug reactions (ADRs)?

Answer 11

Type E - End of treatment

Occur when drug treatment is halted abruptly

E.g. withdrawal seizures after termination of anti-convulsant drugs; latrogenic Addison’s disease if the dose of a glucocorticoid is not tapered prior to stopping treatment

Question 12

What are type F adverse drug reactions (ADRs)?

Answer 12

Type F - Failure

Occur when the expected response is not achieved

Many reasons - look out for examples during the rest of the module. Type F ADRs are rarely due to primary failure of a drug.

Question 13

Why do Adverse drug reactions (ADRs) occur?

Answer 13

ADRs often occur due to human error (e.g. wrong diagnosis, drug dose, route of administration or duration of treatment; response to treatment or inadequately monitored).

These ADRs should be avoidable.

Question 14

What is the frequency of averse drug reactions (ADRs)?

Answer 14

Despite the large number of adverse event reports received annually, when put into context with the number of doses of all products administered to animals throughout the year, the chance of an adverse event remains VERY LOW

Question 15

What do we know about Adverse drug reactions (ADRs) in human medicine?

Answer 15

Are estimated to account for 6-7% of hospital admissions

Are estimated to occur in 10-20% of hospital in-patients
- Equivalent cost of these is ~£380 million a year

~52% of ADRs present at time of hospitalisation/ emergency visit were classified as preventable

ADRs should be reported to the Medicines and Healthcare Products Regulatory Agency (MHRA) if they:
- Are serious, medically significant or result in harm (even if well recognised)
- Associated with new drugs or vaccines

They are particularly interested in ADRs in children, people over 65, associated with delayed drug effects, are related to complementary remedies

Question 16

What are some common ADRs in human patients?

Answer 16

Gastric bleeding

Peptic ulceration

Renal impairment

Hypotension

Wheezing

Constipation

Question 17

What do we know about the incidence of ADRs?

Answer 17

Occurrence of ADRs is not homogeneous throughout a patient population

The incidence will be higher in those with genetic, physiological or pathological predispositions

The likelihood of an ADR being reported is likely to be influenced by factors that include:
- Novelty/severity
- How recently a product has come onto the market
- Media coverage

Question 18

What are the difficulties in diagnosis of Adverse drug reactions (ADRs) in clinicians and clinical signs?

Answer 18

Diagnosis depends on the expertise of the attending clinician(s) and the quality of the available information.

The clinical signs are almost always non-specific and can occur in healthy individuals. They are rarely pathognomonic (a sign or signs so characteristic of a disease that a diagnosis can be based upon it/them.

An ADR may not be detected if the clinical signs are similar to a common disease syndrome.

Question 19

What is the Nocebo effect?

Answer 19

ADRs have been reported by human patients following administration of a placebo

This is known as a nocebo effect.

Question 20

What are the difficulties in diagnosing Adverse drug reactions (ADRs)?

Answer 20

Patients may be on multiple medications.

The underlying pathology may affect the way in which the ADR manifests

It may be assumed that the active principle in the medicinal product caused the ADR but it may be due to an excipient(s) or to degradation products that can be formed during storage.

For new products, there will be limited information available about the ADRs associated with their use.

Question 21

What is pharmacovigilance, why is it important for Adverse drug reactions (ADRs)?

Answer 21

The process and science of monitoring the safety of medicine and taking action to reduce the risks and increase the benefits of medicines. It is a key public health function.

Continued pharmacovigilance is essential if ADRs - particularly those that occur infrequently - are to be identified.

Question 22

What are the factors affecting type A Adverse drug reactions (ADRs)?

Answer 22

1. Species
2. Genetics
3. Body weight
4. Age
5. Gender
6. Pathology
7. Drug interactions

Question 23

How does SPECIES affect type A Adverse drug reactions (ADRs)?

Answer 23

Species causes differences in drug action on the body

E.g. Cats metabolise drugs that depend on conjugation by glucronyl transferases very slowly. Aspirin can be used safely in the cat as long as the dosing interval is increased.

Question 24

How does GENETICS affect type A Adverse drug reactions (ADRs)?

Answer 24

There are examples of species breed and within-breed genetic differences in animals

E.g.
Sulphonamide toxicity in dobermans due to a limited capacity to detoxify hydroxyl amine metabolites.

Question 25

How does BODY WEIGHT affect type A Adverse drug reactions (ADRs)?

Answer 25

Drug doses usually calculated on a Mg/kg basis. However, metabolic rate and the ability to metabolise a drug is more closely linked to body surface area than weight. This can lead to overdosing of large breeds when there is considerable variation in body weight within a species and can be important if a drug has a low therapeutic index (ratio of toxic to therapeutic dose)

Fat is a component of body weight. Therefore when dosed on a mg/kg basis: obese individuals may be overdosed when given poorly lipid-soluble drugs because a higher percentage of their body weight is fat

AND

Lean/malnourished individuals may be overdosed when given highly lipid-soluble drugs because a proportion of the drug dose would be expected to accumulate in fat

Question 26

How does AGE affect type A Adverse drug reactions (ADRs)?

Answer 26

Neonates are likely to metabolise drugs more slowly due to underdeveloped hepatic or renal excretory mechanisms

Drug absorption across the gastrointestinal tract and blood-brain barrier is also greater. There is a higher percentage of body water and drug binding to plasma protein binding is lower.

Elderly individuals may clear drugs more slowly due to impaired hepatic or renal excretory mechanisms. Their body water and lean body mass may be reduced.

Question 27

How does GENDER affect type A Adverse drug reactions (ADRs)?

Answer 27

ADRs are reported to occur more commonly in women. It is not known whether this is the same in (entire) female animals.

As is the case in women, drugs that might affect the foetus or neonate should be used with caution in pregnant or lactating female animals

Question 28

How does PATHOLOGY affect type A Adverse drug reactions (ADRs)?

Answer 28

Pharmacokinetics may be altered by hepatic or renal disease and drug doses may need to be adjusted

Effects of hepatic disease are difficult to predict but, in general, the dosing interval will need to be increased

The higher the proportion of a drug that is excreted unchanged by the kidneys, the greater the effect of renal disease.

For nephrotoxic drugs, the effect will be increased in dehydrated patients or those with renal disease.

Question 29

How does DRUG INTERACTIONS affect type A Adverse drug reactions (ADRs)?

Answer 29

Concurrent administration of one drug can affect the actions of another.

Interactions may be:
- Pharmacokinetic (most common) effects on absorption, distribution, metabolism and excretion can all occur
- Pharmacodynamic
- Chemical

NOTE that dietary supplements, natural or herbal remedies also have the potential to interact with conventional medicines.

Question 30

When is the potential for Type A adverse drug reactions (ADRs) to occur higher?

Answer 30

In:
Individuals with organ dysfunction

The young and the elderly

Obese or cachetic individuals

Individuals on multiple drug therapy

Animal species for which safe use of a drug/class of drug has not been established.

Question 31

How do we avoid life-threatening adverse drug reactions (ADRs)

Answer 31

Some drugs have the potential to produce unwanted effects that can be life-threatening

Always use/administer any drug product with care and adhere to the recommendations ~ About dose, frequency of dosing, route of administration, duration of treatment etc.