Unit 3 Flashcards
What are side-effects?
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.
Why do side effects occur?
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
What are dose-dependent side-effects?
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.
What are the severities of drug side-effects?
Limited significance
Debilitating
Disabling
Fatal
What is adverse drug reaction (ADR)?
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.
What are type A adverse drug reactions (ADRs)?
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
What are type B adverse drug reactions (ADRs)?
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
What are pseudoallergic reactions?
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.
What are type C adverse drug reactions (ADR)?
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)
What are type D adverse drug reactions (ADRs)?
Type D - Delayed
Occur at a time remote from drug treatment
E.g. Second cancers or thalidomide-induced phocomelia
What are type E adverse drug reactions (ADRs)?
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
What are type F adverse drug reactions (ADRs)?
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.
Why do Adverse drug reactions (ADRs) occur?
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.
What is the frequency of averse drug reactions (ADRs)?
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
What do we know about Adverse drug reactions (ADRs) in human medicine?
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
What are some common ADRs in human patients?
Gastric bleeding
Peptic ulceration
Renal impairment
Hypotension
Wheezing
Constipation
What do we know about the incidence of ADRs?
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
What are the difficulties in diagnosis of Adverse drug reactions (ADRs) in clinicians and clinical signs?
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.
What is the Nocebo effect?
ADRs have been reported by human patients following administration of a placebo
This is known as a nocebo effect.
What are the difficulties in diagnosing Adverse drug reactions (ADRs)?
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.
What is pharmacovigilance, why is it important for Adverse drug reactions (ADRs)?
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.
What are the factors affecting type A Adverse drug reactions (ADRs)?
- Species
- Genetics
- Body weight
- Age
- Gender
- Pathology
- Drug interactions
How does SPECIES affect type A Adverse drug reactions (ADRs)?
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.
How does GENETICS affect type A Adverse drug reactions (ADRs)?
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.
How does BODY WEIGHT affect type A Adverse drug reactions (ADRs)?
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
How does AGE affect type A Adverse drug reactions (ADRs)?
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.
How does GENDER affect type A Adverse drug reactions (ADRs)?
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
How does PATHOLOGY affect type A Adverse drug reactions (ADRs)?
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.
How does DRUG INTERACTIONS affect type A Adverse drug reactions (ADRs)?
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.
When is the potential for Type A adverse drug reactions (ADRs) to occur higher?
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.
How do we avoid life-threatening adverse drug reactions (ADRs)
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.