4.1 Pharmacovigilance And Pharmacogenetics Flashcards
What is pharmacovigilance?
Identification, assessment and subsequent prevention of adverse drug reactions whilst optimising benefits
Responsibility lies with prescribers, patients and carers
The most common clinical adverse event is a drug reaction
What are serious ADRs?
Fatal Life-threatening Prolonged hospitalisation Long term disability Congenital abnormalities
What are the common features of type A (augmented) Reactions aka ARDs?
Dose-related
Predictable from pharmacology Common Reversible
Manageable with dose adjustment
E.g Warfarin
What are the common features of type B(bizarre) ARDs?
Not dose-related Uncommon Unpredictable Serious/irreversible Indicative that the drug needs to be stopped
E.g Anaphylaxis with penicillin, agranulocytosis with clozapine, thrombocytopenia
What is the mechanism of ADRs?
Usually mimic disease or syndrome that occur naturally
Importantly, may have non therapeutic causes (causality)
Some syndromes causality solely due to therapeutic agents
Broadly 4 mechanisms of action for ADR
- Exaggerated response (bleeding warfarin)
- Desired pharmacological effect at alternative/additional site (GTN
What are the limitations of pre marketing clinical studies and ADRs?
Small number of patients
Limited by age and possibly gender
Selected following precise diagnoses
Short, well defined duration
Specialist doctors and continuous follow up
Concomitant therapeutics usually excludes
What is pharmacogenetics?
The whole genome and its affects on drugs, considering epigenetics
Understanding will help reduce preventable ADR
What populations is renin usually low on?
Afro Caribbean
Where are steroid hormone receptors?
Classic nuclear receptors
Exert effect via gene transcription
ALSO there is a membrane receptor for oestrogen
What are the major effects of oestradiol?
Stimulates growth of the endometrium and breast; stimulates production of Progesterone receptors
What is the major effect of progesterone ?
Stimulates growth of the endometrium and breast; maintains pregnancy; inhibits production of oestrogen receptors
What are the major effects of testosterone?
Stimulates male characteristics; hairy body; deep voice; anabolism; aggression.
What are the actions and side effects of oestrogen?
Actions
Mild anabolic Sodium and water retention Raises HDL, lowers LDL Decrease bone resorption Impair glucose tolerance Increase blood coagulability
Side effects
Breast tenderness Nausea, vomiting Water retention Increased blood coagulability Thromboembolism Impaired glucose tolerance Endometrial hyperplasia & cancer Ovarian metaplasia & cancer Breast hyperplasia & cancer
What are the actions and side effects of progesterone?
Actions
Secretory endometrium Anabolic Increases bone mineral density Fluid retention Mood changes Maintains pregnancy
Side effects
Weight gain as preparing for pregnancy Fluid retention Anabolic Acne Nausea/vomiting Irritability Depression, PMS Lack of concentration (pregnancy brain)
What are the actions and side effects of testosterone?
Male secondary sex characteristic Anabolic Acne Voice chances Increased aggression
Side effects
Metabolic - adverse effects on lipid profiles particularly the HDL/LDL ratio hence increased risk of atherosclerotic disease in males
How is oestrogen absorbed, metabolised and excreted?
Absorbed in the GI tract and from skin and muscles membranes
Metabolised in liver
Excreted in urine as glucuronides and sulfates
How is progesterone taken in, metabolised and excreted?
Injected progesterone is bound to albumin with some stored in adipose tissue
Metabolised in the liver
Metabolites excreted in the urine conjugated to glucuronic acid
What are the adverse effects of the combined pill?
Small risk of thromboembolism
Smoking increases the risk
Also for long term use in women over 35
Other risk factors include obesity and hypertension
What are the combined and progesterone only contraceptive pills metabolism effected by and why?
Metabolised in liver by CYP450 enzymes
Therefore oral contraceptive efficacy is reduced by enzyme inducing drugs
E.g anti epileptics carbamazepine or phenytoin
Antibiotics e,g rifampicin
Because they all increase the production of hepatic CYP450
How does soya protein effect oestrogen absorption?
Enhances oestrogen absorption and reduces its storage in adipose and muscle and so causes T1/2 to be reduced from 15 to 7 hours
Why would you prescribe hormone replacement therapy?
Alleviate symptoms e.g hot flushes and
However carries risk of stroke
What are the routes of administration of hormone replacement therapy?
Oral Transdermal Implant Transvaginal NasL
