Therapeutics L3 Dr Monem Alshok
Adverse Drug Reactions: ADRs is An undesirable response to drug therapy
Idiosyncratic ,Hypersensitivity reactions or might be a Drug interactions.
ADRs : Can be defined as, ‘an unwanted or harmful reaction experienced following administration of a drug, or combination of drugs, under normal conditions of use and is suspected as being related to the drug (or combination)’
ADR , AD Events & Side Effects :
1 . Medication Misadventures or Adverse drug events these :
n ALL are preventable
n Medication errors that result in patient harm
2 . Adverse drug reactions : these are
n Inherent, not preventable event occurring in the normal therapeutic use of a drug
n Any reaction that is unexpected, undesirable, and occurs at doses normally used
3 . Some adverse drug reactions are classified as side effects.
n Expected, well-known reactions that result in little
or no change in patient management
n Predictable frequency
n The effect’s intensity and occurrence is related to
the size of the dose
Iatrogenic Responses : Unintentional adverse effects that are treatment-induced( e.g. ) Dermatologic ,Renal damage ,Blood dyscrasias , Hepatic toxicity.
Other Drug-Related Effects include :Teratogenic , Mutagenic ,Carcinogenic
Why we take a drug history?Drugs:( Adverse effects ,Allergy , Abused Addiction ) ,can cause disease (early or late) can conceal disease ,can give diagnostic clues., can interfere with diagnostic tests ,history can assist treatment choice
Any History of adverse reactions?
“I can’t take antibiotics, they make me ill, doctor”
n Which specific drugs?
n When?
n Actual adverse reaction, beware “allergy”
n Similar drugs since?
Adverse drug reactions are classified mechanistically and clinically: This can be done using two complementary classification systems: EIDOS and DoTS ,Understanding adverse reactions in this way contributes to areas such as drug development and regulation, pharmacovigilance, monitoring therapy, and the prevention, diagnosis and treatment of adverse drug reactions.
The EIDOS :
Extrinsic species This can be the parent compound, an excipient, a contaminant or adulterant, a degradation product, or a derivative of any of these (e.g. a metabolite).
Intrinsic species :This is usually the endogenous molecule with which the extrinsic species interacts. This can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter, or some other protein.
Distribution: A drug will not produce an adverse effect if it is not distributed to the same site as the target protein that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse effects
Outcome : Interactions between extrinsic and intrinsic species in the production of an adverse effect can result in physiological or pathological changes. Physiological changes can involve either increased actions (e.g. clotting due to tranexamic acid) or decreased actions (e.g. bradycardia due to ?-blockers). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyperplasia, metaplasia and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions) or cell damage (e.g. cell lysis, necrosis or apoptosis
Sequela The sequela of the changes induced by a drug describes the clinically recognisable adverse drug reaction, of which there may be more than one. Sequelae can be classified using the DoTS system
Clinical classification of adverse drug reactions-DoTS Body: The DoTS clinical classification of adverse drug reactions takes into account three aspects of the interaction between the patient and the drug that produces an adverse effect: the relation of the adverse effect to
n the Dose of the drug
n the Time course of the effect
n the Susceptibility of the patient
There are three types of adverse drug effect:
n A toxic effect is one that occurs as an exaggeration of the desired therapeutic effect and occurs at doses at or near the top of the dose-response curve. For example, syncope due to a ?-blocker is a toxic effect; it occurs by the same mechanism as the therapeutic effect (lowering of the blood pressure).
n Collateral effects occur at doses in the middle of the usual dose-response curve but in a tissue other than that in which the therapeutic action is sought. They can occur:
¨ - through the same pharmacological effect as that whereby the therapeutic action is produced (for example, colour vision disturbance from sildenafil)
¨ - through a distinct pharmacological effect (for example, a dry mouth due to an anticholinergic effect of a tricyclic antidepressant).
n Hypersusceptibility effects occur at subtherapeutic doses in susceptible patients. Penicillin allergy is a hypersusceptibility effect.
Toxic effects: can be avoided by using dosages at the lower end of the recommended range and increasing cautiously, monitoring carefully for therapeutic and adverse effects.Collateral adverse effects: may not be avoidable; if they occur despite careful dosage adjustment, it may be necessary to use a different drug. Hypersusceptibility effects :can be avoided by identifying the susceptibility factors that contribute to them; for example, a history of penicillin allergy is a contraindication to the use of any penicillin.
What are the Source of altered susceptibility to ADRs? Please go to Davidson s Pag17
Special problems in ADRs :Delayed drug effects. Some reactions (e.g. cancers, chloroquine retinopathy, and retroperitoneal fibrosis) may become manifest months or years after exposure. Any suspicion of such an association should be reported. The elderly. Particular vigilance is required to identify adverse reactions in the elderly.Congenital abnormalities. When an infant is born with a congenital abnormality or there is a malformed aborted fetus doctors are asked to consider whether this might be an adverse reaction to a drug and to report all drugs (including self-medication) taken during pregnancy.Children. Particular vigilance is required to identify and report adverse reactions in children.
Importance of ADRs :
Causes considerable morbidity and mortality; treating this is very expensive . Data on incidence is poor considering the scope of the problem .Typical figures for the USA (where most studies have been done) suggests( a ) precipitate 1-4% of acute medical admissions , ( b ) 4-9% of inpatients suffer an ADR ,( c ) 7,000 deaths per annum directly reflect an DR & some sources put the figure closer to 100,000 .
Majority are preventable, Strategies for prevention include:
¨ Ward Clinical pharmacists
¨ Electronic prescribing and dispensing (Already in Primary Care/GPs & Extension to Hospitals)
¨ Better education.
Prevention of adverse reactions :
n never use any drug unless there is a good indication. If the patient is pregnant do not use a drug unless the need for it is imperative;
n allergy and idiosyncrasy are important causes of adverse drug reactions. Ask if the patient had previous reactions;
n ask if the patient is already taking other drugs including self-medication drugs, health supplements, complementary and alternative therapies; interactions may occur
n age and hepatic or renal disease may alter the metabolism or excretion of drugs, so that much smaller doses may be needed. Genetic factors may also be responsible for variations in metabolism, notably of isoniazid and the tricyclic antidepressants;
n prescribe as few drugs as possible and give very clear instructions to the elderly or any patient likely to misunderstand complicated instructions;
n whenever possible use a familiar drug; with a new drug, be particularly alert for adverse reactions or unexpected events;
n age and hepatic or renal disease may alter the metabolism or excretion of drugs, so that much smaller doses may be needed. Genetic factors may also be responsible for variations in metabolism, notably of isoniazid and the tricyclic antidepressants;
n prescribe as few drugs as possible and give very clear instructions to the elderly or any patient likely to misunderstand complicated instructions;
Responsibilities of the physician?
n How and when to take the medicine
n What to do about a missed dose
n How long the medicine is likely to be needed
n How to recognise ADRs and how to respond to them
n Important interactions with e.g. alcohol and other medicines
What should you tell the patient ?
n About the condition and why we are treating it
n The name of the medicine :It may help to write this down for the patient
n The objective of the treatment
n Whether and how the patient will judge benefit
n How soon benefit can be expected
n How and when to take the medicine
n What to do about a missed dose
n How long the medicine is likely to be needed
n How to recognise ADRs and how to respond to them
n Important interactions with e.g. alcohol and other medicines
n The prescription – pitfalls :Doses &Route: Choose an appropriate route e.g. is the patient vomiting?Care with doses with different routes e.g. Penicillin 1.2g iv versus 1.2mg intrathecal .Do not use the im route if patient is anticoagulated.Doses of Vancomycin in Cl difficile 125mg qds PO , whereas in Staph aureus 1g bd IV . Dose reduction inElderly, renal failure, hepatic failure . In Children Dose often calculated by weight. Paediatric pharmacopoeia available
Rate :Bolus vs Infusion ( e.g. ) Vancomycin “red man syndrome” , Frusemide and ototoxicity . Over Minutes or hours . In ml or mg . Example : GTN 50mg in 50ml (5% dextrose) at 1 to 10 ml per hour.
Cost In Cl Difficile & PU: Metronidazole 3000-50000 ID .
Vancomycin150 000ID . Rabeprazol Sodium 36000ID
Absolute Beta blockers and asthma ,Misoprostol and pregnancy and
Tetracycline Pregnancy
Relative Ciprofloxacin and epilepsy