بسم الله الرحمن الرحيم

Adverse drug reactions

Dr- Thorayia Ali Mustafa

ADVERSE DRUG REACTIONS

definition:

Adverse dug event:• is “an injury resulting from the use of a drug. includes harm caused by the drug (adverse drug reactions

and overdoses) and harm from the use of the drug (medication error)

• What is an adverse drug reaction (ADR)?An adverse drug reaction is a “response to a drug which is

noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.

• What is a medication error?Medication errors are mishaps that occur during

prescribing, transcribing, dispensing, administering, adherence, or monitoring a drug.

Why learn about ADRs?• Over 2 million serious ADRs occur yearly!• 100,000 deaths occur yearly.• Is the 4th leading cause of death ahead of pulmonary disease, DM,AIDS and automobile accidents deaths.• 136 billion dollars is the yearly economic burden.• Greater than total cost of cardiovascular or diabetic care.• Causes 1 out of 5 injuries or deaths per year to hospitalized patients.• Mean length of stay, cost and mortality for ADRs patients are double

that for control patients.

Classifications:• Type a: augmented reaction• Type B: bizarre reaction dose independent & un

predictable 1- idiosyncratic (genetic) 2- drug allergy & anaphylaxis• Type C: continues reaction• Type D: delayed drug reaction carcinogenesis - teratogenesis• Type E: end of treatment reaction (sudden withdrawal)• Type F: failure of therapy

Type A

Occur in all patientsPredictable and dose dependant1- due to exaggerated normal pharmacological effect:

B-blocker hypotension diazepam sedation diuretic hypokalemia2- due to effect in undesired location: chlorpromazine galactorrhea, parkinsonism cytotoxic drug bone marrow depression

Type B- bizarre reactions

• Occur in some patients onlyUn related to known actions of the drugUnpredictable and not dose dependent• Low incidences but fatal reactions

glucocorticoid eye drops glaucoma oral contraceptives jaundice• can affect any organ, but the most common organs involved are liver, skin, and bone marrow• life-threatening type B adverse reactions include: hepatotoxicity, aplastic anemia, and blood dyscrasias.

Type B- bizarre reactions

1- Idiosyncrasy (genetic) abnormality:

• Slow acetylators• G6P deficiency • Cholinesterase

deficiency

2-Drug allergy and anaphylaxis:

• Penicillin- insulin- heparin

• Management: adrenaline- anti histamine and oxygen.

Type C- continueous drug interaction

• Due to prolonged useAntipsychotic parkinsonismNSAI and analgesics nephropathy

Type D- delayed reaction

• Carcinogenesis:Takes a long time > 3 yearsEstrogens causes endometrial cancerCyclophosphamide mutation. Staff handling cytotoxic drugs protective measures

• Teratogenesis:Stilbosterol abortion & vaginal adenocarcinomaTetracycline discoloration of teeth & altered bone

growthPhenytoin cleft lipValproate spina bifidaMisoprestol abortion

Type E- end of treatment reactions:

• Sudden withdrawal of drugs rebound effects• Clonidine, B blockers rebound hypertention• Corticosteroids adrenocortical insufficiency.• Antiepileptic seizures.

Causes of ADRs:• 1-Patient factors:Age- pharmacokinetic variable- drugs- breast feeding-

disease state.Older and younger patients are more susceptible due to

their insufficient detoxification mechanisms.And their lower liver and renal functions. Chloramphenicol Gray baby syndrome

The elderly are more likely to multiple Drugs so they are more prone to drug interaction

• 2-Drug factors:1-Narrow therapeutic index drugsDigoxin cardiac arrythmiasTheophylline heart & CNS stimulantPhenytoin confusion, nystagmusAnticoagulants haemorrhageLithium nephrotoxicity, tremors

2- allergic drugs : antibiotics

3- cytotoxic drugs: anti cancers 4-Dose of the drug: require regular therapeutic drug monitoring 5-duration of treatment: prolonged treatment by. ---.diazepam may lead to addiction Corticosteroids adrenal suppression6-route of administration.

• 3-Predisposing factors. digitalis + low k arrhythmia atracurium + low Ca paralysis(skeletal muscle

relaxant used during surgery for endotracheal tubing and mechanical ventilation)

• 4-Environmental factors DDT enzyme inducer smokers require higher doses of drug halothane in theatre air pregnant staff abortion &

hepatotoxicity.

• ADRs can occur as a result of: - drug- drug interaction - drug- disease interaction - drug- food interaction

Drug- drug interaction

Interactions can occur before or after administration:

A-Interactions before administration:• Phenytoin precipitate in dextrose solution• Amphotrecine precipitates in saline• Gentamycine is incompatible with most beta-

lactams, resulting in loss of antibiotic effect.

• B-after administrations:• 1-Pharmacokinetic interactions:• -GI: Omeprazole Lansoprazole H2 - antagonist

• - kidney: Aminoglycosides: tubular toxicity Sulfonamides: crystallurea Thiazide: interstitial nefritis

Reduced absorption of ketoconazole and delavirdine

• - liver: Nearly always due to interaction at phase 1 (oxidation, reduction and hydrolysis) rather than phase 2 (conjugation)

hepatitis (a) Viral hepatitis: halothane &Phenytoin (b) focal hepatitis: aspirin (c) Chronic hepatitis : methyledopa, diclofenac cholestasis camoxiclave, carbamazepine,

chloropromazine, flucloxacilline steatosis tetracycline (especially if expired), ketoprofen,

methotrexate, amiodarone, acetaminophen

hepatic necrosis: Paracetamol is a major cause of drug-related morbidity and mortality in humans, capable of producing hepatic necrosis after a single toxic overdose

.

• Pulmonary: Many drugs are known for their adverse effects on the lungs:nitrofurantoin , amiodaronechemotherapy , cyclophosphamide, and methotrexate

Examples of their effects on the lung: drug induced SLE granulomatus lung disease allergies (asthma, bronchitis, pneumonitis) pleural effusion and oedema interstitial fibrosis pulmonary vaculities.

• - blood:• Phenytoin: megaloplastic anaemia Chloramphenicol: aplasti canaemia Aspirin- nitrofurantoin: haemolytic

anaemia.

Consequences of drug metabolism:

•drug

•Toxic metabolite

•Active metabolite

•Inactive metabolite

•Reversible metabolite

•toxicity

•Enhanc

e activity

•Altered activity

•Prolong activity

•Loss of

activity

ADRs as a consequence of drug metabolism:

Enalapril(inactive)

hydrolysis

Enalaprate(active)

activation

Codeine(inactive)

Morphine(active)

activation

• ADR as a result of product similar to parent drug

X

Terfenadinetoxic

fexofenadine.Less toxic

metabolism

accumulation

Obliterated metabolism by

enzyme inhibitors (erythromycin)

Death, cardiac arrest and ventricular arrhythmias

drug disease interaction

• Liver disease• Kidney disease• Cardiac disease (low hepatic blood flow)• Hypo or hyper thyroidsm

drug food interaction:• Warfarin and vitamin K containing food• Grapefruit juice

Management and prevention of ADRs:

• Continues education of health team• Education of patient and family• Special consideration of patients of high

risk• Drug monitoring• Adjustment of dosages• Detection of drug interaction.

rational therapy:

• Cimitidine with NSAIDs• K therapy with diuretics• Anti emetics and iron with cytotoxic drugs• Pyridoxine with isoniazide• Sodium bicarbonate with allopurinol and

sulphonamides

Shields of protection!

How can we manage drug interactions?

• Avoid concurrent use in case of harmful outcome

• Changne the dose, sequence and time of administration

• Use safe alternatives (ranitidine instead of cemetidine)

• Treat any developed symptoms• Monitor drugs levels in the serum• Monitor vital signs.• Separate the drugs 2H in between.

Digoxin RitonavirHigh Digoxin

activity = irregular heart rhythm

aspirin ACE inhDecrees

efficiency of ACE inhs

cordarone warfarinAlter

warfarin actions

cordaroneZocor>20mg

rhabdomyolysis