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Drug Reactions and Interactions (Adverse Drug Reactions (There are 5 types…
Drug Reactions and Interactions
Adverse Drug Reactions
ADRs occur in 10-20% of hospital patients
ADRs include side effects (therapeutic range), toxic effects and hypersusceptibility effects
Side Effect = An unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment
There are 5 types of ADR
Type B
Not related to dosage
Mostly immunological and genetic i.e. hypersensitivity
Example: Heparin causing hair loss
Unexpected and not predictable
Bizarre or
idiosyncrasy
= inherent abnormal response to a drug, caused by genetic abnormality, enzyme deficiency or abnormal receptor activity
Tryptase is a marker - released from mast cells
Must withdraw drug immediately
Type C
Occurs after long term therapy
Example: Analgesic nephropathy
Chronic
Type A
Dose dependent
Extension of the primary clinical effect
Commonest
Example: Anti-hypertensive causing hypotension
Augmented pharmacological
Manage with dose reduction or temporary withdrawal
Type D
Occurs after a long period (decades) after treatment
Example: Teratogenesis in foetus with thalidomide
Delayed
Type E
Occurs after abrupt drug withdrawal
Example: Glucocorticoid steroid withdrawal leads to adrenal gland suppression
End of Treatment
DEFINITION: A response to a drug which is noxious and unintended and is suspected to be related to the drug
Susceptibility to an ADR: Old age, female, pregnancy, liver or renal impairment, drug interactions, genetics
Report ADRs using the yellow card scheme
Hypersensitivity
Type 2
IgG mediated
Drug combines with protein which is treated as foreign by the body.
Antibodies are formed and they combine with the drug antigen. Complement activation damages cells
Type 3
Immune complex deposition
Antigen and antibody form complexes and activate complement
Leucocytes are attracted to site and cause inflammation e.g. procainamide induce lupus
Type 1
IgE forms after exposure to drug. IgE attaches to mast cells and causes release of histamine, prostaglandins and TNF: tumour necrosis factor - these are all acute inflammatory mediators
Clinical features of anaphylaxis: after exposure to drug, there is immediate rapid onset of symptoms, rash, swelling, wheeze, cardiac arrest, hypotension
Anaphylaxis
Management of anaphylaxis: basic life support, stop drug, adrenaline, IV anti-histamine, IV hydrocortisone
IgE-mediated
Adrenaline allows vasoconstriction (alpha-1, allows increase in BP), bronchodilation (beta-2) and increased cardiac output (beta-2)
Type 4
T cell mediated
E.g. contact dermatitis
Antigen specific receptors develop on T-cells so administration of drug leads to tissue allergic reaction
Risk factors for hypersensitivity:
immunosuppression, female
Clinical criteria for allergy:
No linear relation with dose, disappearance on
cessation of drug, re-appearance on exposure,
occurs in minority, does not correlate with
pharmacological properties of the drug
Drug Interactions
Patient risk factors: Polypharmacy, old age, genetics, hepatic or renal impaiment
Drug risk factors: Narrow therapeutic index, steep dose curve, saturable metabolism
Pharmacodynamics
Summative: Effect equals the sum of the parts
Synergism: Effect is greater than the sum of their parts e.g. paracetamol and ibuprofen/morphine
There are 4 classes of pharmacodynamic interactions
DEFINITION: The effect that a drug has on the body
Antagonism: Drugs are opposed e.g. morphine + naloxone
Potentiation: Drug A makes drug B more powerful but drug B does not make drug A more powerful e.g. probenecid (malaria) makes penicillin more powerful
Pharmacokinetic Drug Interactions
Distribution
Occurs with warfarin
Protein binding - this reduces free plasma concentration
Metabolism
Drugs can inhibit CYP450 e.g. drug A blocks metabolism of drug B, leaving more free drug B in the plasma (for pro drugs, there will a decreased effect if they are free in plasma)
Drug can induce CYP450, e.g. drug C induces CYP450 enzyme leading to increased metabolism of drug D - this is why codeine is not allowed for children, in case they are a fast metaboliser
Metabolism is done by CYP450 haemoproteins
Absorption
Acidity e.g. proton pump inhibitors alter PH of stomach so can alter absorption of other drugs as this increases ionised portion of drug
Solubility e.g. eating high fat foods with a fat soluble drug will mean the drug will dissolve and not be absorbed
Motility e.g. erythromycin increases gut motility
Complex formation
Grapefruit juice inhibits p-glycoprotein so increases the uptake of some drugs
Excretion
Renal excretion is PH dependent - weak basic drugs are cleared faster if urine is acidic and vice versa. Can make urine more alkali by adding sodium bicarbonate to blood - this is done for aspirin overdoses as aspirin is acidic
Weak basic drugs: amphetamine, propranolol, salbutamol
Renal mainly, biliary minor
DEFINITION: What the body does with the drug
How to avoid interactions: BNF, medicines information service, ward pharmacist, internet
Some major interactions:
Warfarin with tramadol - causes bleeding
NSAID with ACE inhibitor causes renal failure
SSRIs with tramadol causes serotonin syndrome