Adverse Drug Reaction
Adverse drug reactions:
Adverse effect is ‘any undesirable or unintended consequence of drug administration’.
All drugs can produce adverse effects, and whenever a drug is given a risk is taken.
Adverse effects have been classified in many ways. One may divide them into:
Predictable (Type A or Augmented) reactions (mechanism based adverse reactions)
These are based on the pharmacological properties of the drug, which means that they
are augmented. They are more common, dose related and mostly preventable and
reversible.
Unpredictable (Type B or Bizarre) reactions
These are based on peculiarities of the patient and not on drug’s known actions. They are less
common, often non-dose related, generally more serious and require withdrawal of the drug
Side effects
These are unwanted but often unavoidable pharmacodynamic effects that occur at
therapeutic doses.
Generally, they are not serious, can be predicted from the pharmacological profile of a
drug.
Examples:
Hypotension due to antihypertensives
Hypoglycaemia due to insulin, oral hypoglycaemic agents
It is the appearance of characteristic toxic effects of a drug in some individuals at
therapeutic doses.
Intolerance:
It is the appearance of characteristic toxic effects of a drug in some individuals at
therapeutic doses.
Examples:
A single dose of triflupromazine induces muscular dystonias in some individuals,
specially children.
Only small doses of carbamazepine may cause ataxia in some people.
Secondary effect
These are indirect consequences of a primary action of the drug
Example 1:
Suppression of bacterial flora by tetracyclines paves the way for superinfections.
[Tetracyclines are broad spectrum antibiotics, when we use such antibiotics the useful
bacterial flora in the intestine (which competes with invaded harmful pathogens) will
be killed as a result there will be high chance of infections, such infections are known as
supra-infection/superinfection].
Example 2:
The usage of corticosteroids suppress the host immune system, as a result the chances of
infection (bacterial/viral) will be high
Idiosyncrasy
It is genetically determined abnormal reactivity to a chemical. The drug interacts
with some unique feature of the individual, not found in majority of subjects, and
produces the uncharacteristic reaction.
Example:
Myopathy caused by statins in Chinese
group. Stevens Johnson syndrome by
phenytoin
Toxic effects
These are the result of excessive pharmacological action of the drug due to over
dosage or prolonged use. Over dosage may be absolute (accidental, homicidal, suicidal)
or relative (i.e. usual dose of gentamicin in presence of renal failure).
Toxicity may result from extension of the therapeutic effect itself
Examples:
Coma by barbiturates
Complete A-V block by
digoxin Bleeding due to
heparin.
Respiratory failure in over dosage of morphine
Drug allergy
It is an immunologically mediated reaction producing stereotype symptoms which are
unrelated to the pharmacodynamic profile of the drug, generally occur even with much
smaller doses and have a different time course of onset.
This is also called drug hypersensitivity.
Hypersensitivity reactions are classified by the immune mechanism
A. Humoral
Type-I (anaphylactic) reactions: (also known as immediate hypersensitivity)
Occurs upon the reaction of allergen (an antigen that elicits an allergic response) with
specific IgE antibody that is bound to high affinity receptors on the surface of mast cells
and basophils.
Initial contact with the allergen leads to proliferation and differentiation of B- cells.
This is known as sensitization and does not generate allergic symptoms.
After sensitization, IgE associates with mast cells and allergic reactions can be elicited
upon re-exposure to the allergen.
Release of histamine by mast cells: Do remember that the type of immunoglobulin present
on the surface of mast cell is IgE, when an antigen binds to the surface receptor, then mast
cells will release histamine, which is the mediator of hypersensitivity reaction
On exposure to the drug, AG: AB reaction takes place on the mast cell surface releasing
mediators like histamine, resulting in urticaria, itching, angioedema, bronchospasm,
rhinitis or anaphylactic shock.
Anaphylaxis is characterized by flushing, swelling of lips, generalized itching, wheezing
(due to bronchospasm), palpitation followed by syncope. The manifestations occur
quickly and are called immediate hypersensitivity.
Examples:
Hypersensitivity reaction to penicillin/cephalosporin
Management of anaphylaxis:
1. Easiest means to control allergies or asthma is to avoid exposure to known allergens or
asthma triggers.
2. Modulation of the immunologic response or desensitization
3. Premedication
Dexamethasone 20 mg PO and diphenhydramine 50 mg PO 12 and 6 hours before
treatment, then the same dose IV immediately before treatment.
Consider addition of H1 antagonist.
Have epinephrine readily available for use in case of a reaction.
4. Treatment
Administer epinephrine 0.3 mg IM or SC injection until reaction subsides.
If wheezing is present that does not respond to epinephrine, give salbutamol.
Corticosteroids
Desensitization:
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There are times when doctors try to weaken and eventually overcome a patient's
sensitivity to the penicillin allergen through desensitization. They do this by
administering small but gradually increasing doses of penicillin orally or intravenously.
Important point to remember: Adrenaline (also known as epinephrine) is the only life
saving drug during anaphylaxis reaction
Type-II reactions: (also known as cytolytic reactions)
Type II hypersensitivity reaction involves antibody mediated destruction of cells. It is
also known as cytotoxic reaction.
In this hypersensitivity reaction, specific antibody (IgG or IgM) bound to cell surface
antigen and destroy the cell. If the cell is microorganism, killing of cell is beneficial to
host. However, in Type II hypersensitivity, the cells are own RBC.
When antibody binds to antigen (microorganism or RBC) they form Ag-ab complex.
When complement is activated on the surface of cell (RBC) it causes lysis of cell.
Examples:
Haemolytic anaemia caused by quinidine, penicillin's
Thrombocytopenia( low levels of platelets;thrombocytes)caused by quinine
Aplastic anaemia caused by chloramphenicol
Systemic lupus erythematosus caused by hydralazine, procainamide
Type-III reactions: (also known as retarded/arthus reactions)
Type III hypersensitivity is primarily mediated by antibodies of the IgG and IgM classes
which combine with soluble antigen that are not bound to cell surfaces. The antigens
may be self or foreign (i.e., microbial). Tissue damage is caused mainly by complement
activation and release of lytic enzymes from neutrophils.
When antibody combines with its specific antigen, immune complexes are formed.
Normally, they are promptly removed, but occasionally, they persist mostly due to
their small size and are deposited in tissues resulting into several disorders.
Such complexes are more commonly found to be deposited in joints, kidneys and
blood vessels causing arthiritis, nephritis and vasculitis respectively while less
commonly on other organs leading to organ dysfunction.
Wherever immune complexes are deposited, they activate the complement system,
and macrophage and neutrophils are attracted to the site, where they cause
inflammation leading to tissue injury.
The reaction can take hours, days, or even weeks to develop
Type-III reactions: (also known as retarded/arthus (Vaccination) reactions)
Rashes
Serum sickness (fever, arthralgia, rheumatoid arthritis, lymphadenopathy)
Stevens-Johnson syndrome (erythema, arthritis, nephritis, myocarditis, mental
symptoms)
Important points to remember:
Type-III reaction occur due to antigen-antibody complexes
Serum sickness, Steven-Johnsons syndrome, arthritis are few manifestations of type-III
reactions.
Cell mediated
Type-IV reactions: (also known as cell mediated/ delayed hypersensitivity
reactions)
Typically takes 48 to 72 hours after the introduction of the antigen
These are mediated through production of sensitized T-lymphocytes carrying receptors
for the AG.
On contact with the AG these T cells produce lymphokines which attract granulocytes
and generate an inflammatory response.
Examples:
Contact
dermatitis Some
skin rashes
Photosensitization.
THYMUS GLAND:
The thymus gland is in the chest, between the lungs and behind the breastbone
(sternum). It is just in front of, and above, the heart. The thymus makes white blood
cells called T lymphocytes (also called T cells). These are an important part of the
body's immune system, which helps us to fight infection.
Drug induced diseases
These are also called iatrogenic (physician induced) diseases, and are functional disturbances
(disease) caused by drugs which persist even after the offending drug has been withdrawn and
largely eliminated.
Peptic ulcer by salicylates and corticosteroids.
Parkinsonism by phenothiazines and other antipsychotics.
Hepatitis by isoniazid.
SLE by hydralazine, procainamide
Drug interactions
A change in a drug’s effect on the body when the drug is taken together with a second
drug. A drug-drug interaction can delay, decrease, or enhance absorption of either drug.
This can decrease or increase the action of either or both drugs or cause adverse effects.
Some of the drug interactions will provide useful (therapeutic) effects. For example:
Probenecid will interact with tubular secretion of penicillin/cephalosporins and prevents
its renal excretion. Thus it increases the plasma concentration of
penicillin/cephalosporins.
A drug which causes the interaction is known as a precipitant drug.
A drug which is effected by the interaction is known as an object drug/substrate
Types of drug interactions
Pharmacokinetic interactions occur when the absorption, distribution (protein and
tissue binding), metabolism, or elimination of the drug is affected by another drug.
Pharmacodynamic interactions occur when the pharmacodynamic effect of the drug is
altered by another drug, producing an antagonistic, synergistic, or additive effect.
Pharmaceutical interactions are caused by a chemical or physical incompatibility when
two or more drugs are mixed together. Pharmaceutical interactions can occur during
extemporaneous compounding of drugs.
Drug interactions can affect the rate and the extent of systemic drug absorption
(bioavailability) from the absorption site, resulting in increased or decreased drug
bioavailability.
Alteration in gastric pH can increase or decrease the rate of drug absorption. If gastric
pH is decreased (acidified), weak acid drugs remain unionized and gets absorbed at the
stomach. On the other hand, if the gastric pH is increased (alkaline) by intake of
antacids/H2 receptor blockers/Proton Pump Inhibitors, weak basic drugs remain
unionized and gets absorbed at the stomach.
Absorption of azole antifungals will be high in acidic gastric PH, whereas the absorption
will be impaired in alkaline PH.
Precipitation:
Through complexation and chelation of drug molecules.
Example 1:
Tetracyclines chelates with calcium and other heavy metal ions Magnesium, iron,
aluminium and forms a complex. Thus the absorption of tetracycline would be retarded
when administered with food/supplements containing heavy metal ions.
Example 2:
Fluoroquinolones (ciprofloxacin/ ofloxacin) also chelates with all the heavy metal ions and
form complexes.
Important points to remember are:
Never administer tetracyclines/ fluoroquinolones with milk, as Ca+2 present in the milk
will chelate with these agents. Except doxycycline.
Never administer tetracyclines/ fluoroquinolones with oral iron supplements.
Never administer tetracyclines/ fluoroquinolones with antacids. As most of the
antacids are made of Magnesium and Aluminium salts.
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Example 3.
Cholestyramine which is a bile acid binding resin, used to treat hypercholesterolemia binds
with digoxin, warfarin and reduce their bioavailability.
Drugs which increase the gastric motility like laxatives, metoclopramide, cisapride,
erythromycin (do remember that erythromycin is used as a prokinetic drug for
bedridden patients with gastric regurgitation problem), reduces drug residence time or
the amount of time spent in the optimal environment for absorption of particular drugs.
Finally decreases the absorption of concurrently administered drugs.
Drugs which decrease the gastric motility, best example: all the anti-cholinergic drugs,
increases the drug residence time or the amount of time spent in the optimal
environment for absorption of particular drugs. Finally increases the absorption of
concurrently administered drugs.
Drug distribution
Drugs that are highly bound (70%) to a carrier protein can be displaced if the second drug
introduced has a higher binding affinity to the carrier proteins (albumin & Alpha 1 acid
glycoprotein).
Examples of highly protein bound drugs
Phenytoin
Warfarin
Digoxin
Salicylates
Indomethacin
Ibuprofen
Ketoconazole
Fluoxetine
Drug metabolism may occur with the help of microsomal or non-microsomal
enzymes. Microsomal enzymes (ex monooxygenase, cytochrome P450, glucoronyl
transferase) may be induced or inhibited by other drugs whereas non-microsomal
enzymes are not subjected to these interactions.
Enzyme inducers will increase the metabolism of other drugs and thus their effect will
decrease. Therefore dose of such drugs(object drug) should be increased when
administered along with enzyme inducers (precipitant drug).
Enzyme inhibitors will decrease the metabolism of drugs metabolised by microsomal
enzymes, thus predispose to the toxicity.
Grapefruit
At least you must remember those with asterisk
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Effect of enzyme inhibitors on prodrugs:
A small number of drugs are not active in the form administered to patients. These
drugs are known as prodrugs and require activation by enzymes in the body before they
can produce their effect. Inhibition of the metabolism of these prodrugs may reduce
the amount of active drug formed, and decrease the therapeutic effect.
For example, the analgesic effect of codeine appear to result from its conversion to
morphine by CYP2D6.
Examples of prodrugs:
Levodopa
All ACE-inhibitors (except captopril and lisinopril)
Dipivefrine{ adrenaline}
Sulfasalazine,
Codeine
Sulindac
Methyldopa
Cyclophosphamide,
clopidogrel (activated by 2C19)
Drug excretion
The major route of drug excretion is through kidney. Excretion through kidneys occurs by
glomerular filtration, tubular reabsorption and tubular secretion.
Glomerular filtration: depends on plasma protein binding and renal blood flow. It
doesn't depend on lipid solubility because all substances (either water soluble/lipid
soluble) can cross the fenestrated glomerular membrane.
Tubular reabsorption: It depends on lipid solubility. If a drug is lipid soluble more of it
will be reabsorbed and less will be excreted. As lipid soluability depends on ionization,
the ionized drug will be excreted by the kidney. Thus in acidic drug poisoning (like
salicylates, barbiturates, chlorpropamide, methotrexate etc), urine should be alkalinized
with sodium bicarbonate.
Tubular secretion: it doesn’t depend on lipid solubility or plasma protein binding. In
the nephron separate pumps are present for acidic and basic drugs.
Drugs utilizing same transporter may show drug interactions ex: Probenecid decrease
the excretion of penicillin/cephalosporin.
Pharmacodynamic drug interactions:
Additive Pharmacodynamic Effects. When two or more drugs with similar pharmacodynamic
effects are given, the additive effects may result in excessive response and toxicity.
Example 1:
combinations of drugs that prolong the QTc interval (Class Ia antiarrhythmics like
quinidine, procainamide; Class III antiarrhythmics like amiodarone, bretylium, sotolol,
ibutilide; others like terfenadine, Cisapride, gatifloxacin, sparfloxacin, pentamidine,
ziprasidone) results in ventricular arrhythmias
Example 2:
combination of drugs with hyperkalemic effect. (ACE-inhibitors like captopril, enalapril,
lisinopril; others like spironolactone, amiloride, NSAIDS, succinylcholine, cyclosporine).
Antagonistic Pharmacodynamic Effects. Drugs with opposing pharmacodynamic effects may
reduce the response to one or both drugs. For example, drugs that tend to increase blood
pressure (such as nonsteroidal anti-inflammatory drugs) may inhibit the antihypertensive
effect of drugs such as ACE inhibitors, beta-blockers, CCB’s
