Adverse Drug Reactions and Drug Interactions.


ADVERSE DRUG REACTIONS:
Definition : Adverse Reaction:
“Any response that is noxious and unintended that occur at the doses used for diagnosis, prevention and treatment of disease.”

Drug toxicity may come in many forms:
  1. Acute versus chronic,
  2. Mild versus severe,
  3. Predictable versus unpredictable,
  4. Local versus systemic.
Administration of drug may result in:
          Side effects.
          Untoward effects.
          Toxic effects.

Definition:
Pharmacological effects of drug produced at therapeutic doses that depending upon the condition; may be desirable or undesirable.
For example :
Atropine produces dryness of mouth.
          Dryness of mouth is side effect when atropine is used for treatment of sinus bradycardia,
          but it is desirable when atropine is used as preanesthetic medication.

UNTOWARD EFFECTS:
Undesirable effects produced at therapeutic doses, when severe enough, necessitate cessation of drug therapy.
For example: Hypokalemia produced by loop diuretics.

TOXIC EFFECTS:
          produced when drug is repeatedly administered or given in large doses.
               
For example :
Respiratory depression produced by morphine.

Important systemic adverse effects:

DRUG INTOLERANCE:
Inability to tolerate the drug.
Drug intolerance may be:
A. Quantitative.                       
B. Qualitative
                a) Idiosyncrasy.
                b) Hypersensitivity (Allergy).

QUANITATIVE INTOLERANCE:
          Some persons show increased response to therapeutic or even smaller doses of the drugs such people are called “HYPER REACTORS.”      
For example:
      G.I bleeding and vomiting with single dose of salicylates.

QUALITATIVE INTOLERANCE:
IDIOSYNCRASY:
          Unusual individual response to certain drugs due to deficiency or complete lack of certain enzymes in drug recipient.
                                                                                OR
          Genetically controlled abnormal reaction to a drug..
For example:
     Hemolysis produced by Primaquine and Sulfonamides in patients with G.6.P.D deficiency.

HYPERSENSITIVITY (ALLERGY):
          Exaggerated sensitivity to certain foreign substances which are harmless to great majority of population. It has an immunological basis.
          Allergy can be distinguished from other forms of drug toxicity in some respects
First, prior exposure to drug or closely  related compound.
Second, intensity of response is  usually dose independent.
Third usually similar signs and symptoms produced irrespective  of the drug used .
Drugs commonly producing allergic reactions are:
                          Penicillins,
                          Sulfonamides,
                          Quinidine,
                          Insulin,
                          Dextran.
  
4 groups of allergic reactions:
TYPE-I:
          Immediate form of allergy
          disturbances appear within minutes or hours.
          Immune reaction is initiated by attachment of antigen to IgE antibodies to surface of mast cells and basophils.
         Rupture of these cells liberates histamine and other mediators of inflammation.
          Major signs and symptoms are erythema, urticaria, itching, broncho-constriction, edema, abdominal cramps and diarrhea.

Anaphylaxis:
Severe form of type-I reaction.
          Life threatening reactions are common with parenteral drug injection than oral or topical drug application.
          Epinephrine reverse the manifestation of severe reactions;
          Antihistamines and Corticosteroids are also useful.

TYPE-II Reactions:
          Mediated by circulating IgG.
          usually delayed responses from several hours to days after drug exposure.
Examples:
          Drug induced hemolysis,
          leukopenia and
           thrombocytopenia.
TYPE-III:
          immune complexes are formed between antigen & antibody.
          deposited in small blood vessels or within interstitial spaces resulting in activation of complement cascade that attract neutrophils.
          lysosomal enzymes liberated by neutrophils cause local tissue damage and promote thrombosis of affected blood vessels.
TYPE-IV:
          mediated by sensitized T lymphocytes.
          usually delayed .


G.I.T DISTURBANCES:
          Many drugs produce gastrointestinal disturbances. Like;
          Nausea and vomiting by digitalis, morphine, anticancer drugs.
          Constipation by opioids, verapamil and antidiarrheal agents
Diarrhea by colchicine and purgatives.

HEMOPOETIC TOXICITY:

ANEMIA:
          Chloramphenicol,
          Primaquine,
          Methyldopa,
          Sulfonamides.   

LEUKOPENIA:
          Phenylbutazone,
          Thiouracil,
          Chlorpromazine,
          Imipramine
          Chloramphenicol.
           
THROMBOCYTOPENIA.
          Quinidine,
          Tolbutamide,
          Digitalis
          Rifampin.

BLEEDING:
          Aspirin,
          Corticosteroids,
          Heparin
          Warfarin.
HEPATOTOXICITY:
                Direct:
          Isoniazid,
          Tetracycline and Halothane.   
Immunological:
          Isoniazid,
          Rifampin,
          Pyrazinamide,
          Methyldopa,
          Indomethacin and chlorpromazine.
NEPHROTOXICITY:
          Aminoglycosides,
          Amphotericin B,
          Vancomycin,
          Bacitracin,
          Polymyxins,
          Sulfonamides,
          Hydralazine,
          Pencillamine,
          Phenacetin and Acetaminophen.

BEHAVORIAL TOXICITY:

Reserpine:           Suicidal tendencies.
Amphetamine:     Disorientation, Confusion
Glucocorticoids:  Euphoria.

ELECTROLYTE DISTURBANCES:
          Hypokalemia:                   
                               Diuretics.
          Hypernatremia:               
          Carbenoxolone,                    
          Corticosteroids.

ENDOCRINE DISTURBANCES:
Chlorpromazine:               Menstrual irregularities.
Oral contraceptives:         Suppression of  lactation.
Corticosteroids:                Hyperglycemia
Cimetidine:                        Gynecomastia.
Ketoconazole:                   Gynecomastia.
Lithium carbonate:           Goiter.

SKIN TOXICITY:
                Skin rashes (Urticaria) by
          PENICILLINS,
          CEPHALOSPORINS,
          AMIODARONE
          CLOFAZEMINE,
          SULFONAMIDES AND TETRACYCLINES.
CARCINOGENESIS:
          Estrogens produce breast and endometrial cancer;
          reserpine produces breast cancer,
          metronidazole is mutagenic and produces tumors.

TERATOGENICITY:
          Some drugs produce developmental abnormalities in fetus (teratogenic effect) like phocomalia by thalidomide, cleft palate by phenytoin.when these drugs administered during pregnancy.
DRUG DEPENDENCE:
          Certain drugs when used repeatedly may make the individual psychologically and physiologically dependent upon the drug i.e. discontinuation of drug may produce withdrawal syndrome.
          Morphine alcohol and cocaine can produce drug dependence.
UNMASKING OF DISEASE:
          Thiazides and corticosteroids unmask diabetes mellitus, and epilepsy is unmasked by isoniazid.
IATROGENIC EFFECT:
          Disease produced physician through the use of certain drugs is called iatrogenic effect.
                For example:
          Parkinson’s disease produced by antipsychotic drugs,
          peptic ulcer by NSAIDs.

DEFINITION;
               
It is the modification of the effect of one drug (the object drug ) by the prior concomitant administration of another (precipitant drug).

OUTCOMES OF DRUG INTERACTIONS
  1. Loss of therapeutic effect
  2. Toxicity
  3. Unexpected increase in pharmacological activity
  4. Beneficial effects  e.g additive  & potentiation (intended) or antagonism (unintended).
  5. Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture

STORAGE CONDITIONS:
Pharmacokinitics
involve the effect of a drug interaction from point of view that includes absorption ,distribution , metabolism and excretion.
Pharmacodynamics
are related to the pharmacological activity of the interacting drugs e.g synergism.antagonism, altered cellular transport, effect on the receptor site. 
Drug interactions: Pharmacodynamic and Pharmacokinetic
Pharmacodynamic Interaction
Drug A alters the effect of Drug B without a change in the concentration of Drug B Pharmacokinetic Interaction
Drug A alters the effect of Drug B by changing the plasma concentration of Drug B
Pharmacokinetic interactions
1) Altered GIT absorption.
          Altered pH, Altered bacterial flora, formation of drug chelates or complexes, drug induced mucosal damage and altered GIT motility.
          Altered pH;
          The non-ionized form of a drug is more lipid
          soluble and more readily absorbed from GIT
          than the ionized form does.  

ENZYME INHIBITION:
It is the decrease of the rate of metabolism of a drug by another one.This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity
Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of action is short may be within 24h.
First-pass metabolism
Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor

RENAL EXCRETION
          Active tubular secretion;
It occurs in the proximal tubules (a portion of renal tubules). The drug combines with a specific protein to pass through the proximal tubules.

PREVENTION OF DRUG INTERACTION
1)      Monitoring therapy and making adjustments
2)      Monitoring blood level of some drugs with narrow
                 therapeutic index e.g., digoxin, anticancer agents…etc
3) Monitoring some parameters that may help to
                characterize the the early events of interaction
                or toxicity e.g., with warffarin administration, it
                is recommended to monitor the prothrombin time
                to detect any change in  the drug activity.
Main offenders :
Light  (sodium nitroprusside)
water  (aspirin)
Air  (oxidation of drug)
drug Interactions: Outside Body
Mechanisms of drug interactions


Things to Remember
  • Interactions are easily forgotten when prescribing
  • Interactions are difficult to remember
  • Pharmacodynamic interactions can often be predicted across drug classes
  • Pharmacokinetic interactions can not be predicted – experiments needed
  • Many interactions probably remain undescribed – so look out for them
  • The chances of interaction are 60 times higher in a patient taking 5 drugs than in one taking 2. 
USE OF DRUGS IN PREGNANCY:

·         The FDA to indicate the Potential of  systemically absorbed  drugs for causing birth defects; establishes five pregnancy categories:

CATEGORY A:

·         Controlled studies in the pregnant women fail to demonstrate a risk to the fetus in first trimester with no evidence of risk in later trimesters.
·         The possibility of fetal harm is remote
o   Examples:
o   INSULIN,
o   VITAMIN B,
o   VITAMIN D,
o   PARACETAMOL..

CATEGORY B:

·         Either animal reproduction studies have not demonstrated fetal risk but there are no controlled studies in pregnant women OR animal reproduction.
·         Studies shown an adverse effect (Not Teratogenic) that was not confirmed in controlled studies in women, in the first trimester and there is no evidence of risk in later trimesters.
o   Example:
o   RABEPRAZOLE, AMOXICILLIN, METOPROLOL, METHYLDOPA.

CATEGORY C:

·         Either studies in animals have revealed adverse effects on fetus (Teratogentic) and there are no controlled studies in women,                                                                          OR
o   Studies in women and animals are not available.
·         Drug should be given only if the potential benefits justify the potential risk to the fetus.
o   Examples:
o   ACETAZOLAMIDE,
o   OMEPRAZOLE,
o   ACYCLOVIR.

CATEGORY D:

·         There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk e.g. if the drug is needed in the life-threatening situations or for a serious disease for which safer drugs are ineffective.
·         Examples:
o   DIAZEPAM,
o   METHOTREXATE,
o   PHENYTOIN.

CATEGORY X:

·         Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of use of drug in pregnant women clearly outweighs any possible benefit. The drug is strictly contraindicated in women who are pregnant.
o   Examples:
o   DOXORUBICIN,
o   SIMVASTATIN,
o   TESTOSTERONE.    



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