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IDIOSYNCRASYIDIOSYNCRASY
IDIOSYNCRATIC REACTIONS
Presented To;Presented To;
PROF. DR. AQEEL PROF. DR. AQEEL JAVEEDJAVEEDPh.D, Post doc(Australia)Ph.D, Post doc(Australia)
Presented By;MUHAMMAD FURQAN AKHTAR2011-phd-1005
IDIOSYNCRASYIDIOSYNCRASY
This is an unusual and unexpected sensitivity exhibited by an individual to a particular drug or food
Drug Idiosyncrasy takes the form of undue susceptibility or hypersensitivity, so the standard dose causes an excessive effect.
Idiosyncratic reactions are thought to account for up to 20 % of all adverse drug reactions.
Also known as Type B Reactions/ Bizarre Reactions
These occur rarely and unpredictably amongst the population.
Difference between Dose Difference between Dose Dependent and Idiosyncratic Dependent and Idiosyncratic ReactionsReactions
Differences Dose Dependent Reactions
Idiosyncratic Reactions
Pharmacologically Predictable
Yes No
Dose Dependent Yes No
Incidence High Low
Mortality Low High
Treatment Dose reduction Withdrawal of drug
Seriousness Low High
Reproducible in Animals
Yes No
CAUSES OF IDIOSYNCRATIC CAUSES OF IDIOSYNCRATIC REACTIONSREACTIONS
Pharmaceutical CausesPharmacokinetic CausesPharmacodynamic Causes1.Biochemical2.Immunological
PHARMACEUTICAL CAUSES OF PHARMACEUTICAL CAUSES OF IDIOSYNCRATIC REACTIONSIDIOSYNCRATIC REACTIONSDecomposition products of the active
ingredientToxic By-products of synthesis e.g.,
Tetracycline when introduced contained by-products which caused idiosyncratic reactions
Effect of the non drug excipients (Additives, preservatives, colouring agents and solubilizing agent)
Many additives like propylene glycol, CMC and non-aqueous solvents such as Isopropyl alcohol Acetone, methyl alcohol and benzene may cause hypersensitivity reactions.
E.g., Use of Diethylene glycol as co-solvent in Sulphanilamide Elixir caused several deaths.
PHARMACOKINETIC CAUSES OF PHARMACOKINETIC CAUSES OF IDIOSYNCRATIC REACTIONS;IDIOSYNCRATIC REACTIONS;
Drugs may be bioactivated to yield reactive species.
Binding of such reactive metabolites may result in either direct or immune mediated toxicity.
e.g., Halothane causes hepatotoxicity Clozapine causes agranulocytosis Carbamazepine causes hypersensitivity
reactions such individuals may have overactive or
underactive bioactivation pathways or immunological characteristics that render them more responsive to drugs.
PHARMACODYNAMIC CAUSES PHARMACODYNAMIC CAUSES OF IDIOSYNCRATIC REACTIONS;OF IDIOSYNCRATIC REACTIONS;A. BIOCHEMICAL CAUSES OF
IDIOSYNCRASY1. GLUCOSE-6-PHOSPHATE
DEHYDROGENASE DEFICIENCY Individuals with the disease may exhibit non-
immune hemolytic anemia in response to a number of causes, most commonly infection or exposure to oxidizing drugs or chemicals.
1. GLUCOSE-6-PHOSPHATE 1. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCYDEHYDROGENASE DEFICIENCY
It is an X-linked hereditary diseaseG6PD is a metabolic enzyme involved in
the pentose phosphate pathway, especially important in red blood cell metabolism.
G6PD deficiency is the most common human enzyme defect.
Mild enzyme deficiency in African type ( 8-20%) and severe deficiency in Mediterranean type (0-4% enzyme activity)
DRUGS TO BE AVOIDED IN DRUGS TO BE AVOIDED IN G-6-PD DEFICIENCYG-6-PD DEFICIENCY TrimethoprimSulfonamidesQuinolones including
Ciprofloxacin, Nalidixic acid, Norfloxacin
NitrofurantoinPrimaquineDapsone
2. HEREDITARY2. HEREDITARY METHAEMOGLOBINAEMIAMETHAEMOGLOBINAEMIA It is a disorder characterized by
the presence of a higher than normal level of methemoglobin in the blood.
HEREDITARY HEREDITARY METHAEMOGLOBINAEMIAMETHAEMOGLOBINAEMIA Methemoglobin is an oxidized form of hemoglobin
that has a decreased affinity for oxygen. It occurs due to the decreased activity of
Methemoglobin Reductase which converts methemoglobin back to hemoglobin by converting Fe3+ to Fe2+.
When methemoglobin concentration is elevated in red blood cells, tissue hypoxia can occur.
SYMPTOMS; Shortness of breath Cyanosis Mental status changes Fatigue & Headache Exercise intolerance
DRUGS CAUSING HEREDITARY DRUGS CAUSING HEREDITARY METHAEMOGLOBINAEMIAMETHAEMOGLOBINAEMIA
Trimethoprim Sulfonamides Quinolones including Ciprofloxacin, Nalidixic
acid, Norfloxacin Prilocaine & Articaine Primaquine Dapsone Nitrates
3. MALIGNANT 3. MALIGNANT HYPERTHERMIAHYPERTHERMIA
It is a rare life-threatening condition that is genetic in origin.
The defect is typically located on the 19th chromosome.
It is most commonly due to volatile anesthetic gases, such as halothane, sevoflurane, desflurane or the depolarizing muscle relaxant succinylcholine used primarily in general anesthesia
This defect causes excessive release of Ca2+ involving the ryanodine receptor present in Sarcoplasmic reticulum which leads to excessive muscle contraction.
SIGNS AND SYMPTOMS SIGNS AND SYMPTOMS OF MALIGNANT OF MALIGNANT HYPERTHERMIAHYPERTHERMIA
A very high temperature with more than 2C0 rise in Temperature/ hour
TachycardiaHyperventilationAcidosis HypercapniaRigid muscles
TREATMENT OF TREATMENT OF MALIGNANT MALIGNANT HYPERTHERMIAHYPERTHERMIAThe current treatment of choice is the intravenous The current treatment of choice is the intravenous administration of dantrolene.administration of dantrolene.
4. PORPHYRIA4. PORPHYRIA;;
Derives from the Greek, meaning "purple pigment".
Referenced to the purple discolouration of feces and urine when exposed to light in patients during an attack
The porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway.
PORPHYRIASPORPHYRIAS
a. HEPATICa. HEPATIC PORPHYRIASPORPHYRIAS
It is a condition when porphyrins are overproduced in the liver predominantly. Symptoms include
Abdominal pain & BackacheVomitingAcute neuropathyMental disturbances (including
seizures, hallucinations, depression & anxiety)
Tachycardia
ERYTHROPOIETIC ERYTHROPOIETIC PORPHYRIASPORPHYRIAS;;It is a condition when the
overproduction is confined to the bone marrow and the erythrocytes.
Also called cutaneous porphyriaprimarily affect the skin causing Photosensitivity & Blisters on the
skinNecrosis of the skin and gums
Factors Triggering Factors Triggering Porphyrias;Porphyrias;Drugs which cause enzyme
induction such as barbiturates, phenytoin, carbamazepine, rifampicin, birth control pillsChemicals and activities which
promote red blood cell productionSmokingAlcohol
MANAGEMENT OF ACUTE MANAGEMENT OF ACUTE ATTACKS OF PORPHYRIASATTACKS OF PORPHYRIAS
Carbohydrates and Heme A high-carbohydrate diet in severe
attacks a glucose 10% IV Hematin (heme arginate) is the
drug of choice in acute porphyriaSymptomatic Management Propranolol for Tachycardia Phenothiazine such as Chlopromazine for
Vomiting & Nausea Opiates such as morphine for Backache Diazepam for Seizures
IMMUNOLOGICAL CAUSES IMMUNOLOGICAL CAUSES OF IDIOSYNCRASYOF IDIOSYNCRASY
The proposed mechanism of most idiosyncratic drug reactions
Drug or its metabolite may act as a carrier or a Hapten
Some unaltered drugs such as penicillin will bind avidly to proteins.
Some drugs are metabolized to a toxic compound that will in turn bind to proteins.
HYPERSENSITIVITYHYPERSENSITIVITY
It refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system.
Hypersensitivity reactions require a pre-sensitized (immune) state of the host.
GENETIC BASIS OF GENETIC BASIS OF IDIOSYNCRATIC ALLERGIC IDIOSYNCRATIC ALLERGIC REACTIONS;REACTIONS;
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
These are encoded by a large gene family in all vertebrates.
MHC presnst on the surface of Helper and Cytotoxic T-cells.
These MHC proteins are formed on the basis of a specific gene cluster on chromosome number 6 in Human; this gene cluster is called MHC gene.
HLA STATUSHLA STATUSMHC in human is also called human
leukocyte antigen (HLA) system.Risk of Nephrotoxicity from Penicillamine is increased in patients with HLA type B8 while the patients with HLA-DR7 may be protected
Patients with HLA-DR4 have greater risk of developing SLE and Thrombocytopenia
TYPES OF DRUG TYPES OF DRUG HYPERSENSITIVITY REACTIONSHYPERSENSITIVITY REACTIONS
TYPE I HYPERSENSITIVITY TYPE I HYPERSENSITIVITY REACTIONS (ANAPHYLAXIS): REACTIONS (ANAPHYLAXIS):
IgE-mediated. Antigen binds to IgE (which is bound to
tissue mast cells and blood basophils), This binding triggers release of
preformed mediators (eg, histamine, proteases) and synthesis of other mediators (eg, prostaglandins, leukotrienes, platelet-activating factor, cytokines).
Type I reactions include atopic disorders (eg, allergic asthma, rhinitis, conjunctivitis).
ANAPHYLACTIC ANAPHYLACTIC REACTIONSREACTIONS
Symptoms skin flushing & Angioedema Tightness of the throat and chest Shortness of breath Congestion Sneezing & wheezing Hypotension & Syncope
Drugs causing Anaphylaxis The most commonly reported are Aspirin and other NSAIDs Penicillin Insulin Streptomycin
Management of Anaphylactic Management of Anaphylactic ReactionReaction
Administer epinephrineAdminister oxygenantihistamine such as
diphenhydramine Treat hypotension with IV fluids or
colloid replacement, and consider use of a vasopressor such as dopamine.
Treat bronchospasm with a Beta 2-agonist or use aminophylline
Give hydrocortisone
TYPE II HYPERSENSITIVITY TYPE II HYPERSENSITIVITY REACTIONS (CYTOLYTIC REACTIONS (CYTOLYTIC REACTIONS): REACTIONS):
First, the drug binds to the cell as a hapten (e.g., the platelet or red blood cell).
Antibodies (IgG or IgM) specific for the NeoAntigen bind and initiates a cytolytic reaction.
Cell destruction may be mediated by complement
reaction or by lysosomal enzymes of phagocytic cells that have antibody Fc receptors on their surfaces.
Cells commonly affected by these types of reactions include erythrocytes, leukocytes, and platelets, resulting in hemolytic anemia, agranulocytosis, or thrombocytopenia respectively.
DRUGS CAUSING TYPE II DRUGS CAUSING TYPE II HYPERSENSITIVITY REACTIONS HYPERSENSITIVITY REACTIONS (CYTOTOXIC REACTIONS): (CYTOTOXIC REACTIONS):
This process may be initiated by drugs such as
Penicillin Quinidine Quinine Phenacetin CephalosporinsSulfonamides
TYPE III HYPERSENSITIVITY REACTIONS TYPE III HYPERSENSITIVITY REACTIONS (IMMUNE COMPLEX REACTIONS): (IMMUNE COMPLEX REACTIONS):
These are caused by antigen–antibody complexes that are formed in blood. The complexes form with drug allergen and antibody in varying ratios and may deposit in tissues, resulting in local or disseminated inflammatory reactions.
1. SYSTEMIC LUPUS ERYTHEMATOSUS HydralazineProcainamideIsoniazidPhenytoin
2. SERUM SICKNESS;2. SERUM SICKNESS; The reaction commonly results from the use of
antisera containing foreign (donor) antigens such as equine serum in the form of antitoxins or antivenins.
Onset occurs 7 to 14 days after antigen administration.
The onset may be more rapid with reexposure to the same agent.
SymptomsLymphadenopathy ArthritisNephritisVasculitis
Serum sickness also may be caused by drugs such as •Sulfones•Penicillins,•Minocycline •Cephalosporins especially Cefaclor
Type IV Hypersensitivity Type IV Hypersensitivity Reactions (delayed Reactions (delayed hypersensitivity): hypersensitivity):
Type IV reactions are delayed hypersensitivity reactions that typically are demonstrated as dermatologic reactions and are mediated by T cells (Helper T cells CD4+ or Cytotoxic T CELLS CD8+).
Type IV reactions require memory T cells specific for the antigen.
On exposure to the antigen, T cells become activated and produce an inflammatory response.
These sensitized cells are activated by re-exposure to the antigen.
They damage tissue by direct toxic effects or through release of cytokines, which activate white blood cells, or killer cells depending on type.
e.g., Neomycin creams
THANK YOU
References Oxford Textbook of clinical pharmacology and drug therapy
by D.G. Grahame-Smith Clinical pharmacy and therapeutics by R. Walker Pathological basis of Pharmacotherapy Microbiology and Immunology Lange review