Ppt 0000067

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