IDIOSYNCRASY

IDIOSYNCRATIC REACTIONS

Presented To;

PROF. DR. AQEEL JAVEED

Ph.D, Post doc(Australia)

Presented By;
MUHAMMAD FURQAN AKHTAR 2011-phd-1005

IDIOSYNCRASY

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 Dependent and Idiosyncratic Reactions

Differences Dose Dependent Reactions Idiosyncratic Reactions

Pharmacologically Predictable Dose Dependent Incidence Mortality Treatment Seriousness

Yes

No

Yes High Low Dose reduction Low

No Low High Withdrawal of drug High No

Reproducible in Animals Yes

CAUSES OF IDIOSYNCRATIC REACTIONS Pharmaceutical

Causes Pharmacokinetic Causes Pharmacodynamic Causes 1. Biochemical 2. Immunological

PHARMACEUTICAL CAUSES OF IDIOSYNCRATIC REACTIONS

Decomposition

products of the active

ingredient Toxic By-products of synthesis e.g., Tetracycline when introduced contained byproducts 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 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 OF IDIOSYNCRATIC REACTIONS;

A. BIOCHEMICAL CAUSES OF IDIOSYNCRASY 1. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes, most commonly infection or exposure to oxidizing drugs or chemicals.

1. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

It

is an X-linked hereditary disease G6PD 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 ( 820%) and severe deficiency in Mediterranean type (0-4% enzyme activity)

DRUGS TO BE AVOIDED IN G6-PD DEFICIENCY

Trimethoprim

Sulfonamides
Quinolones

including Ciprofloxacin, Nalidixic acid, Norfloxacin Nitrofurantoin Primaquine Dapsone

2. HEREDITARY METHAEMOGLOBINAEMIA

It is a disorder characterized by the presence of a higher than normal level of methemoglobin in the blood.

HEREDITARY METHAEMOGLOBINAEMIA
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 METHAEMOGLOBINAEMIA

Trimethoprim Sulfonamides Quinolones including Ciprofloxacin, Nalidixic acid, Norfloxacin Prilocaine & Articaine Primaquine Dapsone Nitrates

3. MALIGNANT HYPERTHERMIA
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 OF MALIGNANT HYPERTHERMIA

A very high temperature with more than 2C0 rise in Temperature/ hour Tachycardia Hyperventilation Acidosis Hypercapnia Rigid muscles

TREATMENT OF MALIGNANT HYPERTHERMIA

The current treatment of choice is the intravenous administration of dantrolene.

4. 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.

PORPHYRIAS

a. HEPATIC PORPHYRIAS
It is a condition when porphyrins are overproduced in the liver predominantly. Symptoms include Abdominal pain & Backache Vomiting Acute neuropathy Mental disturbances (including seizures, hallucinations, depression & anxiety) Tachycardia

ERYTHROPOIETIC PORPHYRIAS;
It is a condition when the overproduction is confined to the bone marrow and the erythrocytes. Also called cutaneous porphyria primarily affect the skin causing Photosensitivity & Blisters on the skin Necrosis of the skin and gums

Factors Triggering Porphyrias;

Drugs which cause enzyme induction such as barbiturates, phenytoin, carbamazepine, rifampicin, birth control pills Chemicals and activities which promote red blood cell production Smoking Alcohol

MANAGEMENT OF ACUTE ATTACKS 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 porphyria Symptomatic Management
Propranolol

for Tachycardia Phenothiazine such as Chlopromazine for Vomiting & Nausea Opiates such as morphine for Backache Diazepam for Seizures

IMMUNOLOGICAL CAUSES OF 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.

HYPERSENSITIVITY
It refers to excessive, undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a presensitized (immune) state of the host.

GENETIC BASIS OF IDIOSYNCRATIC ALLERGIC 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 STATUS
MHC 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 HYPERSENSITIVITY REACTIONS

TYPE I HYPERSENSITIVITY 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, plateletactivating factor, cytokines). Type I reactions include atopic disorders (eg, allergic asthma, rhinitis, conjunctivitis).

ANAPHYLACTIC REACTIONS
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 Reaction Administer epinephrine Administer oxygen antihistamine 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 2agonist or use aminophylline Give hydrocortisone

TYPE II HYPERSENSITIVITY REACTIONS (CYTOLYTIC 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 HYPERSENSITIVITY REACTIONS (CYTOTOXIC REACTIONS):

This process may be initiated by drugs such as Penicillin Quinidine Quinine Phenacetin Cephalosporins Sulfonamides

TYPE III HYPERSENSITIVITY REACTIONS (IMMUNE COMPLEX REACTIONS):

These are caused by antigenantibody 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. Hydralazine Procainamide Isoniazid Phenytoin

1. SYSTEMIC LUPUS ERYTHEMATOSUS

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. Serum sickness also may be caused by drugs such as Sulfones Penicillins, Minocycline Cephalosporins especially Cefaclor

Symptoms Lymphadenopathy Arthritis Nephritis Vasculitis

Type IV Hypersensitivity Reactions (delayed 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