DRUG OVERDOSE POISONING

Dr Ranjita Santra (Dhali)Assistant ProfessorDepartment of Clinical & Experimental PharmacologySchool of Tropical MedicineKolkata

Drug Overdose When a drug is eaten, inhaled, injected,

or absorbed through the skin in excessive amounts and injures the body

Overdoses are either intentional or unintentional

If the person taking or giving a substance did not mean to cause harm, then it is unintentional

Drug poisoning is the toxic effect resulting due to drug overdose

The Problem

Drug overdose was the leading cause of injury death in 2012

Among people 25 to 64 years old, drug overdose caused more deaths than motor vehicle traffic crashes

The drug overdose death rate has more than doubled from 1999 through 2013

In 2013, 35,663 (81.1%) of the 43,982 drug overdose deaths in the United States were unintentional, 5,432 (12.4%) were of suicidal intent, and 2,801 (0.06%) were of undetermined intent

The Problem

Among children under age 6, pharmaceuticals account for about 40% of all exposures reported to poison centres

Centers for Disease Control and Prevention. Webbased Injury Statistics Query and Reporting System (WISQARS) [online]. (2014) Available from URL:http://www.cdc.gov/injury/wisqars/fatal.html

Mowry JB, Spyker DA, Cantilena LR, Bailey JEFord M. 2012 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th annual report. Clin Tox 2013;51:9491229.

Centers for Disease Control and Prevention. National Vital Statistics System mortality data. (2015) Available from URL: http://www.cdc.gov/nchs/deaths.html

The Problem

The exact incidence of this problem in our country remains uncertain but it is estimated that about 10-15 million cases of drug overdose poisoning are reported every year, of which, more than 50,000 die

Aggarwal et al. Acute poisoning-Management Guidelines. Journal of Indian Academy of Medical Sciences. 2013;5:142-7

Most Common Drugs Involved in Overdoses

Of the 22,767 deaths relating to pharmaceutical overdose in 2013, 16,235 (71.3%) involved opioid analgesics (also called opioid pain relievers or prescription painkillers), and 6,973 (30.6%) involved benzodiazepines

Benzodiazepines are frequently found among people treated in EDs for misusing or abusing

Drugs People who died of drug overdoses often had a combination

of benzodiazepines and opioid analgesics in their bodies

Substance Abuse and Mental Health Services Administration. Highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drugrelated emergency department visits. The DAWN Report. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration; 2013. Available from URL: http://www.samhsa.gov/data/2k13/DAWN127/sr127DAWNhighlights.

Risk Factors for Drug Overdose Men were 59% more likely than women to die Whites had the highest death rate, followed

by American Indians/Alaska Natives and then blacks Highest death rate was among people 45-49

years of age lowest death rates were among children less

than 15 years old

Source : htttp://www.cdc.gov/homeandrecreationalsafety/overdose/facts 2012.html

Toxicokinetics & Toxicodynamics Toxicokinetics (Determines the no.

molecules that can reach the receptors) Uptake Transport Metabolism & transformation Sequestration Excretion

Toxicodynamics (Determines the no. of receptors that can interact with toxicants)

Binding Interaction Induction of toxic effects

Uptake and Elimination

BiologicalSystemUptake EliminationK1 K2

K1 > K2 : Accumulation & Toxic effect

Toxicokinetics1. Uptake2. Transport3. Metabolism &

Transformation4. Sequestration5. Excretion

Uptake of Toxicants

1. Passive diffusion2. Facilitated transport3. Active transport4. Pinocytosis

Diffusion governed by Flicks law

D/dt = KA (Co - Ci) / X Where:

dD/dt = rate of transport accross the membrane

K= constant A= Cross sectional area of membrane

exposed to the compound Co = Concentration of the toxicant outside the

membrane Ci = Concentration of the toxicant inside the

membrane X= Thickness of the membrane

Toxicokinetic data is best derived using radio labeled dose of the drug. This allows for following the fate of the drug, metabolic products, distribution in the tissue, storage sites, as well as its elimination

Unfortunately, these methods do not provide knowledge about proportion of the drug left intact to its metabolites

Toxicodynamics

Toxicodynamics is the study of toxic actions of xenobiotic substances on living systems.

Toxicodynamics is concerned with processes and changes that occur to the drug at the target tissue, including metabolism and binding that results in an adverse effect.

Simply, TD is concerned with what the toxicant do to the body

Blood and lymph

Liver

Intravenous Intraperitoneal

Subcutaneous

Intramuscular

Dermal

extracellular fluid

fat

Secretory Structures

Bile

Kidney Lung

Bladder Alveoli

Urine Expired Air Secretions

body organs

softtissue bone

Gastrointestinal tract

Lung

feces

InhalationIngestion

distribution

Important principles of toxicokinetics The effect which a drug produces is

dependent on:1. The dose2. The concentration in the target

organ The kinetics of a drug may differ

from therapeutic dose to its toxic dose

Toxicokinetics is important in predicting the plasma concentration of a drug

Toxicokinetics and toxicityToxicity depends on:

Duration and concentration of drug at the portal of entry

The rate and amount (extent) of drug absorbed; toxicity will be low at slow absorption rates.

A highly toxic drug that is poorly absorbed may have same hazard as another with low toxicity but is highly absorbed.

The distribution of drug within the body; where most drugs are distributed in highly perfused organs like brain, liver and kidneys

In some cases, the organ in which the drug is concentrated may not necessarily suffer the damage

An example is organochlorine compounds concentrated in adipose tissue while the target organ is the brain.

The efficiency of biotransformation and nature of metabolites; where, in some cases, a drug may be transformed to a more toxic metabolite or a more lipid soluble or water soluble metabolite, which affects absorption and distribution e.g. paracetamol, INH, dapsone, hydralazine

The ability of the drug to pass through cell membranes and interact with cell constituents. Example, some organochlorines affect the DNA

The amount and storage duration of the drug or its metabolites in the tissue e.g. Lead in bones is an example

The rate and site of excretion; where the more rapid the excretion, the less toxicity it will produce

Cumulative toxicity The state at which repeated administration of a drug may

produce effects that are more pronounced than those produced by the first dose is known as cumulative effect

Results into cumulative toxicity

Anticancer drugs -induced cardiotoxicity Non-cardiac pulmonary edema – Mtx, Cocaine, tocolytics,

hydrochlorothiazide, iodinated contrast agents, opiates (hydrocodone, morphine etc.)

Bronchiolitis obliterans-organizing pneumonia – Acebutolol Amiodarone, Amphotericin B, Bleomycin, Carbamazepine Bronchospasm – Amp B, Aspirin, Amiodarone, ACEIs, inhaled

pentamidine, beta-blockers Iron, lead, mercury, aluminium, arsenic – developmental

disorders, degenerative disorders, haematological disorders

Digoxin

Extracardiac adverse effects

Cardiac adverse effects VT Nodal & Ventricular extrasystoles Pulsus bigeminus VF AFL, AF, severe bradycardia

Antiarrythmic drugs

Qunidine, Procainamide – torsades de pointes

Sotalol – intraventricular conduction defect results into VT AND VF

Adenosine - bronchospasm

Toxidromes

Toxidromes are constellations of symptoms commonly encountered with certain drug classes, including anticholinergics, cholinergics, opioids, and sympathomimetics

Evaluation of possible medication poisonings should include basic laboratory studies, such as a complete metabolic profile, to determine electrolyte imbalances and liver and renal function

Common Toxidromes

Acute drug overdoses

Specific therapies

Specific therapies

Specific therapies

Substance Abuse and Overdose

Addiction Habituation Physiological dependence Psychological dependence Tolerance

Withdrawal Drug Overdose

Common Drugs of Abuse

Common Drugs of Abuse

Common Drugs of Abuse

General survey Directed cardiovascular, respiratory, abdominal and neurological

examination. Vital signs, pupils, etc. mentioned in 'Resuscitation' section, above. Temperature - hypothermia (phenothiazines, barbiturates, or

tricyclics) or hyperthermia (amfetamines, ecstasy, MAOIs, cocaine, antimuscarinics, theophylline, serotonin

syndrome). Muscle rigidity (ecstasy, amfetamines). Skin - cyanosis (methaemoglobinaemia), very pink

(carboxyhaemoglobinaemia, cyanide, hydrogen sulphide), blisters (barbiturates, tricyclic antidepressants (TCAs),

benzodiazepines), needle tracks, hot/flushed (anticholinergics). Breath - ketones (diabetic/alcoholic ketoacidosis), "bitter almonds"

(cyanide), "garlic-like" (organophosphates, arsenic), "rotten eggs" (hydrogen sulphide),

organic solvents. Mouth - perioral acneiform lesions (solvent abuse), dry mouth

(anticholinergics), hypersalivation (parasympathomimetics)

Investigations 12-lead electrocardiogram. Blood glucose, anion gap ± lactate and osmolal gap. LFTs and coagulation profile Arterial blood gases analysis Comprehensive toxicology screens not normally indicated

in the emergency treatment unless in suspected cases Carboxyhaemoglobin levels if carbon monoxide poisoning

is suspected. Urinalysis - query rhabdomyolysis; save sample for

possible toxicological analysis. CXR if pulmonary oedema/aspiration suspected. CT scan of the brain may be needed to exclude other

causes of alterations in conscious level.

Differential diagnosis

Head trauma (especially, in the ethanol-intoxicated patient).

Stroke/subarachnoid haemorrhage (SAH). Meningitis. Metabolic abnormalities (such as

hypoglycaemia, hyponatraemia, or hypoxaemia).

Liver disease. Post-ictal state

Poisoning reporting centres UK National Poisons Information Centres Toxbase®: NHS intranet and internet-based

information from the National Poisons Information Centre (registration free to NHS GPs and hospitals)

Mims Colour index or TICTAC (a computer-aided tablet and capsule identification system available to authorised users, including Regional Drug Information Centres and Poisons

Information Centres.: to aid pill identification. British National Formulary (BNF)/Data Sheet

Compendium