Keep silence…!

“In the name of Allah the most beneficent and merciful”.

References:

• Micheal Kosnett, Heavy metal intoxication and chelators; Bertram G. Katzung, Basic and clinical pharmacology:11:999-1011;2009

• Cutis D. Klassan,Heavy metals and heavy metal antagonists; Goodman and Gilmans, Pharmacological basis of therapeutics; 11;1753-66; 2005.

• Rang and Dale, Chelators, Pharmacology;6;668-75;2009• Tripathi K.D.,Chelating agents; Essentials to medical

pharmacology; 6;865-68;2009• R.S. Satoskar, Metal and their antagonists , Pharmacology

and Pharmacotherapeutics;21;1040-48;2009

Objectives

In this lecture we will learn about

Toxicology

All substances are poisons. There is none

which is not a poison. The right dose

differentiates a poison & a remedy.

- Paracelsus 1532

the father of modern toxicology”

History Socrates was forced to drink Hemlock (Conium

genus of one of the highly poisonous plant, F:

apiacae) for corrupting the youth of Athens

Cleopatra committed suicide through the bite of an

asp; a poisonous snake

In 15th Century in Italy, Cesar and Lucrezia Borgia

assassinated many of their political rivals by

poisoning with arsenic, copper and phosphorus

Lead caused poisoning in hundreds of thousands

from the time of Roman era till 17th and 18th century

as it was used in pottery, cosmetics, paints and in

automobile fuels

History

Mustard Gas and other poisonous gases were used

in many wars started from WW-I in 1914 by

Germans

Newer versions are Neurotoxins, Sarin (

organophosphorous compound)

Chemical toxicities has caused disasters too, like in

Bhopal, India in 1984 where release of methyl

isocyanate killed many thousands

Definitions

• Toxicology – is the science dealing with properties, actions, toxicity, fatal dose, detection of, interpretation of the result of toxicological analysis and treatment of poisons

• Toxin – naturally derived, naturally exposed toxic chemical

• Toxicant – manmade toxic chemical or of natural origin but manipulated, concentrated, or dispersed by humans

• Antidote – medicine given to counteract the influence of poison or an attack of disease

Forensic Toxicology is the study of the chemical and physical properties of toxic substances and their physiological effect on living organisms

Forensic toxicology deals with the medico-legal aspects of the harmful effects of chemicals on human beings

Clinical toxicology deals with diagnosis and treatment of human poisoning

Poison is a substance (solid, liquid or gas), which if introduced in the living body, or brought into contact with any part thereof, will produce ill health or death, by its constitutional or local effects or both

Ideal Suicidal Poison:

Should be cheap and easily available

Should be tasteless or be of pleasant taste

Capable of being administered with food materials

Should be highly toxic and capable of sure shot

death

Should be capable of producing painless death

e.g. Opium and Barbiturates, but commonly used

are Organophosphorus compounds and Endrin

CLASSIFICATION OF POISONS

CORROSIVES:

Strong Acids:

Mineral / Organic Acids:

Sulphuric acid, Hydrochloric acid & Nitric acid

Organic Acids:

Carbolic acid, Oxalic acid, Acetic acid, etc.

Strong Alkalis:

Hydrates and Carbonates of Na, K, NH4

Metallic Salts:

ZnCl2, FeCl2, CuSO4, AgNO3, KCN, etc.

SYSTEMIC POISONS:

Cerebral:

CNS Depressants:

Alcohol, GA, Opioid

analgesics, Hypnotics and

Sedatives.

CNS Stimulants:

Cyclic Antidepressants,

Amphetamine, Caffeine.

Deliriant poisons:

Dhatura, Belladonna,

Hyoscyamus, Cannabis,

Cocaine, etc.

Spinal Poisons:

Nux vomica and Gelsemium

Peripheral poisons:

Conium and Curare.

Cardiovascular:

Aconite, Quinine, Oleander,

Tobacco, HCN.

Asphyxiants:

An asphyxiant gas is a nontoxic or minimally toxic gas which reduces or displaces the normal oxygen concentration in breathing air.

CO, CO2, H2S

Routes of Poison Administration:

Inhalation:

Benzene, Xylene, Acetone, Methyl Chloroform, CCl4, CO,

H2S, Methane, Lead, Mercury, Asbestos, etc.

Injection into blood vessels

Intradermal, Subcutaneous, Intramuscular Inj.

Introduction into Stomach

Introduction into natural orifices

Rubbing into skin:

Organic phosphates, Nicotine, Phenol, Mercury, and Hydro

cyanic acid

Factors Modifying Poison Actions:

Quantity:• Higher the quantity, more severe action

Form of the Poisonous substance:• Poison acts most rapidly in gaseous form

and least in liquid form

• When the combination of chemicals is more soluble, then more is the action

• Alteration of action or efficacy when mixed with inert substances

Mode of Administration

Factors Modifying Poison Actions:

Conditions of the body:

Age factor: Poisons have greater effects at two extremes of age

Idiosyncrasy: Which is inherent personal hypersensitivity

Habit: Effect of certain poisons decreases with habituation. It results from a decreased reaction between the chemical and the biological effectors

State of Health: A healthy person tolerates better than a diseased one

Sleep and Intoxication: Action of some poisons get delayed if a person goes to sleep

Cumulative Action: Those poisons which are slowly eliminated from the body, may gradually accumulate and then may produce poisonous symptoms

The following group of symptoms are suggestive of

poisoning:

Sudden onset of abdominal pain, nausea, vomiting, diarrhea

and collapse (Arsenic)

Sudden onset of coma with constriction of pupils (Organo-

phosphates)

Sudden onset of convulsions

Sudden onset of delirium with dilated pupils. (Dhatura)

Paralysis of LMN (Lower Motor Neurons) type (Strychnine)

Jaundice and hepato-cellular failure (CCl4)

Oliguria with proteinuria and hematuria

Diagnosis of Poisoning

In these cases, collect:

Stomach washings (entire)

Urine (as much as possible)

10ml of Blood

Diagnosis of Poisoning

First, collect all the relevant information from Inquest report and also from the relative

Postmortem examination may show: External findings: STAINS on clothes, marks of vomit or poison

COLOR CHANGES on affected skin and mucous membrane. (black color in H2SO4 & HCl, brown in Nitric acid.

STAINING may be Dark brown/yellow in Phosphorus, Cherry red in CO, Chocolate color in Nitrates, Nitrobenzene etc.

ODOUR from nose and mouth may be GARLIC like (P, Arsine gas, Arsenic), SWEETISH (Ethanol, Chloroform), ACRID (Paraldehyde, Chloral hydrate), ROTTEN EGG (H2S, Mercaptans)

INJECTION MARKS may be detected which may suggest route of administration.

SKIN may show HYPERKERATOSIS (Chr. Arsenic poisoning), JAUNDICE (P, KClO4).

VIOLENCE MARKS such as bruise or other injuries if seen, suggests mode of death from cause other than poisoning.

In the Dead [Cont…]Internal Findings:

SMELL: Peculiar smell seen in Cyanide, Alcohol, Phenol, Chloroform and Camphor poisoning

MOUTH & THROAT: To be examined thoroughly for evidence of corrosion and inflammation or staining

ESOPHAGUS: Marked softening seen in Corrosive alkalis.

UPPER RESPIRATORY TRACT: May show evidence of volatile poisons

STOMACH: May show hyperemia, color changes, softening, ulcers, perforation, etc. All the contents should be emptied in a jar with NaCl and the stomach preserved for chemical analysis

DUODENUM/INTESTINE: Ulceration

beyond pylorus points to natural disease.

Characteristic changes are seen in Hg

poisoning. Normal GI tract rules out

poisoning by Corrosives, Phenols, Hg and

Arsenic compounds

LIVER: Phosphorus, Chloroform, TNT,

CCl4, etc leads to Necrosis of liver. Fatty

liver is seen in case of As, CCl4,

Mushroom poisoning, P4, etc.

RESPIRATORY SYSTEM: Corrosive

poisons leads to glottic edema and

congestion

KIDNEYS: Metallic poisons, Cantharidin

poison leads to degenerative changes. PCT

necrosis is seen with HgCl2, Phenols,

Lysol, CCl4 poisoning

HEART: Subendocardial hemorrhages in

Left Ventricle are seen in Acute Arsenic

poisoning

BLADDER / VAGINA / UTERUS: Should

be specially examined in cases of Criminal

abortion

General Lines of Treatment [ABCD…]

Airway/Antidote

Breathing

Circulation

Decontamination/Dextrose/Drugs

Removal of unabsorbed poisons:

Inhaled poisons: Fresh air

Injected poisons: Ligature application

Contact poisons: Immediate removal of clothing and washing

thoroughly

Ingested poisons: Gastric Lavage

Information resources

• Computerized database: Poisindex is a computerized CD-ROM database that is updated quaterly and is a primary source for poison control centers

• Printed Publications: textbooks, manuals etc

• Internet

• Poison control center (A national poison and drug

information center with a toll-free telephone number (0800-77767) set up at the Jinnah Postgraduate Medical Centre)

Gastrointestinal decontamination

Emesis: It is useful within 3 hrs of ingestion

Done with ipecac syrup(30 ml)

Activated charcoal: It is useful within 1 hr of ingestion

Works by adsorbing poisons

Dose 50gm(adults), 1 gm/kg (children)

Gastric lavage:It is useful within 3 hrs of ingestion

Tube used is Boas tube or Nasogastric tube

Gastric lavage is continued till the pumped out

washings are colorless. At this point a small amount

of the agent is left out inside the stomach

Contra-indications:

Absolute CI is Corrosive poisoning due to danger of

perforation of stomach. (Exception: Carbolic Acid

poisoning)

Can be used but by taking precautions in:

Convulsant poisons

Comatose patients

Volatile poisons

Hypothermia

Gastrointestinal decontamination

Catharsis

It is known to reduce the transit time in GIT

Two types are Ionic/saline and Saccharide cathartics

Ionic/saline cathartics:

Magnesium citrate 4 ml/kg

Sodium sulphate 30 gm.

Saccharide cathartics:

Sorbitol (D - glucitol) 50 ml 0f 70% solution

Whole Bowel Irrigation Involves the administration

of non-absorbable polyethyleneglycol which is instilled at the rate of 2L/hr. in adults

Indications:

Large ingestion of iron, lithium, sustained release or enteric coated drugs

Gastrointestinal decontamination

ADMINISTRATION OF

ANTIDOTESPhysical antidotes: They

neutralize poisons by mechanical action or prevent their absorption.Activated Charcoal:

This is a fine, black, odorless powder

Produced by destructive distillation of various organic materials, usually from organic pulp and then treating at high temperatures. This process increases the absorptive capacity

Particles are small but with high absorptive capacity and it acts mechanically by adsorbing and retaining within its pores organic and some mineral poisons

Usually given mixed with water

Helpful in Barbiturates, Atropine, Benzodiazipine, Opiates, Quinine, Strychnine, Phenothiazines, Pyrethrins, Aluminium Phosphide, etc.

Less useful in Corrosives, Heavy metals, Cyanide, Hydrocarbon and Alcohol poisons

Dose: 50 – 100 mg (Adults) and 15 – 30 mg (Children)

Demulcents:

These are substances which form a protective coating on the

gastric mucous membrane and thus do not permit the poison to

cause any damage

Examples include Milk, Starch, Egg white, Mineral oil, Milk of

Magnesia, etc.

Fats and oils should not be used for fat soluble poisons like,

Kerosene, Phosphorus, OP compounds, Phenol, Acetone, etc.

Bulky Foods:

They act as mechanical antidote to glass powder by

imprisoning the particles within its meshes and thus prevents

damage by the sharp glass particles

Physiological Antidotes:

These are substances which produce exactly the

opposite actions to that of poison

e.g. atropine in organophosphorus poisoning and

naloxone in morphine poisoning

Chelating agents:

These agents act by forming stable and soluble

complexes by the inner ring structure which can

combine with the metallic poisons

e.g. British Anti Lewisite (BAL) and Ethylene diamine

tetra-acetic acid (EDTA)

Methods for enhancing elimination of toxins

Urinary alkalization:

This is also known as alkaline diuresis

IV bicarbonate 1 lit. of 1.26% over 3 hrs is given

Potassium levels can fall, so add 20-40 mmol.

potassium to each lit. of IV fluids given

Aim for a Urinary pH of 7.5-8.5

Indications: poisoning with chlorpropamide,

phenobarbitone, salicylates, phenoxy acetate

herbicides

Extracorporeal

techniques:

Hemodialysis: can be

considered for poisoning with

salicylates,

ethylene glycol, methanol,

ethanol, theophylline &

lithium

Haemoperfusion: can be

considered for poisoning with

theophylline, phenobarbitone

& carbamazepine

Multiple-dose activated

charcoal: This can increase

elimination of some drugs by

interrupting their enteroenteric

& enterohepatic circulation

The dose given is 50 gm (1

gm/kg in children) of activated

charcoal every 4 hrs.

Indications: poisoning with

carbamazepine, dapsone,

quinine, phenobarbitone,

theophylline

Methods for enhancing elimination of toxins

A medical procedure to remove fluid and waste

products from the blood and to correct electrolyte

imbalances

The passage of blood through columns of adsorptive material, such as

activated charcoal, to remove toxic substances from the blood.

Toxicity screening

• Acute toxicity– administration of progressively larger single doses up to

the lethal dose

– “No-Effect” dose – largest dose at which a specific toxic effect is NOT seen

– Minimum Lethal Dose – smallest amount of the drug that can kill a study animal

– LD50 – dose that kills half of the experimental animal population

• Subacute / chronic toxicity– administration of multiple doses to detect any adverse

effects

Toxicity screening

• Mutagenicity –– detection of possible ability to induce genetic

alteration (mutation)

• Carcinogenicity –– detection of possible ability to induce abnormal

clonal uncontrolled proliferation of genetically altered cells

• Teratogenicity –– detection of possible deleterious effects on the

developing fetus

1. Available dosage forms

include oral immediate-release and sustained-release preparations as well as parenteral agents.

1. Toxicokinetics

Some agents have prolonged elimination half-lives (e.g., heroin, methadone).

Clinical presentation

includes Respiratory depression and a Decrease level of consciousness.

Rare effects include Hypotension, Bradycardia, and Pulmonary edema. Seizures have been reported in patients with renal dysfunction in individuals who are receiving meperidine owing to the accumulation of the metabolite normeperidine.

4. Laboratory data

includes baseline ABGs and toxicology screens.

5. Treatment

a) Naloxone is given 0.4-2 mg every 5 min up to 10 mg and 0.03-0.1 mg/kg in pediatric patients.

b) Naloxone has a very short half-life and resedation is a concern in patients overdosing on long-acting opioids or sustained-release dosage forms.

c) Nalmefene (Revex) has a half-life of 4-8 hr. Initial dosage s are 0.5 mg/70 kg. A follow-up dose 2-5 min later is 1 mg/70 kg.

Cocaine

Available forms:Includes alkaloid obtained from Erythroxylyn coca.

Toxicokinetics: Cocaine is well absorbed after oral, inhalational, intranasal, and IV administration. Cocaine is metabolized in liver and excreted in the urine.

Clinical Presentation :Includes CNS and sympathetic stimulation e.g hypertension, nausea, vomiting, seizure, tachycardia). Death may result from respiratory failure, myocardial infarction, or cardiac arrest.

Laboratory Data: Include cocaine and cocaine metabolite urine screens.

Treatment: Benzodiazepine for sedation seizure treatment, Labetalol for hypertension.

1.There are variety of available forms

they are usually pesticides or chemical warfare agents.

1.Toxicokinetics

Organophosphate are absorbed through the lungs, skin, GIT, and conjunctiva.

1.Clinical presentationincludes excessive cholinergic

stimulation.

1.Laboratory datainclude red blood cell acetyl

cholinesterase activity.

1.Treatmenta) Decontaminationb) Atropine is given 0.5-2 mg IV to reverse the

pheripheral muscarinic effects.c) Pralidoxime (2-PAM; Protopam) is given 1g IV over 2

min and repeated in 20 min as needed.

1. Available dosage forms

include liquid, sustained release tablets and capsules as well as parenteral forms.

2. Toxicokinetics

Well absorbed orally with a Vd of approx. 0.5 L/kg. Theophylline is hepatically metabolized and has a half life of 4-8 hr. Theophylline clearance depends highly on age, concomitant disease states, and interacting drugs.

3. Clinical presentation

includes nausea, vomiting, seizures, and cardiac dysrhythmias. Chronic toxicity carries a poor prognosis than acute toxicity.

Laboratory data

Therapeutic Theophylline leaves are 5-20 µg/ml. Hyperglycemia and Hypokalemia are seen with acute ingestions. Other useful laboratory tests include serum electrolytes, BUN, creatinine, hepatic function, and ECG monitoring.

5.Treatment

includes maintaining an airway and treating seizures and dysrhythmias as they occur.

Syrup of ipecac not recommended.

repetitive doses to enhance elimination. Whole-bowel irrigation for massive ingestions (especially with sustained-release products). Charcoal hemoperfusion is used in unstable patients who are in status epilepticus. Hemodialysis is used when hemoperfusion is unavailable.

(e.g., esmolol, brevibloc) are used to treat the hypotension, tachycardia, and dysrhythmias caused by elevated cyclic adenosine monophosphate levels.

1.Available dosage formsinclude a variety of OTC products:

oral, rectal, and topical.

2. ToxicokineticsSalicylates are well absorbed after

oral administration. The half-life is 6-12 hr at lower doses. In overdose situations, the half-life may be prolonged to more than a 20 hr.

Clinical presentationincludes nausea, vomiting,

tinnitus, and malaise (mild toxicity). Lethargy, convulsions, coma, and metabolic acidosis appear in more severe overdoses. Potential complications from therapeutic and toxic doses include GI bleeding, increased PT, hepatic toxicity, pancreatitis, and proteinuria.

4.Laboratory data for the following 6-hr post ingestion levels are;

a) 40-60 mg/dl : tinnitus.

b) 60-95 mg/dl : moderate toxicity.

c) More than p5 mg/dl : severe toxicity.

d) With the presence of acidemia and aciduria, evaluate ABGs.

e) In addition, laboratory evaluation may show leukocytosis, thrombocytopenia, increased or decreased serum glucose and sodium, Hypokalemia, and increased serum BUN, creatinine, and ketones.

5. Treatment

Repetitive doses of activated charcoal every 6 hr, with 1 dose of cathartic for patients who ingested > 150 mg/kg. Whole-bowel irrigation for large ingestions.

is given as noted in decontamination section to enhance Salicylates excretion. This is indicated for levels > 40 mg/dl.

is used for severe intoxications when serum levels are > 100 mg/dl. This method of decontamination is much better than repetitive doses of activated charcoal.

replacement is administered as needed.

are used to correct any coagulopathy.

Barbiturates poisoning

• Large doses

Intentional (suicide )

Accidental

Acute poisoning• Results in

• Marked respiratory depression

• Tachycardia

• Decrease body temperature

• Oliguria (decrease urine production)

• Circulatory collapse

• Renal faliure

• Coma (leads to death )

• Chronic poisoning

• Same signs as in acute poisoning .

• But effects are more pronounced when given to empty stomach.

Treatment of barbiturate poisoning

• Maintenance of respiration and circulation

• Alkalinization of urine

• Eg administration of osmotic diuretic

• In conscious patient – induce emesis

• Gastric lavage with activated charcoal

• Antidote – tacrine

Strychnine

• It is very bitter therefore produces increased salivary secretions when taken orally

• It has been used in mixture meant to increase appetite• It decreases inhibitory tone of spinal cord (inhibiting glycine)• It decreases inhibitory effect of various fibers at synapses in spinal

cordStrychnine poisoning :

Due to strychnine patient goes into convulsionsConvulsions are tetanic type and uncoordinatedThreshold of various stimuli is greatly reduced, therefore all external stimuli will lead to convulsions such as excessive light, noise and by touching patient

47

Strychnine poisoning :

• Due to simultaneous contraction of both groups of muscles the body gets a typical posture and this is called OPISTHOTONUS

In lower limbs extensors are powerful therefore• Legs are stretched• The muscles at the back of the neck

are also powerful therefore• Necks goes backwards• The muscles of trunk and limb region

are contracted and this part gets the shape of an arch

In upper limbs flexors are more powerful therefore • they are flexed on chest• Jaws are totally closed

Strychnine poisoning :

• These convulsions are repeated every 3-4 mins in between convulsions are decreased

• Person may die due to stoppage of respiration• These convulsions are very painful and unfortunately

person remains conscious during convulsionsTreatment :

• I/V thiopental Na• I/V diazepam are used to control convulsions• Muscle relaxants are also helpful• The patient must be kept in very dark places, better in

sound proof room

Available forms Include gas line antifreeze, windshield washer

ToxicokineticsAlcohol dehydrogenase converts methanol to formaldehyde, which is then converted to formic acid

Clinical Presentation

Stage 1: Euphoria, gregariousness, and muscle weakness for 6-36hr, depending on the rate of formation of formic acid.

Stage 2: Vomiting, abdominal pain, diarrhoea, dizziness, headache, dyspnoea, blurred vision, coma, cereberal edema, resp. And cardiac depression & death.

Laboratory Data

Include severe metabolic acidosis, hyperglycaemia, and hyperamylasemia

Treatment

1. Gastric lavage2. Folic acid administred at 1mg/kg IV every 4hr for 6 doses increase the

metabolism of formate.3. Fomepizole4. Na bicarbonate5. Hemodialysis

Methanol

Availableforms

Include chlordiazepoxide. Diazepam, flurazepam, midazolam, lorazepam, alprazolam, and triazolam.

Toxicokinetics These drugs are hepatically metabolized

Clinical Presentation

Include drowsiness, ataxia, and confusion. Fatalities are rare.

Laboratory Data

Drug level monitoring is not indicated

Treatment

1. Suppportive treatment includes gastric emptying , activated charcoal, and a cthartic.

2. Flumazenil is given 0.2mg IV over 30 sec. Repeat doses of 0.5mg over 30sec. At 1min interval max. cumulative dose of 5mg.

Benzodiazepines

Available forms Include oral and parentral

ToxicokineticsDigoxin is well absorbed, primarily renally eliminated, and has a half life of 36-48hr. Its volume of distribution is 7-10L/kg. Equilibration b/w serum level and myocardial binding requires 6-8hr.

Clinical Presentation

Includes confusion, anorexia, nausea, and vomiting in mild cases, cardiac dysrythmias are seen.

Laboratory Data

Include serum digoxin levels, electrolytes, particularly serum potassium levels and an ECG.

Treatment

1. Decontamination with activated charcoal is recommended.2. Suportive therapy includes managing hyperkalemia, or hypokalemia, and

inotropic support is needed.3. Digoxin specific FAB antibodies (Digibind)

Digoxin

Nicotine Forms

• Tobacco-Nicotiana tabacum

– (&Nicotiana rustica)

Smokeable :Cigarette, Pipe, Cigar• Leaf (Chewing)

• Leaf (Dip)

• Snuff (powdered)

– Transdermal Patch…others

Acute Effects• Classic stimulant effects of arousal (e.g. increased

heart rate and blood pressure, alertness, appetite suppression)

• Carbon monoxide (in smoked form) reduces oxygen transport to heart and other organs

• Vasoconstriction

• Can have calming (anxiolytic) effects in some individuals

• Mild euphoria

• Cognitive enhancements

• Antidepressant effects

Chronic Effects: CANCER• Tobacco use accounts for one-third of all

cancers– Cancers relating to tobacco include:

• Mouth

• Pharynx

• Larynx

• Esophagus

• Stomach

• Lung

• Cigarette smoking has been linked to about 90 percent of all lung cancer cases

• 430,000 annual deaths are attributed to

cigarette smoking

• Cervix• Kidney• Bladder• Throat• Pancreas

More Chronic Effects• Emphysema • Chronic bronchitis• Stroke • Vascular disease• Esophageal reflux• Heart Disease

– It is estimated that nearly one-fifth of deaths from heart disease are attributable to smoking

* Many of these are actually caused by other chemicals in cigarette smoke or in smokeless tobacco products

• Secondary smoke also increases the risk for many diseases– Secondhand smoke is

estimated to cause approximately 3,000 lung cancer deaths per year among nonsmokers and contributes to as many as 40,000 deaths related to cardiovascular disease

– Exposure to tobacco smoke in the home increases the severity of asthma for children and is a risk factor for new cases of childhood asthma

– Environmental tobacco smoke (ETS) exposure has been linked also with sudden infant death syndrome

Addiction• Nicotine meets both the psychological and

physiological measures of addiction– Psychological - People who are addicted to something

will use it compulsively, without regard for its negative effects on their health or their life

– Physiological - anything that turns on the reward pathway in the brain is addictive. Because stimulating this neural circuitry makes you feel so good, you will continue to do it again and again to get those feelings back

Recent studies suggest those excitatory

amino acid systems and, in particular, N-

methyl-D-aspartate (NMDA) receptors,

may have an important role in this

phenomenon.

Tolerance & Withdrawal

• Mild tolerance to behavioral and cardiovascular effects

• Prolonged Desensitization of nicotinic acetylcholine receptors (nAChRs), has been proposed as the mechanism of chronic tolerance to nicotine

• Withdrawal may start after as little as one hour, may last for as long as several months, can include:

– Craving

– Irritability

– Anxiety

– Dysphoria

– Anger

– Difficulty concentrating

– Restlessness

– Impatience

– Increased appetite, weight gain

– Insomnia

Treatment options

• Behavior modification

• Nicotine lozenges

• Nicotine gum

• Nicotine patches

• Nicotine inhaler

• Nicotine nasal spray

• Bupropion SR

• Self-help

• Pharmacotherapy

• Combined strategies

“That’s all……….!”