Introduction to Pharmacology Lecture (12) PDF

INTROODUCTION TO PHARMACOLOGY PHL229 Lecture (12) Introduction to Toxicology  Toxicity the ability of a substance to cause harm to a biological system. Definitions Toxicology the study of the potential of a substance to produce...

INTROODUCTION TO PHARMACOLOGY PHL229 Lecture (12) Introduction to Toxicology  Toxicity the ability of a substance to cause harm to a biological system. Definitions Toxicology the study of the potential of a substance to produce adverse health effects on a living organism and the likelihood that the effects might occur under specified exposure conditions  There are many Branches of Toxicology  Mechanistic—Study how a chemical causes toxic effects by investigating its absorption, distribution, and excretion, biochemical and molecular mechanisms.  Forensic—Study the application of toxicology to the law (legal aspects). Investigating cause of death,  Clinical—Usually are physicians or veterinarians interested Branches of in treatment of poisonings and injuries caused by xenobiotics. Toxicology  Environmental—Study the effects of pollutants on organisms, populations, ecosystems, and the biosphere.  Descriptive— Evaluate the toxicity of drugs, foods, and other products.  Regulatory—Use scientific data to decide how to protect humans and animals from excessive risk. Government bureaus such as the FDA employ this type of toxicologist.  Occupational —is the application of toxicology to chemical hazards in the workplace   April 30th, 1945, Eva Braun, committed suicide with a cyanide capsule. Inhibitor of cytochrome c oxidase, which leads to inhibits ATP production resulting in brain death and heart cessation, hypoxia, and death. Examples of Toxicological  Jan 16th, 1975 Bando Mitsugoro, a famous Japanese actor died Cases from eating 4 livers of pufferfish. Active toxic ingredient is tetrodotoxin Tetrodotoxin blocks voltage-gated sodium channels leading to suppression of neurotransmission, numbness, bronchospasms, coma, respiratory failure and death tetrodotoxin  The "father" of toxicology:- (Paracelsus, 1493 – 1541 ). He determined that specific chemicals were actually responsible for the toxicity of a plant or animal poison. Paracelsus is often quoted for his statement: "All substances are poisons; there is none which is not a poison. History of The right dose differentiates a poison and a Toxicology remedy.“ "The dose makes the poison.“. This concept is fundamental to understanding the principles of toxicology. It is also important when trying to protect workers. However, it is often difficult to link the cause and effect of a disease.  The effect may not occur at time of exposure  By the time it occurs the person may not be working with the substance People vary in susceptibility (react differently)  Variations may be due to age, gender, health status Problems etc linking cause Complications of combined effects and effect  Exposure to different substances  Exposure to alcohol, tobacco or prescribed drugs Detailed toxicological information is often not available for many substances Major factors that influence toxicity Route of administration Duration and frequency of exposure Dose or concentration  Acute effects: Occur immediately on exposure or soon after. Usually from relatively high dose. Usually of short duration. Usually reversible. Chronic effects Basic Occur some time after exposure. Toxicological Usually from repeated lower doses over many months / years. Terms Usually irreversible Reversible versus Irreversible Toxic Effects If a chemical produces pathological injury to a tissue the ability of that tissue to repair itself will determine whether the effect is reversible to irreversible. Liver regenerates rapidly CNS does not Carcinogenic and teratogenic effects are generally irreversible  Local effects Occur at the point of contact e.g. Xylene causes de-fatting of skin Sulphuric acid causes irritation / burns on skin Chlorine causes pulmonary inflammation. Systemic effects Basic Occur at target organ remote from point of Toxicological contact e.g. Xylene causes dizziness / unconsciousness Terms Xylene causes damage to liver / CNS Cadmium causes damage to kidney Lead causes damage to blood forming process in bones Xenobiotic substance not normally found or produced in a person  Risk: the probability that harm will occurs under specified conditions. Safety: the probability that harm will not occurs under specified conditions. Basic Tolerance: state of decreased responsiveness to a toxic Toxicological effect of a chemical, resulting from previous Terms exposure. There are 2 types of tolerance:- Dispositional tolerance; a decreased amount of drug reaching the site. It occurs when repeated doses of a drug results in accelerated metabolism such as administration of barbiturates or ethanol. Cellular; reduced responsiveness of a tissue  Additive effect  Combined effect of two substances is equal to the sum of the individual effects (1 + 3 = 4): Toluene and xylene – both are irritant and narcotic, similar chemicals, affect the same Basic target organs Organo-phosphorus insecticides – all organo- Toxicological phosphorous pesticides inhibit cholinesterase Terms activity Independent effects  Toxic effects of each substance are unaffected by simultaneous exposure (1 + 2 = 1 + 2): e.g. Lead and xylene. Main types of combined effects Synergistic effects  Combined effect is greater than the sum of the individual effects if each substance encountered alone e.g. (2 + 2 = 20): Carbon tetrachloride and ethanol – both are hepatoxic – but total liver damage by combined exposure is much greater than expected Smoking and Asbestos – greatly increased lung cancer risk. Potentiation effect Potentiation: Occurs when one substance has no toxic effect but when added to another chemical makes that one much more toxic (0+2=10). Antagonism effect Antagonism: Occurs when two chemicals administered together interfere with each others action or one interferes with the action of the other (2+2=1; 4+0=2) Main types of combined effects There are many types of antagonism effect including: Functional: Occurs when two chemicals counterbalance each other by producing opposite effects on the same physiological function. Chemical: A chemical reaction between two chemicals that produces a less toxic product. Dispositional: Occurs when the disposition is altered, or the concentration or duration of action and the target site is diminished. Receptor: When two chemicals bind to the same receptor and produce less of an effect than the two when given separately (2+2=2 or 2+0=0). INTROODUCTION TO PHARMACOLOGY PHL229 Lecture (13) Principles of treatment of poisoning - Introduction  Definition: “Poison is a substance ( solid/ liquid or gaseous), which if introduced in the living body, or brought into contact with any part there of, will produce illness or death, by its systemic or local effects or both.” Principles of A poison may get into the body through ingestion, treatment of inhalation (gas, vapors, dust, fumes, smoke, poisoning spray), skin contact (pesticides), or injection (bites and stings, drug injection. Poisoning: “The development of dose related adverse effects following exposure to chemicals, drugs or other xenobiotics.”  Types of Poisoning 1. Acute poisoning – excessive single dose, or several smaller doses of a poison taken over a short interval of time. 2. Chronic poisoning – smaller doses over a period of time, resulting in gradual worsening eg. Arsenic , Phosphorus. Nature of Poisoning  Homicidal Types and killing of a human being by another human being by Nature of administering poisonous substance deliberately. Suicidal poisoning When a person administer poison himself to end his/ her life.  Accidental Eg. Household poisons- nail polish remover , acetone.  Occupational Occurs with professional workers. Eg. insecticides, toxic fumes.   History: patient or witness  Circumstantial evidence Suicide note Containers & potential toxins at the scene. Diagnosis of  Physical examination poisoning  Investigations Biochemical investigations ECG abnormalities Radiology Toxicologic screening   History taking Patient  If person is conscious & immediately brought to the emergency department, history may be relevant. If person not conscious: Witness What substance? What route? Diagnosis of What time was ingested? poisoning What dose? When and for how long? Progression of signs and symptoms since ingestion. Family history of epilepsy, mental sub normality, bleeding disorder. Whether the patient is receiving other medications which may interact with the poison.   Physical Examination General appearance  Neurological status- conscious, confused. Diagnosis of  Pupillary examination Normal poisoning Miosis – Opioids, Organophosphate (OP) poisoning Mydriasis – TCA, Theophylline, Methanol  Convulsions - Ethylene glycol, Lithium, SSRI  Muscular fasciculations – Organophosphate (OP) poisoning   Physical Examination Vital Parameters Hypotension with bradycardia  Beta blockers, Benzodiazepines, Barbiturates, Opioids, Alchohol , Organophosphate (OP) insecticides Hypotension with tachycardia  Beta-2 stimulants, Caffeine ,Theophylline. Cardiac arrhythmias Tricyclic antidepressants, amphetamine, digitalis, theophylline, arsenic, Diagnosis of cyanide, chloroquin. poisoning Respiratory depression with failure  Barbiturates, Benzodiazepines, Opiates, Sedative- hypnotics, Snake venom Hyperventilation  Amphetamines , Salicylates, Hallucinogens, Cyanide, CO. Anxiety Hypothermia  Barbiturates, Benzodiazepines, Ethanol, Opiates, Cyclic antidepressants Hyperthermia  Amphetamines, Alcohol withdrawal, MAO inhibitors, Anticholinergic agents, Salicylates   Physical Examination Vital Parameters Hypotension with bradycardia  Beta blockers, Benzodiazepines, Barbiturates, Opioids, Alchohol , Organophosphate (OP) insecticides Metabolic acidosis Diagnosis of Isoniazid, methanol, salicylates, iron, cyanide. poisoning GIT disturbances Organophosphorus, arsenic, iron, lithium, mercury. Hyperkalemia Digoxin, Cardiac glycosides, K + sparing diuretics Hypokalemia Theophylline, Amphetamines, Sympathomimetics   Physical Examination Odors Most common odor detected- Alcohol Odour Toxin 1. Garlic Arsenic, Phosphorous, Selenium, Organophosphorous Diagnosis of 2. Sweet / fruity Ethanol, Chloroform , Nitrites poisoning 3. Bitter almonds Cyanide 4. Rotten eggs Hydrogen sulphide, 5. Smoke Carbon monoxide   Physical Examination Urine Colors Most common urine colors are the following Colour Drug/ toxin 1. Brown Methydopa Diagnosis of 2. Black Naphthalene, Phenols , poisoning 3. Red Rifampicin, Phenytoin, Desferoxamine 4. Green / blue Copper sulphate, Methylene blue 5. Green Propofol, Indomethacin   Physical Examination ECG Abnormalities Usually non-specific ECG abnormality Drugs/ toxins Diagnosis of 1. Bradycardia & Barbiturates, ß- blockers, poisoning atrioventricular node (AV) Antiarrhythmics Block 2. Ventricular Cardiac glycosides, Fluorides, tachyarrhythmias Membrane active agents, Sympathomimetics 3. QRS prolongation Amantidine , Hyperkalemia 4. QT prolongation Amantadine, Amiodarone, Thallium   Physical Examination Studies and Bioassays Radiological studies  Not particularly helpful in diagnosis.  May be useful in confirming. Diagnosis of Bio assays of drugs  Acetaminophen poisoning  Acetone  Ethylene glycol  Methanol  Salicylate  Phenobarbital  Theophylline  Lithium   Physical Examination Toxicological analysis Urine , blood, gastric contents  confirm or rule out suspected poisoning. Interpretation requires various methods:- Diagnosis of  Thin layer chromatography – Acetaminophen poisoning  Gas liquid chromatography – BZD, Amphetamines  High-performance liquid chromatography (HPLC) - BZD  Mass spectrometry- Anticonvulsant Enzyme assays  RBC cholinestrase , serum cholinestrase – Organophosphate (OP) poisoning  Pseudocholinestrase levels – Organophosphate (OP) poisoning INTROODUCTION TO PHARMACOLOGY PHL229 Lecture (14) Principles of treatment of poisoning - Fundamentals of poisoning management  Fundamentals of poisoning management 1. Initial resuscitation and stabilization 2. Removal of toxin from the body 3. Prevention of further poison absorption Fundamentals of 4. Enhancement of poison elimination poisoning 5. Administration of antidote management 6. Supportive treatment 7. Prevention of re - exposure  1- Initial resuscitation and stabilization  First priorities are airway, Breathing & Circulation (ABC’s) airway Proper positioning head tilt and chin lift, suction of secretions from oropharynx, falling back of tongue is prevented by suitable airway tube. Breathing Oxygen via a mask, when cough reflects is absent. Fundamentals of Respiratory stimulants (e.g: caffeine, theophylline) poisoning for severe respiratory depression. management Endotracheal intubation (intubation is the process of inserting an endotracheal tube into the airway to provide oxygen and inhaled gases to the lungs. It is useful in case of:  Unconscious patients  Respiratory depression/ failure Circulation Proper IV access, maintenance of fluid & electrolyte balance, IV drugs for treatment.  2- Removal of toxin from the body If poison contact skin or hair, Copious flushing with water or saline of the body. If poison inhaled, fresh air or oxygen inhalation 3- Prevention of further poison absorption A- GI decontamination. 1. Gastric lavage  Useful IF DONE BEFORE 3 hr of ingestion of a poison. Fundamentals of  Done with water ( except infants – NS), 1:5000 potassium poisoning permangnate , 4% Tannic acid, calcium hydroxide solution or starch solution. management   Performed until clear fluid is obtained or a maximum of 3 L. Complications Aspiration (common) Esophageal / gastric perforation Tube misplacement in the trachea  Contraindications Corrosive poisoning - Esophageal / gastric perforation Petroleum products ingestants- Aspiration pneumonia Compromised unprotected airway Esophageal / gastric pathology Recent esophageal / gastric surgery  3- Prevention of further poison absorption A- GI decontamination.  Gastric Lavage decreases ingestant absorption by an average of :-  52 % - if performed within 5 mins of ingestion  26 % - if performed at 30 mins  16 % - if performed at 60 mins B- Ipecac Syrup induced emesis  Used for home management of patients with  Accidental ingestions Fundamentals of  Reliable history  Mild predicted toxicity poisoning  Administered orally management  MOA Ipecac irritates the stomach & stimulates chemoreceptor trigger zone (CTZ) for emesis. Vomiting occurs about 20 min after administration Dose may be repeated if vomiting does not occur  Side effects Protracted vomiting  Contraindications Gastric / esophageal perforation Corrosives CNS depression or seizures Rapidly acting CNS poisons ( cyanide, strychnine, camphor )  3- Prevention of further poison absorption C- Activated Charcoal  Greater efficacy  Less invasive  Given orally as a suspension ( in water ) or through nasogastric tube  Dose – 1 g/kg body wt. Fundamentals of  Charcoal adsorbs ingested poisons within gut lumen allowing charcoal- toxin complex to be evacuated with stool or removed by induced emesis poisoning  / lavage. Indications management Barbiturates, Atropine , Opiates, Strychnine.  Side effects Nausea , vomiting, diarrhea or constipation May prevent absorption of orally administered therapeutic agents  Contraindications Mineral acids, alkalis, cyanide, fluoride ,iron  Complications Aspiration – vomiting Bowel obstruction  3- Prevention of further poison absorption D- Whole bowel irrigation  Administration of bowel cleansing solution containing electrolytes & polyethylene glycol  Orally or through gastric tube  End point- rectal fluid is clear Fundamentals of  Indication Slow or enteric coated medications poisoning Packets of illegally drugs management Heavy metals Iron , Lithium  Complications Bloating Cramping Rectal irritation  Contraindications Bowel obstruction Unprotected airway  3- Prevention of further poison absorption E- Cathartics  In medicine, a cathartic is a substance that accelerates defecation, so promote rectal evacuation of GI contents  Most effective – Sorbitol  Dose – 1-2 g/kg  There are 2 types of cathartics:  Salts (e.g: Disodium phosphate, Magnesium citrate & sulfate, Fundamentals of Sodium sulfate) poisoning  Saccharides – Mannitol, Sorbitol management  Side effects Abdominal cramps, nausea vomiting  Complications Excessive diarrhea, Hypermagnesemia  Contraindications Corrosives Pre existing diarrhea  4- Enhancement of poison elimination A. Alkalinization B. Acidification of urine C. Hemodialysis/Hemoperfusion D. Chelation A. Alkalization of urine Fundamentals of  Alkalinization achieved by parenteral doses of sodium bicarbonate (NaHCO3) for urine pH 7.5-8.0 poisoning  Uses management Chlorpropamide, Phenobarbital, Sulfonamides, Salicylates.  Contraindications Congestive heart failure Renal failure Cerebral edema B. Acidification of urine  Enhance elimination of weak bases such as Phencyclidine & Amphetamine  Not used anymore  Side effects Metabolic acidosis, Renal damage.  4- Enhancement of poison elimination C. Hemodialysis / Hemoperfusion  Dialysis reserved for specific toxins: salicylates, methanol, ethylene glycol, lithium, and theophylline.  Benefits: removal of toxins already absorbed by gut, ability to remove parent compound and active metabolite.  Less effective when toxin has large volume of distribution (>1 L/kg), has large molecular weight, or highly protein bound  Dialysis rarely contraindicated Fundamentals of poisoning D. Chelation management  Chelation is a chemical process in which a substance is used to bind metals or minerals so they can be excreted from the body.  Complex of chelating agent & metal formed is water soluble & can be excreted by kidneys.  Eg. Dimercaprol, or British anti-Lewisite (BAL), Ethylenediaminetetraacetic acid (EDTA) , Desferrioxamine, Meso-2,3- dimercaptosuccinic acid (DMSA).  Used for heavy metal poisoning. BAL – Arsenic, Lead, Copper, Mercury EDTA- Cobalt, Iron, Cadmium Desferrioxamine – Iron DMSA- Lead, Mercury  5- Administration of antidote  Antidote Definition: is a drug, chelating substance, or a chemical that counteracts (neutralizes) the effects of another drug or a poison.  Not all poisons have antidotes, specific antidotes are useful in < 5% of overdoses Poison Antidote Acetaaminophen (paracetamole) N - acetylcysteine Benzodiazepine Flumazenil Fundamentals of Opioid Naloxone poisoning Cyanide Thiosulphate , nitrite management Iron Oral anticoagulants Desferrioxamine Vitamin K Organophosphate (OP) poisoning Atropine , Oximes Methanol Ethanol , Fomepizole Heparin Protamine sulphate Theophylline, Caffaine Esmolol Anticholinergics (e.g: Atropine) Physostigmine Copper, gold, lead, mercury, zinc Penicillamine poisoning Carbon monoxide Oxygen INTROODUCTION TO PHARMACOLOGY PHL229 Lecture (15) Principles of treatment of poisoning - Supportive care and Prevention of poison reexposure  Fundamentals of poisoning management 1. Initial resuscitation and stabilization 2. Removal of toxin from the body 3. Prevention of further poison absorption Fundamentals of 4. Enhancement of poison elimination poisoning 5. Administration of antidote management 6. Supportive treatment 7. Prevention of poison re-exposure  6- Supportive Care Hemodynamic support Hypotension unresponsive to volume expansion treatment with inotropics. inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular Fundamentals of contractions. Positively inotropic agents increase poisoning the strength of muscular contraction Positive inotropic agents (Norepinephrine, management Dobutamine, Digoxin, Norepinephrine). negative inotropic agents (Verapamil, Cibenzoline, Clonidine, Atenolol). Correction of temperature abnormalities Hypothermia Rewarming of the patient can be achieved by: Active / passive, External / internal methods  6- Supportive Care Passive external rewarming This principle allows the patient's own thermogenic mechanisms to rewarm them. Patients should be moved from the cold environment and wet or cold clothes should be removed. They can then be covered by a blanket or sleeping bag and have their head covered to reduce Fundamentals of heat loss. poisoning This technique can be used for patients with mild hypothermia who can still generate heat by management shivering.  6- Supportive Care Active external rewarming This is where heat is added to the patient from an external source and is the treatment of choice in mild-to-moderate hypothermia patients, whose own thermoregulatory mechanisms are impaired. It can be accomplished by a variety of methods, Fundamentals of including heat packs, heat lamps, warm water poisoning immersion, warmed blankets, and forced air warming systems. management  6- Supportive Care Active Core rewarming The simplest example of active core rewarming is the use of warmed intravenous fluids and warmed, humidified oxygen. Fluids & air/oxygen can be warmed to 44oC. More invasive methods of active rewarming include cavity (gastric, bladder, peritoneal, pleural) lavage using warm fluids. Fundamentals of These methods achieve the most rapid rewarming poisoning rates but, due to their invasiveness and complexity, should be reserved for the most severe and management refractory of cases including hypothermic cardiac arrest.  6- Supportive Care Extracorporeal blood rewarming This aggressively rewarms the blood in the severely hypothermic patient who has been refractory to all other methods of rewarming. There are several methods including haemodialysis, arteriovenous, and cardio-pulmonary bypass. Fundamentals of The biggest advantage of this method is the speed poisoning at which the patient can be rewarmed by directly warming their blood. management  6- Supportive Care Hyperthermia Externally: immersion in iced saline bath. This cooling techniques are usually easier to implement, well tolerated and effective. Internally: This cooling techniques such as ice water Fundamentals of gastric or rectal lavage, extracorporeal blood cooling, and peritoneal or thoracic lavage are poisoning effective, but they are also difficult to manage and associated with complications. management  6- Supportive Care Prevention and treatment of secondary complications (e.g: pulmonary edema, cerebral edema and shock,,, etc.) Pulmonary edema Diuretics. Diuretics, such as furosemide (Lasix), decrease the pressure caused by excess fluid in the heart and lungs. Vasodilator, such as Nitroglycerin that lower the pressure going into or out of the heart. Fundamentals of O2 inhalation / intubation as needed. Narcotic, such as Morphine to relieve shortness of poisoning breath and anxiety management Cerebral edema Mannitol: to decrease brain volume by decreasing overall water content, to reduce blood volume by vasoconstriction, to reduce CSF volume by decreasing water content Steroids such as hydrocortisone & dexamethasone Shock (a sudden drop in blood flow through the body.) isotonic crystalloid solution such as normal saline is typically given for providing volume for the circulatory system during shock and hypovolemia.  7- Prevention of poison re-exposure Adult education Instructions regarding safe use of medications & chemicals Notification of regulatory agencies Fundamentals of In case of environmental or workplace exposure poisoning Psychiatric referral Depressed or psychotic patients should receive management psychiatric assessment, disposition and follow-up Child proofing In household where children live or visit, medications, household products ,non eatable plants should be kept out of reach or in locked, child proof containers.