Transcript General Toxicology

‫أهالً بكم يا سنة خامسة‬
‫دعونا نتفق‬
‫مقرر الطب الشرعى و السموم اإلكلينيكية‬
‫‪ 200‬درجة‬
‫إمتحانان دوريان ‪ +‬إمتحان للمعرفة الشاملة‬
‫‪ %60‬عملى ‪ % 40 +‬نظرى‬
‫تشمل درجة العملى على‪:‬‬
‫ ‪ 3‬إمتحانات عملية (طب شرعى ‪ +‬سموم ‪ +‬طب‬‫شرعى و سموم)‬
‫ تقارير طبية إصابية‬‫‪ -‬أنشطة علمية‬
General Toxicology
Introduction
Prof. Nahed Moustafa
Head of Forensic Med.& Clinical
Toxicology Department
• A 3 -year-old girl was brought to the emergency department (ED) for
evaluation of a seizure. Her mother stated that the child was previously
well and had no other medical problems; 3hours ago the child looked
tired and she noticed that there were missing tablets from the bottle of
medication of her elder son.
• On examination: the girl had a generalized tonic-clonic seizure that
lasted approximately 1 minute; with vital signs of blood pressure, 90/50
mm Hg; pulse 160 beats/ min; respiratory rate 26 breaths/min. Her
pupils were dilated and poorly reactive to light with dry mouth and dry
flushed skin. ECG changes showed prolonged (QRS) interval.
• The residents in ED decided that there should be rapid elimination of
the toxic medication after stabilization of the case. One of them
suggested that the girl needed immediate hemodialysis while the other
suggested that she needed gastric lavage with multiple doses of
activated charcoal.
Toxic substance
• Is any chemical that is capable of producing
detrimental action on a living organism
• As a result of damage, there is an alteration of
structural components or functional process
which may produce injury or death
• Any chemical may be poisonous at a given
dose and route of administration
• Breathing too much pure oxygen, drinking
excessive amount of water can cause
poisoning or even death
Acute toxicity: Subway passengers affected by sarin
gas planted in central Tokyo (quoted from Evison et al,
2002).
‫تسمم حاد‪(:‬لدغ الثعابين)‬
‫األعراض الموضعية‪:‬‬
‫• أثار اللدغ‬
‫• اآلم موضعية‬
‫• تورم األنسجة المحيطة‬
‫• اآلم بالغدد الليمفاوية‬
Opium: (acute/ chronic)
Chronic Toxicity
Chronic toxicity
Copyright ©2004 BMJ Publishing Group Ltd.
Maziak, W et al. Tob Control 2004;13:327-333
Diversity of Toxicology
Occupational
Forensic
Environmental
Veterinary
Medical
Pharmacokinetics: Important Definitions
• Is the mathematical study of the drugs,
• Describe dynamic changes in body drug
concentrations regarding:
-absorption
-distribution
-metabolism
-excretion
• Elimination = metabolism & excretion
• Toxicokinetics: apply the previous def. in an
overdosed pt.
Pharmacodynamics
• Is the interaction of the drug with biologic
receptors & mechanisms of action
• It is the basis for therapeutic or toxic
effects
Knowledge of pharmacokinetics &
toxicokinetics
• Allow the physician to plan a rational
approach to the definitive management of
the intoxicated patient after the
Vital functions have been stabilized
Imp Terms
Volume of distribution (Vd) is:
• Not a “real” vol
• Hypothetical vol of body fluid
that would be necessary if the
total amount of drug were
distributed at the same
concentration as plasma
• Vd = dose/ C
Vd: liters or milliliters per kg
dose: drug in milligram or gram
C: peak conc (milligram, gram)
per liter
Blood concentration (C):
• May be measured to determine
if more specific measures are
needed
• C = dose / Vd
Half- life (t ½):
• Time required to reduce the bl.
Conc. of the drug to half
• T ½= 0.693 / Ke
• Ke = elimination rate constant
• Ke is the % of the total amount
of drug in the body removed
per unit of time & is a function
of clearance and volume of
distribution
Vd
• The apparent Vd is
• When the Vd is large,
useful as it relates the
the tissue conc is
plasma or serum conc
large and the plasma
of the drug to the total
conc small
amount of drug in the • When the Vd is small,
body
most of the drug
• Vd is related to body
remains in the plasma
water
Vd
Vd is affected by:
• Proportion of body fat
• Protein binding of the
drug
- acidic agents bind to
albumin
- basic agents bind to
alpha-1- glycoprotein
• Tissue bindings of the
drugs
• Physiological &
pathological conditions
Vd in Toxicology:
• Calculate the amount of
substance in the body to
help verify the history of
the quantity ingested
• Predict the peak bl conc
of the drug
• Decide whether to apply
extracorporeal elimination
of the toxic substance
Vd - example
A 60-kg patient presents with a history of ingestion twenty
100-mg phenytoin capsule 15 minutes ago.
Will this patient develop manifestations of toxicity?
Answer:
Conc. = dose / Vd
= 20 x 100 mg
0.75 litre/kg x 60 kg
= 2000 mg/ 45 liters
= 44.4 mg / liter
Phenytoin toxicity is expected as this value is above the
normal therapeutic range of 10-20 mg / liter
Imp Terms
Bioavailability is:
• Relative amount of drug that enters the
systemic circulation from an administered
dosage form
• The rate at which the drug appears in the
systemic circulation
Absorption
Is the process by which the drug enters
the body
Absorption
It depends on:
• Route of administration
• Dissociation (ability to become non-ionized,
favoring absorption)
• Dissolution (ability of solid dosage form to
become soluble)
• Concentration
• Blood flow to the site
• Area of the absorptive site
Protein binding
• Drugs are transported in the bloodstream either:
- attached to carrier proteins
- or unbound in solution (free drugs)
• Bound drugs are unable to cross cell
membranes & unable to exert biological effects
• Free drugs are able to cross lipoprotein
membranes & able to exert pharmacologic
effects
Metabolism
• Is the biochemical transformation of a drug
• It is the process by which the body
transforms a drug & makes it more watersoluble so the drug can be eliminated
more rapidly via the kidney into urine
• Biotransformation can produce
metabolites that are active & toxic. Ex;
parathion is metabolized to parathoxon, its
toxic metabolite
Excretion
• Is the final means of drug elimination
either as metabolites or unchanged parent
drug
• Excretion through the lungs is the major
route for gaseous substances
• Kidneys are the most imp route of
excretion of nonvolatile water-soluble
drugs
• Additional routes include sweat, saliva,
milk, bile and feaces
Excretion
Entero-hepatic circulation:
• Drugs & chemicals excreted into the bile enter
the intestine and are either reabsorbed into the
blood or eliminated in the feces
• Some drugs are excreted as water-soluble
glcuronide conjugates that are hydrolyzed by
intestinal bacteria resulting in reforming of the
parent drug or metabolite that is reabsorbed into
the blood
• This process of excretion into bile & reabsorption
into the intestine is known as enterohepatic
circulation
Excretion: entero-hepatic
circulation:
• Examples: digitalis, DDT derivatives, INH,
nonsteroidal antiinflammatory,
phenothiazines, TCAs, salicylates
• Repeated doses of activated charcoal
have been shown to be effective by
preventing reabsorption
• Continuous gastric lavage is also effective
Ion trapping
• Drugs can be weak acids or bases
• They become ionized in solution when they
lose or gain a hydrogen ion
• Ionized (polar) compounds do not easily cross
cell membranes & so they become trapped in
the compartment in which they are more
ionized
• Weak acids (aspirin) is better reabsorbed in
acidic media and better excreted in alkaline
media
• Alkalinization with sodium bicarbonate is used
to hasten the excretion of salicylates
• Weak bases (amphetamine) is better
reabsorbed in alkaline media and better
excreted in acidic media
• Acidification of urine is no longer used
General Toxicology (2)
Prof. Nahed Moustafa
Head of Forensic Med. & Clin. Toxicology
Dep.
The Emergency Management of Poisoning
Poison: is a substance that usually kills, injuries,
or impairs an organism
The General Approach to Poisoning:
• Emergency management
• Clinical evaluation
• Elimination of poison from (GIT, skin, eyes….)
• Elimination of the absorbed part
• Antidotes
• Supportive therapy
• Observation and disposition
(1) Emergency Management
• Airway: adequate ventilation &
perfusion
• Rapid intubation if needed
• Maintenance of all vital signs
(temp,….)
• IV line:
- Naloxone: 2 mg IV
- Thiamine: 100 mg IV
- Dextrose: 50%, 50 ml IV
• Antidotes: if needed:
mentioned later
(2) Clinical Evaluation: History & Physical Exam
Poisoning should be suspected in any
patient with multi-system involvement until
proved otherwise
(2) Clinical Evaluation: History & Physical
Exam
• Acute poisoning often
presents with:
- coma
- cardiac arrhythmia
- seizures
- metabolic acidosis
- GIT disturbance
- Toxidromes or as
isolated events
(2) Clinical Evaluation: History & Physical
Exam
Toxidromes:
• Coma + pinpoint pupils + fasciculation + secretions =
cholinergic (o.ph., nicotine, carbamate)
• Coma + pinpoint pupils + hypothermia + hypotension =
opioids
• Hallucinations + dilated pupils + fever + dry skin+….=
anticholinergics (atropine, antihistaminics….)
(2) Clinical Evaluation: History & Physical
Exam
History:
• What?
• When?
• How much?
- Sudden appearance of symptoms in a healthy
person
- History of drug, poison intake
- Symptoms in a group of persons after sharing
food
(2) Clinical Evaluation: History & Physical
Exam
Clues on Ph. Exam:
• Needle tracks (IV drug abuser)
• Bullous lesions (CO, barbiturates)
• Odour (kerosene, alcohol)
• Perforated nasal septum (cocaine)
• Pul. Edema (heroine)
• Salivation & lacrimation (O. Phs)
(2) Clinical Evaluation: History & Physical
Exam
Metabolic acidosis:
• Assessment: ABGs,
serum Na, K, Cl,
BUN, creatinine,
glucose, urine pH,
anion gap
• Shown in: methanol,
ethanol, cyanide, iron,
salicylates, INH
Cardiac arrhythmia:
• T.C.A.D
• Cocaine
• Digitalis
• CO
• Phenothiazine
• Beta blockers
(2) Clinical Evaluation: History & Physical
Exam
Seizures:
• Anticholinergic
• Cocaine
• O.Phs
• CO
• T.C.A.D
• Theophyline
• TTT: diazepam 10 mg IV,
phenytoin or barbiturates
Laboratory evaluation:
• Acid base balance
• CBC
• Serum electrolytes
• Bl. Conc. Of the drug
• Remember “ treat the
patient not the lab”
(3) Elimination of the Poison
GIT decontamination:
• Preventing the absorption of toxin
is the main line of ttt after ingestion
of a toxin has occurred
• GIT decontamination =
* gastric emptying (emesis, gastric
lavage)
* adsorbent
* catharsis
(3) Elimination of the Poison
Emesis:
The following are not used now:
• Apomorphine (CNS dep. , injection)
• Cu sulphate (very toxic)
• Warm water + salt (hypernatremia)
(3) Elimination of the Poison
Emesis: Ipecac:
• Dried roots of Cephaelis
Ipecaunha Plant
• Formed of:
* emetine: local and central
effects – long half life –
cumulative toxicity
* cephaline: twice potent than
emetine in producing vomiting –
direct action
(3) Elimination of the Poison
Ipecac:
• Forms:
* fluid extract (14
times conc than
syrup, very toxic)
* syrup (form of
choice)
• Contraindications:
* non toxic subs
* non toxic amount
* vomiting
* corrosives
* coma
* seizures
* loss of protective airway
reflexes
* pregnancy
(3) Elimination of the Poison
age
Ipecac dosage
0-6 months
no ipecac
6-12 months
10 ml, not repeated
1-12 years
15 ml, repeated in 20
min
13 years…..
30 ml, repeated in 20
min
(3) Elimination of the Poison
Adsorbent: activated charcoal:
• Carbonaceous materials (eg; wood,
coal, starch) exposed to steam (600900 C) which produces great surface
area. Surface binding area = 900- 1500
m2/g
• Super-activated charcoal: 3 folds
surface area of A. C
• Dose: 1 g/ kg
(3) Elimination of the Poison
Contra-indications of AC:
- Substances not well adsorbed by AC:
• Alcohols (ethanol, methanol)
• Hydrocarbons (kerosene)
• Corrosives
• Metals & inorganic minerals
- Intestinal obstruction, perforation or ileus
(3) Elimination of the Poison
Indications of multiple dose activated
charcoal (MDAC):
• Drugs having enterohepatic circulation:
digoxin, TCA
• Drugs still present in the gut as:
* slow release preparations: theophylline
* produce concretions: salicylates
* slow GI motility: anti cholinergic
(3) Elimination of the Poison
Catharsis:
• Enhance the passage of materials through
GIT thus decrease the time of contact
between the poison & absorptive surface
• Should be avoided in fat soluble poisons
as O.Phs or CCl4
(3) Elimination of the Poison
Catharsis: types:
• Osmotic: Mg sulfate: 15-30 g in glass of water
• Irritants: castor oil: 60-100 ml
Complications:
• Dehydration: imp in extreme of ages
• Electrolyte imbalance
Contraindications:
• GIT hemorrhage
• Recent bowel surgery
• Intestinal obstruction
• Renal failure: Mg load
(3) Elimination of the Poison
Dermal exposure:
• Many poisons can be absorbed
through skin: OPhs, hydrocarbons
• Remove all clothing
• Wash skin with soap& water for 30
min
• Do not use forceful flushing of
shower as it may scratch the skin
& increase absorption
(3) Elimination of the Poison
Eye exposure:
• Wash conjunctiva with running water or
saline up to 20 minutes
• Solid corrosives should be removed first
by forceps
• Consult ophthalmologist
(3) Elimination of the Poison
Elimination of inhaled poison: (CO)
• Remove the patient to fresh air, the
rescuer should use wet mask
• Care of respiration after cleaning the
mouth, O2 inhalation…
Antidotes
Chemical
Physical
Physiological
Antagonism
Competitors
Chelators
Antidotes
Physical:
• Dilution: water in corrosives
• Dissolvent: castor oil in phenol
• Adsorbent: activated charcoal
Antidotes
Chemical:
• Neutralization: not used
• Precipitation:
*tannin for plant alkaloids
*albumin for Hg
*starch for iodine
*Ca hydroxide for oxalic acid
• Oxidation:
*pure oxygen for CO
*M blue& amyl nitrite for cyanide
• Reduction:
*Na thiosulfate for cyanide
Antidotes
Physiological:
• Antagonism:
*atropine (physostigmine)
*digitalis (digibind- digoxin immun fab)
*O Ph (atropine- oximes)
• Competitors:
*morphine (naloxone)
*methanol (ethyl alcohol)
• Chelators:
*BAL, EDTA, DMSA, D.pencillamine