12 Overdose

Question 1

Drug Overdose

Answer 1

• The ingestion or application of a drug or other substance in quantities greater than are recommended or generally practiced;
• Accidentally: e.g. children – e.g. paracetamol;
• Deliberately: e.g. suicide, or drug abuse (next lecture)
• The drugs most frequently used for intentional self-poisoning are benzodiazepines, analgesics and antidepressants, often taken with alcohol;

Question 2

Risks of drug overdose - Drug with Risk

Answer 2

• narrow therapeutic window (digoxin, teophylline)
• steep dose-response curve (warfarin, sulhonylurea der.)
• enzyme inhibitors (ketoconazole, erythromycin)
• enzyme inducers (rifampicin, carbamazepine)
• high toxic potential (aminoglycosides)

Question 3

Risks of drug overdose - Patient with Risk

Answer 3

• polymorbidity
• polypharmacy
• treatment lasting long time
• chronic diseases e.g. disorders of elimination functions
• abusus
• non-compliance • self-treatment
• simultaneous ordination of more drugs by different physicians

Question 4

Therapeutic Index =

Answer 4

Therapeutic Index =

Dose causing toxicity/ Dose providing efficacy

Question 5

Drugs with Narrow Therapeutic Window

Answer 5

Aminoglycoside antibiotics - gentamicin, tobramycin

Anticoagulants - warfarin, heparins, high protein bound

Aspirin (salicylate derivatives),
high protein bound

Carbamazepine
enzyme inducer

Conjugated / Esterified estrogens
OC pills, enzyme inducers

Cyclosporine
immunosupressant

Digoxin
cardiac stimulant/tonic

Hypoglycemic agents

Levothyroxine

Lithium

Phenytoin
nonlinear pharmacokinetics

Procainamide - heart arrhythmia
Quinidine - heart arrhythmia
Theophylline (aminophylline)

Tricyclic antidepressants

Valproic acid

Question 6

Principles of treating overdose

Answer 6

1. Overdose
2. Immediate measures Evaluation,
   Remove contact, ABC, history, evidence
3. Supportive measures
   Cardiac/respiratory arrest Hypotension, Arrhythmia Convulsions, Renal or Hepatic failure, temperature
4. Prevent Absorption
   (Emesis), Activated charcoal, Gastric Aspiration/lavage
5. Elimination
   Alkaline diuresis (sodium bicarb.)
   Acid diuresis (ammonium chloride)
   Haemodialysis
6. Antidotes
7. Psychiatric assessment

Question 7

Supportive care

Answer 7

• ABC (airway, breathing, circulation)
• Protect airway
• Vital signs, mental status, and pupil size
• Pulse oximetry, cardiac monitoring, ECG
• Intravenousaccess
• cervical immobilization if suspect trauma
• Rule out hypoglycaemia

Question 8

Preventing absorption

Gastric lavage

Answer 8

• Flexible tube is inserted through the nose into the stomach
• Stomach contents are then suctioned via the tube
• A solution of saline is injected into the tube
• Not in unconscious patient unless intubated (risk aspiration)

Question 9

Preventing absorption

Induced Vomiting

Answer 9

• Not routinely recommended, due to risk of aspiration

Question 10

Preventing absorption Activated charcoal

Answer 10

• Adsorbs toxic substances or irritants, inhibiting GI absorption
• Oral: 25-100 g as a single dose
• repetitive doses useful to enhance the elimination of certain drugs (eg, theophylline, phenobarbital, carbamazepine, aspirin)
• However, charcoal does not absorb petroleum distillates, inorganic acid and alkali, alcohol, metal ions, cyanide, lithium.

Question 11

Elimination of poisons

Renal elimination

Answer 11

• Medication to stimulate urination or defecation may be given to try to flush the excess drug out of the body faster.

Question 12

Elimination of poisons

Forced alkaline diuresis

Answer 12

• Infusion of large amount of NS+NAHCO3
• Used to eliminate acidic drug that mainly excreted by the kidney eg salicylates
• Serious fluid and electrolytes disturbance may occur

Question 13

Elimination of poisons

Hemodialysis or haemoperfusion

Answer 13

• Reserved for severe poisoning
• Drug should be dialyzable i.e. protein bound with low volume of distribution
• may also be used temporarily or as long term if the kidneys are damaged due to the overdose.

Question 14

Antidotes

Answer 14

Agents with a specific action against the activity or effect of drugs involved in poisoning cases.

Question 15

Antidotes mechanisms and

examples

Answer 15

Pharmacological antagonists
Naloxone (opiate poisoning) Ethanol (methanol poisoning)

Enhance physiological function to compensate
Physostigmine (belladona alkaloid poisoning)

Restore active site of drug target
Pralidoxime (poisoning by organophosphates, e.g. pesticides, war gas)

Bypass block
Glucagon (beta-blocker poisoning)

Sequester poison
Digibind (digoxin poisoning

Speed up excretion
Chloride is used as an antidote for bromide / iodide overdoes.

Question 16

Clinical features

Answer 16

• Stage I (0.5 to 24 hours)
No symptoms; nausea & vomiting (N&V); malaise
• Stage II (24 to 72 hours)
Subclinical elevations of hepatic aminotransferases (AST, ALT)
Elevations of prothrombin time (PT) and total bilirubin
Right upper quadrant pain, with liver enlargement and tenderness Oliguria and renal function abnormalities
• Stage III (72 to 96 hours)
Jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis hypoglycemia, lactic acidosis, renal failure 25%, death
• Stage IV (4 days to 2 weeks)
Recovery phase that usually begins by day 4

Question 17

Paracetamol overdose management

Answer 17

<4 hour : Activated charcoal
May reduce absorption by 50 to 90 percent Single oral dose of one gram per kilogram
<8 hour : acetylcysteine (antidote) a glutathione precursor Limits the formation and accumulation of NAPQI
<24 hour: methionine p.o.
Protect liver from damage
>24 hours: specialist advice for liver transplantation
Liver transplantation is life-saving for fulminant hepatic necrosis The indications for liver transplantation are:
1 - Acidosis (pH < 7.3)
2 – Prothrombin time (PT) > 100 sec
3 - Creatinine > 300 mcg/l,
4 - Grade 3 encephalopathy (or worse)

Question 18

NAPQI

Answer 18

toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol. It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

Question 19

Aspirin

Answer 19

• Antiplatelet therapy
• Inhibition of COX-1 and COX-2
• Interference with metabolism
  i. Prevents the formation of ATP and promotes the formation of lactate and pyruvate
  ii. Inhibits the Krebs cycle enzymes, encouraging lipid metabolism and ketogenisis
  iii. Inhibition of amino acid metabolism.
• Activation of the Respiratory Center in the Medulla

Question 20

Aspirin Overdoes

Answer 20

-Fatal intoxication can occur after the ingestion of 10 to 30 g by adults and as little as 3 g by children;
-Metabolic acidosis
-An acidic pH promotes the movement of
salicylate into the tissues
-Respiratory alkalosis
-Electrolyte imbalance
Increased renal excretion of bicarbonate, Na+, K+ follow Increased pulmonary insensible losses
Vomiting
Hyperthermia causing skin insensible losses

Question 21

Management

Answer 21

• The use of activated charcoal has shown to reduce the amount of active salicylate by 50-80% in the initial presentation,
– in vitro studies suggest that each gram of activated charcoal can absorb approx. 550 mg of ASA
– A ratio of 10:1 charcoal to salicylate has the maximum effectiveness
• Multiple doses of activated charcoal appears to be superior to single doses although current data is presently insufficient
• Fluid replacement is very important in the management of salicylate toxicity
– major fluid losses through tachypnea, vomiting, hypermetabolic state, and insensible perspiration

Question 22

Most important Management

Answer 22

• The most important management is through urine alkalinization with sodium bicarbonate, resulting in enhanced excretion of ionized acid form of salicylate
– Alkalinization can be achieved with a bolus of 1-2 mEq/kg, followed by an IV infusion of 3 ampules of sodium bicarbonate in 1 L of D5% to run at 1.5-2 times maintenance fluid range
• Alkalinizing the urine from a pH of 5 to 8 increased renal clearance from 1.3 to 100 ml/min
• Urine pH must be maintained at 7.5-8.0 and hypokalemia must be corrected

Question 23

Management -Indications of hemodialysis

Answer 23

• Renal failure
• Congestive heart failure
• Acute lung injury
• Persistent CNS disturbances
• Progressive deterioration in vital signs
• Severe acid-base or electrolyte imbalance
despite appropriate treatment
• Hepatic compromise with coagulopathy
• Salicylate concentration (acute) > 100 mg/dL
(in the absence of the above)

Question 24

Opiates overdose

Answer 24

• Opioids bind to specific opioid receptors in the CNS;
• Characteristic of opiates overdoes: – respiratory depression
breathing slows down, sometimes to a stop – pinpoint pupils
an important diagnostic feature in opioid poisoning – decreased level of consciousness
– hypotension and bradycardia
heart rate slows down, sometimes to a stop
blue lips, nails (due to insufficient oxygen in the blood)
• Morphine / Heroin overdoses are the most common single cause of death from drug overdose, account
for 25% of the total;

Question 25

Opiates overdose management

Answer 25

• Antidote – naloxone, a competitive antagonist at opioid m receptors • I.V. (preferred), I.M., intratracheal, SubQ: 0.4-2 mg every 2-3 minutes as needed • Elimination half-life of naloxone is only 60 to 90 minutes • Repeated administration/infusion may be necessary • S/E: BP changes; arrhythmias; seizures; withdrawal

Question 26

Pesticides

Answer 26

Pesticides (and nerve (war) gas) are organophosphate – irreversible anticholinesterases (AChE); - Nicotinic signs: Twitching, Fasciculations, Muscle weakness, Cyanosis, Elevated BP - Muscarinic signs: Bronchoconstriction, Increase secretion, Sweating, GI, Meiosis - CNS signs: Anxiety Restlessness, Confusion, Headache

Question 27

Management of pesticides

Answer 27

• Supportive care – clear airway (why ?); • AChE regenerator, known as oxime agents, which can hydrolyze the phosphorylated AChE; • Pralidoxime (antidote) i.v.1-2 g for over 15-30 min. and for several days in severe poisoning; • must be used quickly after exposure before pesticide conjugate “ages” and becomes unreactive; • It has positive charge and does not enter the CNS, can’t reversing the effects of organophosphate poisoning on CNS; • Simultaneous use of atropine is required to control muscarinic excess. • Pretreatment with reversible inhibitors (e.g. pyridostigmine or physostigmine), to protect against excessive AChE inhibition when possibly lethal poisoning is anticipated,25 e.g., peasants, soldiers (chemical warfare);

Question 28

The principles of treating overdose

Answer 28

Evaluation Supportive Prevent absorption Elimination Antidotes

Question 29

Examples of drug overdoes management

Answer 29

Paracetamol Aspirin Opiates Organophosphate pesticides