Pharmaceuticals Toxicant

Question 1

Thyroid hormone supplements

Answer 1

• L-thyroxine
• poorly absorbed in dogs (10-50%)
• 0.2mg/kg mild signs seen
• 1mg/kg severe signs seen
• 1-9 hours post ingestion
• vomiting, diarrhoea, hyperactivity or lethargy, hypertension, tachycardia, tachypnea, dyspnea and abnormal pupillary light reflexes.
• Tx: decontamination if ingested within 2 hours
• single dose of AC will be sufficient
• only small amount of enterohepatic recirculation occurs
• beta blockers to treat tachycardia
• acepromazine to help if agitation is present

Question 2

Non-steroidal anti-inflammatory medications

Answer 2

*Ibuprofen
-inhibits conversion of arachidonic acid into different prostaglandins by reversing actions of COX enzymes
-When COX-2 enzymes are inhibited: it reduces inflammatory mediators like prostaglandins
-When COX-1 enzymes are inhibited: affects substances necessary for normal physiologic functions such as maintaining gastric mucosal barriers, renal blood flow and platelet aggregation
-highly protein bound
-eliminated via hepatic biotransformation and excreted by the kidney
-marked enterohepatic recirculation
-therapeutic dose for dogs: 5mg/kg
-chronic administration can lead to GI ulceration
-50-125mg/kg : vomiting, diarrhoea, abdominal pain
->125mg/kg: above signs plus hematemesis, melena, and increased risk of acute renal injury (AKI)
-400-500mg/kg: CNS signs and acidosis
-higher doses: death
-cats are twice as sensitive than dogs
Tx:
-decontamination within 2 hours
-multiple doses of AC every 6-8 hourly
-GI Protectants
-diuresis at 2X maintenance for 48 hours IVF
-control seizures with diazepam or barbiturates

• Naproxen
• half-life of 74 hours
• tx similar but need longer IVF
• 5-10mg/kg: GI effects seen
• 20-25mg/kg: kidney injury
• Carprofen
• 20mg/kg (dogs): GI issues
• > 40mg/kg: renal issues
• 4mg/kg (cats): GI issues
• > 8mg/kg: kidney injury

Question 3

Acetaminophen

Answer 3

• Often grouped with NSAIDs
• antipyretic effects
• rapidly absorbed from GIT and metabolised by the liver vis sulfation and glucuronidation
• cat lack glucuronyl transferase to metabolise this
• produces toxic metabolite N-acetyl-p-benzoquinonamine (NAPQI)
• causes oxidative damage to RBCs and liver cells
• RBCs more suspectible to oxidative injury
• methemoglobinemia: Dysnea, cyanosis, dark mm, face and thoracic oedema
• no safe dose
• toxicity seen as low as 10mg/kg
• fatalities at 140mg/kg
• dogs have a dose dependent toxicity
• overdose: liver disease
• 75-100mg/kg
• methoglobinemia: >200mg/kg

Tx:
-decontamination and AC
-n-acetylcysteine (NAC) = antidotal tx
~serves as a substrate for glutathione
~inactivates toxic metabolites and allowing safe excretion
~oral dose or IV
~most effective when given within 8 hours of ingestion
~AC absorbs NAC so separate by a few hours
~ loading dose: 140mg/kg diluted to 5%
~ 70mg/kg q6 for 7 doses (or > prn)
-IVF and GI and hepatic protectants (s-adenosylmethionine [SAM-E], silymarin)

• liver values
• elevates 24-36 hrs post ingestion
• peaks 72 hrs
• keratoconjunctivitis sicca (KCS)
• seen after toxic doses
• thought to be immune reaction
• may need cyclosporine for a few weeks
• can administer cytochrome P-450 (CYP) inhibitors to slow metabolism
• ranitidine
• cimetidine
• contraindicated in cats (they use CYP pathways to convert methemoglobin to hemoglobin)
• prognosis good if tx initiated early
• symptomatic patients have more guarded prognosis

Question 4

Opioids

Answer 4

*groups:
Agonist 
Antagonist 
Mixed agonist-antagonist 
Partial agonist 
-metabolised by liver by glucuronidation 
-hence cats more susceptible 

• Most common sign:
• CNS depression : from ataxia to coma to death
• sometimes opposite: excitement and dysphoria
• respiratory depression
• hypothermia

Tx:

• adequate ventilation
• naloxone (opioid antagonist)
• decontamination if not CNS depressed

Question 5

Anti-depressants

Answer 5

4 groups:

1) Monoamine oxidase inhibitors (MAOIs)
2) Tricyclic antidepressants (TCAs)
3) Selective serotonin reuptake inhibitors (SSRIs)
4) Novel or atypical antidepressants

1) MAOIs
- monoamine oxidase enzyme: breaks down norepinephrine, epinephrine, dopamine, and serotonin
- when this enzyme is inhibited, levels of these neurotransmitters increase
- overdose: hypo- or hypertension, ataxia, restlessness can progress to arrhythmias, tachycardia, respiratory depression, coma and death

2) TCAs
- work by blocking reuptake of norepinephrine and serotonin, increasing their levels
- same overdose signs as above

3) SSRIs
-inhibit reuptake of serotonin
-overdose: ataxia, depression and seizures, fewer cardiac effects
~seretonin syndrome: results from excess seretonergic agonist of the serotonin receptors in the CNS and peripheral nervous systems.
:causes mental status changes
:neuromuscular abnormalities
:autonomic instability
-they present with lethargy that can progress to agitation
-thermoregulatory center can be reset and they can be frequently hyperthermic
-tachycardic, ataxic, muscle tremors or even seizures

Tx:

• decontamination
• multiple doses of AC
• diazepam
• phenobarbital
• supportive care
• cyproheptadine (nonspecific serotonin antagonist) used to treat this syndrome (1.1mg/kg in dogs or 2-4mg/kg in cats q4-6hrs)
• Prognosis: depends on clinical signs
• severe neurological signs = guarded prognosis

4) atypical antidepressants
- increases levels of serotonin, norepinephrine, and dopamine
- same overdose signs as MAOIs