Anti infectives

Question 1

Discuss risk assessment of chloroquine and hydroxycholorquine

Answer 1

Most toxic antimalarial when taken in overdose. Hydroxychloroquine is also used to treat SLE and RA
OD produces rapid onset of hypotension CNS depression cardaic conduction defects and hypokalaemia.

Ingestion of >10mg/kg of chloroquie is potentially toxic
serious toxicity and increasing mortality is expected with ingested doses fo >30mgkg
Ingestion of >5g of chloroquine in adults is usually fatal wihtout intervention
-Dose related risk assessment is less well defined for hydroxychlorquine but appears to be similar

Children: ingestion of even one tablet is regarded as potentially lethal in children less than 6 years of age

Question 2

Dsicuss TM and TK of chloroquines

Answer 2

TM: These drugs have a direct toxic effect on the CNS via effects on voltage dependant Na+ channels. CNS toxicity is compounded by cerebral hypoperfusion from CVS effects. CVS manifestation are related to blocking of multiple inward and outward membrane currents. Hypotension and cardiogenic shock are due to a direct cardio depressant effect. Hypokalaemia is believed to be due to a transport dependant mechanism.

TK: Absorption after ingestion is rapid and complete. They are extensively tissue bound and have a VD of >50L/kg. They are paritally metabolised and have prolonged halflives of several weeks. More than 50% of chloroquine is excreted unchanged.

Question 3

DIscuss clinical features of chlorquine OD

Answer 3

Onsent of symptoms within 1-2 hours
Features include
-non specific symptoms of dizziness, nasuea and vomting

CVS:

• rapid onset of hypotension
• cardiac conduction defects (QRS widening and QT prolonagioatn)
• cardiac arrest

CNS:

• depressed concsious state
• seizures

Metabolic
-Hypokalaemia due to intracellualr shift of potassium

Question 4

Discuss management of chlorquine OD

Answer 4

Resus
ABCD
-Coma prompt intuabtion and venilation is indicated at the first sign of a depressed conscious state -should anticipate catastrophic deterioiatoin in any patient presenting early in overdose
-CVS- broad complex tachy mangaged aggresively with intubation hyperventialtioin and serum alkalinisation. Give sodi bic 1-2mmol/kg IV for QRS prolongation. Aim Ph 7.5-7.55
-Hypotension initially treat with fluid resus but is likley to need pressor support
-High dose diazpam infusion 1mg/kg IV over 24 hours has been adovcated - protective mechanism is unclear

Ensure normokalaemia – hypokalaemia should be anticipated but avoid aggresive replacement as is likley to shift rather than deficit

Question 5

Discuss risk assessment of isoniazid

Answer 5

Rare but potentially fatal. Severe poisoning present with rapid onset of seizures, coma and severe metabolic acidosis

> 1.5 g (20mg/kg) - may develop symptoms
3 g (40mg/kg) -seizures, metabolic acidosis and coma
10 g (130mg/kg) - uniformly fatal without intervention

Question 6

Discuss TM and TK of isoniazid

Answer 6

TM: Structurally related to puridoxine, nicotinic acid and NAD. Toxicity results from a defiency of the active form of pyridoxine (pyridoxine 5 phosphate). Isoniazid interferes with the enzyme responsible for the conversion of pyridoxine to p5p pydiroxine phosphokinase binds to and inactivates p5p and enhances urinary excretion.
p5p is essential co factor in the conversion of glutamic acid to GABA in the CNS and acute GABA defiency manifesting as status seizures develops. Severe lactic acidosis is due to the status seizures and direct inhibiotn of converion of lactate to pyruvate.

TK:
Absorption following oral administration is rapid and compete. Peak levels occur within 1-2 hours. VD is 0.6L/KG . Undergoes hepatic metabolism by either acetylation to form acetyl isoniazid or hydrolysis by Cp450 to form hydrazine. Some drug is excreted unchanged in the urine.

Question 7

Discuss clinical features of isoniazid OD

Answer 7

Initial symptoms are light headedness, blurred vision, photophobia, nausea and vomiting

Physical exam reveals tachycardia, dilated pupils slurred speech ataxia and hyperrelfexia.

If suffieicnt dose is ingested patients rapidly deveop confusion depression LOC coma, status seizures and severe lactic acidosis and death.

Seizures are generally tonic clonic. They may resolve spontaneously then recur promptly. Complications of prolonged status including hyperpyrexia, pulmonary aspiration and rhabdo

Question 8

Discuss IX of isoniazid

Answer 8

General: BSL, paracetamol and ECG

ABG - severe lactic acidosis with ph in the range of 6.8-7.3

Isoniazid levels not routinely available and difficult to interpret