Other Flashcards
Discuss risk assessment of Acute methotrexate OD
The toxic effects of this antimetabolite are employed therapeutically in the treatment of a variety of neoplastic conditions, psoriasis and RA. Toxicity is not described following acute OD but severe toxicity occurs following repeated supratherapeutic dosing. Folinic acid is used as an antidote in selected cases
Single dose
<500mg (5mg/kg in children) - toxic levels unlikley
>500 mg (>5mg/kg) in children) - toxic levels possible
Threshold blood levels for a toxicity following a single acute dose
- 6 hours post ingestion - methotrexate level of 5micmol/L
- 12 hours – 1 micromol/l
- 24 hours - 0.1 micromol/L
Discuss risk assessment of chronic methotrexate overdose
Repeated supratherapeutic ingestion
- associated with potentially lethal bone marrow suppression
- toxicity may develop if the weekly therapeutic oral dose is taken on as a few as 3 consecutive days
- patients with renal failure and the malnourished are more susceptible ot methotrexate induce marrow supression
Describe TM and TK of methotrexate
TM: structural analogue of folate. It acts by competitive inhibition of dihydrofolate reductase and thymidylate synthetase resulting in decreased DNA and RNA synthesis and hence decreased cell replications. Methotrexate toxicity is related to inhibiotin of dividing cells (GIT, Bone marrow, Hair) renal and hepatic injury are also noted
TK: Intestional absorption of orally administered methotrexate is saturable. Peak levels occur at 1-2 hours post ingestion The VD is 0.4-0.8L/kg with 50% protein binding. Up to 80% is excreted in the kidney unchanged. Hepatic metabolism creates a nephrotoxic metabolite which accumulates at high doses . Elimination half increases with dose accounting for accumulation and sever toxicity seen with inadvertent daily dosing. In supratherapeutic toxicity, intracellular polyglumtamated forms of methotrexate mediated prolonged anti metabolite effects
Describe clinical features of methotrexate OD
Following repeated supratherapeutic ingestion patients present with clinical features and complications of GIT, bone marrow, hepatic and renal injury. Stomatitis is an early sign
Nausea vomiting and diarrhoea are common. Pallor and fatigue indicate anaemia which reaches a nadir at 7-14 days.
Discuss IX of methotrexate overdose
Methotrexate levels and renal fucntion
- following acute single overdose, a timed methotrexate level and renal function test determine the need for folinic acid rescure.
- if folinic acid is indicated follow-up methotrexate levels indicate duration of therapy
FBC for bone marrow impairment
Discuss management of methotrexate overdose
ACUTE Ingestion <500mg (<5mg/kg in children) -ensure hydration -check renal function and methotrexate level at 6 or more hours post ingestion Ingestion >500mg -administer activated charcoal -ensure adequate hydration -commence folinic acid -check renal function and methotrexate level at 6 or more hours
If renal function is normal and the serum methotrexate level is below thresholds for toxicity further folinic acid is not indicated and the patient may be medically cleared if otherwise well.
D: - charcoal (1g/kg) 50g is indicated in co-operative patient presenting within 2 hours of acute overdose
E: nil
A: folinic acid 15mg PO, IM or IV every 6 hours. In a single acute toxicity folinic acid may be stopped when below toxic threshold - otherwise it is continued until serum methotrexate is <0.05micrmo/L
- in chronic therapy should be continued for at least 3 days until serum methotrexate is <0.05 micromol/L and evidence of bone marrow recovery is documented n
Describe risk assessment of theophylline
Extremelly narrow therapeutic index and both acute and chronic overdose are potentially life threatening. Agressive supportive care and early accurate risk asseessment is key
Ingestion of >50mg/kg is expected to lead to life threatening toxicity manifest by tachydysrhytmias and seizures
5-10mg/kg –> therapeutic loading dose
>10 mg/kg –> potential for toxicity
>50mg/kg - life threat
patients with chronic toxicity have a poor prognosis
Describe risk assessment of theophylline
Extremelly narrow therapeutic index and both acute and chronic overdose are potentially life threatening. Agressive supportive care and early accurate risk asseessment is key
Ingestion of >50mg/kg is expected to lead to life threatening toxicity manifest by tachydysrhytmias and seizures
5-10mg/kg –> therapeutic loading dose
>10 mg/kg –> potential for toxicity
>50mg/kg - life threat
patients with chronic toxicity have a poor prognosis
Discuss clinical features of theophyline
Early manifestation of toxicity in acute OD include anxiety vomiting, tremo and tachycardia.
Severe poisoning is associated with
1) cardiac dysrythmias
- SVT
- AF and flutter
- VT
2) refractory hyoptension
3) seizures
4) metabolic derangement
- hypokalaemia (severe and refractory)
- hypophosphataemia, hypomagnesaemia
- Hyper glycaemia
- metabolic acidosis
Cardiac dysrythmias and seizures occur late and indicate extremely poor prognosis
Chronic toxicity usually develops in elderly or infant patients and generally presents with vomiting and tachycardia. The metabolic effects are less pronounced than for acute OD but siezures and dysryhtmias occur frequently and at lower serum theophyliine concentration.
Discuss IX of theophyline
Serum levels
- extremely useful in predicting the risk of life threat
- in acute OD levels correlate well with clinical severity and are repeated every 2-4 hours
- levels >60mg/L may be assoicated with severe toxicity in elderly
- in chronic levels >40mg/L can be severely toxic
10-20 --> therapeutic 20-40--> minor tox 40--80 - moderate toxi 80-100 - severe >100 usually fatal wihtout urgent intervention
Discuss management of theophyline OD
RESUS
- Hypotension –> fluids than norad
- seizures –> poor prognosis as per any other tox seizure
- SVT - beta blockade usually carefully titrated doses of propanolol or metoprolol or esmolol infusion.
D: Oral activated charcoal is indicated following acute overdose even if presentaiton is delayed –> antiemetics are required in unitubtated patient
E: HD - is the definitive life saving intervention.
-serum theophyline >100mg/L in acute
-Serum theophuline > 60mg/L in chronci
-clinical manifestaitons of severe toxicity - dysrhythmias, hypotension or seizures
MDAC –> only use if HD is not avaialble.
A: nil
Discuss risk assessment of thyroxine
Majority remain asymptomatic or experience mild to mod symptoms of hyperthyroisims some 2-7 days later .
Symptoms are not expected unless >10mg has been taken
-Severe toxicity is more likley secondary to chronic abuse.
Chronic abuse can cause complciatoisn
- angina pectorsi
- MI
- myocarditis
- Ventricular and atrial dysrhythmias
- LVH
- thyrotoxicosis
- thyoid storm
