Significant GI bleeds are surprisingly infrequent.
Management - therapeutic [salicylate] is <300mg/l (2.2 mmol/l)
Mild/moderate salicylism requires only rehydration + KCl supplements.
Marked salicylism or levels > 750mg/l need specific elimination therapy:
(1) Oral activated charcoal (50g 4 hourly)
(2) Forced alkaline diuresis NO LONGER RECOMMENDED - it is no more effective than simple alkalinisation (eg 1 L 1.26% NaHCO3 over 2 hrs and repeated to keep the urinary pH > 7.5).
(3) Haemodialysis is required for any of the following: level >1000mg/1 (7.25 mmol/l); persistent/progressive acidosis; deteriorating level of consciousness.
Paracetamol (Acetaminophen, Tylenol ® ) NB component of compound analgesics such as co-codamol , co-dydramol & co-proxamol and amongst OTCs some Alka-Seltzer ® , Anadin ® and Beechams-Powders ® preparations.
15 – 20 tablets (7.5-10g) = overdose
Causes severe centrilobular necrosis of the liver
10% have renal toxicity (acute tubular necrosis)
Accounts for ~ 200 deaths/year in UK
PARACETAMOL www.freelivedoctor.com HN C CH 3 OH O
OH HN C CH 3 O O HN C CH 3 O Sulphate O HN C CH 3 O glucuronide O H H O N C CH 3 O 60% 40% CYP2E - minor pathway except in overdose! Paracetamol Metabolism NABQI www.freelivedoctor.com O N C CH 3 O
(Glutathione-S-transferase) O N C CH 3 O δ +ve O H H N C CH 3 O S G GSH Detoxifcation of NABQI consumes GSH www.freelivedoctor.com SH
Protection by glutathione (GSH) and its substitution with exogenous N-acetyl-cysteine - OOC – CH 2 – N – C – CH – N – C – CH 2 – CH 2 - CH O CH 2 SH H H O COO - NH 3+ Tripeptide ( -ECG). Present in all cells – high in hepatocytes ~ 5mM
Exogenous GSH cannot enter hepatocyte
NAC is SH donor to scavenge NABQI
Also protects intracellular levels of GSH in hepatocytes
Depletion of GSH by >80% causes toxicity
Apart from mild nausea, vomiting and anorexia, patients presenting within 24 hrs of ingestion are generally asymptomatic.
Hepatic necrosis becomes apparent at 24-36 hrs with:
right subchondral pain/tenderness
reappearance of vomiting and neuroglycopenia
Deepening Encephalopathy over the next 72 hrs.
The predictable consequences of liver failure i.e. metabolic acidosis, hypoglycaemia, cerebral oedema, cardiac arrhythmias and GI bleeding.
10% of patients develop renal impairment from acute tubular necrosis - occasionally in the absence of hepatic failure.
Very rarely patients with G6PD deficiency develop methaemoglobinaemia and haemolysis.
Untreated, the fatal dose in adults is usually >10g - lower in chronic alcoholics or subjects with underlying liver disease or treated epileptics.
A PT of 20s at 24 hrs indicates significant hepatocellular damage; the more rapid the rise in PT thereafter the poorer the prognosis.
In patients developing hepatic failure, a poor prognosis is suggested by: (1) arterial pH <7.3; (2) prothrombin time >100s; (3) creatinine of >300 mol/l. They should be considered for early liver transplantation .
Within 4 hrs of ingestion lavage (?) or activated charcoal
Paracetamol levels checked at 4hrs & compared to treatment curve (200mg/1 or 1.32mmol/l at 4h joined to with 6mg/1 or 0.04mmol/l at 24h). Some 60% of patients above the line develop severe liver damage defined as AST >1000.
Patients on or above the line should be given IV N-acetylcysteine*
* up to 10% have a rash, bronchospasm or hypotension during the IVI (acts as a mast cell releaser). Stopping and giving chlorpheniramine IV usually allows the IVI to be safely restarted.
HSE limit 200ppm (0.02%) causes headaches in 2-3 hours cf >10,000ppm (1%) that can cause death in a few minutes.
The commonest sources are:
poorly maintained domestic gas/oil appliances
deliberate inhalation of car exhaust fumes
Causes intense tissue hypoxia by two mechanisms :
interrupts electron transport in mitochondria
blocks tissue O 2 delivery
competes with O 2 for binding to Hb (Ka CO 220-fold > 02)
alters shape of the Hb O 2 dissociation curve (less sigmoidal)
Signs of hypoxia without cyanosis - 'cherry-red' colouration most obvious post mortem!
Symptoms & signs correlate with % COHb* :
<30% causes only headache and dizzyness
50-60% produces syncope, tachypnoea, tachycardia and fits
>60% increasing risk of cardiorespiratory failure and death.
NB Pulse-oximetry unhelpful – it measures functional saturation …
* Non-smoker 1%; Smoker 5-8%; Jogger in London 12% … www.freelivedoctor.com
Check ABG - PaO 2 may be normal but metabolic acidosis indicates severe poisoning.
Give O 2 by mask unless comatose then IPPV with FiO 2 =1 (t1/2 COHb 320 mins on room air vs 80 mins at 100%)*. [Also consider if severely acidotic or evidence of myocardial ischaemia.]
Control fits with IV diazepam.
Hyperbaric 02 will shorten the washout of COHb further (half-life of 25 mins at 2 atmospheres), but access and transfer times to a hyperbaric chamber may make this impractical. Recent trial suggest may be worthwhile (cognitive sequelae at 6/52 were reduced from 35/76 to 19/76 by this Rx …. NEJM 2002;347:1057 www.freelivedoctor.com
Sites at particular risk are:
CNS - cerebral, cerebellar or midbrain (Parkinsonism and akinetic-mutism)
Myocardium - ischaemia/infarction
Skeletal muscle - rhabdomyolysis/myoglobinuria
Skin - erythyema to severe blistering.
NB (1) Anaemia, increased metabolic rate (e.g. children) and underlying ischaemic heart disease all increase susceptibility to CO.
(2) Neurological recovery depends on the duration of hypoxic coma : complete recovery has been reported in young subjects (under 50) after up to 21 hrs versus 11 hrs in older ones.
CARBON MONOXIDE www.freelivedoctor.com
Coca leaves chewed by Pre-Columbian Indians for several millennia
1884, Koller discovers efficacy as ophthalmic local anaesthetic
Freud adds his endorsement the same year, ‘Uber Coca’
Merck and Parke Davis compete for commercial production
Widespread addition to wines (Vin Mariani) and ‘tonics’ (Pemberton’s) …
Erythroxylon Coca Leaves contain up to 10mg/g of cocaine ‘ According to forensic experts, around 80 per cent of all banknotes in circulation are contaminated with drugs, a figure that rises to 99 per cent in the London area. Research by Mass Spec Analytical, the Bristol-based forensics company which analyses banknotes seized by police and customs, shows that cocaine is the most common substance’ The Observer from Nov 10, 2002. www.freelivedoctor.com
Traub, S. J. et. al. N Engl J Med 2003;349:2519-2526 COCAINE
Users, Carriers & Routes of Administration
In 1999, an estimated 1.5m Americans were current users and 3.7m had taken it in the past 12 months. Hair analysis for metabolites suggests a 4-5 fold larger problem.
Its subjective and sympathomimetic actions are often indistinguishable from amphetamine even for experienced users.
Onset can be very rapid when snorted or smoked (freebasing 'crack').
Occasionally massive overdose in drug smugglers presents after swallowed/secreted packets rupture.
Seizures common as well as ventricular arrythmias.
Very high doses cause CNS depression particularly in the medullary centres with cardiorespiratory failure.
Vasoconstrictor effects on the coronary circulation - even with angiographically normal vessels.
Psychotic reactions (c.f. amphetamine psychosis).
Cocaine can cause seizures in epileptics in 'recreational' doses but for non-epileptics presentation in status epilepticus generally implies massive overdose which is often resistant to treatment and carries a poor prognosis.
A syndrome of acute rhabdomyolysis, hyperpyrexia, renal failure, severe liver dysfunction and DIC has been reported and also carries a high mortality cf ecstasy.
Patients with deficiency of serum pseudocholinesterase appear to be at particular risk of life threatening cocaine toxicity.
Monitor ECG continuously. Ensure the airway is clear and if the patient is comatose intubate and mechanically ventilate early. Watch for evidence of hyperpyrexia.
Seizures: IV diazepam (10-20mg IV stat and if necessary an IVI of up to 200mg/24hrs). If new focal seizures CT indicated.
Hypertension: IV GTN or phentolamine first-choice; labetalol IV second-choice (inadequate -blockade?) NEVER pure beta-blockers!
Ventricular arrythmias may be treated with lignocaine (100mg stat then an IVI of 4mg/min) provided the patient is paralysed and ventilated otherwise seizures may be precipitated. In concious patients, IV labetalol may be useful. Phenytoin 3rd Iine but especially useful in the presence of seizures.
Hyperpyrexia prompt cooling (aim for rectal temp <38.5). Chlorpromazine ? (25-50mg IM) beware sedation and hypotension. Dantrolene?
OPIATES Papaver Somniferum
Pin-point pupils & Coma
Severe respiratory depression/cyanosis
BP may be low but often well maintained
- NB pentazocine overdose actually BP
Hypotonia often marked
- dextropropoxyphene and pethidine muscle tone and cause fits
All opiates can cause non-cardiogenic pulmonary oedema
- but most frequent with IV heroin.
Rhabdomyolysis is common in opiate-induced coma
- it should be looked for in all cases.
Substances used to dilute ('cut') illicit opiates may be toxic
e.g. talc and quinine.
Non-cardiogenic pulmonary oedema carries a poor prognosis (it is not naloxone reversible)
Patients ingesting paracetamol+opiate combinations (i.e. co-proxamol and co-dydramol) obviously run the additional risk of paracetamol toxicity
Patients with underlying ischaemic heart disease seem more susceptible to haemodynamic disturbance after naloxone is given to reverse opiate intoxication (see below)
NB Renal impairment reduces the elimination of many opiates (or their glucuronidated metabolites), so prolonging their duration of action.
If paracetamol+opiate combinations ingested measure a paracetamol level and treat accordingly.
Specific antidote is naloxone given as IV in boluses of 0.4mg at 2-3 minute intervals until rousable and respiratory depression corrected.
Convulsions (usually pethidine or dextropropoxyphene) usually respond to IV naloxone without additional anti-convulsant therapy.
Pulmonary oedema present on admission generally requires IPPV.
Important points re use of Naloxone ….
If >2mg given with no response, revisit the diagnosis of opiate overdose!
Naloxone has a short half-life compared to most opiates. With long-acting opiates such as methadone a naloxone IVI may be necessary for 48- 72hrs.
Beware Cold Turkey!
… . Giving sufficient naloxone to completely reverse the effect of opiates in an opiate-dependent subject is likely to precipitate an acute withdrawal reaction.
… . Marked hypertension, acute pulmonary oedema and VT/VF have been observed in non-adducts given naloxone to reverse the effects of high therapeutic doses of opiates for pain.
Dextropropoxyphene + alcohol can cause marked CNS depression. Respiratory arrest can evolve within <30 mins of ingestion. Give naloxone even if the patient is only mildly drowsy. It also causes an acute cardiotoxicity with arrhythmias due to a membrane-stabilising effect (naloxone ineffective).
The respiratory depressant effects of buprenorphine are not fully reversed by naloxone . Doxapram has been used in milder cases of buprenorphine overdose as a respiratory depressant (1-4mg/min) although severe cases may require IPPV.
MDMA synthesized by chemists at Merck in 1912 and patent granted in 1914 – later resurfaced in Gottlieb’s CIA campaign, MKULTRA
Used legally by psychotherapists until 1985 when it was first made a schedule I drug in USA
Recreational use now exceeds 750,000 tabs/week in NY – probably similar number in UK.
Single tablet doses typically 50-100mg. Occasionally unexpected adulterants e.g. strychnine.
Jacob Merck’s ‘Engel-Apotheke’, Darmstadt circa 1668 3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy) www.freelivedoctor.com
Presentation – following typical of amphetamines but not features of usual recreational doses of E
Central effects - hyperexcitability, talkativeness and agitation.
[Paranoid features may be obvious especially in chronic users – not applicable to E].
A 'heat-stroke' like syndrome : rhabdomyolysis, hyperpyrexia (>42 C), DIC and acute renal failure. It carries a poor prognosis (see cocaine). ? PK problem ?? CYP2D6 metaboliser status important
[Intracranial (and subarachnoid) haemorrhage (? 2ary to hypertensive effect but can occur after single therapeutic doses and vasospasm reported at angiography 'string-of-beads' sign) – not applicable to E].