Pharmacology and toxicology Flashcards
Agents for CCB and beta blocker OD
• Atropine 1mg stat (can be repeated x 3; often ineffective; muscarinic receptor
antagonist increases SA node discharge, conduction through the AV node and opposes
action of Vagus nerve)
• Adrenaline or Noradrenaline infusion starting at 10-20 g/min and titrate to a MAP > 65
mmHg (+ve inotropy, chronotropy, vasoconstriction)
• Calcium – Chloride or Gluconate can be given (more calcium in CaCl) – 10mls of 10%
solution (can be repeated x3 +/- infusion; competitively increases calcium entry into the
myocardium via non-blocked channels)
• Glucagon 5mg stat (can be repeated x3; increases intracellular cAMP and has been
shown to increase heart rate in BOTH beta-blocker and CCB toxicity).
• 100mls 8.4% NaHCO3 stat (she is already very acidotic)
• Hyperinsulinaemia-Euglycaemia – short acting insulin 1 unit/kg with 50mls 50%
Dextrose bolus, then 0.5 units insulin /kg/hr with 10% dextrose infusion and q1hrly BGLs
and K+ (high dose insulin = +ve inotrope but mechanism not clearly understood)
• Lipid Emulsion – 1ml/kg 20% lipid emulsion bolus (can be repeated x 3 then start
infusion 0.5mls/kg/min; acts as a “lipid sink” surrounding lipophillic drugs rendering them
ineffective & maybe fatty energy source for myocardium)
Theophilline overdose
Symptoms Nausea Vomiting Elevated mood Agitation, anxiety Hallucinations
Signs - Tachypnoea Tachycardia Hypotension Widened pulse pressure Tremor Seizures Increased muscle tone Fasciculations
Biochemistry - Hypokalemia Hypomagnesemia Hypophosphataemia Hyperglycaemia Hypercalcemia Lactic acidosis Respiratory alkalosis Rhabdomyolysis
Management of theophilline overdose
Decontamination
Repeated doses of activated charcoal (MDAC)
Enhanced elimination
Charcoal haemoperfusion
Antidotes
Strangely, SVT does not respond to adenosine. Goldfranks’ Manual (2007 edition, p. 557) recommends calcium channel blockers as a more effective antiarrhythmic therapy (a β-blocker would be just as good but the patient will inevitably be somebody with either asthma or COPD).
Supportive management
Complications of salycilate toxicity
pulmonary oedema cerebral ordema myocardial depression and shock hypoglycaemia seizures haemorrhage from gastric ulceration muscle rigidity leading to respiratory depression
Haemotological changes in salycilate toxicity
Raised PT: The classical coagulopathy which develops (asked about in the SAQs) is a prothrombin deficiency, leading to a prolonged PT and increased INR.
- because of hepatotoxicity and interference with the synthesis of vitamin K dependent factors.
Platelet dysfunction (due to COX enzyme inhibition)
Haemolytic anaemia (either by an autouimmune mechanism similar to that of methyldopa, or by oxidative damage as in G6PD).
options for enhancing salicylate removal
Haemodialysis. Most of the drug is protein-bound, and is concentration dependant. The volume of distribution is small, and binding site saturation leads to large levels of free drug, which is easily dialyzable
Multiple-dose charcoal. Many aspirin forms are slow release and after ingestion they clump together in the GI tract, forming a large slow release preparation. It is also poorly soluble in the stomach leading to delayed absorption.
Forced alkaline diuresis. Renal excretion of salicylates becomes important when the metabolic pathways become saturated. There is a 10 – 20 x increase in elimination when the urine pH increased from 5 – 8. Current role is questionable as haemodialysis is more efficient at removal, with less metabolic disturbance. Reasonable, as initial therapy whilst waiting for circuit prime and line insertion.
Salicylate level may be declining because -
It is clearing renally or by hepatic metabolism
Absorption from a bezoar is diminishing
The intracellular uptake of salycilate has resulted in decreased serum levels
It may indicate that the drug is moving into the tissues, and not necessarily being eliminated - This means that clinical assessment is paramount
Issues specific to substance ingestion in 2 year old
Ingested agent likely to be non-pharmaceutical
Vast majority of ingestions are benign
Other children may be affected (siblings, playmates)
Doses ingested likely to be small (2-3 tablets or small handful) and toxic effects mg/kg the same as adults but some agents can be potentially lethal for a toddler if even 1-2 tablets taken (e.g. amphetamines, Ca channel blockers, sulphonylureas) or a mouthful (e.g. organophosphate insecticides, eucalyptus oil, one mothball)
Unlikely to obtain accurate dosing history – risk assessment and management based on “worst-case scenario”
Need admission to health care facility with resources for paediatric resuscitation
Regular check of blood sugar levels
Usual toxicology screening tests for adult patient not necessary
GI decontamination with activated charcoal is not routine because of increased risks with aspiration – reserved for severe or life-threatening poisoning where supportive care or antidote treatment alone is inadequate
If severe intoxication suggesting large, repeated or unusual exposure, consider NAI
Issues specific to substance ingestion in 30/40
Risks to mother and foetus
Pregnancy-induced physiological changes impact on drug pharmacokinetics
Delayed gastric absorption and GI transit time slows drug absorption and increases period of potential benefit for decontamination
Increased blood volume increases VD and decreases drug plasma levels
Dilution of plasma proteins increases free drug levels
Hepatic enzyme systems altered by circulating hormones
Increased cardiac output increase renal blood flow and GFR
Hypovolaemia and respiratory compromise may go unrecognised until at a late stage
A few agents pose increased risk to foetus and treatment threshold is lowered (e.g.
salicylates, CO, lead, MetHb-inducing agents)
Excellence in supportive care for the mother ensures best outcome for foetus
Obstetric and neonatal as well as toxicology input needed including decision for emergency delivery of baby.
Issues specific to substance ingestion in 75-year-old adult with chronic kidney disease
Limited physiological reserve, deteriorating cognition, multiple co-morbidities and polypharmacy lead to exaggerated and unpredictable response in poisoning
More severe clinical course for same dose of same agent taken by healthy young adult
Pharmacokinetic changes with ageing and CKD o Delayed GI absorption o Decreased protein binding and increased free drug levels o Reduced liver function with decreased drug metabolism o Reduced renal function and reduced elimination o Baseline CKD likely to be made worse o “Therapeutic” drug doses may be toxic
Pharmacodynamic differences from drug effects on impaired organs e.g. poor ability to respond to CVS, respiratory and CNS depressant agents
Greater incidence of complications e.g. delirium, pneumonia, thrombo-embolism
Longer ICU and hospital stay
Pathophysiological change and Management implications in ESRF
Respiratory:
Prone to pulmonary oedema
Fluid restriction/ positive pressure ventilation as needed
Cardiovascular: Hypertension Dyslipidaemia, Atherosclerosis, Pericarditis Appropriate drug therapy, aim higher MAP targets based on baseline BP Monitor for pericardial effusion
Neurological:
Dialysis disequilibrium
Polyneuropathy myopathy
Low dose dialysis to prevent rapid shifts
Renal:
Low/no urine output
Fluid prescribing/restriction, nutrition depends on dialysis plan
Metabolic: Hyperkalaemia Metabolic acidosis K+ restriction, Caution with K-sparing drugs (ARBs, ACE-Is, Spironolactone)
Mineral & Bone disorders: Secondary hyperparathyroidism, Hyperphosphataemia, Hypocalcaemia Phosphate restriction/binders, Calcitriol and calcium supplementation, Care to prevent fractures
Gastrointestinal: Impaired gastrointestinal motility Peptic ulceration & bleeding Malnutrition Aspiration risk, enteral feeding difficulty Stress ulcer prophylaxis Early feeding
Skin:
Fragile skin
Meticulous pressure area care
Haematological: Anaemia Platelet dysfunction (uraemic) Appropriate transfusion, EPO Bleeding risk, DDAVP may have a role
Immunological:
Increased risk of infection
Antimicrobial prophylaxis/therapy as appropriate
Endocrine:
Thyroid dysfunction
Difficult to interpret TFTs during critical illness
Pharmacological:
Altered clearance of renally excreted medications
Dose adjustment based on GFR, dialysis regime
Vascular access:
Consider choice of site avoiding site of fistula, Monitor fistula function during critical illness
Typical acid base changes in salycilate poisoning
Acid-base status:
Increased anion gap metabolic acidosis
Concomitant normal anion gap metabolic acidosis
Respiratory alkalosis
Decreased delta ratio
Investigations for a snake bite victim:
CK (rhabdmyolysis)
Coags (DIC, or “venom-induced consumption coagulpathy)
FBC (DIC, looking for thrombocytopenia and red cell fragmentation)
Fibrinogen (DIC)
EUC (renal failure)
LFTs (hepatic injury)
Snake Venom Detection Kit
Indications for polyvalent antidote:
Unsure which snake species was involved
SVDK not available
monovalent antivenom not available
the patient has been bitten by multiple different species of unidentified snakes.
Evidence for premedication for antivenom administration:
This is no longer recommended in Australia
polyvalent antidote tends to have a higher rate of anaphylaxis
How do you know your monovalent antivenom is working?
The short answer is, you don’t.
It takes tme for some of the irreversible features to resolve (eg. it takes time to synthesis the coagulation factors which have been depleted)
Giving more antivenom will not improve the situation.
Reasons for altered drug clearance in critically ill
decreased spontaneous degradation
- hypothermia
decreased tissue metabolism
- decreased tissue blood flow
- hypothermia
decreased plasma metabolism
- due to poor hepatic synthetic function, many serum enzymes responsible for drug removal are not synthetised in appropriate quantities
decreased metabolism in the liver
- decreased hepatic blood flow
- cytokine-induced decrease in hepatic metabolism
hepatic injury
- hypothermia leading to diminished enzyme function
-hepatic enzyme inhibition by other drugs
increased metabolism in the liver
- pyrexia leading to increased metabolic rate
- enzyme activation by other drugs
decreased clearance in the urine
- decreased renal blood flow
- decreased glomerular filtration rate
- poor tubular function, decreased active transport
- acute renal injury eg. ATN
decreased clearance in the bile
- biliary stasis
- decreased gut transit leading to recirculation
- increased clearance due to decreased portein binding
thus, increased free fraction, which is exposed to clearance mechanisms
effect of critical illness on enteral drug absorption
- Multiple factors may alter gastrointestinal mucosal absorption including mucosal oedema, disordered gastrointestinal motility and disordered mucosal blood flow
- Gastric emptying / gut motility affected by drugs (opioids. Anticholinergics, antacids, inotropes), enteral nutrition, brain or spinal injury, diabetes
- Incomplete oral medication disintegration or dissolution
- Changes in pH
indications for multiple dose activated charcoal
Amitriptyline Carbamazepine Cyclosporine Dapsone Dextropropopxyphene Digitoxin Digoxin Disopyramide Nadolol Phenobarbital Phenylbutazone Phenytoin Piroxicam Propoxyphene Quinine Sotalol Theophylline
Complications of charcoal administration
Its gross. Patients complain. However, actual vomiting appears to be rare (Isbister et al, 2011)
It may absorb usueful medications as well as the toxin.
It may increase the risk of aspiration (but if it does, then not y much)
Aspirated, it may be more harmful than sterile gastric contents (but if it is, then not by much). In their answer to Question 29 from the second paper of 2010, the college lists direct administration of charcoal into the lung as a valid concern.
It may cause bowel obstruction; this is rare, and usually associated with multiple dose charcoal in patients who are poisoned with an agent which affects gut motility.
Use of dialysis in toxicology:
the drug is easily dialysed:
- small molecule
- water soluble
- not extensively protein bound
- small volume of distribution
The drug produces dialysable matabolites, which are toxic (eg. ethylene glycol)
The toxicity produces an acid-base disturbance which cannot be addressed by any other means (eg. lactic acidosis in cyanide toxicity)
charcoal haemoperfusion indications
Paraquat Parathion Theophylline Carbamazepine Phenytoin Paracetamol Digoxin Diltiazem Metoprolol Colchicine Promethazine Amanita phalloides mushroom toxin (phalloidin)
Risk factors for propofol infusion syndrome
Propofol infusion dose of >4mg/kg/hr for over 48 hrs
Traumatic brain injury
Catecholamine infusion
Corticosteroid infusion
Carnitine deficiency
Low carbohydrate intake: because energy demand is met by lipolysis if carbohydate intake is low, thus leading to the accumulation of free fatty acids.
Children more susceptible than adults - probably because their glycogen store is lower, and they depend on fat metabolism.
Congenital weirdness: Medium-chain acyl CoA dehydrogenase (MCAD) deficiency
Clinical features and laboratory findings in propofol infusion syndrome
Acute bradycardia leading to asystole.
A prelude to the bradycardia is a sudden onset RBBB with ST elevation in V1-V3; Kam’s article has the picture of this ECG.
Arrhythmias
Heart failure, cardiogenic shock
Metabolic acidosis (HAGMA) with raised lactate (and also due to fatty acids)
Rhabdomyolysis, raised CK and myoglobin
Hyperlipidaemia
Fatty liver and hepatomegaly
Coagulpathy
Raised plasma malonylcarnitine and C5-acylcarnitine
Management of propofol infusion syndrome
Enhanced elimination
Stop the propofol infusion!
“decontamination” might be impossible, but haemodalysis should be commenced to wash out propofol and its toxic metabolites
Plasma exchange may be required (Da Silva et al, 2010)
Specific antidote
Carnitine
Supportive care
Pacing and atropine may be useless (the bradycardia is refractory)
Vasopressors and inotropes are aso usually ineffective
ECMO is the only answer if circulatory collapse with bradycardia has developed
Nutrition with a satisfactory amount of carbohydrate to reduce the use of fat for metabolism. The college answer quotes a dose rate (6-8mg/kg/min) but it is unclear where the got this value from.
Pathophysiology of propofol infusion syndrome
This tends to happen after about 48 hours of infusion, at over 4mg/kg/hr.
The mechanism is likely the inhibition by propofol of coenzyme Q and Cytochrome C.
This results in a failure of the electron transport chain, and thus the failure of ATP production.
In the event of such a breakdown of oxidative phosphorylation the metabolism becomes increasingly anaerobic, with massive amounts of lactate being produced.
Furthermore, fatty acid metabolism is impaired- the conversion of FFAs to acetyl-CoA is blocked, and thus no ATP is produced by lipolysis.
On top of that, unused free fatty acids leak into the bloodstream, contributing to the acidosis directly.
Pathophysiology of iron toxicity
Abdominal pain, nausea and vomiting is the result of the directly corrosive effect of iron.
Shock is due to fluid loss into the gut
Acidosis is multifactorial (see above) but is mainly lactate-driven, due to mitochondrial toxicity
Hepatotoxicity is partly due to shock, and results in coma, coagulopathy and hyperbilirubinaemia
Renal toxicity is partly due to shock, and partly due to direct toxicity
Stages of iron toxicity
Toxicity manifests in four stages:
Stage I: GI toxicity (0-6 h since ingestion): vomiting, haematemesis, abdominal pain and lethargy
Stage II: “apparent stabilization” (6-12 h since ingestion) - symptoms subside
Stage III: mitochondrial toxicity and hepatic necrosis (12-48 h since ingestion)- acute liver failure, coagulopathy, acute tubular necrosis, metabolic acidosis and shock.
Stage IV: GI scarring (4-6 weeks since ingestion) - gastric scarring and pyloric stricture
Management of iron toxicity
Decontamination
Activated charcoal has no role to play
Whole bowel irrigation - until effluent turns clear - is a good strategy; much of the toxicity is related to gut ulceration, and by diluting the iron in the gut lumen you may be able to ameliorate this direct corrosive effect, even if you don’t manage to prevent toxic absorption.
Surgical removal of tablets - if a bezoar is clearly visible on the AXR
Enhanced elimination
Exhange transfusion: the removal of iron-poisoned blood is ery old-school, but it works (Movassaghi et al, 1969)
Haemodialysis can be considered to help remove the iron-desferrioxamine complexes, as they are renally excreted and there may not be enough renal function to remove this product. Otherwise, apart from correcting acidosis there is no role for dialysis.
Specific antidote
Administer desferrioxamine, a sideramine product derived from Streptomyces pilosus.
Desferrioxamine is indicated if metabolic acidosis is present or iron levels are over 90 micromol/L.
Total intravenous dose should not exceed 80mg/kg/24hrs.
The resulting iron-desferrioxamine complex (ferrioxamine) is water-soluble and biologically inert.
Unfortunately, iron distributed into tissues in inaccessible to desferrioxamine.
Also unfortunately, desferrioxiamine is far from benign, causing hypotension, ARDS, blindness and deafness (Howland, 1996). Its persistent presence in patients with no kidneys promotes the growth of such nightmarish organisms as Mucor.
Supportive care for iron toxicity
Intubation will likely be required to protect the airway not only from the decreased level of consciousness but also from the risks of aspiration associated with whole bowel lavage.
Mechanical ventilation will likely be with mandatory mode, to decrease the demands on the failing myocardium
Circulatory support should consist of simultaneous fluid resuscitation, inotrope and vasopressor infusions
Sedation should be rationalised, given that the patient is already in a coma before the sedation is given, and that the liver is doing little metabolically.
Correction of acidosis with bicarbonate may be indicated if catecholamine responsiveness is lost.
Electrolyte replacement -losses must be anticipated, the leaky gut and bowel lavage will result in potassium and phosphate depletion.
Haemodialysis may be required to maintain metabolic normality, as well as to remove ammonia which may accumulate due to the acute hepatocellular necrosis
Hypoglycaemia and ketosis will likely develop. The patient will need a dextrose infusion, as hepatic and skeletal muscle glycogen stores will be depleted.
Nutrition will likely be parenteral for some time, depending on the extent of gastric ulceration.
Coagulopathy will develop due to hepatocellular necrosis. Coagulation factor replacement will be required.
Features of iron toxicity and the causes
Tachypnoea- Metabolic acidosis
Shock, circulatory collapse - Third space fluid losses
Blood and fluid loss from the ulcerated gut
Cardiotoxic effects, with cardiogenic shock
Vasodilation due to SIRS
Hypoglycaemia - Acute hepatotoxicity
Coma- Hypoglycaemia, Acute cerebral oedema due to liver failure
High anion gap metabolic acidosis- Lactic acidosis, Ketosis, Minor contribution from iron itself (conversion of Fe3+ to Fe2+ produces a net loss of a cation, and therefore contributes to the decrease in the SID)
Hyperlactatemia - Acute hepatotoxicity and liver failure, Shock state, Direct mitochondrial toxicity
Renal failure - Shock state, mitochondrial (tubular) toxicity, ATN
Gastric ulceration - direct corrosive effect of the drug
Haemorrhage, melaena from ulcerated gut surface
Beta blockers
Glucagon, high dose insulin
Bupivacaine
Intralipid
Carbon monoxide
Oxygen, potentially even hyperbaric oxygen
Serotonin syndrome
Cyproheptadine
Dystonic crisis due to classical antipsychotics
Benztropine
Paraquat
Fuller’s Earth, bentonite clay
Class 1 antiarrhythmics
Sodium bicarbonate
Tricyclic antidepressants
Sodium bicarbonate
Cyanide
Cyanocbalamin/ Sodium thiosulphate
