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
Antimuscarinic agents
Physostigmine
Methotrexate
Folinic acid
Magnesium
Calcium
Clonidine
Naloxone
Calcium channel blockers
Calcium, glucagon, high dose insulin
Iron
Desferrioxamine
Valproate
Carnitine
Digoxin
Fab
Ethylene glycol
Ethyl alcohol, Fomepizole
Isoniazid
Pyridoxine - a co-factor in the synthesis of GABA; isoniazid interferes with this synthesis, and causes seizures in overdose. The supplementation of pyridoxine seems to prevent the worst of isoniazid toxicity
Methanol
Ethyl alcohol, Fomepizole
Methemoglobinemia
Methylene blue, vitamin C (ascorbic acid)
Organophosphate
Atropine, pralidoxime
Lead
Dimercaprol (also works for mercury, antimony, gold, chrome, cobalt and nickel poisoning), BAL
Anticholinergic syndrome features
Blind as a bat: mydriasis, dilated pupils and the inability to accomodate Mad as a hatter: delirium Dry as a bone: inability to form sweat Red as a beet: skin flushing Hot as a hare: fever Also... ileus urinary retention tachycardia coma
Cholinergic syndrome
SLUDGEMS:
Siallorhoea Lacrimation Urination Diarrhoea Gastrointestinal distress: abdominal pain due to hypermotility Emesis Miosis - constricted pupils Seizures Also... tachycardia bronchorrhoea hypothermia diaphoresis muscle fasciculations paralysis
Sympathomimetic syndrome
HAH STUPOR
Hypertension Agitation Hyperreflexia Seizures Tachycardia Urination Piloerection Ocular- pupil dilatation, mydriasis Rhabdomyolysis
Opiate syndome
BUM HIDE:
Bradycardia Urinary retention Miosis Hypotension Ileus Decreased respiratory drive Emesis Also... decreased cough reflex hypothermia hyporeflexia
Serotonin syndrome
RASCAL
Rhabdomyolysis Agitation / hypervigilance Seizures Clonus Autonomic overdrive - tachycardia, hypertension Large pupils - mydriasis also...
hyperreflexia
hyperthermia
Neuroleptic malignant syndrome
FEVER LAD
Fever Encephalopathy Vitals unstable - hyper or hypotension, brady or tachycardia Elevated enzymes - CK Rigidity of the muscles, hypertonia Leucocytosis Acidosis Diaphoresis Also, low serum iron (acute phase response)
Telling serotonin sysndrome from neuroleptic malignant syndrome
Serotonin syndrome has an earlier onset (~ 12hrs)
Serotonin syndrome has HYPER-reflexia, whereas in NMS the reflexes are depressed
Serotonin syndrome has clonus - NMS merely has rigidity
Serotonin syndrome features dilated pupils - NMS does not
Serotonin syndrome has hyperactive bowels, whereas NMS may have ileus
Mechanisms of bicarbonate in TCA overdose
The indication for the use of bicarbonate in tricyclic overdose is the widening of the QRS interval
Increased protein binding of TCAs in an alkaline bloodstream, thus decreasing the biologically active free fraction.
Increased availability of sodium in sodium bicarbonate, as a substrate for the voltage-gated channels.
Decreased binding of TCAs to the voltage gated sodium channel
Correction of metabolic acidosis
Volume expansion because of the dilutional effect on TCA concentration
Cellular membrane hypopolarisation results from bicarbonate-induced intracellualr shift of potassium.
Specific features of toxins which make them susceptible to removal by dialysis:
Small molecule size
Highly water soluble
Small volume of distribution (i.e. ideally limited to circulating volume, or the extracellular fluid)
Large protein-unbound free fraction
Specific toxins which are susceptible to clearance by dialysis
Barbiturates Lithium Alcohols eg. ethylene glycol, methanol Paraquat Salycilates Valproate Metformin Methotrexate It is generally accepted that extracorporeal elimination is worthwhile if it increases total body clearance by 30% or more
Complications of haemoperfusion
Erratic electrolyte derangement - hypocalcemia - hypophosphatemia - hypoglycemia Coagulopathy - Low fibrinogen - Thrombocytopenia: on average the count decreases 20–50% from baseline - Depletion of all other coagulation factors - Complement activation leading to DIC Immune suppression - Low WCC - Depleted immunoglobulins - Depleted cytokines - Low complement Malnutrition due to adsortion of amino acids Feberile reaction to the circuit Charcoal embolization Haemolysis "Reverse adsorption" - redistribution of the toxin back into the bloodstream
Use of plasmapheresis in toxicology
Toxidromes which benefit from dialysis and haemoperfusion will also benefit from plasmapheresis.
Plasmapheresis is specifically beneficial in situations where the toxin has high plasma protein binding and a low volume of distribution (i.e. limited essentially to the circulating pool of proteins)
If the toxin has a large volume of distribution (i.e. it is distributed widely to the tissues) several sessions of plasmapheresis will be required. In such a situation, there will be “rebound” toxicity as sequestered toxin redistributes into the bloodstream between sessions.
Rationale and mechanism of clearance by haemoperfusion
Many drugs are either highly protein bound or highly lipophilic
These qualities make them unavailable for haemodialysis or ultrafiltration clearance, which can only access the ionised water-soluble fraction
Adsorption can be used to clear these substances from the bloodstream
The high surface area of resins and charcoal can compete with serum proteins for drug binding. The drugs are bound reversibly by Van der Waal forces (attractive forces between molecules not due to covalent, electrostatic or hydrogen bond interaction)
Large surface area of resin or charcoal filter enhances adsorption by presenting a larger contact surface for the filtered blood.
Charcoal is a “broad-spectrum” adsorption agent, whereas resins typically favour lipophilic substances.
Resin filters may also be impregnated with drug-specific antibodies
The rate of adsorption generally depends upon the size of the granules, and the capacity of each cartridge is determined by its size (i.e. how much charcoal is inside).
Ideal body weight:
definition - “the ideal weight associated with maximum life-expectancy for a given height”.
Ideal body weight (kg) = height (cm) - 100
(100 for males, and 110 for females.)
Effect of obesity on absorption:
Gastric emptying may be increased OR decreased (and it is unpredictable).
Absorption from the subcutaneous compartment will be slowed due to poor blood flow to subcutaneous fat
Intramuscular injection (or intrathecal, or even intravenous for that matter) is made difficult by poor access.
Effect of obesity on distribution:
Increased volume of distribution for lipid-soluble drugs
Increased accumulation of drugs in the fat compartment
Blood flow in fat is poor in people of normal weight: it is only about 5% of the total cardiac output. - In obese individuals, blood flow to fat is even poorer.
Obese individuals are also likely to have a degree of heart failure which further decreases blood flow.
Body fluid volume is also increased, increasing the volume of distribution of water-soluble drugs
Protein binding may be altered (but this is far from clear: most papers seem to say that albumin binding is unchanged)
Effect of obesity on drug metabolism:
Hepatic clearance is slowed not only by decreased cardiac output but also by fatty infiltration. But, you never actually know whether metabolic activity is going to be mre or less rapid. remember that lean tissue (and potentially metabolic organ mass) may be increased.
However, increased CYP450 (2E1) activity has been observed
Increased Phase II conjugation activity may be present
Effect of obesity on clearance:
Diabetes which co-exists with obesity tends to damage kidneys, slowing the renal clearance. However, glomerular filtration rate may be increased in healthy obese individuals.
Biliary clearance may be slowed by bile stasis or existing bile duct disease
Effect of obesity on pragmatic drug dosing and monitoring:
Obese people have a larger absolute lean body mass (LBM), as well as fat mass. Lean components account for 20-40% of the absolute body weight
- Exactly how much muscle is hidden in any given obese individual is difficult to est accurately with the aid of standard equations.
The net effect of this is that both under-dosing and over-dosing is more likely than with individuals of normal weight, and monitoring of therapeutic levels is important.
Pharmacokinetic data in obesity does not exist for most drugs.
In obese individuals, the ideal body weight is likely to underestimate their lead body mass, leading to under-dosing. The total body weight is likely to over-estimate the dose and lead to overdosing.
Thus, in such patients, most drug dosing should be tailored to lean body weight (LBW).
Lean body weight and pharmacokinetics
Lean body weight is the difference between total body weight and fat mass.
Lean body weight is significantly correlated to cardiac output.
It is probably the best method of dose adjustment for morbidly obese patients. - easy method is to add 20% on to ideal body weight to calculate LBW
Clinical features of paraquat toxicity
Mild overdose: Nausea and vomiting Diarrhoea Intestinal hemorrhage Haemoptysis Oliguria Minimal renal dysfunction
Moderate overdose: Renal failure (ATN within 12-24hours) Pulmonary oedema Hepatotoxicity Pulmonary haemorrhage Shock Pulmonary fibrosis
Massive overdose:
multi-organ system failure
rapidly fatal
Phases of paraquat poisoning
Phase I: corrosion; mucosal linings ulcerate and swell; there may be haematamesis.This is the first two days.
Phase II: organ failure; between the second and fifth days following ingestion, renal failure and hepatocellular necrosis develop. Most patients with severe overdose will die during this phase.
Phase III: pulmonary fibrosis; death after many days/weeks of hypoxia.
How to approach overdose
Decontamination
Enhanced elimination
Specific antidote
Supportive care
Management of paraquat toxicity
Decontamination
- Fuller’s Earth: calcium montmorillonite, or bentonite - a absorbent aluminium phyllosilicate, formed from the weathering of volcanic ash.
- Activated charcoal may have equal efficacy, and is more widely available
Cation exchange resins (eg. resonium) may be of use
The “window of opportunity” is very narrow, only a few hours at most. Absorption from the gut is very rapid.
- Remove contaminated clothes
- Wash skin with soap and water to prevent transdermal absorption
Enhancement of elimination
- Charcoal haemoperfusion works very well, but contributes little to the overall prognosis because the drug is rapidly cleared from the plasma anyway, and the pulmonary reserve is trapped there (it is not available for removal).
Dialysis is probably going to be useless, as paraquat is rapidly eliminated. The alveolar and renal damage will have been done by then, so you have nothing to gain (other than a more rapid control of the acid-base disturbance).
Specific antidotes
None exist.
Supportive management
- Intubation to protect the rapidly swelling airway after corrosive ingestion
- Avoidance of hyperoxia: it has been demonstrated to exacerbate the oxidative toxicity of paraquat.
- Circulatory support (there will be shock from myocardial necrosis and third space losses
- Analgesia and sedation which is almost palliative in its intent - many of these people will die in spite of everything you do.
- Specifically, propofol seems to have some sort of unique scavenging effect.
Differences between beta blocker and CCB overdose
Clinical features
Both - Bradycardia, Hypotension, Heart block
BB - HYPOglycaemia, Bronchospasm, stupor/coma/seizures
CCB -Hyperglycaemia, Constipation/ileus, seizures uncommon
Management:
Decontamination - both Activated charcoal
Enhancement of clearance
- Hemoperfusion for verapimil
- Hemoperfusion for metoprolol
Antidote
Both - Glucagon, Insulin-dextrose, Inotropes and vasopressors
CCB - Ionised calcium (eg. calcium chloride)
Clinical features of cyanide toxicity -
bradycardia tachypnoea severe metabolic acidosis - predominantly due to lactate high central venous oxygen saturation (low OER) acute renal failure acute hepatic dysfunction acute heart failure and pulmonary oedema circulatory failure, shock coma and seizures
Diagnosis of cyanide toxicity rests on historical features which are strongly suggestive (eg. inhalation of smoke in a plastic-based fire) as well as severe lactic acidosis, and in the absence of carbon monoxide poisoning. This might be enough to merit some doses of the (reasonably safe) empirical antidote therapy. The gold standard of diagnosis is the serum cyanide level, which may take too long.
Mechanism of cyanide toxicity:
Lactic acidosis develops due to the uncoupling of oxidative phosphorylation: cyanide interferes with the electron transport chain by binding to the ferric Fe3+ ion of cytochrome oxidase.
Neurotoxicity occurs at modest doses; initially there is CNS stimulation (dizziness, confusion, restlessness, and anxiety) which is followed by stupor, opisthotonus, convulsions, fixed dilated pupils and unresponsive coma. This is due to the cyanide-stimulated release of excitatory neurotrasmitters, such as NMDA and glutamate.
Oxidative damage to lipid bilayers due to free radical generation tends to break the blood-brain barrier and causes a vasodilated SIRS-like state of cardiovascular collapse (but this tends to happen only with very large doses)
The development of pulmonary oedema, pulmonary vasoconstriction and coronary artery spasm are blamed on “biogenic amines”, vasoactive substances which are supposedly liberated from cyanide-affected endothelia. There is not a lot to back this up in the literature.
Antidotes to cyanide
Decontamination may to be effective (however most cyanides are rapidly absorbed).
Cyanide has a short half-life (~ 2 hours), but in massive overdose the decontamination of plasma by dialysis may be feasible and has contributed to the survival of at least one historical victim (Wesson et al, 1985).
Hydroxycobalamin - binds cyanide and forms cyanocobalamin
This is the antidote of choice
Advantages include a lack of toxicity for non-poisoned victims (thus, it may be given empirically)
The onset of action is rapid
It may be given in the pre-hospital setting and requires no monitoring.
The side efects are relatively minor; perhaps the most striking is the tendency for the body fluids to turn a vivid red-orange color.
dicobalt edetate may be an alternative cobalt-based binder, but hydroxycobalamin is more widely available, and much less toxic. LITFL mentions that dicobalt edetate causes “seizures, chest pain and dyspnoea, head and neck swelling, hypotension, urticaria and vomiting”
Sodium thiosulfate
Sulfur donors in general act by offering a sulfur ion to the endogenous rhodanese enzyme which converts cyanide to thiocyanate
Like hydroxycobalamin, this is a reasonably safe option - there are few side effects.
Induction of methaemoglobinaemia
Methaemoglobin binds free cyanide and forms cyanmethaemoglobin.
Various drugs are available for this. Sodium nitrite and amyl nitrite are the most frequently quoted. Methylene blue is also available, but is not without its side-effects.
Classical pharmacological classification of adverse drug reactions
Dose-related reactions
This can include adverse effects at either normal dose or overdose.
These may include expected extesions of the therapeutic effect of the drug, eg. bleeding in heparin.
Toxic effects eg. serotonin syndrome
Side effects are included, eg. anticholinergic effects of tricyclics
Non-dose-related reactions
This refers to drug effects which are totally unrelated to the dose (i.e. any exposure is enough to trigger such a reaction).
Allergic reactions
Anaphylaxis
Idiosyncratic reactions, eg. purpura or drug-induced SLE
Dose and time related reactions
This refers to drug effects which occur due to dose accumulation, or with prolonged use
Adrenal suppression with corticosteroids is one example.
Time related reactions
This refers to drug effects which occur due to prolonged use in a drug which doesnt tend to accumulate.
An example might be tardive dyskinesia afte decades of using typical antipsychotics
Withdrawal reactions
This refers to the undesired effects of ceasing the drug
Classical examples might include opiate withdrawal and rebound hypertension after stopping clonidine.
Unexpected failure of therapy
This category has been added to describe an undesirable reduction in the drug’s efficacy (or, the undesirable increase thereof)
Examples may include increased clearance by dialysis and plasmapheresis, drug interactions alterinc metabolism, and the effects of critical illness on protein binding and elimination.
Management of adverse drug reactions
Immediate management:
ABCs
Identification and withdrawal of the offending agent
Immediate IM adrenaline (500mcg) for anaphylaxis
Hydrocortisone and antihistamines for allergic reactions
Investigation
need for thorough drug history
search for evidence of previous drug reactions
thorough history of allergies
search for predisposition to adverse effects
Assessment of drug interactions
Investigations (such as plasma concentration measurements, biopsies, and allergy tests)
Organ system function assessment (EUC, LFTs, TFTs, FBC for neutropenia, etc)
Rechallenge with the drug should be considered
Prevention of adverse drug reactions
- awareness of impaired clearance mechanisms due to organ pathology
- careful prescribing
- attention to drug interactions
- rational management of polypharmacy
- monitoring of drug levels
- staff education regarding safe prescribing and administration
- pharmacist participation in ICU rounds
Rationale for decontamination
In any overdose, especially early, there is some proportion of the ingested drug which still has not absorbed.
This unabsorbed drug could potentially be cleared from the gut
This would result in a reduced total dose of the drug
The reduced total dose should also result in a reduced total toxicity
Ergo, the removal of undissolved drugs should reduce the toxicity of the overdose
Techniques of decontamination and their indications
Activated charcoal, single or multiple doses
Induced emesis (abandoned)
Gastric lavage (largely abandoned; only indicated within the first hour)
Whole bowel irrigation (only indicated for iron and slow release enteric coated tablets)
Surface decontamination for skin-absorbed toxins
Situations which merit the use of gut decontamination
The overdose is recent (within the last hour)
There is reason to believe a large number of undissolved tablets is still present in the stomach or gut
There is no adequate antidote to the drug, and the overdose is lifethreatening
Diagnostic features of valproate overdose
hypotension
hypothermia
CNS depression
tremor
Complications of valproate overdose
Lactic acidosis hyperammonaemia and encephalopathy acute hepatic failure pancreatitis cerebral oedema hypernatremia Hypocalcemia Hypocarnitinemia, if you actually test for carnitine Bone marrow suppression
management of valproate overdose
Supportive management (ventilation, vasopressors, etc) gastrointestinal decontamination with charcoal or whole bowel lavage
L-Carnitine supplementation: the loading dose is 100 mg/kg IV over 30 minutes (maximum 6 g) followed by 15 mg/kg IV over 10–30 minutes every 4 hours until clinical improvement occurs.
(valproate metabolism depletes the stores of carnitine)
Valproate is 90% protein bound and therefore poorly cleared by dialysis, but ammonia is, and therefore haemodialysis is indicated to prevent cerebral oedema
generic principles of managing drug withdrawal:
prevention
detection/diagnosis - Hx/Exam/Ix
Supportive cares -
- Sedation (for comfort)
- Analgesia (to combat post-opioid hyperalgesia)
- Control of physiological derangements (eg. clonidine to block the sympathetic storm of opiate withdrawal)
- Protection of the CNS from seizures (i.e. in benzodiazepine and alcohol withdrawal)
sedation
replacement
Potential complications of intentional corrosive ingestion include:
Airway:
Airway burns, leading to airway compromise
Potential acute tracheo-oesophageal fistula due to corrosive effect on oesophagus
Assessment and immediate airway control is a priority
Breathing:
Potential aspiration of caustic gastric/oesophageal contents, thus acute lung injury
Hypoxia may be present; supplemental oxygen may be required. NIV may be contraindicated in case of full-thickness oesophageal injury
Circulation:
Potential hypovolemic shock due to fluid loss into the corroded gut, or haemorrhage though ulcers
Need for rapid fluid replacement or surgical haemostasis
CVC access, as this patient is likely to require long-term TPN
Neurological state:
Potential for disorganised behaviour due to psychiatric condition, or obtundation due to shock
Analgesia issues need to be addressed
Electrolyte disturbance
Absorption of corrosive agent may result in electrolyte and acid-base disturbance
Fluid balance
Likely, hypovolemia will exist and need correction
renal impairment may be present, with implications on drug dosing
Gastrointestinal problems:
Extent of corrosive damage will need to be assessed by CT and/or direct endoscopy (earlier is better, before significant tissue softenting makes endoscopy risky)
Perforation of hollow organs must be ruled out with CXR and/or CT
Specific issues
Decontamination by NG aspiration may be possible if it is safe to pass an NGT
Withdrawal affecting GABAA
Agents - Alcohol Barbiturates Benzodiazepines Organic solvents
Withdrawal syndrome - CNS excitation (agitation, tremor, hallucinations, seizures) Autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis)
Management -
Benzodiazepines
Dexmedetomidine
Withdrawal affecting GABAB
Agents -
GHB
Baclofen
Withdrawal syndrome - Dyskinesia, seizures, hypertension, hallucinations, psychosis, and coma.
Management -Benzodiazepines
Withdrawal affecting Opioid receptor
Agents - opiates
Withdrawal syndrome -
CNS excitation (agitation, tremor, hallucinations)
Diarrhoea, mydriasis, nausea.
Autonomic stimulation (tachycardia, hypertension, hyperthermia, diaphoresis)
Management - Clonidine
Dexmedetomidine
Withdrawal affecting Adenosine receptor
Agents - Caffeine
Withdrawal syndrome - Head-ache (cerebral vasodilation), fatigue, and hypersomnia (motor inhibition)
Withdrawal affecting Nicotinic acetylcholine
receptor
Agents - Nicotine
Withdrawal syndrome - Agitation, insomnia, poor concentration, poor gut motility, poor feed tolerance.
Management - Varenicline?
Withdrawal affecting Noradrenenaline receptor
Agents - Amphetamines
Withdrawal syndrome - Agitation, dysphoria, somnolence
Withdrawal affecting Dopamine receptor
Agents - Cocaine
Withdrawal syndrome - Anhedonia, irritability, exhaustion
Withdrawal affecting Cannabis receptor
Agents - cannabis
Withdrawal syndrome - Agitation, insomnia, poor gut motility
Management - Mirtazapine ?
