Toxicology 1 to 10
Describe the mechanism of Paracetamol hepatotoxicity?
- In normal doses, Paracetamol undergoes glucuronidation and sulphation to the corresponding conjugates, making up 95% of total excreted metabolites.
- The alternative P450 dependant GSH conjugation pathway accounts for 5%.
- When intake far exceeds therapeutic intake, glucuronidation and sulphation pathways are saturated, so P450 dependent pathway becomes impt. So long as there is hepatic GSH available for conjugation, no hepatotoxicity occurs.
- Once hepatic GSH is depleted faster than its regeneration, a reactive toxic metabolite-N-acetylbenzoiminoquinone is produced. This reacts with the nucleophilic groups of cellular proteins to produce hepatotoxicity
- Concept of 2 paths with saturation
- Glutathione key word
What is the antidote and how does it work?
- NAC glutathione substitute, binding to the toxic metabolite
- Anti oxidant
- NAC + donor/substitute (GSH)
In a poisoned patient what modalities are available for decontamination?
- Skin – remove clothes, wash contaminated skin
- GIT – emesis, gastric lavage, activated charcoal & cathartics / whole-bowel irrigation
- 3 of 5 to pass
How does activated charcoal work?
- Adsorption due to its large surface area
Name some drugs or agents that activated charcoal is NOT effective in adsorbing?
- Ions: Fe, Li, K
- Alcohols, cyanide
- Corrosives (acids and alkalis)
- 2 examples
Name a drug where repeated doses of activated charcoal may assist in elimination of the drug?
- One Drug
What are the therapeutic uses of Penicillamine?
- Wilsons disease
- Copper poisoning
- Severe rheumatoid arthritis (occasionally)
List the adverse effects of D-Penicillamine (occur in up to 1/3 of patients).
• Nausea and Vomiting
• Nephrotic Syndrome
• Hypersensitivity (avoid if history of penicillin allergy)
• Optic atrophy
Describe the pharmacokinetic mechanisms for drug interaction with oral anticoagulants?
Enzyme induction or enzyme inhibition -reduced plasma protein binding (all 3)
NOTES: Pharmacokinetic: amiodarone, metronidazole, trimethoprim
Describe a pharmacodynamic interaction with warfarin?
-competitive antagonism Vit K
Pharmacodynamic: aspirin, heparin, 3’d gen cephalosporin
-altered physiologic control loop – hereditary resistance
-clotting factor conc-spironolactone
At least 2 examples
Prompt “what happens to a patient on warfarin who is given Vit K”
“why does the TAIR alter?”
Outline the clinical features of salicylate toxicity?
Prompt if required: What are the acid base disturbances in salicylate toxicity?
Any CNS: coma
Uncoupling Oxidative Phosphorylation
Describe the enhanced elimination strategies employed in managing a patient with salicylate overdose.
pH Manipulation /urinary alkalinisation
Prompt for both
1. Peritoneal dialysis
What specific modalities of treatment are available for the treatment of severe methanol poisoning?
- Talk about alcohol dehydrogenase substrate, ETOH.
- Mention fomepizole as an ADH antagonist.
- Correcting acid/base status should be a priority because serious metabolic acidosis is common and a pH less than 7 is associated with poor prognosis.
- Need to add adjuncts to minimise accumulation of formic acid – folic acid The elimination of methanol may be enhanced by administering folic acid, a cofactor in the conversion of formic acid to carbon dioxide
Pass: Alcohol + 1
Describe the pharmacologic effects of glucagon.
1. Metabolic —
• Binds with receptors on liver cells (G protein-linked l’ adenylyl cyclase & cAMP)
• Catabolism of stored glycogen, raising blood glucose level
• No effect on skeletal muscle
• Also cause release of insulin from B-cells, catecholamines from Pheo and calcitonin from medullary carcinoma cells
2. Cardiac effects
• Potent inotropic & chronotropic effect on heart via cAMP without requiring functioning beta-receptor
3. Large doses of glucagon produce relaxation of smooth muscle (not via cAMP)
2 of 3 to pass
What are the indications for using glucagon clinically?
1. Severe hypoglycaemia
2. Overdose on Betablockers (5-10mg IV will reverse hypotensionlbradycardia)
3. Relaxation of intestine during radiology of bowel
4. Diagnosing endocrine disorder-
• Type I Diabetes (no C-peptide response to glucagen)
• Suspected tumours, eg Insulinoma, Pheo, medullary carcinoma (cause rise in hormone)
2 of 3 to pass
What are the adverse reactions produced by glucagon?
• Transient nausea & vomiting
• Relatively free from severe adverse reaction
What is an antivenom?
Immunoglobulin or antibody (specifically IgG FAB) produced by another animal in response to a venom. Used in humans IV or IM to neutralise venom after an envenomation.
Pass: Must get Ab or Ig produced by animal
What antivenoms are used in Australasia?
Snake –polyvalent and monovalent (black, brown, death adder, tiger, taipan, sea snake); stonefish, redback spider, box jellyfish, funnelweb spider
Pass: Must get Snake – polyvalent & monovalent & 2 others
What are the side effects of antivenom?
Allergy, anaphylaxis, serum sickness
What animals are used in the production of different antivenoms?
Horse –snake, stonefish, redback; Sheep –box jellyfish; Rabbit –funnel web
Pass: Must get horse/snake and 1 other
Name some drugs that are used in the treatment of opiate addiction.
Methadone, N acetylmethadol, buprenorphine clonidine, lofexidine, Naltrexone, naloxone
Pass: Must get methadone and 1 other
Outline the principles of how these agents work.
Methadone –longer acting, opiate angonist, orally active –patient can
be stabilised and gradually withdrawn but addictive also. N acetylmethadol –an even longer acting methadone analogue. Buprenorphine –partial opiod antagonist that can be given once daily, low doses for detoxification and higher doses for maintenance.
Clonidine –central acting sympatholytic agent that mitigates signs of withdrawal sympathetic
Lofexidine –clonidine analogue with less hypotensive effects
Naltrexone-long acting orally active pure opiod antagonist, patients must be detoxified first
Naloxone – rapid onset pure antagonist, short half-life, precipitate withdrawal
Pass: Must get methadone principles and state that overall agents must be orally active and long acting. 1 other agents PD also.
What is an antagonist?
- Receptor antagonists bind to receptors but do not activate them. The primary action of antagonists is to prevent agonists from activating receptors.
- Bold to pass
What is the difference between a competitive and non-competitive antagonist?
- Competitive antagonist
- In the presence of increasing concentration of antagonist, higher concentrations of agonist will produce a given effect e.g. propanolol and noradrenaline/adrenaline
- Irreversible or non-competitive antagonist
- Bind via covalent bonds or just binding so tightly to receptor so receptor unavailable for agonist
- Duration of action of antagonist depend on rate of turnover of receptor-antagonist molecules
- Bold to pass
What type of antagonist is naloxone?
What effect does a competitive antagonist have on the concentration-effect curve?
- Shift agonist vs effect curve to right. Higher concentrations of agonist can overcome competitive antagonist.