Clinical Pharmacology/ Toxicology Flashcards
what is ciclosporin
immunosuppressant which decreases clonal proliferation of T cells by reducing IL-2 release. It acts by binding to cyclophilin forming a complex which inhibits calcineurin, a phosphatase that activates various transcription factors in T cells
Adverse effect of ciclosporin
note how everything is increased - fluid, BP, K+, hair, gums, glucose) nephrotoxicity hepatotoxicity fluid retention hypertension hyperkalaemia hypertrichosis gingival hyperplasia tremor impaired glucose tolerance hyperlipidaemia increased susceptibility to severe infection
Indications for ciclosporin
following organ transplantation rheumatoid arthritis psoriasis (has a direct effect on keratinocytes as well as modulating T cell function) ulcerative colitis pure red cell aplasia
effects of organophosphate insecticide poisoning
inhibition of acetylcholinesterase leading to upregulation of nicotinic and muscarinic cholinergic neurotransmission. In warfare, sarin gas is a highly toxic synthetic organophosphorus compound that has similar effects.
Features of organophosphate insecticide poisoning
Salivation Lacrimation Urination Defecation/diarrhoea cardiovascular: hypotension, bradycardia also: small pupils, muscle fasciculation
Management of organophophate insecticide poisoning
atropine
the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit
P450 inhibitors
antibiotics: ciprofloxacin, erythromycin isoniazid cimetidine,omeprazole amiodarone allopurinol imidazoles: ketoconazole, fluconazole SSRIs: fluoxetine, sertraline ritonavir sodium valproate acute alcohol intake quinupristin
p450 inducers
antiepileptics: phenytoin, carbamazepine
barbiturates: phenobarbitone
rifampicin
St John’s Wort
chronic alcohol intake
griseofulvin
smoking (affects CYP1A2, reason why smokers require more aminophylline)
Management of paracetamol overdose
activated charcoal if ingested < 1 hour ago
N-acetylcysteine (NAC)
liver transplantation
Management of salicylate overdose
urinary alkalinization with IV bicarbonate
haemodialysis
Management of opioid overdose
Naloxone
Management of benzodiazepines overdose
Flumazenil
The majority of overdoses are managed with supportive care only due to the risk of seizures with flumazenil. It is generally only used with severe or iatrogenic overdoses.
Management of TCA overdose
IV bicarbonate may reduce the risk of seizures and arrhythmias in severe toxicity
arrhythmias: class 1a (e.g. Quinidine) and class Ic antiarrhythmics (e.g. Flecainide) are contraindicated as they prolong depolarisation. Class III drugs such as amiodarone should also be avoided as they prolong the QT interval. Response to lignocaine is variable and it should be emphasized that correction of acidosis is the first line in management of tricyclic induced arrhythmias
dialysis is ineffective in removing tricyclics
Management of lithium overdose
mild-moderate toxicity may respond to volume resuscitation with normal saline
haemodialysis may be needed in severe toxicity
sodium bicarbonate is sometimes used but there is limited evidence to support this. By increasing the alkalinity of the urine it promotes lithium excretion
Management of warfarin overdose
vitamin K , prothrombin complex
Management of heparin overdose
protamine complex
Management of Beta Blocker overdose
if bradycardic then atropine
in resistant cases glucagon may be used
Management of ethylene glycol overdose
ethanol has been used for many years
works by competing with ethylene glycol for the enzyme alcohol dehydrogenase
this limits the formation of toxic metabolites (e.g. Glycoaldehyde and glycolic acid) which are responsible for the haemodynamic/metabolic features of poisoning
fomepizole, an inhibitor of alcohol dehydrogenase, is now used first-line in preference to ethanol
haemodialysis also has a role in refractory cases
Management of methanol overdose
fomepizole or ethanol
haemodialysis
Management of digoxin overdose
Digoxin-specific antibody fragments
Management of iron overdose
Desferrioxamine, a chelating agent
Management of lead overdose
Dimercaprol, calcium edetate
Management of Carbon Monoxide overdose
100% oxygen
hyperbaric oxygen
Management of cyanide overdose
Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and sodium thiosulfate
Indications for verapamil
Angina, hypertension, arrhythmias
Highly negatively inotropic
Should not be given with beta-blockers as may cause heart block
Side effects of verapamil
Heart failure, constipation, hypotension, bradycardia, flushing
Side effects of diltazem
Hypotension, bradycardia, heart failure, ankle swelling
indications for diltazem
Angina, hypertension
Less negatively inotropic than verapamil but caution should still be exercised when patients have heart failure or are taking beta-blockers
Indications for nifedipine/amlodipine/felodipine (dihydropyridines)
Hypertension, angina, Raynaud’s
Affects the peripheral vascular smooth muscle more than the myocardium and therefore do not result in worsening of heart failure but may therefore cause ankle swelling
Side effects of dihydropyridines
Flushing, headache, ankle swelling
Digoxin - mechanism of action
decreases conduction through the atrioventricular node which slows the ventricular rate in atrial fibrillation and flutter
increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ ATPase pump. Also stimulates vagus nerve
digoxin has a narrow therapeutic index
Monitoring of digoxin levels
digoxin level is not monitored routinely, except in suspected toxicity
if toxicity is suspected, digoxin concentrations should be measured within 8 to 12 hours of the last dose
Features of digoxin toxicity
generally unwell, lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision
arrhythmias (e.g. AV block, bradycardia)
gynaecomastia
Precipitating features of digoxin toxicity
classically: hypokalaemia
digoxin normally binds to the ATPase pump on the same site as potassium. Hypokalaemia → digoxin more easily bind to the ATPase pump → increased inhibitory effects
increasing age
renal failure
myocardial ischaemia
hypomagnesaemia, hypercalcaemia, hypernatraemia, acidosis
hypoalbuminaemia
hypothermia
hypothyroidism
drugs: amiodarone, quinidine, verapamil, diltiazem, spironolactone (competes for secretion in distal convoluted tubule therefore reduce excretion), ciclosporin. Also drugs which cause hypokalaemia e.g. thiazides and loop diuretics
Management of Digoxin toxicity
Digibind
correct arrhythmias
monitor potassium
Rifampicin - MOA and SE
mechanism of action: inhibits bacterial DNA dependent RNA polymerase preventing transcription of DNA into mRNA
potent liver enzyme inducer
hepatitis, orange secretions
flu-like symptoms
Isoniazid - MOA and SE
mechanism of action: inhibits mycolic acid synthesis
peripheral neuropathy: prevent with pyridoxine (Vitamin B6)
hepatitis, agranulocytosis
liver enzyme inhibitor
Pyrazinamide - MOA and SE
mechanism of action: converted by pyrazinamidase into pyrazinoic acid which in turn inhibits fatty acid synthase (FAS) I
hyperuricaemia causing gout
arthralgia, myalgia
hepatitis
Ethambutamol - MOA and SE
mechanism of action: inhibits the enzyme arabinosyl transferase which polymerizes arabinose into arabinan
optic neuritis: check visual acuity before and during treatment
dose needs adjusting in patients with renal impairment
Drugs that impair glucose tolerance
thiazides, furosemide (less common) steroids tacrolimus, ciclosporin interferon-alpha nicotinic acid antipsychotics
what are phosphodiesterase type 5 inhibitors
Phosphodiesterase type V (PDE5) inhibitors are used in the treatment of erectile dysfunction. They are also used in the management of pulmonary hypertension. PDE5 inhibitors cause vasodilation through an increase in cGMP leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum.
Examples
sildenafil (Viagra) - this was the first phosphodiesterase type V inhibitor
tadalafil (Cialis)
vardenafil (Levitra)
Contraindications of phosphodiesterase type V inhibitors
patients taking nitrates and related drugs such as nicorandil
hypotension
recent stroke or myocardial infarction (NICE recommend waiting 6 months)
Side effects of phophodiesterase type V inhibitors
visual disturbances e.g. blue discolouration, non-arteritic anterior ischaemic neuropathy nasal congestion flushing gastrointestinal side-effects headache
cytochrome p450 inducers
reduce the concentration of drugs metabolised by P450
CRAPS out drugs
- Carbomazepine
- Rifampicin
- bArbituates
- Phenytoin
- St Johns’ Wort
Cytochrome p450 inhibitors
increase the concentration of drugs metabolised by P450
Some Certain Silly Compounds Annoyingly Inhibit Enzymes, Grrrrrr
Sodium Valproate Ciprofloxacin Sulphonamides Cimetidine/omeprazole Antifungals/amiodarone Isoniazid Erythromycin/clarithromycin Grapefruit
Features of CO poisoning
headache: 90% of cases nausea and vomiting: 50% vertigo: 50% confusion: 30% subjective weakness: 20% severe toxicity: 'pink' skin and mucosae, hyperpyrexia, arrhythmias, extrapyramidal features, coma, death
Investigations CO poisoning
pulse oximetry may be falsely high due to similarities between oxyhaemoglobin and carboxyhaemoglobin
therefore a venous or arterial blood gas should be taken
typical carboxyhaemoglobin levels
< 3% non-smokers
< 10% smokers
10 - 30% symptomatic: headache, vomiting
> 30% severe toxicity
an ECG is a useful supplementary investgation to look for cardiac ischaemia
Management of CO poisoning
100% high-flow oxygen via a non-rebreather mask
from a physiological perspective, this decreases the half-life of carboxyhemoglobin (COHb)
should be administered as soon as possible, with treatment continuing for a minimum of six hours
target oxygen saturations are 100%
treatment is generally continued until all symptoms have resolved, rather than monitoring CO levels
hyperbaric oxygen
due to the small number of cases the evidence base is limited, but there is some evidence that long-term outcomes may be better than standard oxygen therapy for more severe cases
therefore, discussion with a specialist should be considered for more severe cases (e.g. levels > 25%)
in 2008, the Department of Health publication ‘Recognising Carbon Monoxide Poisoning’ also listed loss of consciousness at any point, neurological signs other than headache, myocardial ischaemia or arrhythmia and pregnancy as indications for hyperbaric oxygen
Mechanism of action for cocaine
cocaine blocks the uptake of dopamine, noradrenaline and serotonin
Adverse effects of cocaine
coronary artery spasm → myocardial ischaemia/infarction
both tachycardia and bradycardia may occur
hypertension
QRS widening and QT prolongation
aortic dissection
Neurological effects of cocaine
seizures
mydriasis
hypertonia
hyperreflexia
Psychiatric effects of cocaine
agitation
psychosis
hallucinations
other effects of cocaine
ischaemic colitis is recognised in patients following cocaine ingestion. This should be considered if patients complain of abdominal pain or rectal bleeding
hyperthermia
metabolic acidosis
rhabdomyolysis
Management of cocaine toxicity
in general, benzodiazepines are generally first-line for most cocaine-related problems
chest pain: benzodiazepines + glyceryl trinitrate. If myocardial infarction develops then primary percutaneous coronary intervention
hypertension: benzodiazepines + sodium nitroprusside
the use of beta-blockers in cocaine-induced cardiovascular problems is a controversial issue. The American Heart Association issued a statement in 2008 warning against the use of beta-blockers (due to the risk of unopposed alpha-mediated coronary vasospasm) but many cardiologists since have questioned whether this is valid. If a reasonable alternative is given in an exam it is probably wise to choose it
Phase 1 reactions: oxydation, reduction, hydrolysis
Mainly performed by the P450 enzymes but some drugs are metabolised by specific enzymes, for example alcohol dehydrogenase and xanthine oxidase. Products of phase I reactions are typically more active and potentially toxic
Phase 2 reactions: conjugation
Products are typically inactive and excreted in urine or bile. Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved
First pass metabolism
This is a phenomenon where the concentration of a drug is greatly reduced before it reaches the systemic circulation due to hepatic metabolism. As a consequence much larger doses are need orally than if given by other routes. This effect is seen in many drugs, including: aspirin isosorbide dinitrate glyceryl trinitrate lignocaine propranolol verapamil isoprenaline testosterone hydrocortisone
Zero order kinetics
Zero-order kinetics describes metabolism which is independent of the concentration of the reactant. This is due to metabolic pathways becoming saturated resulting in a constant amount of drug being eliminated per unit time. This explains why people may fail a breathalyser test in the morning if they have been drinking the night before
Drugs exhibiting zero-order kinetics phenytoin salicylates (e.g. high-dose aspirin) heparin ethanol
