Pharmacology and toxicology Flashcards
pathophysiology amiodarone induced hypothyroidism
The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due to the high iodine content of amiodarone causing a Wolff-Chaikoff effect, an autoregulatory phenomenon where thyroxine formation is inhibited due to high levels of circulating iodide
Amiodarone may be continued if this is desirable
Amiodarone induced thyrotoxicosis type 1
Excess iodine-induced thyroid hormone synthesis
present goitre
Mx
Carbimazole or potassium perchlorate
Amiodarone induced thyrotoxicosis type 2
Amiodarone-related destructive thyroiditis
no goitre
corticosteoids Mx
common causes of drug induced peripheral neuropathy
I AM Very Numbed
Isoniazid Amiodarone Metronidazole Vinicristine Nitrofurantoin
p450 inducers
PC BRAS- phenytoin,carbamazepine,barbiturates,rifampicin,alcohol (chronic),sulfonylurea
p450 inhibitors
SICKFACES.COM Sodium valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol...binge drinking Chloramphenicol Erythromycin Sulphonamides (.) Ciprofloxacin Omeprazole Metronidazole
heparin mechanism of action
Activates antithrombin III. Forms a complex that inhibits thrombin, factors Xa, IXa, Xia and XIIa
low molecular weight heparin mechanism of action
Activates antithrombin III. Forms a complex that inhibits factor Xa
heparin monitoring
Activated partial thromboplastin time (APTT)
LMWH monitoring
Anti-Factor Xa (although routine monitoring is not required)
pathophysiology HIT
immune mediated - antibodies form against complexes of platelet factor 4 (PF4) and heparin
these antibodies bind to the PF4-heparin complexes on the platelet surface and induce platelet activation by cross-linking FcγIIA receptors
usually does not develop until after 5-10 days of treatment
despite being associated with low platelets HIT is actually a prothrombotic condition
features include a greater than 50% reduction in platelets, thrombosis and skin allergy
address need for ongoing anticoagulation:
direct thrombin inhibitor e.g. argatroban
danaparoid
heparin reversal
protamine sulphate, although this only partially reverses the effect of LMWH.
pathophysiology paracetamol overdose
The liver normally conjugates paracetamol with glucuronic acid/sulphate. During an overdose the conjugation system becomes saturated leading to oxidation by P450 mixed function oxidases*. This produces a toxic metabolite (N-acetyl-B-benzoquinone imine)
Normally glutathione acts as a defence mechanism by conjugating with the toxin forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death. This occurs not only in hepatocytes but also in the renal tubules
why is NAC used in paracetamol overdose
N-acetyl cysteine is used in the management of paracetamol overdose as it is a precursor of glutathione and hence can increase hepatic glutathione production
ciclosporin side effects
(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
what should be checked before starting allopurinol
The most significant adverse effects are dermatological and patients should be warned to stop allopurinol immediately if they develop a rash:
severe cutaneous adverse reaction (SCAR)
drug reaction with eosinophilia and systemic symptoms (DRESS)
Stevens-Johnson syndrome
Certain ethnic groups such as the Chinese, Korean and Thai people seem to be at an increased risk of these dermatological reactions.
Patients at a high risk of severe cutaneous adverse reaction should be screened for the HLA-B *5801 allele.
allopurinol interactions
Azathioprine
metabolised to active compound 6-mercaptopurine
xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid
allopurinol can therefore lead to high levels of 6-mercaptopurine
a much reduced dose (e.g. 25%) must therefore be used if the combination cannot be avoided
Cyclophosphamide
allopurinol reduces renal clearance, therefore may cause marrow toxicity
Theophylline
allopurinol causes an increase in plasma concentration of theophylline by inhibiting its breakdown
avoid ciprofloxacin in whcih genetic disorder
G6PD
MDMA use features
neurological: agitation, anxiety, confusion, ataxia
cardiovascular: tachycardia, hypertension
hyponatraemia
hyperthermia
rhabdomyolysis
MDMA management
supportive
dantrolene may be used for hyperthermia if simple measures fail
aspirin overdose management
urinary alkalinization with IV bicarbonate
haemodialysis
benzodiazipine overdose management
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.
TCA overdose management
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
Lithium overdose management
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
beta blocker overdose management
if bradycardic then atropine
in resistant cases glucagon may be used
ethylene glycol overdose management
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
methanol poisoning management
fomepizole (competitive inhibitor of alcohol dehydrogenase) or ethanol
haemodialysis
organophosphate management
atropine
the role of pralidoxime is still unclear - meta-analyses to date have failed to show any clear benefit
digoxin overdose management
Digoxin-specific antibody fragments
iron poisoning Mx
Desferrioxamine, a chelating agent
lead poisonin Mx
Dimercaprol, calcium edetate
cyanide Mx
Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and sodium thiosulfate
DRESS syndrome
extensive skin rash, high fever, and organ involvement
sulfonylureas side effects
Hypoglycaemic episodes
Increased appetite and weight gain
Syndrome of inappropriate ADH secretion
Liver dysfunction (cholestatic)
drugs contraindicated in pregnancy
Antibiotics tetracyclines aminoglycosides sulphonamides and trimethoprim quinolones: the BNF advises to avoid due to arthropathy in some animal studies
Other drugs ACE inhibitors, angiotensin II receptor antagonists statins warfarin sulfonylureas retinoids (including topical) cytotoxic agents
MoA abciximab
Glycoprotein IIb/IIIa receptor antagonist such as abciximab used in primary angioplasty has shown a tendency towards reducing the incidence of adverse coronary events (e.g. death or myocardial infarction) within the first 30 days.
lithium toxicity precipitated by
dehydration
renal failure
drugs: diuretics (especially thiazides), ACE inhibitors/angiotensin II receptor blockers, NSAIDs and metronidazole.
lithium toxicity features
coarse tremor (a fine tremor is seen in therapeutic levels) hyperreflexia acute confusion polyuria seizure coma
why does alcohol make you pee
Ethanol reduces the calcium-dependent secretion of anti-diuretic hormone (ADH) by blocking channels in the neurohypophyseal nerve terminal.
how does mathanol cause vision changes?
formic acid. The actual pathophysiology of methanol-associated visual loss is not fully understood but it is thought to be caused by a form of optic neuropathy
causes of hypomagnesimia
drugs: diuretics, proton pump inhibitors
total parenteral nutrition
diarrhoea
alcohol
hypokalaemia, hypocalcaemia
conditions causing diarrhoea: Crohn’s, ulcerative colitis
metabolic disorders: Gitleman’s and Bartter’s
features of hypomagnesaemia
paraesthesia tetany seizures arrhythmias decreased PTH secretion → hypocalcaemia ECG features similar to those of hypokalaemia exacerbates digoxin toxicity
cocaine mechanism
cocaine blocks the uptake of dopamine, noradrenaline and serotonin
cocaine side effects
Cardiovascular effects myocardial infarction both tachycardia and bradycardia may occur hypertension QRS widening and QT prolongation aortic dissection
Neurological effects seizures mydriasis hypertonia hyperreflexia
Psychiatric effects
agitation
psychosis
hallucinations
Others 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
cocaine toxicity management
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
how does cyanide work
Cyanide inhibits the enzyme cytochrome c oxidase, resulting in cessation of the mitochondrial electron transfer chain.
cyanide presentation
‘classical’ features: brick-red skin, smell of bitter almonds
acute: hypoxia, hypotension, headache, confusion
chronic: ataxia, peripheral neuropathy, dermatitis
lowers seizure threshold
ciprofloxacin
pilocarpine MoA
muscarinic agonist
It can be used to treat acute closed-angle glaucoma as it causes miosis, or to treat dry mouth following head and neck radiotherapy (or in sjogren’s disease).
drugs which impair glucose tolerance
TASTINg (SUGAR)
Thiazide Antipschotics Steroids T cell (tacrolimus/ciclosporin) Interferon Alpha Nicotinic Acid
metformin mechanism
acts by activation of the AMP-activated protein kinase (AMPK)
increases insulin sensitivity
decreases hepatic gluconeogenesis
may also reduce gastrointestinal absorption of carbohydrates
metformin adverse effects
gastrointestinal upsets are common (nausea, anorexia, diarrhoea), intolerable in 20%
reduced vitamin B12 absorption - rarely a clinical problem
lactic acidosis* with severe liver disease or renal failure
starting metformin
metformin should be titrated up slowly to reduce the incidence of gastrointestinal side-effects
if patients develop unacceptable side-effects then modified-release metformin should be considered
aspirin mechanism
Aspirin, non-reversible cyclooxygenase (COX) 1 and 2 inhibitor so decreases the formation of thromboxane A2 resulting in decreased platelet aggregation
ciclosporin monitoring
trough
digoxin monitoring
atleast 6-hrs post dose
phenytoin monitoring
Phenytoin levels do not need to be monitored routinely but trough levels, immediately before dose should be checked if:
adjustment of phenytoin dose
suspected toxicity
detection of non-adherence to the prescribed medication
phase 1 reaction
phase I reactions: oxidation, 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 reaction
phase II 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
