Clinical pharmacology and toxicology Flashcards
how to differentiate drug induced lupus from normal lupus
Features: arthralgia, butterfly rash, pleurisy
don’t get neuropsych, rare to get renal (exc hydralazine)
liver enzyme inducers
Induction = PC BRAS Phenytoin Carbamazepine Barbituates Rifampicin Alcohol (chronic excess) St John’s wart
CYP450 inhibitors
CYP450 inhibitors: AODEVICCES allopurinol (xanthine oxidase inh) Omeprazole PPI Disulfiram aldehyde dehydrogenase erythromycin Valproate gaba transaminase Isoniazid [nucleic acid synthetase] & itiaconazole/fluconazole (ergosterol synth) Ciprofloxacin ****Cimetidine Ethanol (acute) Sulfonamide (dihydropteoate synthase)
nephrotoxics
Nephrotoxics Diuretics (esp high dose loops) ACEi/ARB/aminoglycosides/amphotericin NSAIDs incl high dose aspirin Cytotoxics eg cisplatin Calicneurin inh (cylcosporin, tacrolimus)
is rifampicin an inducer or inhibitor
inducer
haemodialysis doesn’t clear what (6)
but it does clear (5)
benzo's CCBs TCAs • dextropropoxyphene (Co-proxamol) • digoxin • beta-blockers
can be cleared -BLAST
• Barbiturate
• Lithium
• Alcohol (inc methanol, ethylene glycol)
• Salicylates
Theophyllines (charcoal haemoperfusion is preferable)
adrenaline doses in anaphylaxis and cardiac arrest
anaphylaxis: 0.5mg - 0.5ml 1:1000 IM
heart attack: 1mg - 10ml 1:10000 IV(or 1ml 1:1,000 IV)
SE of these common cytotoxics
- asparagine
- cisplatin
- vincristine/vinblastine
- bleomycin
- doxorubicin
- cyclophosphamide
- methotrexate
toxicity bear
- asparagine: neurotoxic
- cisplatin: ototoxic/nephrotoxic
- vincristine/vinblastine: christ my nerves, blast my bones - vincr = peripheral neuropathy, vinblas = myelosuppression
- bleomycin - pulmonary fibrosis
- doxorubicin - cardiotoxic
- cyclophosphamide - nephro/bladder toxic, SIADH
- methotrexate - nephrotoxic, myelosuppression
drinks bottle of anti freeze
- whats the toxin in it?
- tx?
ethylene glycol
tx: fomepizole (competitive inh of alcohol dehydrogenase in liver)
windshield washer fluid: methanol - also tx with fomepizole
lithium
- triggers of toxicity
- fts
- mx
Triggers of toxicity: dehydration, renal failure
- Diuretics (esp thiazides), ACEi/ARB/NSAID, metronidazole
Fts of tox:
- Coarse tremor (fine in therapeutic level) - Hyper-reflexia - Acute confusion - Polyuria - Seizure - Coma
Mx:
- Mild-mod NaCl - Severe: haemodialysis
st johns wort
- effect on p450?
- does it work? how does it work
- adverse effects 2
KEY BITS • Inducer of p450 NOTES · As effective as TCAs in mild-mod depression · Thought to act like SSRIs Adverse effects • profile in trials similar to placebo • can cause serotonin syndrome • inducer of P450 system (decreased levels of warfarin, ciclosporin. Reduced effectiveness of COCP)
DETAILS
mechanism: thought to be similar to SSRIs (although noradrenaline uptake inhibition has also been demonstrated)
NB ‘may be of benefit in mild or mod depression, but its use should not be prescribed or advised because of uncertainty about appropriate doses, variation in the nature of preparations, and potential serious interactions with other drugs’
paracetamol OD
- increased risk (2)
- protective (1)
single most important factor for prognosis?
Mx incl criteria for liver transplant
metabolic reason for overdose
Enzyme inducers»_space; increase risk of hepatotoxicity
- Chronic alcohol - Rifampicin - Carbamazepine - St john's wort
Other increased risk: malnourished pt (anorexia) or not eaten for a few days
prognosis: arterial pH
Acute alcohol intake - may be protective
Mx
1. Present <1hr: charcoal 2. NAC - Indications: Staggered OD (taken over a period >1h), doubt over time of ingestion; Nomograph - Anaphylactoid reaction common - stop and restart at slower rate 3. Liver transplant - Arterial pH <7.3 (24h after ingestion) - All of: PT >100s, Cr >300 + grade 3 or 4 encephalopathy
NAC = cysteine = precursor of glutathione
OD occurs when glutathione runs out»_space; increase in NAPQI
cocaine - abdo pain/PR bleeding, think? - 1st line mx? mx of CP, of HTN? - ABG pic mechanism effects on preg (2)
Mx: generally benzos 1st line
- MI due to cocaine: give IV benzo + ACS tx
Abdo pain or PR bleeding in coke pt = ischaemic colitis
Metabolic acidosis
NOTES
Mx
- Chest pain: benzo + GTN (if MI: go for PCI)
- HTN: benzo + sodium nitroprusside
Middle
Mech: Blocks uptake of dopamine, noradrenaline and serotonin
preg: IUGR, prem labour
metformin - acts by? 2 main effects CI (2) SE (3) does it cause hypos or wt gain? what do you do if giving contrast
Metformin
- Acts by activation of AMP-activated protein kinase - Increases insulin sensitivity, decreases hepatic gluconeogenesis - Leave at least 1 week between increasing doses
Metformin
- CI CKD - review dose if Cr>130 (eGFR <45), stop If >150 (eGFR <30)
○ Periods of tissue hypoxia eg recent MI/sepsis/aki/dehydration - if give metformin > lactic acidosis
- SE
○ GI upset (nausea/anorexia/diarrhoea)
○ Reduced vit B12 abs
○ lactic acidosis w severe liver/renal disease
- Uptitrate the dose slowly (reduce chance of GI SE)
- If unacceptable SE consider MR metformin
Extra
- Biguanide
- Doesn’t cause hypoglycaemia or wt gain
- Tx t2dm, nafld, pcos
- Improve glucose tolerance; may reduce GI abs of carbs
Discontinue metformin on day of contrast and for 48h after
allopurinol - mech - most sig adverse effects (3) - whos most at risk? what should they be screened for interactions w 3 drugs how to start it indications
Key bits
- Inhibits xanthine oxiase (oxidates 6-mercaptopurine > 6-thiouric acid)
NOTES
Adverse effects
Most sig: derm - warm to stop allopurinol immediately if they develop a rash:
• severe cutaneous adverse reaction (SCAR)
• drug reaction with eosinophilia and systemic symptoms (DRESS)
• SJS
Certain ethnic groups (Chinese, Korean and Thai): increased risk of these reactions
- Pts at a high risk of severe cutaneous adverse reaction should be screened for HLA-B *5801 allele.
Interactions
Azathioprine
• metabolised to active compound 6-mercaptopurine
• xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid
• allopurinol»_space; high levels of 6-mercaptopurine
• 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
DETAILS
Starting it
• Wait until inflam settled so pts not making choices in pain
• initial dose: 100 mg od (lower if low eGFR); titrate every few wks to aim for uric acid of < 300
• Consider colchicine cover when starting. If not tol, consider NSAIDs - take for 6 months
Indications for allopurinol
• all patients after their first attack of gout
• esp if: >= 2 attacks in 12 months, tophi, renal disease, uric acid renal stones, prophylaxis if on cytotoxics or diuretics
patients with Lesch-Nyhan syndrome often take allopurinol for life
actions of these adrenoreceptors - a1 a2 b1 b2 b3
Alpha-1 • vasoconstriction • relaxation of GI smooth muscle • salivary secretion • hepatic glycogenolysis Alpha-2 • mainly presynaptic: inhibition of transmitter release (inc NA, Ach from autonomic nerves) • inhibits insulin • platelet aggregation Beta-1 • mainly located in the heart • increase heart rate + force Beta-2 • vasodilation • bronchodilation • relaxation of GI smooth muscle Beta-3 • Lipolysis
Pathways • all are G-protein coupled • alpha-1:activate phospholipase C → IP3 → DAG • alpha-2: inhibit adenylate cyclase • beta-1: stimulate adenylate cyclase • beta-2: stimulate adenylate cyclase beta-3: stimulate adenylate cyclase
quinolones
- eg abx?
- SE (4), CI (3)
- mech
= ciprofloxacin
SE - Lower seizure threshold in epilepsy - Tendon damage (increased on steroids - MUM) - Cartilage damage - Prolonged QT CI: pregnant, breast feeding, G6PD
Mech: inh topoisomerase 2 (DNA gyrase) + topoisomerase 4
Mech of res: mutations to DNA gyrase, efflux pumps > reduce quinolone conc
G6PD = heinz bodies
Drugs affected by acetylator status (5)
50% of the UK population are deficient in hepatic N-acetyltransferase
Drugs affected by acetylator status • isoniazid • procainamide • hydralazine • dapsone sulfasalazine
zero order kinetics - what is it, what 4 drugs see it
Zero-order kinetics
= metabolism which is indep 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
1st pass metabolism
what is it
eg drugs
= 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
what are phase 1 and 2 reactions in drug metabolism
where are they usually
Drug metabolism usually involves 2 types of biochem reactions - phase I and phase II
• phase I reactions: oxidation, reduction, hydrolysis.
○ Mainly done by P450 enzymes but some drugs are metabolised by specific enzymes, EG alcohol dehydrogenase and xanthine oxidase.
○ Products of phase I reactions are typically more active and potentially toxic
• phase II reactions: conjugation.
○ Products are typically inactive and excreted in urine or bile.
○ Glucuronyl, acetyl, methyl, sulphate and other groups are typically involved
Most phase 1 & II reactions take place in the liver
statin
- mech of action
- SE (2)
if on a statin and hx of myalgia, what drug do you avoid adding?
HMG CoA reductase inhibitor
myositis, deranged LFTs
avoid adding fibrates - risk of muscle toxicity
