2.3 metabolic pharmacology Flashcards
What are the basic principles of the pharmacotherapy of hyperuricaemia & gout?
- If no clinical symptoms, but elevated uric acid levels: no therpy needed
- treatment goal: uric acid < 300-360µg/L
- mediaction should start earliest 2 weeks after acute arthitis and shoud not be too high dosed as the opposite can lead to intesification and gout flairs
- difference between urate lowering (uricostatic or uricosuric) and acoute gout flare treatment
- patient education and lifestyle modification should not be forgotten
Please discuss the pharmacological properties of allopurinol
1st line therapy: Prodrug of oxipurinol (formed by ADH)
Competetive inhibition of xanthine oxidase leads to less urate, more (hyo)xanthiine, less purine –> urocostatic
it is not for acute gout flares and ADRs are mostly harmless, but rarely fatal as immunological skin reactions occure (Stevens-Jonhson-Symptom, Toxix epidermal necroloysis) due to a ctotoxic T-Cell attack agains the epithelia (HLA-associated)
Please discuss the pharmacological properties of benzbromarone
If CI or no effect from allopurinol: 2nd line therapy
Inhibtion of tubular urate reabsorption via URAT1 leads to enhanced urate excretion (uricosuric)
ADRs are mostly harmles but rarely fatal through hepatic failure wherefore CI are renal/hepatic insuffiency
Please discuss the pharmacological properties of colchicine
Treatment of acoute gout flare (>3/year), when NSAIDS and Glucocorticoids dont work or have CI:
inhibtion of microtubule polymerisation by binding tubulin which inhibts the migration of neurophils and therefore acts antiinflammatory indiretly
Derived from the colchium plants (deadly, no antidot available)
Please discuss the pharmacological properties of canakinumab
Human monoclonal antibody that target interleukin 1beta and are therefore antiinflammatory
It can be used one time for an acute gout attack, but costs 12.000 per injection making it a 3rd line therapy
Please give an overview of the pharmacotherapy of an acute gout attack.
- 1st line NSAIDs due to antiinflammatory and analgesic properties: Ibuprofen, dicolfenac (not ASS as it inhibtis renal urate excretion) + PPI
- 2nd line or if CI: Glucocorticoids with antiinflammatory and immunosuppresive use
- 2nd line (if more than 3 attacks per year): Colchine
- 3rd line Canakinumab
What are the major classes of drugs for the treatment of hypercholesterolaemia? Explain their MOA and give examples of drugs.
- Statins (simavastain): competetive inhibitors of HMG-CoA reducatase (CSE) which is the rate limiting step in cholesterol biosynthesis in the liver leading to less cholesterol, more LDL-recetpros and therefore higher LDL uptake and less LDL in blood (-45%) + pleiotropic effects
- Fibrates (bezafibrate): activate PPAR-alpha in hepatocytes leading to higher HDL
- Cholestyramine: bile acid sequestrant preventing bile acid reabsorption
- Ezetimibe: antagonsim at NPC1L1 inhibtis cholesterol absorption in small intestine
- PSCK9 targeted antibodies (3rd line Alirocumabi, Evolocumab): bind LDL receptors on hepatocytes and lead to their degradation –> more LDL-R are rececyled and exxpreesd leading to a higher uptake of LDL
What are the differential effects of statins, fibrates, cholestyramine and ezetimibe on HDL-C, LDL-C, triglycerides and mortality?
Statins lower LDL –> effect on mortality
Fibrates higher HDL lower TG –> ?
Cholesteramine lower LDL –> ?
Ezetimbe lower LDL –> no effect on mortality
What are the differential effects of statins on HDL-C, LDL-C, triglycerides and mortality?
Statins: lower LDL very effectilvy, only increase HDL a little as well as minimal TG lowering –> but overall effect on mortality
What are the differential effects of fibrates on HDL-C, LDL-C, triglycerides and mortality?
Fibrates: small effect on lowering LDL, medium effect on highering HDL, very effectiv eon reducing TG –> effect on mortality is not clear
What are the differential effects of cholestyramine on HDL-C, LDL-C, triglycerides and mortality?
effectively lower LDL, increase HDL a little, but do not affect Tgs –> effect on motaliy unknown
What are the differential effects of ezetimibe on HDL-C, LDL-C, triglycerides and mortality?
small effect on lowering LDL, minimal increase of HDL/lowering of TGs unsure –> no effect on mortality
Please explain the mechanism of pleiotropic effects of statins and provide examples.
-lipid-lowering activities
LDL biosynthesis decreased
LDL receptors incerased
- anti-thrombotic activities
NO release increased
fibrinolytic activity increased
endothelin-1 decreased
- antioxidant activities eNOS increased reduced glutathione increased ROS production decreased lipid peroxidation decreased
- anti-inflammatory activities
pro-inflammatory cytokines dereased
neointimal inflammation decreased
less MMPs , less CRP
Therfore lead to:
vascular endothelium:
stabilisation of plaques, lower BP
less vascular dementia (?)
immunomodulation:
less multiple sclerosis (?)
blood clotting:
less stroke
bone metabolism:
less osteoporosis (?
What are the mechanisms and symptoms of statin-induced myotoxicity? How can this toxicity be managed?
statin-induced myalgia (10 – 15 % of all patients) (exact pathophysiology of statin-induced myopathy is not fully known)
1. myopathy/myositis
increased muscle soreness/muscle pain, muscle weakness
2. rhabdomyolysis
breakdown of skeletal muscles
acute renal failure due to increase of myoglobin in circulation myoglobin
muscle pains
myoglobinuria, hyperuricaemia
electrolyte imbalances, cardiac arrythmias
Managments:
- Check co-medication for interactions! (CYP3A4 inhibitors)
- Is the drug taken in the evening? (dose reduction might be possible!)
- Use of red yeast rice? Stop it!
- Reduce alcohol consumption! (esp. in the evening!)
- Check vitamin D! (correct any deficiency)
- Reduce statin dose!
- Try fluvastatin!
- Combine statin with colestyramin! (& reduce statin dose)
- Combine statin with ezetimibe! (& reduce statin dose)
Please give examples of statin-food and statin-drug interactions.
drugs: amlodipine, fibrates, macrolides, fluroquinons
food: grapefruit
