pharmacology Flashcards
Antimetabolite (mycophenolate or azathioprine)
Synthetic derivative of mycophenolic acid
noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase ◦ inhibits DNA replication
◦ suppress B- and T-cell proliferation.
Adverse effects
◦ GIT: nausea & diarrhea
◦ Haematologic: cytopenias
Calcineurin inhibitor (tacrolimus or cyclosporine)
Calcineurin inhibitors
major mode of action is inhibition of the production of cytokines involved in the regulation of T-cell activation. In particular, cyclosporine inhibits the transcription of interleukin 2.
Uses
◦ Steroid resistant/dependent nephrotic syndrome (Steroid sparing)
◦ Transplantation
Toxicity
◦ Nephrotoxicity
◦ Hypertension, hyperlipidaemia
◦ Hirsuitism,Gingivalhyperplasia(seenmorewithciclosporin) ◦ Neurotoxicity, tremor
◦ Electrolyte disturbances: hypomagnesaemia
◦ Insulinresistance
Drug interactions
◦ Cytochrome p450
Furosemide
potent loop diuretic. It inhibits sodium and chloride absorption in the ascending limb of Henle’s loop and in both the proximal and distal tubules. The high degree of efficacy is due to this unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase or aldosterone.
Furosemide (frusemide) may promote diuresis in cases which have previously proved resistant to other diuretics.
Furosemide (frusemide) has no significant pharmacological effects other than on renal function.
Thiazide diuretic
hydrochlorpthiazide
indications: Hypertension.
May be used alone or in combination with other antihypertensive drugs.
Oedema.mAssociated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, premenstrual tension, and drug induced oedema.
MOA: Dithiazide interferes with the distal renal tubular mechanism of electrolyte reabsorption (Na/Cl from distal tubule so water follows Na). This compound increases the excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium, magnesium and bicarbonate. Urinary calcium excretion may be decreased.
Thiazide: hypocalciuric Smaller natriuretic effect
effect on HTN is unknown but it works
DDAVP/ADH
cranial diabetes insipidus;
primary nocturnal enuresis in patients from 6 years of age with normal ability to concentrate urine, who are refractory to an enuresis alarm or in whom an enuresis alarm is contraindicated or inappropriate.
MOA: By mimicking the actions of endogenous ADH, desmopressin acts as a selective agonist of V2 receptors expressed in the renal collecting duct (CD) to increase water re-absorption and reduce urine production.
=ADH
•Synthesised in hypothalamus•Stored posterior pituitary
•Short T ½ in circulation (15-20 min)
•Stimulated by
•hypovolemia(carotid baroreceptors)& •hyperosmolality(Na+ osmoreceptors)•Many others…stress, nausea, pain, drugs (carbamazepine, oxcarbazepine, cyclophosphamide, vincristine), opioids, AngioII
Aldosterone
mineralocorticoid: Acting on the nuclear mineralocorticoid receptors (MR) within the principal cells of the distal tubule and the collecting duct of the kidney nephron, it upregulates and activates the basolateral Na+/K+ pumps, which pumps three sodium ions out of the cell, into the interstitial fluid and two potassium ions into the cell from the interstitial fluid. This creates a concentration gradient which results in reabsorption of sodium (Na+) ions and water (which follows sodium) into the blood, and secreting potassium (K+) ions into the urine (lumen of collecting duct).
Aldosterone upregulates epithelial sodium channels (ENaCs) in the collecting duct and the colon, increasing apical membrane permeability for Na+ and thus absorption.
Cl− is reabsorbed in conjunction with sodium cations to maintain the system’s electrochemical balance.
Aldosterone stimulates the secretion of K+ into the tubular lumen.[11]
Aldosterone stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+.
Aldosterone stimulates secretion of H+ via the H+/ATPase in the intercalated cells of the cortical collecting tubules
Aldosterone upregulates expression of NCC in the distal convoluted tubule chronically and its activity acutely.[12]
prostaglandin 2
Prostaglandins (PGs) with best-defined renal functions are PGE2 and prostacyclin (PGI2). These vasodilatory PGs increase renal blood flow and glomerular filtration rate under conditions associated with decreased actual or effective circulating volume, resulting in greater tubular flow and secretion of potassium. Under conditions of decreased renal perfusion, the production of renal PGs serves as an important compensatory mechanism. PGI2 (and possibly PGE2) increases potassium secretion mainly by stimulating secretion of renin and activating the renin-angiotensin system, which leads to increased secretion of aldosterone.
ACE inhibitor
Renin catalytically cleaves these circulating angiotensinogen and forms angiotensin I. Angiotensin-converting enzymes then convert angiotensin I to its physiologically active form, angiotensin II. Angiotensin II causes contraction of the muscles surrounding blood vessels, effectively narrowing vessels and increasing blood pressure. It also stimulates the release of aldosterone, which stimulates water and sodium reabsorption, thereby, increasing blood volume and blood pressure.
ACE inhibitors stimulate the dilation of blood vessels by inhibiting the production of angiotensin II.
ACE inhibitor lisinopril effectively reduces blood pressure and proteinuria in renal disease. The latter effect is not only the result of a lower blood pressure, but is probably also due to a fall in intraglomerular capillary pressure.
Amiloride
Amiloride: inhibits ENaC, which means Na can’t get into the collecting tubule lumen and the water stays outside with it. K+ sparing
spironolactone
Spironolactone: Competes with ALDO-R. K+ sparing
Aldosterone takes Na–> water out of the collecting tubule and into the blood, so the water stays in the urine, but the k is still being pumped actively into the blood.
Eculizumab
Eculizumab is an anti-C5 antibody that inhibits complement activation. Eculizumab is used to treat atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria
Methotrexate
Mechanism of immunomodulatory effects in autoimmune diseases is unclear and may differ from its action as a folic acid antagonist in cancer treatment; it suppresses inflammation and immune responses.
– Most commonly used for JIA and uveitis
– S/E: nausea, GI upset, LFT ↑, haem abn
– Folic acid supplementation to alleviate GI S/E
– Monitor FBP and LFTs at least 3 monthly
– Previous recommendation to avoid live vaccines* – Ok to stop temporarily if fevers
– Teratogenic
Anakinra
mode of action: Recombinant form of human interleukin‑1 (IL‑1) receptor antagonist; it neutralises the activity of IL‑1, which is involved in acute inflammatory response.
Abatacept
Co-stimulation modulator; binds to CD80 and CD86 on antigen-presenting cells, which prevents full activation of CD28 T lymphocytes, thus reducing cytokine production and inflammation.
Tocilizumab
Binds to and inhibits the activity of interleukin‑6 (IL‑6), a cytokine involved in the pathogenesis of rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and giant cell arteritis (GCA).
precautions: Absolute neutrophil count (ANC) <2x109/L—starting tocilizumab is not recommended as it can cause neutropenia; do not use when <0.5x109/L.
Platelets <100x109/L—use tocilizumab cautiously as it can cause thrombocytopenia; do not use when <50x109/L.
Previous TNF-alpha antagonist treatment—may be at greater risk of infections and neutropenia with tocilizumab.
Adalimumab
Bind to TNF alpha and inhibit its activity. TNF alpha is a cytokine involved in inflammatory and immune responses and in the pathogenesis of diseases such as psoriasis, rheumatoid and psoriatic arthritis, ankylosing spondylitis and inflammatory bowel disease.
Precautions: disease activity.
Heart failure—contraindicated in moderate or severe heart failure (NYHA class III–IV) and left ventricular ejection fraction <50%; use cautiously in mild disease as TNF-alpha antagonists may worsen heart failure.
Treatment with other immunosuppressants—increases risk of infection; use with another cytokine modulator is not recommended. TNF-alpha antagonists are contraindicated with anakinra; golimumab is contraindicated with abatacept.
History of blood dyscrasias—rare cases of serious blood dyscrasias (some fatal) have been reported; monitor complete blood count regularly.
Respiratory disease—may be at increased risk of interstitial lung disease with TNF-alpha antagonists.
Antibodies against double-stranded DNA (eg lupus)—TNF-alpha antagonists are associated with the formation of autoantibodies. They may worsen or induce a lupus-like syndrome.
Etanercept
Bind to TNF alpha and inhibit its activity. TNF alpha is a cytokine involved in inflammatory and immune responses and in the pathogenesis of diseases such as psoriasis, rheumatoid and psoriatic arthritis, ankylosing spondylitis and inflammatory bowel disease.
Infliximab
Bind to TNF alpha and inhibit its activity. TNF alpha is a cytokine involved in inflammatory and immune responses and in the pathogenesis of diseases such as psoriasis, rheumatoid and psoriatic arthritis, ankylosing spondylitis and inflammatory bowel disease.
Biologics side effects
Localized injection site pain, rash, swelling
• Minor: transient fever, abdominal pain, nausea, headache
• Abnormal FBP, UEC, LFT
• Infections: lower threshold for treating infections
• Serious adverse effects are rare – malignancy, serious infections
what is V and how is it calculated?
V= volume of drug in th ebody (vol distribution) V= Vplasma x [v tissue x (conc. tissue x conc plasma)]
what is k and what does it mean?
k is the extraction constant ans means the time in hours for the drug to leave the body. k = 0.2hr-1 means 20% per hour
What is Cl how is it calculared?
Cl = blood flow x extraction (q x e) is clearance from the body
t1/2
time for half the original dose to leave the body. t1/2 = 0.693/k
What is AUC?
the amount of drug in the body x infinity
CL = F. D(ose) / AUV
