Pharmacology Flashcards
what do uricosuric drugs do
promote excretion of uric acid into the urine
what is the role of diuretic
increase urine flow (usually by inhibiting the reabsorption of electrolytes at various sites of the nephron)
to enhance secretion of salt and water in conditions with tissue swelling due to increase ECF (oedema)
what ions are mostly excreted by duiretics
sodium and chloride
what diseases increase plasma hydrostatic pressure causing oedema
nephrotic syndrome
CHF
hepatic cirrhosis with ascites
what is nephrotic syndrome
a disorder of glomerular filtration which allows large protein (mainly albumin) to appear in the urine (protein uria)
how does nephrotic syndrome cause oedema
as protein lost from plasma into urine
decreased capillary oncotic pressure (water not sucked into capillaries as much as a result)
increased interstitial fluid (=oedema)
ALSO increased ECF= decreased blood volume and CO
= activation of RAAS
= Na+ and H20 retention
= increased plasma hydrostatic pressure and decreased oncotic pressure
= makes oedema worse
can you have protein in filtrate normally
can be filtered after exercise but always reabsorbed within proximal
what causes oedema in congestive heart failure
reduced cardiac output = renal hypoperfusion = activates RAAS = increased blood volume= increased venous and capillary pressures + reduced plasma oncotic pressure = pulmonary and peripheral oedema
how does hepatic cirrhosis cause ascites
increased pressure within the hepatic portal vein + decreased production of albumin = loss of fluid into the into the peritoneal cavity = ascites
what causes activation of RAAS
decreased circulating volume
what do loop duiretics target
Na+/K+/2Cl- co transporter in the thick ascending limb of the loop of henle, bind to Cl- site
what do thiazide like diuretics target
Na+/Cl- co transporter in the early distal convoluted tubule
what do carbonic anhydrase inhibitors target
Na/H+ exchange in the proximal convoluted tubule
used for reducing intra-ocular pressure and altitude sickness prophylaxix
what do potassium sparing diuretics target
Na/K+ exchanger in the collecting tubule and duct
why is potassium lost in the use of non potassium sparing diuretics
Na+/K+ exchanger in the collecting tubule and duct
anything that increases the amount of sodium that gets into the late/ distal tubule will also cause potassium loss
how do duiretics reduce oedema
cause the excretion of salt and water- concentrating the albumin in plasma- increasing plasma oncotic pressure
water drawn in from from the interstitial fluid
helped by the reduced hydrostatic pressure of the vessels aswell
where do most duiretic work (cellular level)
on the apical membrane of tubular cells (why they need to enter the filtrate to work if hydrophilic)
how do duiretics enter the filtrate
glomerular filtration (for drug not bound to large plasma proteins) secretion via organic anion transporters (acidic drugs) or organic cation transporters (basic drugs)
what drugs enter tubular epithelium cells via organic anion trasnporters at the apical membrane
duiretics (furosemide, hydrocholorothiazide)
simvastatin, penicillins, NSAIDs, endogenous urate
why does furosemide precipitate gout
as competes at organic anion transporters to get into lumen epithelium and be excreted
what drugs enter tubular epithelium via organic cation transporters
duiretics (amoliride), atorpine, metformin, morphine, procainamide, endogenous catecholamines
what drives the reabsorption of calcium and magnesium in the thick ascending limb (paracellular route)
potassium recycling
how are calcium and magnesium reabsorbed in the thick ascending limb
via paraceelular route, driven by electrogradient created by potassium recycling, in thick ascending limb
what are the two main loop duiretics
furosemide and bumetanide
what are the actions of loop duiretics
decrease tonicity of interstitium of the medulla (by decreases reabsorption)
prevent dilution of the filtrate in the ascending limb (as AL water impermeable)
increase load of Na+ delivered to distal nephron (causes K+ loss)
increase excretion of Ca and Mg+
has a venodilator effect before diuresis
how much water loss do loop diuretics cause
‘torrential’
15-25% of filtered load of Na+
why are loop duiretics good in pulmonary oedema cause by heart failure
as have a venodilator effect before duiresis effect
where are loop duiretics absorbed
from GI tract (can vary in CHF due to oedema of the intestines, esp furosemide)
what do loop duiretics bind to in blood
plasma proteins
how do loop duiretics enter the nephron
via OAT
what are the clinical indications for loop duiretics
to reduce salt and water overload associated with:
- acute pulmonary oedema
- chronic kidney/ heart failure
- hepatic cirrhosis with ascites
- nephrotic syndrome
to increase urine volume in AK failure
HPTX (thiazides preferred- used if resistant/ cormorbid renal insufficiency)
acute hypercalcamia
what do nitrates do
vasodilate - good for pulmonary oedema
what are the contraindications for loop duiretics
severe hypovolaemia/ dehydration
cautioned in severe hypokalaemia and /or hyponatraemia, hepatic encephalopathy, gout
what are the adverse affects of loop duiretics
hypokalaemia (co prescribe potassium sparing duiretic. potassium supplements)
metabolic alkalosis (increased H+ secretion)
hypocalcaemia and hypomangesaemia
hyperuricaemia - can precipitate gout
loss of hearing
how do thiazide duiretics work
block the Na+/Cl- co transporter in the distal convoluted
tubule by binding to Cl- site
what do thiazide like duiretics do
prevent dilution of filtrate in early distal tubule
increase the load of Na+ delivered to the collecting tubule (causing K+ loss)
increase reabsorption of Ca2+
cause vasodilation- helpful in treating hypertension
what are the main thiazide duiretics
bendroflumethiazide (thiazide)
chlortalidone
indapamide and
metolazone (thiazide-like)
how much duiresis do thiazides cause
5% of Na+ to be excreted- moderate
where are thiazides absorbed
GI tract
how do thiazides enter the nephron
via OAT
what is the clinical indication for a thiazide
mild heart failure
hypertension
severe resistant oedema
renal stone disease (reduced calcium excretion in urine stops stone formation)
nephrogenic diabetes insipidus
what causes nephrogenic diabetes insipidus
diminished vasopressin responsiveness of the collecting ducts
what are the contraindications for thiazides
hypokalaemia
cautioned in:
hyponatraemia, gout (block urate transport system in proximal tubule)
what are the adverse effects of thiazides
hypokalaemia metabolic alkalosis hypovolaemia hypotension hypomagnaesmia (NOT hypocalcaemia) hyperuricaemia erectile dysfunction impaired glucose tolerance in diabetes
why is there an advantage of using thiazides instead of loops in the elderly
if patients have osteoporosis then thiazides wont cause hypocalcaemia
what does aldosterone do
increases synthesis of a protein that activates the epithelial Na+ channel (ENaC)
=increases intracellular sodium, decreases potassium
what do ROMK and BK channels do
secrete K+ into the urine in the collecting channel
what does Na+ reabsorption cause
potassium secretion
explain how potassium is lost when there is high Na+ in the distal tubule/ collecting duct
more excretion further up causes more excretion further down
this creates negative charge in lumen
increases driving force on K+ across the lumenal membrane = enhanced secretion
potassium washed away by increased urine flow
how do potassium sparing duiretics work
amiloride + triametrene= block the apical sodium channel to decrease Na+ reabsoprtion in the late and distal collecting tubule
spironolactone + eplerenone = compete with aldosterone for binding to intracellular (cytoplasmic) receptors prevent the actions of aldosterone (increases Na, decreases K)
where are sprionolcatine, eplerenone and triamterene absorbed
GI tract
how do potassium sparing duiretics enter the luminal epitheliem
amiloride and triamterene= OCT in proximal tubule
sprinolonatone and eplerenone= basolateral membrane
what are the clinical indications for potassium sparing duiretics
used in conjunction with other agents that cause potassium loss (cant give alone)
what do potassium sparing duiretics cause when given alone
hyperkalaemia
what do thiazide and loop duiretics activate
RAAS
what can be given to potentiate the actions of thiazides and loop agents
aldosterone receptor antagonists (block action of aldosterone- increasing Na and decreasing K+)
what are aldosterone antagonists used in
heart failure
conns (primary hyperaldosteronism)
resistant essential hypertension
secondary hyperaldosteronism (hepatic cirrhosis with ascites)
what are the contraindications for a potassium sparing duiretic
severe renal impairment, hyperkalaemia, addisions
how do osmotic diuretics enter the nephron
glomerular filtration
name an osmotic duiretic
mannitol
how do osmotic diuretics work
increase the osmolarity of the glomerular filtrate, opposing the reabsorption of water in nephron
what are the major sites of action of osmotic diuretics
proximal tubule (where most iso-osmotic reabsorption of water re-occurs)
how do osmotic diuretics affect sodium
cause decrease of reabsorption in proximal tubule (more water decreases sodium conc and electrochemical gradient for reabsorption)
when are osmotic diuretics used
in the prevention of acute hypovolaemic renal failure to maintain urine flow
in urgent treatment for acutely raised intraocular and intracranial pressure
how do osmotic diuretics lower intra-ocular/ intra-cranial pressure
solute cannot pass blood brain barrier (cant enter brain/ eye) - increased plasma osmolarity extracts water from these compartments (ICF)
what are the adverse effects of osmotic diuretics
transient expansion of blood volume
hyponatraemia
when can osmotic diuresis also occur
in hyperglycaemia (glucose remaining in filtrate retains fluid)
as a consequence of contrast dye in imaging (filtered but not reabsorbed creating an osmotic load)
name a carbonic anhydrase inhibitor
acetazolamide
what do carbonic anyhydrae inhibitors do
increase excretion of HCO3- with Na+, K+, and H20
= alkaline diuresis and metabolic acidosis
what are carbonic anhydrase inhibitors used for
glaucoma and following eye surgery to reduce IOP (suppress the formation of aqueous humour from ciliary body)
prophylaxis of altitude sickness
infantile epilepsy
how does aldosterone affect the kidney
causes enhanced tubular Na+ reabsorption and salt retention
(increases activity of sodium channel ENaC and increases synthesis of Na/K ATPase channels. binds to cystoplasmic mineralocorticoid receptor to alter gene expression)
(in collecting tubule)
hoe does vasopressin affect the kidney (ADH)
enhanced H20 reabsorption
bins to V2 GPCR to increase cAMP, increases number of aquaporins in the collecing tubule
cause causes neurogenic DI
lack of vasopressin secretion from the posterior pituitary
what is the treatment for neurogenic DI
desmopressin (synthetic analogue of vasopressin)
what causes nephrogenic DI
inability of the nephron to respond to vasopressin (usually caused by AR/ X linked mutations)
what are aquaretics/ vaptans
competitive antagnoists of vasopressin receptors
what do vasopressin receptors do
V1A mediates vasoconstriction
V2 mediates H20 reabsorption (directs AQP2)
what does the blackage of vasopressin receptors (by aquaretics/ vaptans do)
causes excretion of eater without accompanying Na+= raises plasma Na+ conc
when is tolvaptan used
SIADH
where does reabsorption of glucose occur
proximal tubule of
what mediates glucose reabsorption
SGLT 1 and 2 (should be 100% efficient)
when would glucose appear in the urine
if filtrate concentration of glucose exceeds the renal threshold (11 mmol)
where are SGLT 1 and 2 expressed
SGLT 1 in intestine and kidney
SGLT 2 in the kidney (proximal tubule of nephrone)
SGLT 2 absorbs 90% and SGLT 1 absorbs 10% (2 before 1)
what type of movement is glucose reaborsption
secondary active transport (apical membrane) facilitated diffusion (basolateral membrane)
SGLT both transport glucose against concentration gradient by coupling with Na+ influx glucose
what does inhibition of SGLT 2 cause
glycosuria - excretion of glucose
decrease in HbA1c
weight loss (calorific loss and mild osmotic diuresis)
what are the adverse effects of SGLT inhibitors
increased genital bacterial/ fungal infections
name some SGLT 2 inhibitors
canagliflozin
dapagliflozin
empagliflozin
what are the major prostaglandins made by the liver
PGE2 - medulla
PGI2- glomeruli
what do prostaglandins do
vasodilate natruietic synthesised in response to ischaemia mechanical trauma angiotensin II ADH bradykinin
when are prostaglandins useful
when there in vasoconstriction/ decreased effective arterial blood volume = they cause compensatory vasodilation
how do prostaglandins affect GFR
cause vasodilation of the afferent arteriole
= releases renin
= increases angiotensin II
=vasoconstriction of the efferent arteriol
= filtration pressure increases
how can NSAIDs cause renal failure
inhibit COX (enzyme that forms prostaglandins) which causes greatly decreases GFR and can precipitate acute renal failure in conditions where renal blood flow is dependent upon vasodilator prostaglandins (cirrhosis, heart failure, nephrotic syndrome)
what is the triple whammy effect
combo of ACEi/ ARB, duiretic and NSAIDs = decreased GFR = acute renal failure
what forms uric acid
the catabolism of purines
what are the treatments for gout
NSAIDS and colchine
(probenecid and sulfinpyrazole can block reabsorption of urate in the proximal tubule)
allupurinol inhibits urate synthesis, used as prophylaxis not in acute flares
what is pharmacokinetics
behaviour of a drug with regard to absorption, distribution, metabolism and elimination
where are most drugs excreted
by kidneys
name a drug that is directly nephrotoxic to the kidneys
gentamicin
give an example of how a drug can be indirectly nephrotoxic
taking a diuretic when already dehydrated
what drugs cause renal vasoconstrictions
NSAIDs
ACEi/ARB
radiocontrast
what drugs cause rapidly progressing GN
penicillamine
hydralazine
propythiourcil
what drugs can cause acute tubular necrosis
radiocontrast
heavy metals
cisplatin
aminoglycosides (gentamicin)
what drugs can cause acute interstitial nephritis
antibiotics (penicillins, cephalosporins, rifampicin, cirpofloxacin) NSAIDs loop and thiazide diuretics allopurinol mesalazine
what drugs can cause intratubular obstruction and crustal formation
acyclovir
methotrexate
sulphonamide
what drugs can cause post renal obstruction
papillary necrosis- NSAIDs, compound analgesics
urinary retention- anticholinergics, tricyclic antidepressants
what drugs can cause pre renal azotemia (hypernataemia)
antihypertensive agents
duiretics
what enzyme do statins inhibit
HmgCoA reductase
what are the types of calcium channel blockers
dihydrapyridine (-ipines used for hypertension)
and non dihydrapyridine (Verapamil, Diltiazem which also slow HR)
when can you not use a beta blocker
asthma, COPD and peripheral vascular disease (causes peripheral vasoconstriction)
why can you go into heart failure in AF
as LA contributes 20% of cardiac output
what are the signs of heart failure of CXR
cardiomegaly pulmonary oedema blunting of costophrenic angle upper lobe diversion of fluid (blood cant get oxygenated in lower lobes) periphilar oedema curly B lines (lymphatic engorgement)
how can NSAIDs cause HF
as cause Na and fluid retention
would you stop bendroflumethiazide in gout
yes as increased uric acid
what will taking an ACEi or diuretic when dehydrated do
cause AKI/ decrease renal function
what do you get high levels of circulating in HF
ADH as RAAS system activated
why would you give diuretics IV in HF
as wont absorb as well orally due to GI oedema
what should you do to the dosage of drugs in renal dysfunction
reduce them
with digoxin half or quarter the load dose
what are the features of digoxin toxicity
heart block, brady cardia, yellow vision, vomiting, abnormal renal function
what is the treatment for HF
diuretics
CCBs
amiodarone
anticoagulants
do you give ACEi in an AKI
NO (can introduce them if needed once kidney function has stabilised)
what drugs to you need to monitor when a patient with an AKI taking them
diuretics, ACEi/ ARBs, digoxin,
what happens to half life of digoxin in CKD
it doubles
what are the signs of hyperkalaemia on ECG
broadened QRS
tall tented T waves
flattening of P waves
sine waves
what is the management for hyperkalaemia
IV calcium gluconate 10mls 10% (to stabilise the cardiac membrane)
IV insulin and dextrose (moves potassium into the cells
Salbutamol (forces potassium into the cells)
fluids (saline) if hypovolaemic (or IV sodium bicarbonate if metabolic acidosis present)
what is a CVP
central line (tells you filling pressure of heart so you dont overload the patients with fluid)
what is ACEi good for
improve survival in HF
reduces pressure in kidney
reduces endothelial dysfunction
reduces RAAS system (upregulated in HF)
what do penicillamine do
given in wilsons (collates copper)
immunosuppressant, reduces RF (given in RA)
what is diclofenac
an NSAID (v toxic, long term CV risk) useful in gout
why is diclofenac given with misoprostol
misoprostol is a prostaglandin analogue so given with diclofenac which is a very potent COX2 inhibitor
what can you get as a result of NSAIDs
hypertension (cause Na retention)
what happens to kidneys in hypertension
get glomerular sclerosis
what is a potential side effect of penicilliamine
bone marrow aplasia (if see platelets falling stop drug, restart when platelets recover)
what deposits can you get in RA
amyloid
what do you need to monitor in RA
BP as increased risk of CVD and hypertension
is a thiazide or a loop more potent
loop on its own more potent but when given together thiazide is v potent
how do you assess fluid status
Mucous membranes, skin turgor, E+S BP, JVP, (creps in chest)
Bloods: urea, haematocrit, osmolarity + urine osmolarity
can you be dehydrated and have peripheral oedema
yes just means fluid is in the wrong place
what drugs improve survival in HF
ACEi/ARB (with monitoring), beta blocker
what is sprionolactone
a potassium sparing diuretic
is an aldosterone antagonist- reduces BP by dampening RAAS and prevents myocardial fibrosis (caused by aldosterone)
what are side effects of allopurinol
steven johnson syndrome
bone marroe suppression
what is solpadol
soluble mix of paracetamol and codeine- has v high salt content
