EDEMATOUS STATES
AND
RENAL DISEASE
Jan Bultas
Jitka Patočková
Ústav farmakologie, 3. LF UK, Praha
2009
Edema – the main reasons
• Cardiac failure (failure as a „pump“)
- left ventricle (pulmonary edema)
- right ventricle (edema of lower extremities, ascites,
hydrothorax)
• Failure of water excretion (from renal reasons, extrarenal
– e.g. hormonal reasons etc.)
• Decrease of oncotic pressure - hypalbuminemia
(proteinuria, protheonsynthesis failure – hepatopathy, …)
• Venous drainage failure (venous insufficiency,
phlebotrombosis, etc.)
• Lymphatic drainage failure
HOW TO AFFECT
WATER AND IONS
RETENTION
?
The best…
….According to the reason
(Causal Therapy)
● Systemic edema
● Local edema (no diuretics!)
DIURETICS
Drugs affecting water and ions retention
DIURETICS
• Heterogenous group of drugs which are able to increase
diuresis and excretion of electrolytes
• Main indications:
• fluid retention (heart failure, pulmonary congestion, edemas,
ascites, hydrothorax)
• hypertension
• Main clinical effects:
• in heart failure they improve the quality of life, but we do not
have enough information about their influence on the life
prognosis
• In hypertension they decrease the incidence of cerebral and
myocardial attacks, they decrease mortality
DIURETICS – mechanism of action
• Transport proteins inhibition (inhibition of
transport of ions in tubular system) (loop
diuretics, thiazides, potassium sparing diuretics)
• Glomerular filtration increase (osmotic
diuretics, methylxantines)
• Aldosterone inhibition (aldost. receptors
blocators) or vasopressin inhibition (vasopres.
receptors blocators – „aquaretics“, ev. alcohol)
DIURETICS – main groups
Henle´s loop diuretics
Distal tubule diuretics (thiazides)
Potassium-sparing diuretics
Mechanism of action of diuretics
osmotic
diuretics,
methylxantines
Triamterene, amiloride
Na+
Na+,
H2O
Carbonic
anhydrase
inhibitors
osmotic
diuretics
H2O
Na+
Clthiazides,
indapamid
Na+
K+
Na+
Clloop
diuretics
Aldost.
receptors
antagonists
H2O
„aquaretics“
LOOP DIURETICS
Na+/K+/2Cl- co-transport inhibition in Henle´s loop
(- increase of ion (Na, K, Mg, H) and water excretion)
• Furosemide: huge diuretic effect, quick onset, short
biological half life (1,5 hr), suitable for patients with
significant renal failure, variable bioavailability . In
patients with chronic heart failure, wide dose range
20mg -2g, not suitable as antihypertensive drug (short
half life)
• torasemide: better profile, longer diuretic effect, stable
bioavailability, enormous price
• bumetanide, ethacrynic acid – not used
LOOP DIURETICS
ADVERSE EFFECTS
• Potassium depletion, hypokalemia
• hyponatremia, hypomagnesaemia, hypovolemia Glomerular filtration decrease in hypovolemia
• ototoxicity
• Increase of nephrotoxicity of a lot of nephrotoxic drugs
(i.e. ATB)
DISTAL TUBULE DIURETICS - THIAZIDES
Na+/Cl- co-transport inhibition in distal tubule
• Weaker diuretic effect, slow onset, long biological half
life, stable bioavailability, narrow therapeutic window,
• No effect in patients with glomerul. filtration decrease
(no effect in patients with renal insufficiency)
• Loop diuretics effect potentiation (convenient
combination)
• Basic antihypertensives
• hydrochlorothiazide (6-12 hr, 6,25-25 mg),
chlorthalidon (48-72 hr, 6,25-25 mg)
• indapamid: also vasodilatation (16-36 hr, 2,5 mg)
DISTAL TUBULE DIURETICS - THIAZIDES
ADVERSE EFFECTS
• Potassium depletion, hypokalemia
• hyponatremia, hypovolemia, hypotension
• metabolic effect in higher dosage:
- glycid and lipid metabolism disturbances,
hyperurikemia
• Clear tendency to use  doses,
• Be careful in diabetics
POTASSIUM - SPARING DIURETICS
Direct antagonism of mineral corticoid receptors
(spironolactone)
Na+ flux inhibition in collecting tubule
( triamterene, amiloride)
• amiloride: weak diuretic effect, slow onset, long biological half
life (days), suitable for combinations (with loop diuretics,
thiazides), as antihypertensive drugs and in the treatment of heart
failure
• triamterene: less profitable, shorter effect
a combination of loop diuretics with potassium-sparing
diuretics improve a life prognosis of the patients in
comparison to the use of loop diuretics only
AE : hyperkalemia
Aldosterone receptors
Aldosterone rec. in distal tubule
mineral corticoid effect (Na+/K+ exchange)
Aldosterone rec. in myocardial tissue
Stimulation of fibro-proliferation
Aldosterone rec. in smooth muscles of
blood vessels and endothelium
Stimulation of fibro-proliferation
Aldosterone receptors antagonists
Na+
Na+
ClNa+, H2O
Na+
Aldosterone
receptors
K+ antagonists
Na+
ClH2O
H2O
SPIRONOLACTONE
aldosterone receptors antagonism in:
• heart muscle: inhib. of fibroblast proliferation ( doses 25
mg/d)
• kidneys: inhib. of Na/K pump in distal tubule – kalium
retention and natriuresis ( doses 50-300 mg/d)
• androgen-like effect (gynecomastia, menstruation
disturbances)
• Active metabolite with longer half life (15 hr)
• Cave! Risk of hyperkalemia
EPLERENONE
• Myocardial and renal effect - same as spironolactone
• No androgen-like effect, better tolerated, expensive
Aldosterone receptors antagonists
indication
• Chronic heart failure (decrease of mortality to
75%), „sub diuretic“ doses, main effect is
prevention of hyperplasia of fibrous tissue in heart
and vessels, combination with ACE-I, beta
blockers, cardiac glycosides and diuretics
• hyperaldosteronismus (higher dosage)
• cilium depletion and its prevention (medium
dosage)
Diuretics indication
Loop diuretics
• Acute and chronic cardiac failure
• Massive fluid retention, ev. retention in renal failure
Thiazides
• Antihypertensives of first choice
• In combination with loop diuretics in poor diuretic
response
Potassium-sparing diuretics
• In combination with saluretics (loop d., thiazides)
• Kalium depletion
AFFECTING
RENIN-ANGIOTENSINALDOSTERON
SYSTEM
RAA System
• Main role: keeping the body fluid volume and BP
• AT1 receptors: vasoconstriction
thirst stimulation
retention of fluids and Na in kidneys
natriuretic pept. release stimulation
aldosterone stimulation
• AT2 receptors: vasodilation
• AT3 receptors : trombocytes activation
• RAA system is in balance with the kinin system and
natriuretic peptide
RAA system activation
- short time and long time effects
ACUTE ADAPTATION
CHRONIC MALADAPTATION
 increase of the volume of
 natrium and water retention
fluid in circulation
 perif. vasoconstriction
(to keep heart output and
perfusion pressure)
 maintenance of
circulation
 myocytes
necrosis and apoptosis
 fibrous tissue proliferation
 fibrinolysis inhib. PAI-1
 sympathic syst. activation
 break down of circulation
Renin-Angiotensin-Aldosterone System
angiotensinogen
RENIN
angiotensin I
ACE
angiotensin II
rec. AT1
aldosteron
Fibroblasts
proliferation
ANP,BNP thirst Na+ resorp. vasoconstriction
Na+ retention
Renin-Angiotensin-Aldosterone System
angiotensinogen
RENIN
angiotensin I
ACE
angiotensin II
AT inhibitores
Beta- blockers,
Renin inhibitores
ACE
Inhib.
rec. AT1
aldosteron. rec.
antagonists
aldosterone
Fibroblasts
proliferation
ANP,BNP thirst Na+ resorp. vasoconstriction
Na+ retention
ACE-INHIBITORS – MECHANISM OF ACTION:
1) Inhibition of A I to A II conversion
2) Inhibition (slow down) of bradykinin degradation
Pharmacodynamic:
- decrease of peripheral vessels resistance
- specific dilation of vas efferens (intraglomerul. pressure
decrease, GF decrease)
- decrease of ALDOSTERONE and ADH release
+ thirst suppress (decrease of Na and H20 retention)
- decrease of NORADRENALIN release
- Stimulation of fibrinolysis
- Antimitogenic activity + inhibition of apoptosis
“ Chalk and talk“
NSAD´s effect on vas afferens (constriction)
Indication of ACE-I
• arterial hypertension
• Chronic heart failure
• Prophylaxis of nephropathy progression (specially Diabetic
nephropathy )
• For better prognosis and decrease of morbidity in patients
with cardial ischemia and after cerebral attack
Adverse effects and contraindications of ACE-I
AE:
• cough (cca in 5% of patients should discontinue a drug)
• angioedema (less than 1%)
• hypotension, first dose phenomenon (kaptopril, hypovolemia)
• Worsening of renal function (decrease of intraglom. pressure)
• hyperkalemia
• KI:
• gravidity!!!
• bilat. stenosis of ren. Art., signif. AO stenosis and obstructive
cadiomyopathy
Widely used ACEI
Enalapril
Fosinopril
Imidapril
Lisinopril
2x 5-20 mg
1x 10-20 mg
1x 5-10 mg
1x 20-80 mg
Moexipril
Perindopril
Quinapril
1x 7,5-15 mg
1x 4-8 mg
1-2x 5-20 mg
Ramipril
Spirapril
Trandolapril
1x 2,5-10 mg
1x 6 mg
1x 2-4 mg
Influence on mortality in patients after
myocardial infarction – different ACEI
(ONTARIO)
100%
90%
ramipril
perindopril
lisinopril
enalapril
quinapril
fosinopril
kaptopril
80%
0
6
12 měs.
Pilote L et al, Ann Intern Med, 2004
AT1 receptor antagonists,
angiotensin II receptor antagonists
ARB´s
„sartans“
Renin-Angiotensin-Aldosterone System
angiotensinogen
RENIN
angiotensin I
ACE
angiotensin II
rec. AT1
aldosterone
Fibroblasts
proliferation
ANP,BNP thirst Na+ resorp. vasoconstriction
Na+ retention
Differences in Effect of AT1 blockers
and ACE-I
BK
AII
ACE
ACE-I
ACE
natriuréza
vazodilatace
stimul. NOS
ACE-I
Differences in Effect of AT1 blockers
and ACE-I
ACE
AII
ARB
rec. AT1
ANP,BNP thirst resorp. Na+ vasoconstriction
retence Na proliferation
rec. AT2
rec. AT3
aktivace
trombocytů
antiproliferativní
vazodilatace stimul. NOS
Effects of AT1 receptor antagonists
• vasodilation, decrease of peripheral resistency (weaker effect
than in ACE-I, there is no effect on bradykinin)
• decrease of fluid retention
• inhibition of LV remodelation ( apoptosis, necrosis)
• suppression of sympaticotonia
• specif. dilation of vas efferens (decrase of intraglom. pressure)
• there is no evidence of the effect on correction of edothelial
dysfunction
Advantages and disadvantages of
AT1 rec. antagonists
advantages
disadvantages
• better tolerability (less
• weaker effect on
vasodilation and
antihypertensive effect (no
effect on bradykinin)
cough and angioedema)
Indication of AT1 receptor antagonists
• Arterial hypertension
• Profylaxis of nephropathy progression (spec.
diabetic)
• Better prognosis and decrease of mortality in patients with cardiac
ischemia and in patients after stroke
• Chronic cardiac failure
AE and contraindications of sartans
AE:
• hypotension, (namely in hypovolemia)
• Worsening of renal function (decerase of glom.
pressure)
• hyperkalemia
• Cough and angioedema (rarely)
CI:
• gravidity!!!
• bilat. Stenosis of renal art., significant AO stenosis,
obstructive cardiomyopathy
Therapy of venous insufficiency
• Pathogenesis - increase of venous pressure in distal
part of venous system (LE namely)
• Participation of inflammatory agents
• Therapy is focused on profylaxis and regime
changes
• Pharmacotherapy has limited importance, there is
some effect on decrease of pain, cramps, heaviness,
and in some cases acceleration of varicose ulcers
Pharmacotherapy
of venous insufficiency
• Natural substances (flavonoides) – diosmine,
hesperidine, aescin etc.
• semisynthetic – troxerutin
• synthetic – calcii dobesilat etc.
• The combination diosmine + hesperidine seems to
be the most evidential (EBM)
PHARMACOTHERAPY
IN RENAL DISEASE
Renal excretion of drugs and their
metabolites
a) Glomerular filtration
b) Tubular secretion
c) Passive Tubular diffusion
Glomerular filtration
• Filtration of molecules (drugs) up to molecular weight
20 000
• Hydrophilic drugs - mainly free filtration
• Lipophilic drugs - binded to albumin, just free fraction
is filtrated (cca 2%)
• cca 20% of renal perfusion – i.e.. Cca 20% of drug
excretion
Tubular secretion and passive diffusion
• 80% of renal perfusion - plasma / drug – in
peritubular capillary syst.
• In prox. Tubulus the transport systems excrete
xenobiotics to urine
• Tubular secretion is the most effective system in drug
clearance
• Lipophilic molecules move freely through the tubular
wall and back to plasma (diffusion)
• Hydrophilic molecules (ionized) – no diffusion
• pH changes influence significantly drug ionization –
drug excretion
Drug dosage in renal failure
• Drug dosage (in acute and chronic treatment)
– Loading (first) dose – without reduction
– Maintenance (repeated) dose - reduced
• Dosage reduction information
– SPC, AISLP, Cocroft Gault formula, etc.
• TDM in drugs with narrow therapeutic window
and renal excretion only
– Digoxin, amino glycosides, vancomycin
Drug dosage in renal failure - examples
Antihypertensive drugs:
– No reduction: calcium channel blockers, AT1 antagonists, Lipophilic
beta blockers (metoprolol), furosemide
– Mild reduction: ACE-I (to half of normal dosage)
– Reduction according to GF: hydrophilic BB (atenolol, bisoprolol)
•
•
•
•
•
•
statines: no reduction
insulin: cave: biol. half time prolongation, higher effect!
Opioid analgesics: biol. Half time prolongation (tramadol)
NSAIDs: different / according to molecular structure
corticoids: no reduction
digoxin: reduction according to GF, in renal failure up to 0,125
mg 2x weekly
– Always consider the indication and do TDM!
Dosage of ATB in renal failure
• Penicillin ATB + betalactamase inhibitors (Augmentin, Unasyn)
– Prolongation of dosage interval to double
• cephalosporines, chinolones
– Prolongation of dosage interval to double
• macrolides – no reduction
• Co-trimoxazol - Prolongation of dosage interval to double
• aminoglykosides
– Significant reduction (see guidelines), always TDM
• vancomycin
– Significant reduction (see guidelines)
– Dosage interval up to 7 days
– Always TDM
Diuretics in Treatment of renal failure
•
•
•
•
Decrease of GF is not an indication of diuretic treatment
thiazides – thiazides only - no effect in GF < 0,5 ml/s
- in combination with loop diuretics – in any GF
Loop diuretics – ekvipotent dose increases exp. with the GF reduction
Diuretic treatment indication:
– Fluid retention / edema
– Heart failure with fluid retention
– hyperkalemia
– Antihypertensive therapy
Severe AE of drugs in renal failure
hyperkalemia
ACE-I, AT1 rec. antagonists, spironolaktone, amiloride,
KCl
decrease of GF
ACE-I, AT1 rec. antagonists, NSAID
Cave: in renal perfusion disturbances take care about
blood pressure (be careful in hypotension)
Drug nephrotoxicity in renal failure
• Higher risk in
• Renal hypoperfusion
• Risk combinations (spec. with NSAID)
• Elderly people
- Possibly irreversible damage!
• Potentially nephrotoxic drug
–
–
–
–
Consider indication!
discontinue other potentially dangerous drugs
After good hydration
Renal function control afterwards
Drug nephrotoxicity- examples
– Rtg contrast substances
– aminoglykosides
– Some other ATB (cotrimoxazol, cephalosporines,
vancomycin)
– NSAIDs (significant ren. Vasoconstriction in prostanoid
synthesis inhibition)
– ACE-I and AT1 antagonists – GF decrease, mild
worsening of renal function, but nevertheless
nephroprotective effect
Drugs contraindicated in renal failure
• Oral antidiabetics
– metformine – absolutely contraindicated
– Most of sulphonylurea derivates
• nitrofurantoin
• Aldosterone receptor inhibitors (spironolaktone,
eplerenone)
Mistakes in pharmacotherapy
in renal failure
•
Renal failure is not recognized
•
Potentially risk combination is given without any control
•
AE of NSAID are not enough considered
•
Dehydration is not enough considered
•
Treatment with loop diuretics where is no indication for
them
THANK YOU
FOR YOUR
ATTENTION
IMMMUNOSUPRESSANTS
Immunosupression
The Aim:
• To diminish selectively immune activity, ie. selective
depression of T and B lymphocytes activation
• To keep nonspecific immunity, ie. To keep the function of
Polymorphonuclears and monocytes/macrophages
Indications:
• To reach transplant acceptation and to keep resistance
against infection and tumor growing
• To decrease activity of diseases based on immunoalteration
Immunosupression
Mainly combination of
• Substances with complex antiinflammatory effect cortiocoids
• Substances with antimetabolit effect – mycophenolat,
azathioprim
• Substances inhibiting transfer of activating signal in T
lymphocytes – cyclosporin A, tacrolimus, rapamycin
• Lymphocyte antibodies (antilymphocytes)
Glucocorticoids
• Anti-inflammatory effect: depression of function of Tlymphocytes and mono/macrophages, depression of
(inflammatory) cytokines production, decrease of vascular
permeability, depression of fibroprolipheration,…
• Metabolic effect:
- Decrease of glucose utilization - Increase of
gluconeogenesis - hyperglycemia
- Increase of protein degradation (catabolism)
- Redistribution of fat
• Bio-feedback: decrease of glucocorticoids production
Cyclosporin A
• Inhibition of signal transfer from activating
receptor on T-lymphocyte to nucleus – block of
cytokines synthesis and secondarily also Tlymphocytes activation
• Cyclic peptide, very potent immunosuppressant
• Significant nephrotoxicity, vasoconstriction
Tacrolimus, rapamycin
• Similar mechanism of action in T- lymphocytes
• Very potent immunosupression
• Better tolerability, rapamycin is not nephrotoxic