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

Na+, H2O

H2O

Na+

Cl-

H2O

Na+

Na+

K+Carbonic anhydrase inhibitors

osmoticdiuretics „aquaretics“

Aldost. receptors antagonists

Triamterene, amiloride

Na+

Cl-

loop diuretics

thiazides,indapamid

Mechanism of action of diureticsosmoticdiuretics,methylxantines

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 DIURETICSDirect 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

Na+, H2O

H2O

Na+

Cl-

H2O

Na+

Na+

K+

Aldosterone receptors antagonists

Na+

Cl-

Aldosterone receptors antagonists

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

• Myocardial and renal effect - same as spironolactone• No androgen-like effect, better tolerated, expensive

EPLERENONE

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-ANGIOTENSIN- ALDOSTERON

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

increase of the volume of

fluid in circulation

perif. vasoconstriction

(to keep heart output and

perfusion pressure)

maintenance of

circulation

CHRONIC MALADAPTATION natrium and water retention myocytes

necrosis and apoptosis fibrous tissue proliferation fibrinolysis inhib. PAI-1 sympathic syst. activation

break down of circulation

Renin-Angiotensin-Aldosterone System

angiotensinogen

angiotensin I

angiotensin II

aldosteron

ANP,BNP thirst Na+ resorp. vasoconstriction

RENIN

rec. AT1

ACE

Fibroblasts proliferation

Na+ retention

Renin-Angiotensin-Aldosterone System

angiotensinogen

angiotensin I

angiotensin II

aldosterone

ANP,BNP thirst Na+ resorp. vasoconstriction

RENIN

rec. AT1

ACE

Fibroblasts proliferation

Na+ retention

Beta- blockers, Renin inhibitores

ACEInhib.

AT inhibitores

aldosteron. rec.antagonists

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-IAE: • 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 2x 5-20 mg

Fosinopril 1x 10-20 mg

Imidapril 1x 5-10 mg

Lisinopril 1x 20-80 mg

Moexipril 1x 7,5-15 mg

Perindopril 1x 4-8 mg

Quinapril 1-2x 5-20 mg

Ramipril 1x 2,5-10 mg

Spirapril 1x 6 mg

Trandolapril 1x 2-4 mg

Influence on mortality in patients after myocardial infarction – different ACEI

(ONTARIO)

ramiprilperindopril

lisinoprilenalaprilquinaprilfosinoprilkaptopril

100%

90%

80%

0 6 12 měs.Pilote L et al, Ann Intern Med, 2004

AT1 receptor antagonists,

angiotensin II receptor antagonistsARB´s

„sartans“

Renin-Angiotensin-Aldosterone System

angiotensinogen

angiotensin I

angiotensin II

aldosterone

ANP,BNP thirst Na+ resorp. vasoconstriction

RENIN

rec. AT1

ACE

Fibroblasts proliferation

Na+ retention

Differences in Effect of AT1 blockers and ACE-I

ACE ACE natriuréza

vazodilatace stimul. NOS

AII

BKACE-I

ACE-I

Differences in Effect of AT1 blockers and ACE-I

ANP,BNP thirst resorp. Na+ vasoconstriction retence Na proliferation

rec. AT1

ACE

antiproliferativní vazodilatace stimul. NOS

rec. AT2

AII

ARB rec. AT3

aktivace trombocytů

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

• better tolerability (less

cough and angioedema)

disadvantages• weaker effect on vasodilation and antihypertensive effect (no effect on bradykinin)

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 sartansAE: • 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 - examplesAntihypertensive 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

hyperkalemiaACE-I, AT1 rec. antagonists, spironolaktone, amiloride,

KCl

decrease of GFACE-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

ImmunosupressionThe 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 T-lymphocytes 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 T-lymphocytes 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