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1

DIURETIC DRUGS: GENERAL MECHANISMS

- Main drugs that work by altering renal function
- Diuretics increase the rate of urine flow to create a loss of fluid
- NaCl in the body is a major determinant of extracellular fluid volume
- Sustained positive Na+ balance results in volume overload with pulmonary oedema
- Sustained negative Na+ balance results in volume depletion and cardiovascular collapse
- Clinically useful diuretics increase the rate of excretion of Na+ (natriuresis) and of an accompanying anion, usually Cl-
- Achieved by decreasing reabsorption of Na+ by tubles
- Increased electrolyte excretion via osmosis

2

DIURETIC DRUGS: CLINICAL USES

- Oedema (especially pulmonary) in congestive heart failure
- Some renal diseases (e.g. nephrotic syndrome, renal failure)
- Hepatic cirrhosis complicated by ascites (abdominal cavity)
- Hypertension

3

RENAL FUNCTION

- The kidneys maintain internal environment by eliminating waste products and regulating volume, pH and electrolyte content of extracellular fluid
- Produce 120L of filtrate per day
- NA and 99% of the filtered water is reabsorbed and some substances are actively secreted into filtrate from blood
- Produce 1.5L of urine per 24 hrs (1 ml/min)

4

PROXIMAL CONVOLUTED TUBULE (PCT)

- Epithelium of PCT is leaky, permeable to ion and H2O
- Main driving force for absorption of solutes and H2O from the lumen is the Na+/ K+ATPase pump in basolateral membrane
- After passage through PCT
- 40% of H2O reabsorbed
- 70% of Na+ reabsorbed
- >90% of HCO3- reabsorbed
- Some drugs (organic acids and bases) are secreted into PCT

5

LOOP OF HENLE

- This part of nephron enable kidney to excrete urine that is either more or less concentrated than plasma
- Descending limb is permeable to H2O
- Thick ascending limb has low permeability to H2O→ 20-30% of Na+ is reabsorbed here

6

DISTAL CONVOLUTED TUBULE (DCT)

Na+/ Cl- symport driven by Na+/ K+ ATPase reabsorbs 5-10% of filtered Na+

7

COLLECTING TUBULES

- Impermeable to H2O
- Movement of ions and H2O under hormonal control
- Absorption of NaCl enhanced by aldosterone
- Absorption of H2O enhanced by antidiuretic hormone (ADH a vasopressin)

8

LOOP DIURETICS: OVERVIEW

- Furosemide, bumetanide, ethacrynic acid
- Most powerful diuretic, causing excretion of 15-25% of filtered Na+
- Major action on the thick ascending limb of the loop of Henle
- Inhibit the Na+/ K+/ 2Cl- symport (bind to Cl- site)
- Also cause vasodilation before onset of diuresis

9

LOOP DIURETICS: POSSIBLE MECHANISMS OF VASODILATION

- Decreased responsiveness to noradrenaline and angiotensin II
- Increased formation of vasodilating PGE2 and PGI2 (NSAID interaction)
- Decreased formation of endogenous vasoconstricting NA/K ATPase inhibitor
- K+ channel activation in resistance arteries

10

LOOP DIURETICS: SIDE EFFECTS

- Excessive Na+ and H2O loss
- Also increased delivery of Na+ to collecting tubule causes loss of K+ and H+ (metabolic alkalosis)
- K+ supplements may be required to prevent hypokalemia
- Hypomagnesaemia
- Hyperuricemia (due to decreased urate excretion)

11

LOOP DIURETICS: CLINICAL USES

- Peripheral and pulmonary oedema in moderate and severe heart failure
- Useful in patients with renal impairment since not dependent on glomerular filtration rate
- Secreted into proximal tubule by organic acid transporter (also urea)

12

THIAZIDES: OVERVIEW

- Drugs acting on the distal convoluted tubules
- Chlorothiazide, hydrochlorothiazide, bendroflumethiazide, chlorthalidone, indapamide metolazone (thiazide-like)
- Less powerful than loop diuretics but better tolerated than them
- Act at distal convoluted tubule to block a Na+/ Cl symport (bind to Cl- site) independent of actions on CAH
- Additional 5-10% of filtered Na+ is excreted
- Effects of thiazides on Na+, K+, H+, Mg+ balance are similar to loop diuretics→ but smaller in magnitude

13

THIAZIDES: CLINICAL USES

- Preferred treatment of hypertension and mild heart failure
- When used in the treatment of hypertension, initial fall in BP is due to decreased blood volume, but there is also vasodilation during later phase
- Mild heart failure
- Prevent idiopathic hypercalciuria
- Nephrogenic diabetes insipidus

14

THIAZIDES: PHARMACOKINETIC ASPECTS

- Effective orally
- When used in treatment of hypertension, initial fall in BP is due to decreased blood volume, but there is also vasodilation during later phase

15

THIAZIDES: SIDE EFFECTS

- Increased urinary frequency
- Most common unwanted effect- erectile dysfunction
- Excretion of Na+ and Cl- accompanying H2O is increased
- Increase Na+ excretion in collecting tubules stimulates Na+ exchange with K+ and H+ → results in hypokalaemia, hyponatraemia, gout
- Impaired glucose tolerance

16

DIURETIC BRAKING

- Continued diuretic administration would cause a sustained net deficit in total- body Na+
- The time course of natriuresis is finite, however because renal compensatory mechanisms bring Na+ excretion into line with Na+ intake→ diuretic braking

Mechanisms include
- Activation of sympathetic nervous system and renin- angiotensin- aldosterone axis
- Decreased arterial blood pressure (reduces pressure natriuresis)
- Increased renal epithelial transporter expression

17

POTASSIUM BALANCE

- Extracellular K+ concentration- critical for excitable tissue function - is controlled by kidney
- Most diuretics cause K+ loss by increasing Na+ concentration in filtrate
- Na+ reabsorption is then coupled to K+ secretion
- Thus K+ is lost when more Na+ reaches the collecting duct and can be retained with K+ sparing diuretics, ACE inhibitors or aldosterone aldosterone antagonists
- Therefore drug interactions are possible with drugs whose toxicity is increased by low plasma K+

18

POTASSIUM SPARING DIURETICS: OVERVIEW

- Weak diuretics but usually given with thiazides or loop diuretics to prevent hypokalemia
- Spironolactone, eplerenone → synthetic steroids
- Antagonists of aldosterone in DCT and collecting ducts
- Aldosterone normally acts to stimulate Na+ reabsorption which stimulates K+ and H+ secretion so spironolactone/ eplerenone will prevent K+ secretion

19

POTASSIUM SPARING DIURETICS: MECHANISMS OF ACTION

- Blocks binding of aldosterone to its cytoplasmic receptor and therefore causes
- Increased Na+ secretion
- Decreased K+ and H+ excretion
- Limited action→ only 2% of total Na+ reabsorption is under aldosterone control

20

POTASSIUM SPARING DIURETICS: PHARMACOKINETIC ASPECTS

- Spironolactone is well absorbed in gut
- Slow onset of action, taking several days to develop

21

POTASSIUM SPARING DIURETICS: SIDE EFFECTS

- Predispose to hyperkalaemia
- Potassium supplements are contraindicated
- Can interfere with gonadal hormone- testicular atrophy and menstrual disorders

22

POTASSIUM- SPARING DIURETICS: AMILORIDE, TRIAMTERENE

- Act on late segments of DCT and collecting ducts
- Block lumental NA+ channels and thus Na+/ K+ exchange
- Limited diuretic efficacy- 5% of filtered Na+ is excreted
- Often combined with thiazides and loop diuretics to reduce loss of K

23

OSMOTIC DIURETICS: OVERVIEW

- Diuretics that acts indirectly by modifying the content of the filtrate
- Mannitol, Sorbitol, Isosorbide
- Inert polyhydric alcohol sugars, undergo glomerular filtration but can't be transported across the tubule cell membrane
- Passive H2O reabsorption is reduced by the presence of the solute
- Main effect is to increase the amount of water excreted
- Excrete relatively little Na+
- Given by IV and acts mainly on PCT

24

OSMOTIC DIURETICS: CLINICAL USES

- Brain edema causing raised intracranial pressure
- Raised intraocular pressure (acute glaucoma)

25

HAEMOSTASIS

- The arrest of blood loss from damaged blood vessels (wound)
Wounds cause:
- Vasoconstriction or vasospasm
- Adhesion and activation of platelets
- Blood coagulation (fibrin formation)
- Platelet activation leads to formation of haemostatic plug that is then reinforced by fibrin

26

THROMBOSIS

Pathological formation of a haemostatic plug (thrombus) in the absence of bleeding

Venous Thrombosis (‘Red thrombosis’)
- Usually associated with stasis of the blood
- Small components of platelet (head), large component of fibrin trapping RBC (tail)

Arterial Thrombosis (‘White thrombosis’)
- Usually associated with atherosclerosis
- Large platelet and leukocyte component, in fibrin mesh
Interrupts flow causing ischaemia or death (infarction)

27

Virchow’s triad

Definines the predisposing factors:
1) Injury to the vessel wall → endothelial injury or ruptured atheromatous plaque
2) Altered blood flow→
Long periods of inactivity results in decreased blood flow in deep veins (e.g. stasis of blood in deep veins when sitting cramped on long journey)
Changes in diameter of blood vessels (varicose veins)
3) Abnormal coagulability of the blood→ during late stages of pregnancy or during treatment with certain oral contraceptives

28

EMBOLUS

- Thrombus can break away forming a embolus (Sudden blocking of an artery)
- May lodge in lungs to form pulmonary embolism
- Most commonly due to clot in the veins of the lower legs (DVT)
- If from left heart or carotid can lodge in brain or other organs

29

BLOOD COAGULATION (FIBRIN FORMATION)

- Cascade of proteolytic enzymes and cofactors
- Inactive precursors of clotting factors are activated to catalyse conversion
- Main event is conversion by thrombi of soluble fibrinogen to insoluble strands of fibrin
- 2 pathways→ extrinsic or intrinsic

30

ANTICOAGULANTS

- To treat or prevent red venous thrombus
Prevent
- DVT and Extension of established DVT
- Pulmonary embolism
- Thrombosis on prosthetic heart valves
- Clotting in extracorporeal circulations (e.g. during haemodialysis)
- Myocardial infarction in patients with unstable angina