WEEK 8 Flashcards
(45 cards)
1
Q
DIURETIC DRUGS: GENERAL MECHANISMS
A
- 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
Q
DIURETIC DRUGS: CLINICAL USES
A
- 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
Q
RENAL FUNCTION
A
- 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
Q
PROXIMAL CONVOLUTED TUBULE (PCT)
A
- 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
Q
LOOP OF HENLE
A
- 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
Q
DISTAL CONVOLUTED TUBULE (DCT)
A
Na+/ Cl- symport driven by Na+/ K+ ATPase reabsorbs 5-10% of filtered Na+
7
Q
COLLECTING TUBULES
A
- 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
Q
LOOP DIURETICS: OVERVIEW
A
- 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
Q
LOOP DIURETICS: POSSIBLE MECHANISMS OF VASODILATION
A
- 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
Q
LOOP DIURETICS: SIDE EFFECTS
A
- 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
Q
LOOP DIURETICS: CLINICAL USES
A
- 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
Q
THIAZIDES: OVERVIEW
A
- 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
Q
THIAZIDES: CLINICAL USES
A
- 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
Q
THIAZIDES: PHARMACOKINETIC ASPECTS
A
- 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
Q
THIAZIDES: SIDE EFFECTS
A
- 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
Q
DIURETIC BRAKING
A
- 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
Q
POTASSIUM BALANCE
A
- 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
Q
POTASSIUM SPARING DIURETICS: OVERVIEW
A
- 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
Q
POTASSIUM SPARING DIURETICS: MECHANISMS OF ACTION
A
- 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
Q
POTASSIUM SPARING DIURETICS: PHARMACOKINETIC ASPECTS
A
- Spironolactone is well absorbed in gut
- Slow onset of action, taking several days to develop
21
Q
POTASSIUM SPARING DIURETICS: SIDE EFFECTS
A
- Predispose to hyperkalaemia
- Potassium supplements are contraindicated
- Can interfere with gonadal hormone- testicular atrophy and menstrual disorders
22
Q
POTASSIUM- SPARING DIURETICS: AMILORIDE, TRIAMTERENE
A
- 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
Q
OSMOTIC DIURETICS: OVERVIEW
A
- 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
Q
OSMOTIC DIURETICS: CLINICAL USES
A
- 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
31
INJECTABLE ANTICOAGULANTS: Unfractionated Heparin (UFH)
- Inhibits coagulation by activating antithrombin III, by binding to and increasing activity of the inhibitor antithrombin III (AT III) that inactivates
- Thrombin (factor IIa) very sensitive as acts directly or via At III
- Factor Xa- less sensitive as only interacts via AT III
- Also acts on some other activated clotting factors
- Not absorbed through GIT due to charge and large size→ Given IV or SC
- Activated partial thromboplastin time or other clotting test used to adjust dose
- Fibrin- bound thrombin less inactivated than circulating tthombin
- Higher concentration needed to treat than to prevent thrombosis
- Major bleeding occurs in 6% of patients even with monitoring→ Higher risk with aspirin, hepatic dysfunction and renal failure
32
INJECTABLE ANTICOAGULANTS: Low Molecular Weight Heparins
- LMWHs (dalteparin, enoxaparin) - longer acting heparin fragments
- Smaller than UFH
- Longer half life, dosing less frequent
- Increase action of AT III to inhibit factor Xa but not its action on thrombin (IIa)
- Given SC and have longer elimination times than UFH, effects are more predictable
- Similar risk of major bleed
- Renally excreted→ UFH preferred in renal failure
33
ORAL ANTICOAGULANTS: WARFARIN
- Main Vit K antagonist
- Impairs utilisation of Vit K → reduces synthesis of clotting factors and anticoagulant proteins C and S
- Absorbed rapidly and completely from gut
- With small distribution volume, being strongly bound to albumin
- Teratogenic → causes intracranial bleed in baby during delivery
34
PLATELETS: OVERVIEW
- Are not true cells but fragments of megakaryocytes
- Are non nucleated and have a 10 day lifespan
- Are light and tend to flow near vessel wall in circulating blood
- Adhere to damaged vessels, change shape, secrete granule contents, acidic phospholipid on surface is exposed
35
PLATELET ADHESION
- Adhesion following vascular damage via von Willebrand factor
36
PLATELET ACTIVATION
- Secretion of granule contents
- Release of labile mediators
- Aggregation
- Fibrinogen binding
37
ANTIPLATELET DRUGS
- Healthy vascular endothelium prevents platelet adhesion
- Platelets adhere to diseased/ damaged areas
- Aggregation entails fibrinogen binding to GPIIb/ IIIa receptors on adjacent platelets
- Cyclooxygenase (COX) catalyses production of
- Prostacyclin (PGI2) in endothelial cells (vasodilation and platelet aggregation inhibitor)
- Thromboxane A2 (TXA2) in platelets (vasoconstriction and platelet aggregator)
38
ASPIRIN
- Low dose in chronic use inhibits TXA2 synthesis
300mg single dose, then 75mg OD once sufficient to inhibit COX irreversibly
- Platelets cannot regenerate COX-I (no nuclei)
- Endothelial cells can regenerate
- Therefore overall aspirin decreases thrombosis
- Side effects→ GIT bleeding, exacerbation of renal failure, allergy, gout
39
Clopidogrel
- Blocks ADP- induced platelet aggregation by irreversibly blocking P2Y12 receptors
- Platelets are affected for their lifespan (7-10 days)
- Used in patients who cannot tolerate aspirin for prevention of stroke/ MI and in combination with aspirin for MI, unstable angina
40
Platelet glycoprotein IIb/ IIIa receptor antagonists
- Antagonists of GPIIb/ IIIa receptor on the surface of platelets
- Prevent binding of fibrinogen and other adhesive molecules and blocks platelet aggregation
- Adjuncts to heparin and aspirin for angioplasty and stenting
- All require dosage adjustment in renal dysfunction/ failure
41
Dipyridamole
- Coronary vasodilator→ causes vascular smooth muscle relaxation
- Inhibits platelet aggregation by several mechanisms:
- Inhibiting cGMP phosphodiesterases
- Inhibition of TXA2 synthesis (a vasoconstrictor and platelet aggregator)
- Used in combination with aspirin for secondary prevention of transient ischaemic attacks (mini stroke) and ischemic stroke
42
CLINICAL USES OF ANTIPLATELET DRUGS
- Mainly relate to arterial thrombosis
- Acute myocardial infarction (MI)
- High risk of MI (history, angina or claudication )
- Following coronary bypass grafting
- Unstable coronary syndromes (clopidogrel and aspirin)
- Following coronary artery angioplasty or stenting
- Transient ischaemic attack (mini strokes) or thrombotic stroke to prevent recurrence
- Atrial fibrillation, if oral anticoagulant is contraindicated
43
FIBRINOLYSIS (THROMBOLYSIS)
- When coagulation system is activated, fibrinolytic system is also activated via endogenous plasminogen activators
- Plasminogen activators are serine proteases that cleave plasminogen and release plasmin
- Plasmin then cleaves fibrin in thrombus to release fibrin degradation products
- Any plasmin that escapes into the circulation are inactivated by plasmin inhibitors
44
FIBRINOLYTIC DRUGS: STREPTOKINASE
- Converts plasminogen to plasmin which breaks fibrin threads
- IV infusion within 12 hrs reduces mortality in MI
- Action blocked within 3-4 days due to antibodies; can’t give repeatedly → at least 1 year must past before can be used again
- Allergic reactions, fever, chills, bronchospasm, anaphylaxis and hypotension
45
FIBRINOLYTIC DRUGS: ALTEPLASE, TENECTEPLASE, RETEPLASE
- Recombinant tissue plasminogen activators (tPAs)
- Activates thrombus plasminogen in preference to circulating plasminogen - ‘clot selective’
- Recombinant tPA is not antigenic and can be used in patients with streptokinase antibodies
