Renal pharmacology Lec: 11 - PowerPoint Presentation

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Renal pharmacology

Lec: 11

Diuretics

Mohammed Al-Manna

Doctor of pharmacology and therapeutics

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Filtration rate = GFR

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Edema

Edema

is movement of fluid from vascular compartment into

interstitial space.

Edema is normal response of the body to injury or inflammation .Ex: twisted ankle , bee sting , skin infection , and in some cases of renal cardiac , and liver diseases..

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Mechanism of Edema

Increased

vascular hydrostatic pressure

.

Reduced plasma oncotic pressure.Increased blood vessels

permeability

, ( caused by infection or inflammation for example).

Obstruction of fluid clearance

in the lymphatic system, for example after mastectomy usually the surgeon remove axillary lymph nodes or due to post surgical complication such as injection , cannula , tight cloths on the hand besides the breast removed.

Sodium & H2O retention :

Low cardiac output

or

Hypovolemia

→

renin secretion →Aldosterone →

Na &H2O retention → Edema

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Classification

Edema can be classified as :

Generalized edema:

in which fluid retention occur in various body parts including abdomen , arms , legs , face and feet.

Causes : -Congestive heart failure -Nephrotic syndrome

-Liver cirrhosis

2) Localized edema :

in which fluid retention occur in part or organ of the body

Causes:

Trauma

Infection

Lymphatic obstruction (radical mastectomy or

filariasis

Venous obstruction ( deep venous thrombosis)

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Filariasis

Feature of DVT :

1)swelling

in

foot

, ankle, or leg, usually on one side

2)cramping

pain in

affected

leg

(

Humans test

)

https://

youtube.com/watch?v=1Aph5Uyr-VE&feature=share

3)skin warmer

than the skin on the surrounding areas4)skin over the affected area turning pale or a reddish or bluish colorComplication : pul embolism

DVT

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DDX

Edema can also be classified as pitting or non-pitting

1) Pitting edema :

after pressure is applied to a small area , the indentation persists after the release of the pressure.

Causes

Systemic diseases ( liver , heart , renal )

Pregnancy

2)Non –pitting edema

Is observed when the indentation does not persist

Causes :

Lymphedema , myxedema (

face edema and leg thickening &edema due to hypothyroidism

) , inflammatory edema, drugs induced

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Myxedema

Hypothyroidism

(underactive thyroid) is a condition in which

thyroid

gland doesn't produce enough

thyroxine

Hypothyroidism

asymptomatic

in the early stages. Over time, untreated hypothyroidism can cause a number of health problems, such as obesity, joint

pain

,

infertility and

bradycardia.

Thyroid

function

tests showed increased TSH and decreased T3&T4 Treatment : Thyroxine tab.

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Slide11

Myxedema

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Symptoms of Graves, disease

Graves disease is most common cause of hyperthyroidism ( 80%) .

It is autoimmune disease , causes production of antibodies against ( TSI , thyroid stimulating immunoglobulin) TSH receptor .

TSI effects:

Thyroid stimulation causes thyroid hypertrophy and hyperplasia with diffuse goiter.

Increase syntheses and release of T3 and T4 { tachycardia , arrhythmia , headache , heat intolerance ,

wt

loss , nervousness , tremor and sweating)

Stimulation of fibroblasts in eye orbit causes increased production of glycosaminoglycan that leads to local inflammation , swelling and exophthalmos and lid retraction.

Diagnosis :

Decreased TSH

Increased T3 , T4 , TSI

Treatment :

anti-thyroids ( carbimazole ) + beta blockers

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Types

of Edema

Peripheral edema:

most common type of edema

Occur in the legs , feet and ankles.

Causes :

pregnancy , heart failure , renal , drugs induced , prolonged standing

Note : drugs induced edema:

1- Calcium channel blockers such as

Nifedipine

or

amlodipine

causes bilateral leg edema

2-Corticosteroids ( facial edema)

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b) Pulmonary edema

Is accumulation of fluid in the lungs due to blockage of the pulmonary vein .

So as blood pressure rises in the blood vessels of the lungs , fluids rush in to fill the lungs.

Plural cavity can also be filled with fluid . In such cases , the pulmonary edema is said to also present with pleural effusion.

Clinical features -Breathing difficulties , and it’s

worse when patient lie down

.

-Patient

have tachycardia

and tachypnea

-feel

suffocated,

-cough

up a foamy spittle, sometimes with blood.

Causes of pul edema

Left ventricular failure ( increased pul. vein pressure which causes increased hydrostatic pressure)

Acute respiratory distress syndrome

High altitude

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c. Cerebral edema

Fluids accumulation in the intracellular and extracellular spaces of the brain

Caused by

Metabolic abnormalities ( high altitudes)Head traumaBrain tumor

Hyponatremia

Carbon monoxide poisoning

Treatment

Dexamethasone amp

+

mannitol

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Causes of generalized edema

1) Edema in heart failure:

In heart failure , blood supply to kidney will be reduced leading to compensatory mechanism of activation

renin angiotensin aldosterone system

; aldosterone causes sodium water retention leading to edema .2) Edema in

liver

cirrhosis :

A.

In

liver disease albumin will be reduced so that oncotic pressure will be decreased that leads to edema

B.

Also

in liver cirrhosis , portal hypertension will occur this leads increased intravascular hydrostatic pressure that causes tissue edema

.

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3

) Edema in Nephrotic syndrome

Physiology :

Renal

glomeruli normally permits water and electrolyte filtration while albumin is large molecules so that it will be retained in

the blood

(normally loss only 150mg /day)

.

I

n

nephrotic diseases the basement glomerular membrane damaged that

increases

size of pores that leading to loss albumin in urine

; 3.5g in urine /day is lost

this

leads to reduce oncotic pressure that causes shift of fluid from blood into interstial leading to edema .

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Treatment of edema

Localized type :

treated the underlying cause

Generalized type

: diuretics + Rx underlying causeHowever non-pharmacological

Movement.

 Moving

in

the part of

body

affected by edema, especially legs,.

Elevation. 

Hold the swollen part of

body

above the level of

heart

several times a day. Massage. Stroking the affected area toward heart using firm, but not painful, pressure may help move the excess fluid out of that area.Compression. If one of limbs is affected by edema, wearing compression stockings is very useful.Reduce salt intake. 

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Diuretics

Aldosterone

Vasopressin

There is no drug act on PCT

Uric acid

Urea NH3 excretion

Also

Ca

Mg

H

Also

H

K

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Introduction

In proximal convoluted tubules reabsorption of 65-70% of each of sodium and H2O , amino acid , k+.

Also uric acid and other acid are secreted through acid transporter system in PCT , when we give acidic drugs this will compete with uric acid , so that uric acid will be retained causing hyperurecimia

.

Remaining fluid volume transported through loop of Henle and when reach upper ascending part about 25% reabsorbed of sodium , k , cl and water and also majority of calcium and Mg

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Cont..

The remaining fluid go to distal convoluted (DCT) tubules ,

where sodium

and H2O reabsorbed

by 5%On the other hand calcium will also absorbed in DCT by parathyroid hormoneOn collecting duct about 2% of sodium and water reabsorbed by affect of aldosterone in replacing with

H+

and

K+

.

In the lower part of collecting

duct

water are

reabsorbed by the effect of vasopressin that act on v2 receptor

.

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Diuretics

Diuretic :

drugs that increased urine volume.

Natriuretic :

drugs that increased sodium secretion.Renal diuretic: carbonic anhydrase inhibitor, loop diuretic , thiazide , k sparing diuretic , osmotic diuretic

Extra renal diuretic:

Ex 1:

drugs causes diuresis but not act on kidney such as

digoxin

( used in HF treatment that increased cop leading to increase blood supply to kidney so less renin is secreted with subsequent less edema) .

Ex2:

in liver failure albumin decreases and oncotic pressure also decreases causes edema , so by give

albumin

IV twice weekly leading to increased oncotic pressure causes return of fluid to plasma and then to excreted by kidney .

Ex 3:

high

intake water

causes leading to decrease blood osmolality so this will inhibits central antidiuretic hormone (vasopressin ) so diuresis occur.

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1) Carbonic anhydrase inhibitors

Acetazolamide

and

dorzolamide

MOA: Act on PCT to inhibit reabsorption of bicarbonate leading to urinary alkalosis ( metabolic acidosis) and in turn water exist with bicarbonate.These drugs not used nowadays as diuretic ?because it causes metabolic acidosis and also undergoes intolerance and adaptation (self limiting effect 2-3days ).

Uses

Glaucoma :

carbonic anhydrase in ciliary body responsible for aqueous humor formation

So these drugs decreases IOP (used as eye drops in glaucoma )

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Carbonic anhydrase inhibitors

2) Mountain sickness (high altitudes)

At 2000m the

O

2 tension is decreased so the person undergo nausea and acute mountain sickness ; at this case CO2 expel outside lung causing metabolic alkalosis that may causes cerebral or pul edema .

So

acetazolamide

taken orally before climbing that causes metabolic acidosis and prevent cerebral and pul edema

Dose : start

24-48 hours before ascent and continue for 48 hours at high altitude or

longer.

3) Alkalization of urine

to dissolving

uric acid

and

cystine

renal stones4) Treatment of metabolic alkalosis associated with excessive use of loop diuretics in heart failure5) Catamenial epilepsy

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Calcium phosphate stones

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Loop diuretics

2

Also loop diuretics increase systemic PGE2 &PGI2 leading to vasodilator action

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Side effect

Loop diuretics are

High

celling

diuretics

;

act even GFR reach 10ml/min (end stage renal failure)

Reduces preload and afterload

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Side effects of loop diuretics

Hypovolemia

and

hypotension

Hypokalemia and arrhythmia Hypocalcaemia

Hypomagnesemia

5)Metabolic alkalosis

6)Ototoxicity (

Inner

ear contain same

receptor Na/k/cl

transporter so it is effected by loop diuretic

(

vasoconstriction

) causes ototoxicity (tinnitus

,

hearing

loss )7) Hyperuricemia ( in PCT loop diuretic are acidic cpd that compete with uric acid on transporter of uric acid so this leads to increase uric acid reabsorption) 8) Hyperglycemia ( diuretic decreases insulin release due to hypokalemia ; hypokalemia inhibits

insulin release Also glucose inter cells by glut4 , this transporter dependent on k9) Sulfa allergic reaction

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Drug- interactions

Concomitant use with aminoglycoside antibiotics or cisplatin , increases the risk of nephrotoxicity and ototoxicity.

Concomitant use with NSAIDs , decreases the diuretic action

Audio graph

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3) Thiazide diuretics

Hydrochlorothiazide , chlorthalidone ,

indapmide

Low celling diuretic loss efficacy in renal failure

Onset of action 1-2 hrs.

MOA

:

inhibit

Na /

Cl

transporter on distal convoluted tubules , leading

to loss 5% of

Na

,

H2o

,

Cl , K, H+Also these drugs stimulate Ca reabsorption under control of parathyroid hormone Thiazide action 1)Deceases blood pressure by decreases blood volume

2) Direct vasodilator effect3) Calcium reabsorption

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Indication of thiazide

Hypertension (

single drug or in combination

)

Chronic mild renal failure (not effective in severe renal failure)Congestive HF (

loop diuretic is preferable

)

Edema (

loop diuretic is preferable

)

Nephrogenic diabetes insipidus

Prevention of

ca

excretion in osteoporosis and calcium renal stone

Note :

thiazides are not effective in Rx pul. Edema.

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Side effects of thiazides

Hypovolemia

1)Hypovolemia and hypotension

2) Hyponatremia

3)Hypokalemia

4)Metabolic

alkalosis

5) hypercalcemia

6) Hyperuricemia(

in PCT

thiazides are

acidic cpd that compete with uric acid on transporter of uric acid so this leads to increase uric acid reabsorption

7) Hyperglycemia (

diuretic

decreases insulin release due to hypokalemia ; hypokalemia inhibits insulin release

Also glucose inter cells by

GLUT4 , this transporter dependent on k )8) Hyperlipidemia9) Sulfa allergic reaction

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Potassium sparing diuretics

Act on sodium channels on DCT (2% of Na & H2O)

and H

4

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Indication of K sparing diuretics

Weak diuretic action and delayed onset of action (

2days

)

Usually used in combination (to potentiate efficacy and avoid electrolytes disturbances).Congestive heart failure

Long term use of spironolactone can prevent myocardial hypertrophy and myocardial fibrosis (

prolongs survival

)

Hyperaldosteronism

(Conn's

disease)

Liver disease

(high aldosterone)

Spironolactone

antagonize testosterone receptor

(used in hairsuitism and alopecia androgenism in female)

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Side effect

Spironolactone causes gynectomastia in male

Hyperkalemia

Metabolic acidosis

Hyperammonemia ( in renal failure) Not effect on glucose , lipid , uric acid

Contraindication

Renal failure

NOT used with ACE inhibitors (captopril) to avoid exaggerated hyperkalemia

pregnancy

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5) Osmotic diuretic

Mannitol prototype (iv)

Others rarely used

isosorbide , glycerin (orally used)

Mannitol given iv increases osmotic pressure in blood so water from interstial shifted to mannitol .Also in kidney act to withdrawal waterUses (

Used in

emergency

)

Acute glaucoma (rare)

Cerebral edema

{

reduce brain volume by extracting water from tissue into the blood }

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Side effect of mannitol

Dehydration

On kidney it withdrawal water causing

dilutional

hypernatremia

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Clinical considerations of diuretics

Congestive heart failure:

Features of CHF:

Weak cardiac muscles

→ ↓

COP

HT (

↓

ed

COP →stimulate kidney to produces rennin that causes sodium –H2O retention)

Lung congestion ( by physical examination through stethoscope we heard crepitation ) , on x ray showed below:

Patients with CHF are usually uses digoxin

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Advantages

of diuretic in CHF:

Decreased preload and afterload with subsequent decrease cardiac work that improve contractility.

Decreased lung congestion with better oxygenation

Decreases BP

Spironolactone treats remodeling and so increase survival

Disadvantages

Diuretic causes hypokalemia or hyperkalemia , which may induced digoxin arrhythmia.

Diuretics may causes acid base disturbances which may induce digoxin arrhythmia

Patient with renal failure should not given

k sparing diuretic

(already hyperkalemic) and

carbonic anhydrase inhibitors

causes acidosis ( already acidotic) , also

thiazides

not preferred because it is not effective in renal failure and also may decreases blood flow

- Just loop diuretic can be used in renal failure.

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2

) Liver

diseases (Ascites

)

Features :

Edema

Hyperammonemia ( coma)

High aldosterone (liver cannot metabolize aldosterone)

Advantages of diuretic in liver diseases

-

Decrease edema and ascites

- Decreases sodium water retention

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Disadvantages of diuretic in liver diseases

-

Kidney resistant to loop and thiazide diuretic (low efficacy) so we should give high doses .

-

Normally ammonia (NH3 , Tertiary cpd) that when infiltrated from blood to renal tubules will bind with tubular H+ to forming NH4 (quaternary cpd ) that cannot be reabsorbed , so by this way the kidney remove ammonia ..

however by using

K sparing diuretic

withdrawals H+ from urine that leads to prevent formation NH4

so that ammonia will be reabsorbed into circulation that may precipitate hepatic encephalopathy ..

So we give combination of

loop diuretic

and

k sparing diuretic

and also give

lactulose syrup

that causes acidification of colon preventing reabsorption of ammonia from gut.

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