Renal Pharmacology (Jarir Atthobari) - Regular Class - Block 1.4 - Feb 2009

8/20/2019 Renal Pharmacology (Jarir Atthobari) - Regular Class - Block 1.4 - Feb 2009

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Basic Renal Pharmacology

Jarir AtthobariDept. Pharmacology and ToxicologyFaculty of Medicine !ad"ah Mada

#ni$ersity

%ogya&arta


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Kidneys:♦ Represent 0.5% of total body

weight, but receive ~25% of thetotal arterial blood puped by theheart

♦ !ach contains fro one to twoillion nephron:

' "he gloerulus

' "he pro#ial convoluted

tubule' "he loop of $enle

' "he distal convolutedtubule

Renal haracology


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&oral Kidney 'unction

(. !#tra )ellular 'luid *olue control

2. !lectrolyte balance

+. aste product e#cretion

-. rug and horoneeliination/etabolis

5. lood pressure regulation

1. Regulation of heatocrit

. regulation of calciu/phosphatebalance 3vitain + etabolis4


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loerular'iltration

"ubulus 6ecretion

Renal process

"ubular Reabsorption

7n 2- hours the 8idneys reclai:

' ~ (,+00 g of &a)l

' ~ -00 g &a$)9+

' ~ (0 g glucose

' alost all of the (0 ; of water that entered the


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Renal haracology

♦ lood enters the gloerulusunder pressure

♦ "his causes water, sallolecules 3but not acro

olecules li8e proteins4 andions to =lter through thecapillary walls into theowan>s capsule

♦

"his ?uid is called nephric =ltrate ' &ot uch di@erent fro interstitial ?uid

♦ &ephric =ltrate collects within the owan>s capsuleand ?ows into the pro#ial tubule


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lasa =ltrate is coposed of

?uids and soluble constituents

'R

'R rate A (20 l/in

6ubstances norally not =ltered included cell,plasa proteins or substances bound to the,lipids and another acroolecules


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Renal Pharmacology

♦ 7n pro#ial tubule, all of theglucose and aino acids, BC0%of the uric acid, and ~10% ofinorganic salts are reabsorbed

by active transport 3D"4' D" of &aE out of the pro#ial

tubule is controlled byangiotensin 77.

♦ Ds these solutes are reoved fro the nephric =ltrate,a large volue of the water follows the by ososis:

' 0F5% of the (0 liters deposited in the owan>scapsules in 2- hours


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Renal haracology

♦ Ds the ?uid ?ows into thedescending segent of theloop of $enle, water continuesto leave by ososis because

the interstitial ?uid is veryhypertonic:

' "his is caused by the active transport of &aE out of the tubular ?uid as it oves up theascending segent of the loop of $enle

♦ 7n the distal tubules, ore sodiu is reclaied byactive transport, and still ore water follows byososis.


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rug enter to body


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rugs e#cretion

7portant in deterining both the durationof drug action and rate of drug eliination.

D process whereby drugs are transferredfro the internal to the e#ternalenvironent 38idney, lungs, biliary systeand 74

Kidney is the priary organ for drugse#cretion, especially for those that arewater soluble and not volatile


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,hemically unchanged ormetabolite

,hemically unchanged ormetabolite

*ascular wall structure gloerularcapillaries

*ascular wall structure gloerularcapillaries

rugs


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loerular'iltration

assive "ubularreabsorption

Renal !#cretion

Dctive tubularsecretion


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concentration drug

in tubule

Glomerular filtration

of drug

primary urine

final urine

loerular =ltration


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loerular =ltration

Restricting to copounds having relativelylarge


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&eonates&eonates

7n?aation7n?aation

!lderly!lderly

'actors that a@ect 'Ralso can in?uence the rate of drug clearance

rug )learance

9rganic disease9rganic disease

)ongestive $eart 'ailure)ongestive $eart 'ailure

DntihypertensiveDntihypertensive


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Dctive tubular secretion

ro#ial "ubular 6ecretion

!pithelia pro#ial

tubules into tubular?uid via energyJconsuing transportsyste liitedcapacity

hen severalsubstrates presentsiultaneously

copetition for carrier


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ro#ial renal tubule

♦ )arrierJediated tubular secretion adddrug to the tubular ?uid.' "ransporters 3Jglycoprotein4 glucuronides,

sulfates, and glutathione adducts4

' Ddenosine triphosphate 3D"4Jbinding cassette3D)4 transporters selective for organiccationic drugs

♦


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concentration drug

in tubule

Glomerular filtration

of drug

primary urine

final urine


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istal "ubular Reabsorption

assive di@usion

Reabsorption dependentupon urinary p$ or degree

of dissociation 3pKa4

Raising or lowering p$ and

pKa will in?uencedreabsorption. ;ower p$ andpKa ore drug will be reJabsorb


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"his plot of cuulative e#cretion of drug in urine vs.tie deonstrates the a wea8 base of drug

3barbiturate4

T-M

Acidic urine

Al&alineurine

/drugsexcreted


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$ydrophilic vs. ;ipophilic

( ) * +

0ydrophilicdrug

1ipophilicdrug

2lo3 metabolism

1ipophilicdrug

4o metabolism

1ipophilicdrug

Rapid metabolis


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(. opaine F stiulates alpha, beta and dopainereceptors and increases renal blood ?owincreases gloerular =ltration rate ain e@ect is to

increase renal blood ?ow increases &aE e#cretion

2. rostaglandins F !2 and 72 increase renal blood?ow, proote diuresis and natriuresis. )oplications ofprostaglandin inhibition with nonJsteroidal antiJ

in?aatory drugs: acute renal failure, hyper8aleia.

+. Kinins F 3rady8inin4 potent vasodilator, ay prooteprostaglandin synthesis and nitric o#ide release.7ncreases c


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(. "hrobo#ane D2 F 'ored in the 8idney during

pathophysiologic conditions 3e.g., obstruction ofa ureter4. !2 and 72 are released tocounteract the vasoconstriction.

2. &orepinephrine.

+. Dngiotensin 77 J potent vasoconstrictor.

!ndogenous substances in the

8idney 3vasoconstrictor4


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iuretics

♦ ;oop

♦ "hiaHide

♦

Dldosterone antagonist♦ 9sotic


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Tubule transport systems and sites of action of diuretics


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Renal haracologyiuretics:

;oop diuretics 3A high ceiling diuretics4:' 6trong, but brief diuresis 3within ( hr, lasts ~ -hrs4

' Lsed for oderate to severe ?uid retention and hypertension

'


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Renal haracology

iuretics:)arbonic anhydrase inhibitors:♦ DHetaHolaide

' )an trigger etabolic acidosis

' &ot in use as diuretic anyore' riary indications is glaucoa

3prevents production of aeIuous

' huor4

orHolaide

)DJinhibitors are sulfonaides ABcrossJallergenic with antibiotics etc.


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Renal haracology


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Renal haracologyiuretics:

otassiuJsparing diuretics:' Dct on the distal portion of the distal tube 3where &aE is e#changed for

K E4

' Dldosterone prootes reabsorption of &aE in e#change for K E 3transcriptionally upregulates the &aE/K E pup and sodiu channels4

♦ 6pironolactone

' Dldosterone receptor antagonist

' 9nset of action reIuires several days

♦ Diloride "riterene

' loc8 sodiu channels

' Ouic8 onset

Aldosterone Spironolactone


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Renal haracology

iuretics:

9sotic diuretics:' 6all, nonJreabsorbable olecules that inhibit passive

reabsorption of water

' redoinantly increase water e#cretion withoutsigni=cantly increasing &aE e#cretion AB liited use

' Lsed to prevent renal failure, reduction of intracranialpressure3does not cross bloodJbrain barrier AB water is pulled out of

the brain into the blood4

♦


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A Schematic Portrayal of the Three Major Physiological Pathways Regulating Renin Release.


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"he rate of urinary drug e#cretion will dependon the drugPs volue distribution, its degreeprotein binding and the following renalcondition:

"he rate of urinary drug e#cretion will dependon the drugPs volue distribution, its degreeprotein binding and the following renalcondition:

)linical 7plication of renal e#cretion

loerular =ltration rateloerular =ltration rate

"ubular ?uid p$ "ubular ?uid p$

!#tent of bac8Jdi@usion of the unioniHed for!#tent of bac8Jdi@usion of the unioniHed for

!#tent of active tubular secretion of copound!#tent of active tubular secretion of copound

ossibly, e#tent of active tubular reabsorptionossibly, e#tent of active tubular reabsorption


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Renal Pharmacology (Jarir Atthobari) - Regular Class - Block 1.4 - Feb 2009

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Transcript of Renal Pharmacology (Jarir Atthobari) - Regular Class - Block 1.4 - Feb 2009