Nephrology – Hypertension Division ofInternal Medicine Medical Faculty

Sebelas Maret University of Surakarta

HipertensiHipertensi

Prof. Dr. HM.Bambang Purwanto, dr. SpPD-KGH, FINASIM

PENDAHULUAN

Faktor risiko mayor :

Coronary Heart Disease (CHD)

Myocard Infarct (MI)

Cerebrovascular Accidents (CVA)

Chronic Kidney Diseases (CKD)

Congestive Heart Failure (CHF)

Risiko menjadi hipertensi > 90%

Reappraisal of European Guidelines on Hypertension Management: A European Society of Hypertension Task Force Document, Blood Pressure. 2009; 18: 308–347

KLASIFIKASI

JNC 7 Report 2003

WHO/ISH Statement on Management of Hypertension 2003

ESH/ESC Guidelines for the Management of Arterial Hypertension 2007

Primer: Belum diketahui (mis:genetik)

Sekunder :RenalAdrenalFaktor Biologi lainEksogen

ETIOLOGI

Hypertension and Chronic Renal Disease: Hemodynamic Abnormalities

Mean BPTotal Systemic

Vascular Resistance= X

Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity

Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity

IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane

IncreasedVasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane

CardiacOutput

DecreasedVasodilation Prostacyclin Nitric oxide EDHF*

DecreasedVasodilation Prostacyclin Nitric oxide EDHF*

Textor SC. Atlas of Diseases of the Kidney, 2001.

*Endothelium-derived Hyperpolarizing Factors

Hypertension ; basic mechanism..

Serangan Stroke

Penyakit Arteri

Gangguan pada Jantung Gangguang Fungsi Ginjal

Hipertensi kronisHipertensi kronis

Merusak autoregulasi ginjalMerusak autoregulasi ginjal

Permeabilitas kapiler Permeabilitas kapiler ↑↑

Proteinuri (miProteinuri (mikkroalbuminuri)roalbuminuri)

Hukum HomeostasisHukum Homeostasis

Reabsorbsi protein Reabsorbsi protein oleh sel tubulus berlebihanoleh sel tubulus berlebihan

(stressor)(stressor)

Ekspresi sitokin :Ekspresi sitokin :- TNFαTNFα Apoptosis, nekrosis Apoptosis, nekrosis- IL1βIL1β Plag Plag Ateroskleroris Ateroskleroris- TGFβ1TGFβ1FibrosisFibrosis

Patogenesis Komplikasi Hipertensi pada GinjalPatogenesis Komplikasi Hipertensi pada Ginjal

Robbin, 2005

Chronic Chronic hypertensionhypertensionEndothelial Endothelial

StressorStressorExpressioExpressionn TNFTNFαα IL1IL1ββ TGFTGFββ11

ApoptosisApoptosis PlaquePlaque FibrosisFibrosisNecrosisNecrosis

AtherosclerosisAtherosclerosis

Renal Renal FailureFailure

Coronary Coronary Heart DiseaseHeart Disease

CerebralCerebral- StrokeStroke- DementiaDementia- Parkinson Parkinson

Hypertension Complication PathogenesisHypertension Complication Pathogenesis

Robbin, 2008

IL6IL6

HCRPHCRP

TNF αα

Hypotalamus

PG2

+ ILIAspirin

FEVER

(Endogenic Pyrogen)

Hepatosit

↑ Syntase

Coagulation↑

Strong Activation

Chachexia

Serum Amyloid

Fibrinogen

CRP

↓ Contraction• Vascular smooth muscle cells• Heart

Vasodilatation

Shock

Fat Cells

PermeabilityExudation

Inflammation cells

Congestion

↓

Endhotel• ↑ Tissue Factor

• ↓ Trombo Modulin

• Shringking

Protealitic

Membrane Receptor DisruptionEritropoietin Receptor Disruption

Anemia

• Vasopressor receptors• Proteolitic

(Brata Widjaya, 2009; Bambang P, 2010)

ILI

IL6

KAKHEKTIN ↓ Appetite CHACECTIC (THIN)

Disfungsi EndothelDisfungsi Endothel

oxLDLoxLDL

HipertensiHipertensi Angiotensin IIAngiotensin II MerokokMerokok

HomoHomosisisteinstein

DiabetesDiabetes

(Bambang P; Prevent Vascular Damage 2013)

-Anti Oksidan

-Bradikinin

Stres Oksidatif

RESIKO KARDIOVASKULER DAN RESIKO KARDIOVASKULER DAN DISFUNGSI ENDOTHELDISFUNGSI ENDOTHEL

NatriumNatrium

ENZIM NADPH OKSIDASE

TNF-TNF-

AterosklerosisAterosklerosis

EndothelinEndothelin

PDGFPDGF

Result of All Risk Factors in Kidney Disease

Age Family HistoryGender Diabetes

Uremia-related 10 – 20 x Morbiditas / Mortalitas

Hypertensio Smoking High oxidant stressDyslipidemia Inflamation

Non-modifiable

Modifiable

Anemia ↑ ET↑PTH ↑ CRP↑ PO4 ROS↓GFR - AGEP↑ ADMA - AOPP - Homosistein

Uremia-related

LVH

CHF

PVD CAD

MI

(Bambang P; Prevent Vascular Damage 2013)

L-ArginineL-Arginine

NO SynthaseNO Synthase

NONO + + CitrullineCitrulline

ADMAADMAAsymetric DimethylAsymetric Dimethyl

ArginineArginine

CitrullineCitrulline

Renal excretionRenal excretion

DDAHDDAHDimethylaminoDimethylamino

hydrolasehydrolase

OxidativeOxidativestressstress

JASN 15:S77, 2007JASN 15:S77, 2007

Angiotensin II plays a central role in atherosclerosis

Schmieder et al. Lancet 2007;369:1208–19

Angiotensin II

Vascular permeability , leukocyte infiltration

Activation of signalling pathways

Proliferation of vascular smooth muscle cells (VSMCs)

Matrix deposition

Platelet aggregation Matrix metalloproteinase (MMP) activation

Inflammatory mediators• Adhesion molecules (VCAM-1, ICAM-1...)• Chemokines (MCP-1, interleukin 8…)• Cytokines (interleukin 1 & 6, TNFα)• Growth factors

Activation of plasminogenactivator inhibitor type-1 (PAI-1)

NAD(P)H oxidase activity

Reactive oxygen species

Nitric oxide

Vasoconstriction

LDL peroxidation, LOX-1

Oxidative stress Inflammation

Endothelial dysfunction Tissue remodelling

(Weiss et al., 2013; Obasi et al., 2012)

Merusak Gliko Protein & Nephrin

APOPTOSISENDOTEL

Merusak IKB

Albuminuri ↑ Sitokin Pro Inflamasi (TNF-, IL-1, IL-6)

↑ NFKB

ATEROSKLEROSIS

STROKE KORONER PGK

PGK

ROS AgepAOPPHomosistein

(Bambang P, 2012)

Makrofag

SKEMA PENGARUH STRES OKSIDATIF (ROS) PADA PGK YANG BERAKIBAT PROGRESIFITAS ATEROSKLEROSIS

Angiotensin II

Endotelin

Vasokonstriksi

Iskemi

Defisiensi Aerob Metabolik

Gangguan pompa Na

Retensi Na

Retensi Air Intra Sel

Udem Intra Sel

Sel pecah / Onkosis

Robbin, 2007

The renin system plays a central role inregulation of BP

Juxtaglomerular cells

Glomerulus

Renin is releasedinto the vasculature

Renin secretion is regulated by 4 mechanisms

Distal tubule

Pressure in theafferent arteriole

1

Renin secretion is regulated by 4 mechanisms

Na+ at the macula densa

Distal tubule

3

Renin secretion is regulated by 4 mechanisms

Negative feedback by Ang IIDistal tubule

4

Renin Angiotensin Renin Angiotensin System System (1)(1)

Classical "circulating" system (RAS):

Angiotensin II

Angiotensin I

Angiotensinogen

Aldosterone

Na+-retentionK+-loss

glomerular zone

ACE

Renin

Blood pressure Na+

Sympathetic system

Renin

maculadensa

adrenalglands

Adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)

t-PA = tissue plasminogen activatorCAGE = chymostatin-sensitive angiotensin generating enzyme

Local "tissue-bound" system (RAS):

AT1 AT2

Bradykinin

inactive fragments

B2B1

Angiotensin II

Angiotensin I

Angiotensinogen

ACE

Renin

specific cellular response

ChymasesCathepsin G

CAGE

t-PACathepsin G

Tonin

specific cellular response

Adapt. from Dominiak & Unger (eds.) in Ang II-AT1-Receptor Antagonists, Steinkopff (1997)

Renin Angiotensin Renin Angiotensin System System (2)(2)

Distribution of ACE:

Mod. from Dzau V, Arch Intern Med 153 (1993)

Renin Angiotensin Renin Angiotensin System System (3)(3)

R A S 10%10%

Acute and short-term effectscardiovascular/

renal homeostasis

Long-term effectslocal "organ adaptation"

90%90%

Circulating (Plasma) Local (Tissue)

PROTECTIONPROTECTION

1. Monitoring tekanan darah & faktor resiko

2. Managemen pola hidup

3. Farmakologi

Pengelolaan Hipertensi

Baseline tekanan darah diukur periodik pada semua dewasa muda, lebih intensif pada pasien dengan :

1.Sudah/baru terdeteksi hipertensi2.Punya kerusakan target kardiovaskular 3.Punya faktor resiko lainnya4.Dalam terapi hipertensi

Monitoring tekanan darah & faktor resiko

1. Tidak Merokok –sama sekali, hindari secondhand smoke

2. Aktivitas Fisik –4-7x/mg, 30-60mnt, skala sedang, dinamik

3. Pengurangan Berat Badan –BMI normal, LP <90cm / 80cm

4. Rekomendasi Diet –tinggi serat/sayuran, rendah lemak/kolest

5. Asupan Garam –garam (NaCl)<5,8gr/hr. Natrium<2,3gr/hr.

6. Konsumsi Alkohol –sama sekali atau 0-2 minuman standar

7. Manajemen Stres –modifikasi perilaku dan relaksasi

Managemen Pola Hidup

KONDISI TEKANAN DARAH

Hipertensi Sistolik/Diastolik ≥ 140/90

Diabetes ≥ 130/90

CKD ≥ 130/90

Proteinuria > 1gram/24jam ≥ 125/75

Target Terapi

The Canadian Hypertension Education Program (CHEP) Guidelines, 2009

Diuretik

Short acting

Furosemid (lasix)2

chlorothiazide(Diuril)3

Intermediate

Hidroclrotiazide(Apo-Hydro, AquazideH,Dichlotride, Hydrodiuril, HydroSaluric, Hydrochlorot, Microzide, Esidrex, and Oretic)4

Benzthiazide (Aquatag, Dihydrex, Diucen, Edemax, Exna, Foven )4

Long Acting

Chlorthalidone(Hygroton, Tenoretic)3

Hidroflumetazid (Saluron)4

Bendrofluazide(aprinox)4

Clopamide (aquex)4

Polythiazide(Renese)4

Spironolacton (Aldactone, Novo-Spiroton, Aldactazide, Spiractin, Spirotone, Verospiron or Berlactone)5

Acetazolamide (Diamox)6

Obat-Obat Beta Blocker1

1. Selektif dan Non Selektif

a. Selektif: b. Non Selektif

- Asebutolol - Propanolol

- Metoprolol - Timolol

- Atenolol - Nadolol

- Bisoprolol - Sotalol

- Pindolol

- Oksprenolol

- Alprenolol

- Labetalol*

2. Hidrofilik dan Lipofilik

a. Hidrofilik c. Hidrofilik dan LIpofilik

- Sotalol - Oksprenolol

- Nadolol - Labetalol*

- Atenolol - Metoprolol

b. Lipofilik - Timolol

- Propanolol - Bisoprolol

- Alprenolol - Asebutolol

- Pindolol

3. ISA(Intrinsic Sympatomimetic Activity) dan Non ISA

(Non Intrinsic Sympatomimetic Activity)

- ISA:

- Pindolol

- Oksprenolol

- Alprenolol

- Asebutolol

- Labetalol**

- Non ISA:

- Metoprolol

- Atenolol

- Bisoprolol

- Propanolol

- Timolol

- Nadolol

- Sotalol

Caantagonis1

1. Long Acting:

Amlodipin(Norvasc)

Felodipin(Plendil)

Short Acting:

Dehidropiridin:

Nifedipin (Adalat)

Non Dehidroperidin

Diltiazem(Cardizem)

Verapamil(Calan, Isoptin)

1. Pencegahan hipertensi harus sedini mungkin (pre-hipertensi)

2. Pengelolaan hipertensi harus diwaspadai faktor resiko yg lain (sindrom metabolik)

3. Program non-drug treatment wajib dijalankan penderita

4. Patogenesis hipertensi harus dipelajari dengan baik dalam rangka :

a. Memilih obat yang tepat

b. Memilih kombinasi obat

c. Meminimalkan efek samping

5. Target penurunan tensi sedapat mungkin mendekati ideal (harus bertahap)

6. Pengelolaan krisis hipertensi harus memilih obat yg tepat, target penurunan tensi sesuai protokol (supaya reversibel)

KESIMPULAN

Terima kasih