Losacar Co

CONTENT • INRODUCTION • BASICS OF HYPERTENSION • DIFFERENT GUIDELINES • LOSARTAN CO

INTRODUCTION

Introduction : What is Blood Pressure ?

Blood Pressure Classification

BP Classification SBP mmHg* DBP mmHg

Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 Hypertension 140-159 or 90-99

Stage 2 Hypertension ≥ 160 or ≥ 100

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

Hypertension even today is a triple paradox which is :

Easy to diagnose OFTEN remains undetected

Simple to treat OFTEN remains untreated

Despite availability of potent drugs, treatment all too OFTEN is ineffective

Hypertension

Hypertension In South Africa

• Around 25% of all men and 15% of adult women are thought to be suffering from hypertension

• Black hypertensive patients in South Africa are prone to cerebral haemorrhage, malignant hypertension, kidney disease leading to uraemia and congestive heart failure, whereas coronary heart disease (CHD) is relatively uncommon.

• In contrast, CHD is the major outcome related to hypertension in the white and Indian communities.

Factors for Hypertension in SA

1. Food : HIGH SALT INTAKE-High amount of salt used to preserve food

or to make food tastier .-Bread is staple food for many people in

SA containing high salt. -Low potassium intake due to less

consumption of Fruit - Average salt intake 7.8 gm by black ,8.5

gm by colored and 9.5 g in white South Africans

Factors for Hypertension in SA

2.Herediatary: -Risk of hypertension is higher in white & indian men

than coloured and African men- African women had lowest risk of hypertension

3. Genetic :-In European ancestry :ACE gene contributing in male &

angiotensinogen (AGT) gene contributing in female-In African 217G-AAGT variant gene contributing BP

-β2 receptor gene not associated with HTN in African ancestry

Hypertension is the Silent Killer

Heart AttackStroke

Kidney Failure

CRITICAL POINT for SA• Death risk increased by 60 % with increase in 20mmHg of diastolic BP in African population • The African Health Report 2007 deaths from CVD were 37% and 21% of years of life lost due

to premature death in SA

South Africans are different!!!!

• Black patients are poor responder to beta blocker & ACE inhibbitors

• Above agents are need to combined with a thiazide diuretic to increase efficiency*

* Krisela Steyn “ Hypertension in South Africa “Chronic Diseases of Lifestyle in South Africa since 1995 – 2005 ,chapter 8

BASICS OF HYPERTENSION

Heart

HR

Arteries

SVR

Veins

Stroke Volume

Physiologic Components of BP

Determinants of Blood Pressure

Mean Arterial Pressure = X Arteriolar

Diameter

BloodVolume

StrokeVolume

HeartRate

Filling PressureContractility

Blood Volume Venous Tone

CRITICAL POINT!Change any physical factors controlling

CO and/or TPR and MAP can be altered.

Algebra of Blood Pressure

BP = Cardiac Output x SVR

CO = HR x Stroke Volume

↓

BP = HR x Stroke Volume x SVR

General Treatment Strategy of Hypertension

1. Diagnosis- 3- 6 independent measurements.2. Determination of primary vs. secondary hypertension.3. If secondary, treat underlying pathology.

5. Pharmacological treatment by Anti hypertensive drugs

4. If primary, initiate lifestyle changessmoking cessationweight lossdietstress reductionless alcohol etc.

Classes of Antihypertensive Agents

1. ACE inhibbitor Captopril,ramipril ,lisinopril,enalpril,Perindopril,imidapril etc

2 . AT1 blocker (ARB) Losartan,candesartan,irbesartan,valsartan,telmesartan,olmesartan

3.Calcium channel blocker

Amlodipine ,Nifedipine ,verapamil,diltiazem,felodipine , etc

4. Diuretics Hydrochlorothiazide,Chlorthalidone,Indapamide, furosemide,spirinolactone

5.Beta blockers Propanolol,metoprolol,atenelol, labetelol,carvedilol

6.Alpha blockers Prazocin ,Terazocin ,Doxazosin,phentolamine,

7.Central Sympatholytics

Clonidine, methyldopa

8. Vasodilator Hydralazine,minoxidil,Diazoxide,Sodium Nitroprusside

Diuretics as anti hypertensive

2. Mechanism of Action

Urinary Na+ excretionUrinary water excretion

Extracellular Fluid and/or Plasma Volume

3. Effect on Cardiovascular System

Acute decrease in CO

Chronic decrease in TPR, normal COMechanism(s) unknown

1. Site of Action Renal Nephron

Diuretics (cont)4. Adverse Reactions

dizziness, electrolyte imbalance/depletion,hypokalemia, hyperlipidemia,hyperglycemia (Thiazides)gout

5. Contraindicationshypersensitivity, compromised kidney functioncardiac glycosides (K+ effects)hypovolemia,hyponatremia

Diuretics (cont)

6. Therapeutic Considerations -Thiazides (most common diuretics for HTN) -Generally start with lower potency diuretics -Generally used to treat mild to moderate HTN - Use with lower dietary Na+ intake, and K+ supplement or high K+ food -K+ Sparing (combination with other agent)

- Loop diuretics (severe HTN, or with CHF) Osmotic (HTN emergencies)

- Maximum antihypertensive effect reachedbefore maximum diuresis- 2nd agent indicated

Anti-Angiotensin II DrugsAngiotensin II Formation

2. Ang II Receptor Antagonists losartan (Cozaar); candesartan (Atacand); valsartan (Diovan)

1. Angiotensin Converting Enzyme- Inhibitors enalopril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten)

Ang I

Ang II

ACE

ACE

Ang II

Renin

Angiotensinogen

Ang IAT1

AT2

LungVSMBrainKidneyAdr Gland

Effect on Cardiovascular System

Anti-Angiotensin II Drugs, cont

Volume Aldosterone Vasopressin

CO

Angiotensin II

Vasoconstriction

TPR

SymNS

HR/SV Angiotensin II Norepinephrine

CO

SymNS

GUIDELINE -JNC 7- ISH WHO- South African Hypertension guideline 2011

Blood Pressure Treatment in NutShell

BP Classification SBP mmHg* DBP mmHg Lifestyle Modification

Drug Therapy**

Normal <120 and <80 Encourage No

Prehypertension 120-139 or 80-89 Yes No

Stage 1 Hypertension 140-159 or 90-99 Yes Single

Agent

Stage 2 Hypertension ≥ 160 or ≥ 100 Yes Combo

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

*Treatment determined by highest BP category; **Consider treatment for compelling indications regardless of BP

Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 HTN (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 HTN (SBP 140–159 or DBP 90–99 mmHg)

Thiazide-type diuretics for most. May consider ACEI, ARB, BB,

CCB, or combination.

Without Compelling Indications

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

With any single drug, not more than 25–50% of hypertensives achieve adequate blood pressure control

J Hum. Hypertens 1995; 9:S33–S36For patients not responding adequately

to low doses of monotherapy

Increase the dose of drug. This, however, may lead to

increased side effects

Substitute with another drug from a different class

Add a second drug from a different class

(Combination therapy)

Add second drug from different class (Combination therapy)

If inadequate response obtained

Combination therapy for hypertension

Recommended by JNC-7 guidelines and 1999 WHO-ISH guidelines

South African Hypertension Guideline 2011

-First Step for uncomplicated hypertension : low dose thiazide or ACEI / ARB (CCB in black patients)

-Second step If still uncomplicated, then ACEI or ARB OR CCB .

-Beta-blockers, such as atenolol, are no longer considered as routine step one to step three therapies due to their risk of inducing diabetes and relative ineffectiveness.

- Stroke ,Diabetis with protein uria,CKD : ARB or ACEI with diuretics

LOSARCO Losartan plus Hydrochlorothiazide

Losartan

• Prototype angiotensin II receptor antagonist

• Particularly valuable in patients who are intolerant to ACE inhibitors

• Prevents and regresses LVH• Offers advantage in CHF by increase in

exercise tolerance

Losartan

· Significant antiproteinuric effects in diabetic nephropathy- Renoprotective effects

· Has significant fibrinolytic activity which reduces the risk of ischaemia

· Good Urocosuric amongst ARB s· Once daily dose offers convenience

ANGIOTENSINOGEN

ANGIOTENSIN 1

ANGIOTENSIN 2

VASOCONTRICTIONSYMPATHETIC STIMULATIONALDOSTERONE RELEASE

AT1 AT2

GOOD EFFECTS

LEADING TO NORMALISING BLOOD PRESSURE WITHOUT COUGH AND IT IS A COMPLETE RAAS BLOCKER

CARDIACCHYMASE

CATHEPS INELASTIN

ACE

LOSARTAN

BRADYKININ

INACTIVE FRAGMENTS

NO COUGH

MECHANISM OF ACTION : LOSARTAN

HIGHEST COMPLIANCE

64%58%

50%43%

38%

0%

10%

20%

30%

40%

50%

60%

70%

LosartanPotassium

ACE Inhibitors CaAntagonists

Beta blockers ThiazideDiuretics

% P

ATIE

NTS

LOWEST INCIDENCE OF GOUGH

29.20% 34.10%

71.70%

0.00%10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%

LOSARTAN

POTASSIUM

Hydrochlorthiazide lisinopril

% PA

TIENT

S

Hydrochlorothiazide• Prototype thiazide diuretics• Commonly the first line treatment in mild-moderate

hypertension • Often used in combination with other

antihypertensive agents• Proven benefit in stoke and myocardial infarction

reduction

Hydrochlorothiazide

• Used at doses lower than those used to obtain a diuresis

• Full antihypertensive effect may take 10-12 weeks

• At the doses used diabetes and hypercholesterolaemia are not problems

Thiazide diuretics: mechanism of action

K id n e yNa loss

Arteriolar relaxation

BV

TPR

A P

Thiazides

R e f l e x e s

S y m p a t h o a c t i v a t io nR e n in re le a s e

T P RC a r d ia cco n tra c t i l i t yV e n o u s t o n e

CO Then

Why combination therapy

• Multiple mechanisms involved in the pathogenesis of hypertension

• Effectiveness of monotherapy limited by stimulation of counter-regulatory mechanisms

• Effective BP control seen in only 50% of patients on monotherapy; combination therapy results in a much higher responder rate (>80%)

• BP goals difficult to attain with monotherapy in patients with diabetes or target organ damage

Combination Therapy: Rationale• Improved BP reduction

– Increased efficacy of two drugs in combination compared to either as monotherapy, due to their additive and/or synergistic effects

• Broader spectrum of response– Effective response over a wider range of patient groups

• Improved tolerability– Reduced likelihood of dose-dependent side effects,

clinical and metabolic, by combining smaller doses of two drugs vs high doses of a single agent

– Side effects associated with a particular drug may be modified by the pharmacologic properties of the second drug

Epstein M, et al. Arch Intern Med. 1996;156:1969–1978.

Losartan-Hydrochlorothiazide Combination: Advantages

Synergistic Anthihypertensive effectLOSARTAN HYDROCHLOROTHIAZIDE

¯RAAS ¯ SNS

Inhibits effects of ANG II

¯ Blood Pressure

¯ Plasma volume and natriuresis

¯ Cardiac output

¯ Peripheral resistance

­ Blood Pressure

­ RAAS ­ SNS

­­¯BP

­ ANG II

+

(–) (–)

Losartan-Hydrochlorothiazide Combination:

Potassium AdvantagesLOSARTAN

¯ RAAS

¯ Aldosterone

­ Serum Potassium

Serum potassium levelsremain within normal limits

Hydrocholorothiazide

¯ Plasma volume and natriuresis

­ RAAS

­ Aldosterone

¯ Serum Potassium

+

Losartan-Hydrochlorothiazide Combination: Gout Advantages

Hydrochlorothiazide

¯ Uric acid excretion

Gout

No Gout

Losartan

­ Serum uric acid¯ Serum Uric Acid

+

Improved Safety

­ Serum uric acid excretion

n = 39

0

10

20

30

40

50

60

70

80

n = 63

With HCTZ Without HCTZ

Response = SBP < 140 mm HgP = .002

SBP Response to Two-drug Combinations That Include or Do Not Include a Diuretic

Per

cen

t R

esp

on

se

Materson BJ, et al. J Hum Hypertens. 1995;9:791–796.

Losacar-CO: Indications

Losacar-H is indicated for the treatment of hypertension in patients who do not respond to monotherapy alone.

LOSACAR-HDosing Considerations

A patient whose blood pressure is not adequately controlled with losartan monotherapy may be switched to Losacar-H (losartan potassium 50mg/ hydrochlorothiazide12.5mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets once daily

Losacar -Co: Adverse Effects

• Generally well tolerated• Amongst the commonly reported adverse effects

include : dizziness, abdominal pain, edema, palpitations, back pain, cough, sinusitis, upper respiratory infection and skin rash.

LOSACAR-CoContraindications

Losartan-Hydrochlorothiazide are contraindicated in patients who are hypersensitive to any of their components.

Due to the thiazide component, Losartan -Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

CONCLUSION• Better blood pressure control

• Lesser incidence of individual drug’s side-

effects like potassium inbalance ,gout.

• Neutralisation of side-effects

• Increased patient compliance

• Effective response over a wider range of

patient groups