Antihypertensive DrugsAntihypertensive Drugs

Azza BarakaAzza Baraka

Prof of Clinical Pharmacology Prof of Clinical Pharmacology

Faculty of MedicineFaculty of Medicine

Alexandria UniversityAlexandria University

DefinitionDefinitionElevation of ABP > 140/90 mm Hg. Can be caused by:•primary or essential hypertension

Primary Hypertension cannot be cured, but it can be controlled

•Secondary hypertension, e.g. hyperthyroidism cured by treating cause

Classification of blood pressure Classification of blood pressure levelslevels

Category Systolic (mmHg) Diastolic Category Systolic (mmHg) Diastolic (mmHg)(mmHg)

Normal Normal <120 <80 <120 <80

High Normal High Normal 120 120––139 80139 80––89 89

Hypertension Stage1Hypertension Stage1 140 140––159 159 9090––99 99

Hypertension Stage 2Hypertension Stage 2 >160 >160 >100>100

Major Risk Factors That Increase Mortality Major Risk Factors That Increase Mortality in Hypertensionin Hypertension

SmokingSmoking DyslipidemiasDyslipidemias Diabetes MellitusDiabetes Mellitus Age >60Age >60 Gender: men, postmenopausal Gender: men, postmenopausal

womenwomen Family history Family history

Treatment Thresholds for Essential Hypertension

Stages Risk group A(no major risk factors, no target organ damage)

Risk Group BOne or more major risk factors (except diabetes), no target organ damage

Risk Group CTarget organ damage and/or diabetes

High Normal

Lifestyle Modification

Lifestyle Modification

Lifestyle Modification and Drug Therapy

Stage 1 Lifestyle Modification (up to 12 months)

Lifestyle Modification and Drug Therapy

Lifestyle Modification and Drug Therapy

Stage 2 Lifestyle Modification and Drug Therapy

Lifestyle Modification and Drug Therapy

Lifestyle Modification and Drug Therapy

Treatment GoalsTreatment GoalsShort-term goal of antihypertensive therapy:

Reduce blood pressure

Long-term goal of antihypertensive therapy:

Reduce mortality due to hypertension-induced end organ damage:

Encephalopathy (Stroke) Left ventricular hypertrophy(LVH) -

Congestive heart failure Nephropathy

ABP=COPX PVRABP=COPX PVR =SV X HR X PVR =SV X HR X PVR

Modulators of COP – SV( blood volume, venous return,

Contractility).– Heart Rate .

Modulators of PVR - Diameter of peripheral arterioles

To To ↓BP: ↓BP: 1.1.↓↓ LV systolic LV systolic

performance: negative performance: negative inotropes and inotropes and chronotropes chronotropes

2. 2. ↓↓ blood volume blood volume3. 3. ↓↓ venous tone and thus venous tone and thus

venous return.venous return.4. 4. ↓↓ PVR PVR

Blood pressure treatment goalsBlood pressure treatment goals Systolic BP be reduced to less than 140 mmHg Systolic BP be reduced to less than 140 mmHg

and diastolic BP to less than 90 mmHg in the and diastolic BP to less than 90 mmHg in the general population of patients. general population of patients.

Lower systolic BP goal (<130 &<80 mmHg) in Lower systolic BP goal (<130 &<80 mmHg) in diabetics and in patients at a very high diabetics and in patients at a very high cardiovascular risk .cardiovascular risk .

Management of Management of hypertensionhypertension

Non pharmacological therapyNon pharmacological therapy 1. Sodium Restriction 2. DASH – high fruit , vegetable, whole grains

& low fat dairy foods

Pharmacological therapyPharmacological therapyABCDEsABCDEs

• AACE inhibitors and AT-II antagonistsCE inhibitors and AT-II antagonists• ßß-adrenoceptor blockers -adrenoceptor blockers • CCaa2+2+ channel channel blockersblockers• DDiureticsiuretics• EExtras: Vasodilators, centrally acting symptholytics,..xtras: Vasodilators, centrally acting symptholytics,..

Considerations for choice of initial Considerations for choice of initial antihypertensive monotherapyantihypertensive monotherapy

Target end organ damage (A or B)Target end organ damage (A or B)Coexisting : IHD(B or C), or Coexisting : IHD(B or C), or diabetes (A or C).diabetes (A or C).Renin status (Age). High renin (A Renin status (Age). High renin (A or B), low renin (C or D). or B), low renin (C or D). Presence or absence of side effects Presence or absence of side effects to the selected drug. to the selected drug.

Ideal antihypertensive drugIdeal antihypertensive drug

(1)(1) decrease BPdecrease BP

(2)(2) couple the antihypertensive effectiveness couple the antihypertensive effectiveness with no harmful side effectswith no harmful side effects

(3)(3) provide greater protection against the provide greater protection against the organ damage associated with organ damage associated with hypertension. hypertension.

(4)(4) provide inhibition of the counter-provide inhibition of the counter-regulatory mechanisms (SNS & Na regulatory mechanisms (SNS & Na retention). i.e. retention). i.e. does not cause reflex does not cause reflex tachycardia nortachycardia nor fluid retention fluid retention

First line antihypertensive drugs (A B C First line antihypertensive drugs (A B C D ) for simple HTN not associated wih D ) for simple HTN not associated wih IHD or diabetesIHD or diabetes

Hypertension (HTN) can be classified as: Hypertension (HTN) can be classified as:

High renin hypertension (younger<55)High renin hypertension (younger<55)

Low renin hypertension (elderly>55)Low renin hypertension (elderly>55)

Therefore HTN treated initially with one of two Therefore HTN treated initially with one of two categories of AHDs:categories of AHDs:

1-those that inhibit RAS, namely ACE inhibitors 1-those that inhibit RAS, namely ACE inhibitors (A) and beta-blockers (B) (A) and beta-blockers (B)

2- those that do not, namely calcium channel 2- those that do not, namely calcium channel blockers (C) and diuretics (D)blockers (C) and diuretics (D)

I- DiureticsI- Diuretics

IndicationsIndications– Drug of choice for uncomplicated Drug of choice for uncomplicated

mild-moderate HTN in elderly mild-moderate HTN in elderly patients (low renin)patients (low renin)

– Synergistic with other AHDs in Synergistic with other AHDs in severe HTNsevere HTN

AT start of their use, they lower BP by AT start of their use, they lower BP by causing diuresis leading to a fall in plasma causing diuresis leading to a fall in plasma volume & COPvolume & COP. .

After chronic use they cause a reduction in After chronic use they cause a reduction in BP by VD BP by VD ↓ PVR, ↓ PVR, likely related to shift of likely related to shift of sodium from vascular smooth muscle wall to sodium from vascular smooth muscle wall to ECF.ECF.

In In low doseslow doses, their side effects seem to be , their side effects seem to be minimized. minimized.

I-a Low dose Thiazide I-a Low dose Thiazide diureticsdiuretics

AdvantagesAdvantages Well tolerated with few side effects.Well tolerated with few side effects. Have synergistic effect when added Have synergistic effect when added

to other AHDs .to other AHDs . Relatively inexpensive.Relatively inexpensive. Disadvantages Disadvantages Metabolic adverse effects Metabolic adverse effects

(hypokalemia,hypercalcemia etc); (hypokalemia,hypercalcemia etc); are dose- related.are dose- related.

Lose their effectiveness in renal insufficiency.Lose their effectiveness in renal insufficiency.

I-b Loop diuretics (Furosemide-Lasix)

Loop diuretics are used for hypertension associated Loop diuretics are used for hypertension associated with renal insufficiency.with renal insufficiency.

II- ßII- ß-Adrenoceptor blockers, e.g. -Adrenoceptor blockers, e.g. atenololatenolol

Complicated HTNComplicated HTN Drugs of 1Drugs of 1stst choice for uncomplicated HTN in choice for uncomplicated HTN in

high renin patients (<60).high renin patients (<60). HTN associated with IHDHTN associated with IHD

ßß-Adrenoceptor blockers-Adrenoceptor blockers Mechanism of blood pressure reductionMechanism of blood pressure reduction

– Reduction of HR and myocardial Reduction of HR and myocardial contractilitycontractility

– Inhibition of renin releaseInhibition of renin release

Types of Types of ßß-blockers-blockers

Non cardioselective ,e.g. propranolol Cardioselective, e.g. atenolol.

Side effects: bronchoconstriction especially by non-cardioselective beta blockers.

Contraindications: diabetes mellitus patients treated with insulin. Because they mask symptoms of hypoglycemia.

III-Drugs Interacting With the III-Drugs Interacting With the RASRAS

Angiotensin converting enzyme Angiotensin converting enzyme inhibitors(ACEis) inhibitors(ACEis)

Angiotensin receptor Angiotensin receptor blockers(ARBs)blockers(ARBs)

Physiology of Renin-Physiology of Renin-Angiotensin SystemAngiotensin System

Physiological Effects of AII:Physiological Effects of AII:

1.1. VC of arteries & veinsVC of arteries & veins

2.2. + aldosterone secretion + aldosterone secretion

3.3. + renal sodium resorption & ↓RBF, + renal sodium resorption & ↓RBF, ↑ glomerular capillary pressure

4.4. + LVH+ LVH

5.5. Facilitate adrenergic transmission Facilitate adrenergic transmission

Mechanism of action of ACEIsMechanism of action of ACEIs

Inhibition of ACEInhibition of ACE

Angiotensin II Angiotensin II

BradykininBradykininVDVD

Angiotensin II

Angiotensin I

BradykininInactive product

CE

Mechanism of Mechanism of ↓BP by↓BP by ACEIs ACEIs1111 aldosterone release aldosterone release salt & water salt & water

retentionretention

2.2. VD of both arterioles & veins VD of both arterioles & veins 3.3. Decrease adrenergic activityDecrease adrenergic activity

Therapeutic Uses in HypertensionTherapeutic Uses in Hypertension

Drug of choice in high renin hypertension (<55)Drug of choice in high renin hypertension (<55) Drug of choice in hypertension with end organ damage Drug of choice in hypertension with end organ damage

(nephropathy, LVH)(nephropathy, LVH) Drug of choice in hypertension with concomitant: Drug of choice in hypertension with concomitant:

diabetes mellitusdiabetes mellitus..Why drug of choice in HTN with diabetes?Why drug of choice in HTN with diabetes? ↓↓Intraglomerular pressure Intraglomerular pressure thus reduce proteinuria. No adverse metabolic effects on blood glucose or lipid No adverse metabolic effects on blood glucose or lipid

profileprofile

Types of ACE InhibitorsTypes of ACE Inhibitors

Active molecules: Captopril, Active molecules: Captopril, lisinopril lisinopril

ProdrugsProdrugs: Enalapril: Enalapril

All metabolized by liver except All metabolized by liver except lisinopril by kidney.lisinopril by kidney.

Adverse effects of ACEIsAdverse effects of ACEIs

1. Hypotension esp in volume depleted individuals

2. Cough : dt accumulation of BK in the lung– It is a dry cough. Occur in 30% of patients

3. Angioedema: dt BK

4. Teratogenicity

5. Hyperkalemia

Contra-indication for Contra-indication for ACEIsACEIs

1. Pregnancy2. Bilateral renal artery stenosis3. Low blood pressure: SBP< 90mmHg4. Hyperkalemia

ARBsARBs Block angiotensin II receptors

Differences vs ACEIs: ARBs do not affect BK system, No cough and No angioedema

IV-CaIV-Ca2+2+ Channel Blockers Channel Blockers

Indications in hypertension:Indications in hypertension: Low renin hypertension when diuretics are Low renin hypertension when diuretics are

contraindicated.contraindicated. Hypertension with diabetes in presence of Hypertension with diabetes in presence of

contraindication to ACEIs & ARBscontraindication to ACEIs & ARBs

CCBs Mechanism of antihypertensive CCBs Mechanism of antihypertensive actionaction

Block calcium channels in the Block calcium channels in the arterial arterial smooth musclessmooth muscles VD VDPVRPVR

Block calcium channels in the Block calcium channels in the cardiac cardiac musclesmuscles HR & HR & force of contraction force of contraction Types;Types;– Dihydropyridines, e.g. nifedipine, Dihydropyridines, e.g. nifedipine,

amlodipine amlodipine – Non dihydropyridines, e.g. verapamil & Non dihydropyridines, e.g. verapamil &

diltiazem diltiazem

DihydropyridinesDihydropyridines NifedipineNifedipine

Non dihydropyridinesNon dihydropyridines Diltiazem Diltiazem –– Verapamil Verapamil

>> selective action on vascular CC>> selective action on vascular CC= action on vascular and cardiac CC= action on vascular and cardiac CC

Arterial vasodilation++++ Arterial vasodilation++++ Reflex tachycardiaReflex tachycardia

Arterial vasodilation ++Arterial vasodilation ++↓↓Heart rate Heart rate Therefore VD with no reflex tachycardiaTherefore VD with no reflex tachycardia

Uses :Uses :Essential hypertensionEssential hypertensionAngina pectorisAngina pectoris

Uses :Uses :Essential hypertensionEssential hypertensionAngina pectorisAngina pectorisSupraventricular arrhythmiaSupraventricular arrhythmia

Side effects:Side effects:1.1.Hypotension Hypotension 2.2.Reflex tachycardia Reflex tachycardia 3.3.FlushingFlushing

Side effects:Side effects:1.1.Hypotension Hypotension 2.2.Bradycardia Bradycardia

Contra-indication: tachyarrhythmiaContra-indication: tachyarrhythmiaCan be safely combine with BBCan be safely combine with BB

Contra-indication: HF & heart block, severe Contra-indication: HF & heart block, severe bradycardiabradycardiaCombination with BB is not safeCombination with BB is not safe

- -Vasodilators to A&V: Sodium nitroprussideVasodilators to A&V: Sodium nitroprusside Acts by releasing NO that increase Acts by releasing NO that increase

cGMP that dilate A & V.cGMP that dilate A & V.Clinical use: Clinical use:

– Emergency treatment of severe Emergency treatment of severe hypertensionhypertension

Given by IV infusion( it has a very short t Given by IV infusion( it has a very short t ½½) ) Adverse effectsAdverse effects– Hypotension,Reflex tachycardiaHypotension,Reflex tachycardia– ProlongedProlonged infusion ( more than 72 hrs) infusion ( more than 72 hrs)

Cyanide & Thiocyanate accumulationCyanide & Thiocyanate accumulation

Preferred antihypertensive drugs Preferred antihypertensive drugs for hypertension in pregnancyfor hypertension in pregnancy

AgentAgent

MethyldopaMethyldopa

labetalollabetalol

CCB(nifedipine )CCB(nifedipine )

Drug Interactions of AHDs

Prolonged use of NSAIDs e.g. aspirin (>1 week) may decrease the efficacy of beta-blockers, ACE inhibitors, and diuretics. (Other pain relievers such as paracetamol can be used to avoid this side effect.

Caution should be taken when using local anesthesia (containing adrenaline) with non cardio-selective beta-blockers (propanolol, nadolol, pindolol & esmolol) as hypertension may result due to unopposed alpha -1 stimulation.

Dental Management Guidelines

Defer elective care and provide only urgent care for patients with Stage 2 HTN or those experiencing hypertensive signs and symptoms. Avoid long, stressful appointments.

Minimize the use of local anesthesia with vasoconstrictor ( NO more than 2 cartridges per setting).

Raise the chair slowly to avoid orthostatic hypotension.

Drug ClassSide EffectsDiureticsXerostomia, postural

hypotension, 

ACE inhibitorsXerostomia, teeth discoloration, taste

disturbancesCalcium channel

blockersGingival enlargement, postural hypotension

Alpha-methyl dopaSalivary gland pain or swelling

Please be acquainted Please be acquainted withwith::

other diseases treated with antihypertensive drugs (such as atenolol, amlodipine,) as headaches, regional pain, renal failure, glaucoma, and congestive heart failure.

measuring BP will be done in the dental office to every new patient, for each visit.