Download HYPERTENSION

12/11/2010
HYPERTENSION
Dr. Ahmed A. Elberry, MBBCH, MSc, MD
Assistant Professor of Clinical Pharmacy
Faculty of pharmacy,
KAU
1
Hypertension
•
It is a sustained  of arterial bl. pr. ≥ 140/90
•
Causes:
1.
2.
1ry: “Essential” or “Idiopathic”: 90-95% of cases
2ry: about 5% of cases
 Disease:
 Renal or renovascular disease
 Coarctation of the aorta
 Endocrine disease: eg:
 Phaeochomocytoma
 Cushing syndrome
 Acromegaly
 Drugs (Iatrogenic)
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Dr. Ahmed Elberry, MD
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12/11/2010
Drug-Induced HT:
1- Hormones:
3- CNS:
 Steroids
 Anxiolytic: Buspirone
 Estrogens & OC
 Anesthetic:
 Ketamine
 Desflurane
 Erythropoietin
2- Autonomic:
 Phenylpropanolamines
 Clonidine withdrawal
 Ergotamine
 Sibutramine
 Antiparkinsonian: Bromocryptine
 Antiepileptic: Carbamazepine
 Antiemetic: Metoclopramide
 Antidepressants: Venlafaxine
4- Antiinflammatory: NSAIDs
 Methylphenidate
5- Immunosuppressive:
cyclosporine/tacrolimus
Risk factors for 1ry HT
Controllable Risk
Factors
Dr. Ahmed Elberry, MD
Uncontrollable Risk
Factors
1- Salt intake
2- Alcohol
3- Stress
4- Weight (Obesity)
1- Heredity
2- Age
5- exercise
3- Race :More in
- Men: 35 – 50
- Women: after
menopause
African Americans
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JNC 7 Classification of BP:
 The 7th report of the Joint National Committee on Detection, Evaluation
& Treatment of High Bl Pr (JNC 7) classifies adult BP as shown
Classification
Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension
Systolic BP
Diastolic BP.
(mmHg)
<120
120–139
140–159
≥160
(mmHg)
<80
80–89
90–99
≥100
NB.:
• If systolic & diastolic lie in different stages, the highest is considered
• Diastolic bl.pr. is generally more reliable, while, systolic is more important in elderly
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Manifestations
 Usually NO SYMPTOMS! “The Silent Killer”
 May have:




Headache
Blurry vision
Chest Pain
Frequent urination at night
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Dr. Ahmed Elberry, MD
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12/11/2010
Complications of HT
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Treatment of HT
• Nonpharmacological
• Pharmacological
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Dr. Ahmed Elberry, MD
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12/11/2010
Non pharmacological therapy
 Include:
Approximate SBP Reduction
1- Adopt DASH eating plan
8-14 mmHg
2-  Dietary sodium
2-8 mmHg
3-  Alcohol consumption
2-4 mmHg
4-  Weight
5-20 mmHg/ 10 kg weight loss
5-  Physical activity
4-9 mmHg
 Indication:
 patients with prehypertension.
 Patients diagnosed with stage 1 or 2 hypertension should be
placed on lifestyle modifications & drug therapy concurrently.
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DASH Eating Plan
1.  saturated fat, cholesterol & total fat
2.  red meat
3.  sweets & sugar containing
beverages
4. fruits, vegetables & fiber
5.  low fat diary products & plant protein
6.  magnesium, potassium & calcium
 DASH Can reduce BP in 2 weeks
(SBP, 8-14 mmHg)
Dr. Ahmed Elberry, MD
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12/11/2010
Pharmacological treatment
 1st line 1ry options: (ABCD)
 Diuretics, ACE inhibitors (or ARBs)* , CCBs & β-Blockers**
 Alternatives:
 Sympatholytics:
 central α2-agonists,
 α1-Blockers,
 peripheral adrenergic neurone antagonists (guanithidine, reserpine,
α-methyldopa)
 direct renin inhibitors (Aliskiren)
 Direct arterial vasodilators: (hydralazine, minoxidil, diazoxide)
*ACE inhibitors (or ARBs) are contraindicated in pregnancy
**BBs are not indicated as first line therapy for elderly (age 60 and above)
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The A B C D classes (1st line)
D
A
Diuretics
ACEI, ARB
Ca
channelBlockers
DIURETICS
βBlockers
ACEI
and
ARB
D A
Fourth
Choice,
Useful
First
Good
and
third
Best
Choice
Choice
Second
Best
Choice
B C
Can
be combined
combined
with
D,
AC
Can
be
be
combined
with
A,
D
Can Can
be
combined
with with
D,
B,A,
CB,
B
C
β-Blockers
Ca-Blockers
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Dr. Ahmed Elberry, MD
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12/11/2010
GOAL OF THERAPY
-PLUSHypertension
With Framingham
risk factor ˂10%
1-Framingham risk factor
˃10%
2- DM
3- Renal Disease
4- CAD
< 140/90
mmHg
< 130/80
mmHg
-PLUSHF
< 120/80
mmHg
 Stage 1: monotherapy
 Stage 2: combination therapy
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Dr. Ahmed Elberry, MD
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Algorithm for Treatment of HT
Lifestyle Modifications
Not at Goal Blood
Initial Drug Choices
Without Compelling
Indications
Stage 1 HTN
Thiazide diuretics for most.
May consider ACEI, ARB,
BB, CCB, or combination.
With Compelling
Indications
Stage 2 HTN
2-drug combination for most
(usually thiazide diuretic and
ACEI, or ARB, or BB, or CCB)
Drug(s) for the compelling
indications
Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
Compelling Indications
Compelling
Indication
Initial Therapy Options
Sequential therapy
Diabetes
ACEI (or ARB)
THIAZ, BB, CCB
Chronic kidney
disease (CKD)
ACEI (or ARB)
CAD
BB + ACEI (or ARB)
Recurrent
stroke
prevention
ACEI (or ARB) + THIAZ
HF
BB + THIAZ + ACEI (or
ARB)
Dr. Ahmed Elberry, MD
- THIAZ for BP control
- CCB fro ischemia control
- Aldosterone antagonist for
severe HF
- Hydralazine or nitrates for
black patients
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Diuretics
1. Thiazides:
 As hydrochlorthiazide (HCTZ) or chlorthalidone
2. Loop Diuretics:
 Furosemide (lasix) twice daily
 Torsemide once daily
3. Potassium-Sparing Diuretics:
Non-aldosterone antagonists: Triamterene & Amiloride.
Aldosterone antagonists (more potent) : Spironolactone &
Eplerenone
1.
2.
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1- Thiazide Diuretics
• Indication:


of choice for treating HT (it has both diuretic & direct VD effect)
all are equally effective.
• Dosage:


Starting dose of HCTZ (Esidrex) or chlorthalidone of 12.5 mg once daily.
Maintenance dose of 25 mg once daily effectively lower BP with low
incidence of SE.
• SE:


Hpokalemia , Hyponatremia , Hypomagnesemia, Hypochloremic
alkolosis
Hyper uricemia , Hyper glycemia , Hyper lipidemia , Hyper sensitivity

Hypercalcemia
Ca++
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Dr. Ahmed Elberry, MD
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2- Loop diuretics
• Indication:
 of choice for:
 severe CKD (GFR<30 mL/min./1.73 m2)
 Lt ventricular dysfunction, or severe edema (because potent
diuresis is often needed in these patients).
•
SE:
 Hpokalemia , Hyponatremia , Hypomagnesemia, Hypochloremic
alkolosis
 Hyper uricemia , Hyper glycemia , Hyper lipidemia , Hyper
sensitivity
 Hypocalcemia, Deafness, Dehydration
Ca++
 NB.: Loop diuretics have less effect on serum lipids & glucose
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Hypokalemia
K+
• Manifestation:


Muscle fatigue or cramps.
Serious cardiac arrhythmias may occur, esp. in patients:



receiving digitalis,
with LV hypertrophy,
with IHD.
• Monitoring:

Serum K+ should be measured at baseline & within 4 w of
initiating therapy or after increasing diuretic doses.
• Management:
1.
2.
3.
4.
Intermittent use of the least effective dose
K+ rich food (bananas, potatoes, avocados)
KCl supplement (20 – 40 mEq/day)
Add K+ sparing diuretic
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Dr. Ahmed Elberry, MD
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3- K+-Sparing Diuretics
 Indication:
 Patients who develop hypokalemia while on a thiazide diuretic.
 SE:
 Hyperkalemia, especially in:
 chronic kidney disease
 DM,
 concurrent treatment with an ACE.I, ARB, NSAID, or K+
supplement.
 Gynecomastia with Spironolactone
(in up to 10% of patients), but this effect occurs
rarely with eplerenone.
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ACEIs
Dr. Ahmed Elberry, MD
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12/11/2010
ACEIs
1. S.H containing:

Captopril (capoten): [Active drug, given 2-3 times
daily, absorption is affected by food]
2. Non-S.H containing:

Active drug
 Lisinopril (zestril) & Enalaprilate (given IV in emergency
hypertension)

Prodrugs
 Enalapril (renitec) - Perindopril - Benazepril Ramipril – Trandolapril - Fosinopril
NB.:

Enalaprilate (enalaprilic acid) is the active metabolite of Enalapril
 ACE.I is more effective in young white patients than in black or elderly
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Dr. Ahmed Elberry, MD
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ACEIs
Side effects:
1) Related to S.H:
1. Allergy
2.  Taste (Dysgeusia)
3. Protinuria
4. Neutropenia
2) Related to  ACE
1.
2.
3.
4.
Cough due to  bradykinin
1st dose Hypotension (esp. in elderly & heart failure). So tart with
low dose with slow dose titration
Hyperkalemia
ARF esp. in bilateral renal art. stenosis
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ACEIs
Contraindications:
1.
2.
3.
Hypotension
Pregnancy (They are fetopathic may cause
oligohydramnios – pulmonary hypoplasia – growth
retardation – fetal death)
Bilateral renal artery stenosis
Drug interactions:
1.
2.
3.
4.
Na+ depleting diuretics   initial Hypotension
K+ retaining diuretics   hyperkalemia
NSAID   Hypotensive Effect Through Inhibition of
Bradykinin & PGs
Antacids   absorption
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Dr. Ahmed Elberry, MD
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12/11/2010
AT-II Blockers (ARBs)
 Candesartan - Losartan (Cozar) - Olmesartan –
Valsartan – Eprosartan -Irbesartan – Telmisartan
 Actions & Uses  As ACEI
 Side effects  As ACEI but with less cough
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CCB
 Classification:
 Dihydropyridine:
 Short acting: Nifedipine (Adalat, Epilat)
 Long acting: Amlodipine (Norvasc) – nisoldipine – felodipine –
isradipine
 Non-dihydropyridine: Verapamil (isoptin) – Diltiazem
(cardizem)
 Side effects:
1. Bl.V.: Headache – flush – Hypotension – ankle oedema
2. Heart:
 Bradycardia with Diltiazem & marked with verapamil
 Reflex Tachycardia with nifedipine
3. G.I.T.: Constipation is marked with verapamil.
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Dr. Ahmed Elberry, MD
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12/11/2010
β-Blockers

Mechanism of antihypertensive effect:
1.
2.
3.
4.
5.
6.

Block -1 of Heart  COP.
Block -1 of CNS  Sympathetic outflow.
Block -1 of Kidney Renin.
Block Pre-synaptic  Release of Nor-adr.
Resetting the sensitivity of Baro-receptors.
 Prostacyclin (VD) synthesis
PGs
Classification:
1.
2.
according to Selectivity
according to Lipid solubility
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Classification according to Selectivity
ISA
A. Non- selective:
Pindolol
Oxprenolol
Propranolol (Inderal)
Sotalol
Nadolol
Timolol
B. Cardio-selective (B1)
Acebutolol
Atenolol (Tenormin)
Bisoprolol (Concor)
Betaxolol
Metoprolol (Lopressor)
Esmolol
L.A
+
+
No
No
No
No
+
+
+
No
No
No
+
No
No
No
No
No
+
No
No
No
+
No
Notes
Extensive hepatic 1st pass metabolism
Eye drop in glaucoma.
Ultrashort. I.V. Infusion.
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Dr. Ahmed Elberry, MD
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12/11/2010
NB.: Vasodilator B- Blockers:
1.  2-Partial agonist:
 Celiprolol: (Selective 1 Block – No ISA – No LA)
2. Nitrogenic effect ( production of NO):
 Nebivolol
3. 1-blocking effect:
 Labetalol – Bucindolol – Carvedilol (dilatrend) - Medraxalol
Classification of according to Lipid
solubility
Lipophilic
Hydrophilic
1. G.I.T. Absorption:
2. Passage across
B.B.B.:
-
Well Absorbed.
Pass BBB
has CNS. effects.
-
Poorly absorbed.
Not pass BBB
has little CNS effect
3. Metabolism:
4. Duration of Action:
5. Examples:
-
Extensive hepatic.
Short (4-6 Hours)
Propranolol.
Oxprenolol.
Metoprolol.
Timolol
-
Mainly Renal.
Longer (12-24 Hs)
Nadolol.
Atenolol.
Sotalol.
Bisoprolol
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Dr. Ahmed Elberry, MD
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SE & contraindications
Side effects
Contraindications
- Sedation - depression - sleep disturbances
(only in lipophilic B.B. crossing BBB)
I. CNS:
II. CVS:
1.Heart:
1.Heart failure - Heart block - Bradycardia ----
2.B.V.
2.Cold extremities, Raynaud's phenomenon, numbness,
tingling
3.B.P.
3.Hypotension---------------------------------------
III. Respiration
IV. Metabolism
- Precipitate acute attack of B.A. in asthmatics
1.
2.
3.
V. Others
Hypoglycemia (severe in patient receiving insulin or
oral hypoglycemic [coma can occur without warning
(silent death) ]
Hyperkalemia
Atherosclerosis ( HDL &  Triglycerides)
Sudden withdrawal withdrawal syndrome 
sympathetic over activity and precipitation of anginal
attack even myocardial infarction
Severe depression
(use hydrophilic B.B.)
•
•
•
•
H.F. - Hear block - severe bradycardia
With Verapamil:  H.F. & H. Block
Variant angina .
Raynaud's phenomenon & P.V.D & alone
in pheochromocytoma
• Hypotension
- Bronchial asthma (use selective B1)
• Hypoglycemia in insulin or oral
hypoglycemic treatment.
• Never stop suddenly.
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α1-Receptor Blockers
Prazosin (Minipress), terazosin, and doxazosin (Cardura)
 Side Effects:
1.
2.
3.
Initial Syncopal Attack (1st dose phenomenon). An αattack of
severe postural hypotension. Start by small dose while patient
is recumbent (At Bed Time), then increase the dose gradually
Sexual dysfunction after long use in males & failure of
ejaculation
Salt & H2O retention as it C.O.  R.B.F. So, Diuretic is
added.
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Dr. Ahmed Elberry, MD
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12/11/2010
Central α2-Agonists
 Include:
 Clonidine, guanabenz, guanfacine, & methyldopa
 Mechanism:
 Selective α2 & Imidazoline I1 Agonist (15 : 1) Hypotension by:
1.  Sympathetic outflow from C.N.S.
2. Presynaptic Release of N.A.
3. Kidney:  Release of Renin
 Side effects of centrally acting drugs
Sudden Withdrawal  Rebound severe hypertension
Treat by Re-using Clonidine or by -Blocker + -Blocker.
2. Sedation
3. Dry mouth (xerostomia) & Dry nasal mucosa
1.
35
 Moxonidine (physiotens) & Rilmenidine (Hyperium):
 They are selective I1 agonist used in ttt of
hypertension
 Less liable to cause sedation
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Dr. Ahmed Elberry, MD
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12/11/2010
Peripheral adrenergic neurone
depressants
 Include
 Guanethidine
 Reserpine
 Methyldopa (act centrally also)
37
Guanethidine
Reserpine
*Kinetic
- Incompletely absorbed
- Not pass B.B.B
- Slowly excreted in urine
*Kinetic:
- Well absorbed
- Passes B.B.B
- Slowly excreted in urine
Mechanism (Release)
Mechanism: (Depletion)
* Side effects:
1) Parasymp. Predominance:
1. Nasal congestion
2. Bradycardia
3. Postural hypotension
4. Diarrhea
* Side effects:
1) Parasymp. Predominance:
1.Nasal congestion
{Stuffiness}
2.Bradycardia
3.Hypotension
4.Diarrhea
2) Others:
2) Others:
1. Na & H2O retention
1. Parotid pain
2.Weight gain
2. Failure of ejaculation
3.Peptic ulcer
4.Endocrinal disturbance
5.Breast cancer.
6.Impotence
3) C.N.S:
1. Psychic depression
2. Nightmares
3. Parkinsonism
Dr. Ahmed Elberry, MD
-Methyldopa
*Kinetic
- Well absorbed
- Passes B.B.B
- Transformed to -methyl
NA
Mechanism ( synthesis &
Central)
* Side effects:
1) Parasymp. Predominance:
1.Nasal congestion
2.Bradycardia
3.Hypotension
4.Diarrhea
2) Other:
1.Na & H20 retention weight
gain
2.Liver toxicity
3.Bone marrow
Depression
3) C.N.S:
1. Psychic depression
2. Night mares
3. Parkinsonism
4. Sedation
38
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Direct renin inhibitors
(Aliskirin (Tecturna®))
 Inhibit directly the renin
 Similar to ACEIs & ARBs & contraindicated in
pregnancy
 Used once orally as an alternative antihypertensive
agent
Direct Arterial Vasodilators
 Include:
 Hydralazine - Minoxidil - Diazoxide
 Actions & effects :
1.
2.
Direct Arterio-dilator   Bl.Pr  useful in Hypertension
 Bl.Pr   symp & after load  Co  useful in H.F
 Disadvantages & general SE:
1.  Bl.Pr   sympathetic leading to:
 Tachycardia & Angina  [Add - blockers]
 Rennin  edema  [Add diuretic]
(So, they are not used alone, but used in combination
with  - blockers & diuretics)
2. V.D  Headache – congestion – flush
40
Dr. Ahmed Elberry, MD
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12/11/2010
(1)Hydralazine
(2) Minoxidil
(3) Diazoxide
Side effects
1. Hypersensitivity in the form of: . Hypertrichosis
- Rash
- Rheumatoid arthritis
- Systemic lupus
erythematosus like
syndrome
2. GIT upset
3. Peripheral neuritis
1. Hyperglycemia
2. Hyperuricemia
(as it is related to Thiazide
diuretic)
Uses
Orally& I.V
1. Hypertension & emergency
2. H.F
Orally
1. Hypertension
2. H.F
3. Locally in alopecia
I.V
Emergency Hypertension
41
SPECIAL POPULATIONS
•
Pregnancy:



•
African Americans:


•
Methyldopa is the drug of choice
Alternatives: ΒB & CCBs.
ACEI & ARBs are contraindicated (teratogens).
Thiazides & CCBs are particularly effective.
Response is significantly  when either class is
combined with a BB, ACEI, or ARB.
Older People:

Diuretics & ACEI can be used safely, but in smallerthan-usual initial doses, and titrations should occur
over a longer period to minimize the risk of
hypotension.
 Centrally acting agents & BB should be avoided or
used with caution because they are associated with
dizziness & postural hypotension.
Dr. Ahmed Elberry, MD
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HYPERTENSIVE CRISIS
This image cannot currently be display ed.
 ˃ 180/110 & may be classified into:
 Hypertensive urgency:
 without target organ damage (TOD) (eg. Encephalopathy,
unstable angina, renal failure & papilledema)
 ttt: adjusting maintenance therapy by adding a new
antihypertensive and/or increasing the dose of a present drug.
 Hypertensive emergency:

with TOD
 ttt: require immediate BP reduction to limit new or progressing
target-organ damage.
43
Goal in treatment of hypertensive
crisis
 The goal:
 not to lower BP to normal; as rapid drops in BP may cause end-
organ ischemia or infarction.
 The initial target is  MAP 25% within minutes to hours.
 If BP is then stable, it can be reduced to 160/100 -110 mm Hg
within the next 2-6 hours.
 Additional gradual decrease toward the goal BP after 24 -48
hours.
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Dr. Ahmed Elberry, MD
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12/11/2010
Treatment of hypertensive crises
Hypertensive urgency:
Acute administration of short-acting
oral drugs (captopril or labetalol)
followed by careful observation for
several hours to ensure gradual BP
reduction.
• Captopril 25-50 mg may be given
at 1- to 2-hour intervals. The onset
of action is 15- 30 min.
• Labetalol 200-400 mg, followed by
additional doses every 2- 3 h.
Hypertensive emergency:
Nitroprusside is the drug of choice in
most cases.
• Given as a IV infusion (0.25 to 10
mcg/kg/min.)
• Onset of action is immediate &
disappears within 1-2 min of
discontinuation.
• When infusion is continued ˃72 h.,
serum thiocyanate levels should be
measured, & infusion should be
stopped if the level ˃12 mg/dL.
Other Parentral drugs used in
emergency HT
 Nitroprusside
 Nitroglycerin
 Nicardipine




Diazoxide
Esmolol
Enalaprilate
Fenoldopam
 Hydralazine
 Labetalol
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Dr. Ahmed Elberry, MD
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12/11/2010
Causes of Resistant HT
1. Improper BP measurement
2. Identifiable causes of HTN
3. Excess sodium intake
4. Excess alcohol intake
5. Inadequate diuretic or medication therapy
6. Drug actions and interactions:
• NSAIDs, sympathomimetics, oral contraceptives,
OTC drugs & herbal supplements
Dr. Ahmed Elberry, MD
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12/11/2010
[email protected]
Dr. Ahmed Elberry, MD
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