Hypertension ( PHL 461 NEW)

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Transcript Hypertension ( PHL 461 NEW)

Hypertension
Hypertension
Hypertension is much more than a "cardiovascular
disease" because it affects other organ systems of
the body such as kidney, brain, and eye.
Most peopol are not even aware of being
hypertensive because it is usually asymptomatic
until the damaging effects of hypertension (such
as stroke, myocardial infarction, renal dysfunction,
etc.) are observed.
Path physiology:
Arterial blood pressure reflects the force exerted on
arterial walls by blood flow.
-Blood pressure normally stays relatively constant because
of homeostatic mechanisms that adjust blood flow to
meet tissue needs.
-The two major determinants of arterial blood pressure
are:
1-cardiac output (systolic pressure)
2-peripheral vascular resistance (diastolic pressure).
-Regardless of the cause, arterial pressure becomes
elevated either due to an increase in cardiac output, an
increase in systemic vascular resistance, or both.
B.P.=C.O x P.R.
S.V.
Neurohumoral
activation
H.R.
blood volume
Kidney disease
Neurohumoral
activation
V.C. of Bl.V.
Excretion
+v chronotropic
Urine output
Blood volume
H.R.
S.V.
C.O.
B.P.
HYPERTENSION
Hypertension is persistently high blood pressure that results
from abnormalities in regulatory mechanisms. It is defined
as a systolic pressure above 140 mm Hg or a diastolic
pressure above 90 mm Hg on multiple blood pressure
measurements.
Classification
Systolic
(mmHg)
Diastolic
(mmHg)
Normal
<120
<80
Prehypertension
120-139
80-89
Mild
140-159
90-99
Moderate
>160
>110
Sever
>180
>120
Hypertension
Primary Hypertension
(idiopathic)
Secondary Hypertension
(secondary to a disease)
Primary Hypertension
It represent 90% to 95 % of high blood pressure cases,
as there's no identifiable cause. This type of high blood
pressure is called Essential hypertension or primary
hypertension which tends to develop gradually over
years.
Risk factors that may lead to hypertension include:
• Age & Race
• Obesity
• Elevated serum cholesterol (total and low-density
lipoprotein) and triglycerides
• Cigarette smoking
•Excessive alcohol, Xanthenes& Sodium intake
• Family history of hypertension or other cardiovascular
disease
•Stress.
Secondary Hypertension
Secondary hypertension accounts for about 5-10% of all cases of hypertension.
Patients with this hypertension are best treated by controlling or removing the
underlying pathology, although they may still require antihypertensive drugs.
These diseases may be :
1. Renal disorders
cases of glomerulonephritis, and other permanent damage of the kidneys, where
salt and water retention dominates. Renal artery stenosis (atherosclerosis)
sufficient to reduce the glomerular pressure leads to rennin release from the
juxtaglomerular apparatus and finally aldosterone release and thus increased
salt-water retention . All of the previous can lead to secondary systemic
and prevent high blood pressure:
hypertension .
2. Hyperaldosteronism has a primary and a secondary form. This condition is
characterised by an isolated rise in serum aldosterone that leads to increased
salt-water retention & finally secondary systemic hypertension .
3. Cushing’s syndrome describes clinical conditions with increased glucocorticoid
concentration in the blood plasma increased salt-water retention ,that can lead to
secondary systemic hypertension .
4.Cardiovascular disorder - as coarctation of the aorta - is the cause of
hypertension in a few young patients. Atherosclerosis is characterised by a
special systolic hypertension frequently found in the elderly without any
diastolic hypertension. These patients do not have any arteriolar disease
5. Phaeochromocytoma. This is a tumour of the sympathetic nervous system
releasing both noradrenalin and adrenaline. The signs are intermittent or
constant systemic hypertension, tachycardia with other arrhythmias,
orthostatic hypertension and flushing.
6. In the last three months of pregnancy some females develop hypertension,
oedema and proteinuria (pre-eclampsia or toxaemia of pregnancy). If this
condition develops into severe hypertension with fits and lung oedema, it is
called eclampsia. This is a life threatening condition, which must be treated
immediately with intravenous hydralazine or minoxidil, and if necessary
termination of pregnancy.
7.Drugs such as steroids or oral contraceptives with high oestrogen,
sympatomimetics, aldosterone, and vasopressin all cause severe systemic
hypertension.Monoamineoxidase-inhibitors combined with tyramine
(cheese) or wine sometimes cause hypertension. A careful medical history is
helpful.
8-Sleep Apnea
Sleep apnea is a disorder in which people repeatedly stop breathing for
short periods of time (10-30 seconds) during their sleep. This condition
is often associated with obesity, although it can have other causes such
as airway obstruction or disorders of the central nervous system. These
individuals have a higher incidence of hypertension. The mechanism of
hypertension may be related to sympathetic activation and hormonal
changes associated with repeated periods of apnea-induced hypoxia
and hypercapnea, and from stress associated with the loss of sleep
9-Hyper- or hypothyroidism
Excessive thyroid hormone induces systemic vasoconstriction, an increase
in blood volume, and increased cardiac activity, all of which can lead to
hypertension. It is less clear why some patients with hypothyroidism
develop hypertension, but it may be related to decreased tissue
.metabolism .
Symptoms and Signs
Hypertension is usually asymptomatic until complications develop in target
organs.
Dizziness, flushed faces, headache, fatigue, sweating, and nervousness are caused
by uncomplicated hypertension.
• Eventually, signs and symptoms occur as target organs are damaged:
-Heart damage is often reflected as angina pectoris, myocardial infarction, or
heart failure( Chest pain, tachycardia, dyspnea, fatigue, and edema may occur).
-Brain damage may be indicated by transient ischemic attacks or strokes of
varying severity.
-Renal damage may be reflected by proteinuria, increase in (BUN), and increased
serum creatinine.
-Ophthalmoscopic examination may reveal hemorrhages, sclerosis of arterioles,
and inflammation of the optic nerve (papilledema). Because arterioles in the
eye be visualized in the retina of the eye, damage to retinal vessels may indicate
damage to arterioles in the heart, brain, and kidney.
Diagnosis
Hypertension is diagnosed and classified by sphygmomanometry.
-History
-Physical examination.
-Other tests (to identify etiology and determine whether
target organs are damaged .Tests include urinalysis,
albumin: creatinine ratio, blood tests (creatinine, K, Na,
fasting plasma glucose, lipid profile), and ECG. Thyroidstimulating hormone is often measured. chest x-ray,
.screening tests for pheochromocytoma.
-BP must be measured twice, first with the patient supine
or seated, then after the patient has been standing for ≥ 2
min (on 3 separate days) .
Treatment goals
Short term goal
reduce blood pressure
Long term goal
•reduce
mortality due to hypertension-induced
disease as:
•stroke
•congestive
•coronary
heart failure
artery disease
•nephropathy
•retinopathy
Treatment of hypertension
Non–Pharmacological
Treatment
Lifestyle changes can help control
and prevent high blood pressure:
.Diet low in sodium.
.Diet that promotes weight loss
.Regular exercise program.
Quitting smoking.
.Avoiding stress.
Pharmacological Treatment
Mono-(Tailored) Therapy
AND
Stepped Therapy
-In monotherapy if the initial drug
(and dose) does not produce the
desired effect, options for further
management include :Increasing
the drug dose or substituting with
another drug.
- In stepped therapy : treatment begin
with one drug then adding second
drug from a different group if there
is no good response.
If the response is still inadequate, a
third drug may be added.
Principally, systemic hypertension is treatable
through one or more of the following strategies:
1. Reduction of the total blood volume (and thus the
stroke volume) with diuretics results in reduction
of the driving pressure.
2. Reduction of the Heart rate reduces cardiac
output and thus the driving pressure (as with β
blockers and calcium channel blockers) .
3. Reduction of TPR with vasodilatator, alpha1
adrenergic receptor antagonists and ACE
inhibitors reduces the driving pressure.
Drug Selection
Hypertension: an elevation of arterial blood pressure
above an arbitrarily defined normal value
Mild
Moderate
Next slide
Cont. :Drug Selection
Angiotensin-converting enzyme inhibitors(ACEI) & angiotensin receptor blockers (ARB):
-They are recommended for hypertensive adults with diabetes mellitus and heart failure
-Avoided with renal artery stenosis ,acute renal failure & pregnancy .
Beta blockers(BB):
These drugs are first choice for clients younger than 50 years of age with high-rennin
hypertension, tachycardia, angina pectoris, myocardial infarction and with
thyrotoxicosis (Why??).
Contraindicated for patients who have asthma,COPD, peripheral vascular disease,
diabetes mellitus, or second or third degree heart block.
Calcium channel blockers (CCB) :
Ca channel blocker is preferred to a β-blocker in patients with variant angina (with
coronary spasms and a bronchospastic disorder, certain arrhythmias or with
Raynaud's disease.
Contraindicated in patients with heart failure .
Diuretics are preferred for patients with heart failure
Avoided with D.M. & gouty patients.
Vasodilators
They are used in combination with a beta blocker and a diuretic to prevent hypotensioninduced compensatory mechanisms (stimulation of the SNS and fluid retention) that
raise blood pressure
Summary of Drug Targets
CCB
e.g. ; α 2 agonist
DIURETICS
They decrease blood volume and thus cardiac output is decreased. With long-term
administration of diuretic, cardiac output returns to normal, but there is a persistent
decrease in peripheral vascular resistance. This is because of
1-A persistent small reduction in extracellular water and plasma volume.
2-Decreased receptor sensitivity to vasopressor substances.
3-Arteriolar vasodilatation secondary to electrolyte (mainly Na) depletion in the vessel wall.
Loop diuretics: (furosemide, bumetanide, torsemide)
They are the most effective diuretics mainly used in
emergency as in hypertensive crisis.
Thiazide diuretics (chlorothiazid & Hydrochlorothiazide)
They act on the distal tubules and are less effective than
loop diuretics. Monotherapy for mild to moderate
hypertension.
Potassium sparing diuretics: (Aldosterone antagonists :Spironolactone & Sodium channel
blockers : Amiloride and Triamterene)
not effective antihypertensive drugs because they have weak diuretic effect . However they
are used with other diuretics to decrease their hypokalemic effect.
ADVERSE EFFECTS OF LOOP
DIURETICS
Profound ECFV
Depletion
Hypocalcaemia
Hypokalemia
Ototoxicity
Metabolic
Alkalosis
Hyperuricemia
Hypomagnesemia
Hyperglycemia
ADVERSE EFFECTS OF
THIAZIDE DIURETICS
ECFV
Depletion
Hypokalemia
Metabolic
Alkalosis
Hypomagnesaemia
Impotence
Hypocalcaemia
Hyponatremia
Hyperuricemia
Hyperglycemia
Increased LDL
β blockers
1. Block β 1 receptors of the heart: reducing contractility and cause bradycardia
(-ve inotropic ,-ve chronotropic )
2. Blocking β receptors in the kidney: decrease the release of rennin
Non selective β1 & β2 blocker: Propranolol .
β1 selective: Atenolol , Metoprolol , Esmolol, Betaxolol & Timolol
Adverse effects:
-Cold extremities (NA effect on BV. will be mainly on α1 receptors) so NOT taken
by patients with PVD).
-Bronchospasm .
-heart failure.
-insomnia & depression .
-Impotence.
-Increased triglycerides & decrease HDL.
-They are contraindicated in insulin dependent diabetic patients because they
mask symptoms of hypoglycemia (tachycardia)& also can themselves produce
hypoglycemia by inhibiting glycogenolysis (by blocking β receptors in liver).
-Withdrawal syndrome :may result in tachycardia if it is removed suddenly.
- Do not use in conjunction with Ca2+ channel blockers, conduction effects in
heart
Calcium Channel Blockers
The depolarization of vascular smooth muscle relies on the influx of
Ca2+ (rather than Na+ ). These drugs relax arteriolar smooth
muscle by reducing calcium entry via L type calcium channels
(which are also present in the heart)· There are various types of
Ca2+ channels blockers:
· Nifedipine: arterioselective
· Amlodipine: arterioselective
· Diltiazem: cardioselective
· Verapamil: cardioselective
Adverse effects:
.Reflex tachycardia (Verapamil and Diltiazem do not cause reflex
tachycardia …Why?)
· Flushing
· Edema
· Dizziness
. Bradycardia ,AV blockade (with cardioselective agents)·
. Verapamil must also never be used in conjunction with a β blocker
because of their additive effects on depressing the heart leading to
complete heart block.
Angiotensin Converting Enzyme Inhibitors
Ex.: Active : Captopril (Capoten) & Lisinopril. .1
Prodrugs: must be biotransformed for activity by esterase :Enalapril (Vasotec)
&Fosinopril.
Adverse effects:
· Dry cough (due to bradykinin)
· Loss of taste
· Hypotension
· Rash
· Angioedema (due to bradykinin).
. Hyperkalemia (due to decreased aldosterone).
. Renal insufficiency & proteinuria (protein in urine).
.Teratogenic.
Angiotensin II receptor antagonists
Ex. Lorsatan & valsartan
· It is selective for AT1 receptors
· It inhibits the cardiovascular effects of angiotensin II
· Similar efficacy to ACE inhibitors but without the bradykinin associated side effects:
There is no cough and no chance of angioedema
However, other side effects may be:
· Pathological effects on the fetus
· GI adverse effects
α1-blockers
Selective: Prazosin, Doxazosin, Terazosin
inhibit vasoconstriction
decrease total peripheral resistance
Selective α-blockers used as monotherapy or adjunct therapy in resistant
patients
Side Effects:
•First dose phenomenon
•hypotension
•tachycardia
•baroreceptor reflex
•GI effects
•Fluid retention
•use with diuretic
Vasodilator (not used as monotherapy….WHY??)
1-Hydralazine
Mechanism of action
The mechanism is unknown. It dilates arterioles· It can cause reflex stimulation of the sympathetic
nervous system, since the vasodilatation causes sever transient drop in blood pressure. This reflex
stimulation causes increased heart rate and contractility, and also rennin release (causes marked
fluid retention and edema).
In order for hydralazine to be useful, it needs to be combined with a β blocker (to prevent the cardiac
effects) and a diuretic (to overcome the fluid retention).
Side effects:
· Headache (due to vasodilatation)
· Nausea
· Tachycardia & edema (reflex stimulation of sympathetic)
SO; Need to be used in conjunction with β blockers and diuretics.
· A systemic lupus like condition.
2-Minoxidil
Relaxes blood vessels by opening K+ channels· This causes K+ to rush out of the cell, hyperpolarizing
the smooth muscle and so making it less excitable.
Adverse effects:
It can cause reflex stimulation of the sympathetic nervous system which leads to reflex tachycardia &
salt and water retention.
SO: Need to be used in conjunction with β blockers and diuretics.
· Causes hair growth (hypertrichosis)· Another therapeutic use of this drug is in the treatment of
baldness
3-Diazoxide
Diazoxide (Hyperstat) is chemically similar to the thiazide diuretics. It is devoid of
diuretic activity, but it is a very potent vasodilator.
It produces direct relaxation of arteriolar smooth muscle with little effect on
capacitance beds.
Side effects
Increased workload on the heart, which may precipitate myocardial ischemia and
Na and water retention.
These undesirable effects can be controlled by concurrent therapy with a -blocker
and a diuretic.
Diazoxide may cause hyperglycemia, especially in diabetics, so if the drug is used
for several days, blood glucose levels should be measured.
4-Sodium nitroprusside
-It releases NO which directly relaxes smooth muscle in blood vessels·
-Reserved for acute use only(i.e.) It is used in emergency situations where a rapid
drop in blood pressure is required·
- The drug metabolism lead to release of CN, cyanide poisoning may develop
Centrally acting antihypertensive
-The 2 drugs which are used are both α2 agonists · As α2 receptors are located
presynaptically and centrally, once stimulated they will inhibit the release of NA from
the sympathetic nerve terminal & reduce sympathetic outflow from CNS.
α-methyldopa
Enters the CNS via active transport into the brain· Converted to a methyl NA by the same
enzymes (dopadecarboxylase) which are involved in NA synthesis & form α-methyl
NA which is a false transmitter .
Selective α2 agonist causes reduced sympathetic outflow to the blood vessels and heart
Adverse effects:
Sedation, depression
Dry mouth (due to inhibition of the medullary areas controlling salivation)
Postural hypotension
Clonidine
Selective α2 agonist ,it causes reduced sympathetic outflow & NA release
It can cause rebound hypertension on cessation, therefore the patient needs to be
titrated off the drug slowly
Both drugs have weak postural hypertensive effect
-Adrenergic neuron blockers (rarely used)
1- Guanethidine; (inhibits NA release)
Highly polar, therefore does not get into the CNS, acts peripherally
Taken into secretory vesicles (by the same uptake mechanism as NA) and displace NA from
its storage granules . Then, it prevents NA release from the presynaptic terminal
(stabilize the nerve membrane)- hence no NA release with gradual depletion of NA
stores.
Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence
reducing cardiac output
Side effects:
Postural hypotension
Weakness
Impotence & Diarrhea
2- Reserpine (inhibits NA storage)
Blocks NA transport into synaptic vesicles. May also interfere with NA uptake mechanisms
( but it enters the CNS).
Blocks dopamine transport into storage vesicles, so decrease synthesis of NA
Decrease blood pressure by vasodilatation, thus reducing venous return and afterload hence
reducing cardiac output
Side effects:
Postural hypotension
Sedation& Depression
Parkinsonism
Peptic ulcer
Adverse
effects
Caution
Contraindication
Indication