loop diuretics
1) more natriuresis than thiazides *but less effective in treating HTN 2) lead to hyponatremia
potassium sparing diuretic
1) little effect on natriuresis 2) prevent hypokalemia combine treatment with loop diuretics and thiazides
thiazide & thiazide-related diuretic
decrease peripheral vascular resistance mechanism of reduced PVR
sodium content reduced in arteriolar smooth muscle cells
*diet of sodium to resolve the natriuretic effect of thiazide*
thiazide
Reduced BP (about 10-15mmHg)
hydrochlorothiazide (most commonly use to treat HTN)
indapamide (extra function as vasodilator)
chlorthalidone
offer protection to osteoporosis (it decreases excretion of calcium in the urine)
use in combination with other anti HTN drugs
combination of indapamide (thiazide diuretics) and angiotensin inhibitor
effective In controlling BP
risk of stroke
MI
hydrochlorothiazide/ angiotensin inhibitor/ ccb
mild to moderate HTN
main function of diuretic
PREVENT compensatory fluid retention induce by other agents
Adverse drug (thiazide) reaction
hypokalemia induced-cardiac arrhythmia
muscle weakness
possibly elevate level of glucose, uric acid, lipids
cause hematologic toxicity
exacerbate hepatic disease
stimulate renin secretion (combination with angiotensin receptor to resolve the problems)
Loop diuretics
indications
poor renal function
serum creatinine greater than 2.3mg/dL
Potassium-sparing diuretic
drugs
amilorides
spironolactone
triamterene
K+sparing
mild Natriuretic prevent hypokalemia caused by thiazide and loop diuretics
mineral corticoid receptor antagonists
spironolactone
eplerenone
function :
*combination with other drugs show significant lowering bp
* treat HTN that can be controlled by three or more other drugs
*eplerenone similar to spironolactone but associate with less side effects *improve left ventricular hypertrophy in HTN *improve microalbuminuria in type 2 diabetes patient
Sympatholytic drug
adrenoreceptor antagonist
a-adrenoreceptor antagonist (not suitable for initial treatment of high blood pressure)
b-adrenoreceptor antagonist
doxazosin,prazosin, erazosin (combine with diuretics)
adverse drug effect -SNS reflex activation - causes elevated heart rate, NE, increased oxygen demand, fluid retention via RAAS, orthostatic HTN (first dose syncope)
central acting a-2 adrenoreceptor antagonist
Mechanism of action of b-adrenoreceptor antagonist-
1) block B1 receptor on renal juxtaglomerular cells -inhibit renin secretion -reduce sympathetic outflow -reduce formation of AII (via inhibition of renin) -reduce secretion of aldosterone
B-Blocker indication-
-coronary heart disease -MI
-heart failure
-diabetic (for people with PRE-EXTISITING cardiac condition) (use selective b1antagonist) benefits: reduce risk of myocardial infarction, reduce myocardial ischemia -cardioprotective (reduce ventricular arrhythmia, heart rate) -enhance symptoms and survival -improve cvs outcome in diabetic patients
side effect: 1) fatigue, sleep disturbances, sexual dysfunction, reduce exercise capacity due to decrease heart rate *in diabetic patient it may cause slight impaired in glycemic control (as a result of decreased insulin sensitivity), however CARVEDILOL will improve insulin sensitivity.
non-selective b blocker may delay the patient from recovering from hypoglycemia (by blocking b2-receptor- mediated GLYCOGENOLYSIS and hepatic glucose production)
indication for HTN without pre-existing heart condition
angiotensin inhibitor
Calcium channel blocker
diuretic
contraindication of non-selective b blocker
*asthma *copd
may cause bronchospasms via b2 receptor blockade
so use selective B1-blocker in caution selective b1 blocker
atenolol (less lipophilic- more side effects on CNS) bisoprolol metoprolol nebivolol (third-generation)-nebivolol elevate nitric oxide release from endothelial cells (potent vasodilators), use to treat HTN patient with heart failure, diabetes, cardiac arrhythmias
non-selective b blocker
nadolol propranolol (more lipophillic) timolol a and b blocker
carvedilol (third generation) labetalol (chronic HTN/ in HTN emergency)
carvedilol is antioxidant (protect vascular from free radical)
orthostatic hypertension emergency HTN, surgical HTN, ultra-short acting B1 blocker with IV administration
Centrally acting drugs
sympatholytic drug
clonidine
guanfacine
methyldopa (convert to active metabolite (methyl -norepinephrine)
should not be used with tricyclic antidepressant drugs (as it will block the effects of centrally acting drug)
function
Decrease sympathetic outflow from central vasomotor center to the blood circulation Alpha 2 adrenoreceptor is activated in the brain stem medulla Decrease blood pressure via reducing peripheral vascular resistance Less effect on heart rate and cardiac output
Clonidine
more s/e than other anti HTN drugs
not recommended for chronic HTN
Used in outpatient urgency due to its effect on slow reduction of BP to a safe level (single oral dose)
reduce SNS symptoms by alcohol, opioid/ nicotine withdrawal.
Methyldopa
use in pregnant woman
does not harm fetus
immunologic effects (Coombs-positive hemolytic anemia, autoimmune hepatitis, organ dysfunction)
S/E
sedation
dry mouth
impaired mental activity
rebound HTN if stop abruptly
Discontinuations of methyldopa
tapered gradually
over 1 to 2 weeks
ejection fraction
% of blood ejected from the left ventricle during each systole
Angiotensin Inhibition
Angiotensin Inhibitors
ACE inhibitors (-pril) (cerebroprotective)
Angiotensin Receptor Blockers (-sartan) (cerebroprotective)
Direct renin inhibitor (aliskiren)
Initial treatment of HTN
ACE Inhibitor (MILD to SEVERE HTN acts by reducing PVR ,can decrease venous pressure )(decreased cardiac preload and afterload),
little effect on Cardiac output & Blood volume)
Angiotensin receptor blocker
effective in reducing risk of stroke
renoprotective (decrease progression of renal failure & subsequent dialysis) effective for patient with diabetes (albuminuria, raised serum creatinine levels)
or heart failure
protective against MI
enhance survival of left ventricular dysfunction (cardiac ejection fraction less than 40%)
ACE inhibitor Mechanism of action
bind to zinc atom in active site of enzyme
varying degree of first-pass hepatic inactivation
most ACE inhibitor (except captopril) actions is about 24h
drug administration: once/ twice daily (for HTN and others)
catalyze inactivation of bradykinin
hypotensive effect can be increased by increase renal prostaglandin production
compensatory elevated renin secretion is counteracted by direct renin inhibitor (aliskiren)
consequent of treatment: serum potassium levels increased by 0.5mEq/L
stimuli for renin secretion
decreased arterial pressure in renal afferent arterioles
decreased NaCl in dista renal tubule
SNS activation of B1-adrenoreceptors on renal juxtaglomerular cells
AT1 receptor activation
increased production of IP3
Increased production of arachidonic acid metabolites
Decreased formation of CAMP
Effects after activation of AT1 (angiotensin II receptor type I)
general vasoconstriction
aldosterone secretion from adrenal cortex
increased proximal tubule reabsorption of sodium
increased NE production from SNS nerves
stimulation of cell growth arteries and heart
AT2 (angiotensin II receptor type II)
CVS
involve in metabolism
adverse drug reactions,ACE inhibitor
FETAL & NEONATAL injury and death (2nd and 3rd trimesters)
renal failure in those with bilateral renal artery stenosis (dependent on AII)
S/E
dry cough (elevated bradykinin levels)
chronic bradykinin accumulation leads to angioedema (manifests as painful swelling of the lips, faces, throat)
sulfhydryl group -zinc binding moiety S/E
rash
abnormal taste sensation (Eg INDUCED BY captopril)
Augmentation of antiHTN
1)diuretics 2)CCB (calcium channel blocker)
Hyperkalemia caused by
potassium sparring diuretics, k+ supplements with ACE inhibitor
Lithium toxicity
lithium used in treatment of bipolar disorders
increased serum lithium by the ACE inhibitor
NSAID impedes the effect of ACE inhibitor and other antiHTN drugs
phosphoryl
fosinopril (ace inhibitor)
carboxyl
benazepril, enalapril, lisinopril, quinapril, ramipril
prodrug of ACE Inhibitor
all except captopril and lisinopril
PO (oral administration)
1) all except enalaprilat (active form of enalapril) IV 2) bioavailability is 25-75%
frequency of administration
1) captopril 2-3 times a day (shorter half life than others) 2) the rest twice a day
Angiotensin receptor blocker
selectively block AT1 receptor
decrease vasoconstriction
decrease aldosterone secretion
decrease sodium reabsorption
decrease NE released from SNS nerve terminal
effectiveness
effective when used alone
combination with calcium channel blocker
combination with other anti HTN drugs
combination of ACE inhibitor with Angiotensin receptor blocker for high risk diabetic nephropathy & others.
as effective as ACE inhibitor but rarely cause dry cough as in with ACE inhibitor.
PO angiotensin receptor blocker
candesartan
irbesartan
losartan
telmisartan
valsartan
losartan vs atenolol (similar blood pressure lowering effect)
losartan effect- a greater reduction of left ventricular hypertrophy, reduce risk of stroke, reduce onset diabetes (new-onset diabetes)
telmisartan
enhance insulin sensitivity
via activation of peroxisome proliferator-activated receptor gamma (involve in glucose homeostasis and regulate adipocytes differentiation (negative regulator of macrophage activation) (expressed in adipose tissue, adrenal gland and spleen)
same effectiveness as ramipril
more powerful blood pressure lowering ability than ramipril
Advantages of angiotensin receptor blocker
does not increase serum glucose
does not increase uric acid
does not increase cholesterol level
s/e
hyperkalemia
neutropenia
elevated serum hepatic aminotransferase enzymes
Angiotensin receptor blocker contraindications
not to be used in pregnant women as it cause harm in fetus and death
Aliskiren- decrease plasma renin thereby Angiotensin I and AII
-protective against compensatory rise in AII induced by other anti HTN drug.
-equal to superior blood-pressure lowering effect than other drugs
-resemble placebo side effect profile
-contents : hydrochlorothiazide, amlodipine, valsartan
Vasodilators
calcium channel blocker
hydralazine
minoxidil
nitroprusside
Indications for calcium channel blocker
HTN
angina pectoris
peripheral vascular disorder
cardiac arrhythmias
Calcium Channel Blocker Mechanism of action
Inhibit Ca2+ channel on the Plasma membrane of vascular smooth muscles
Relaxation of vascular smooth muscle
Vasodilation
Greater effect on arteriolar smooth muscle than venous smooth muscles
Greater effect on reduction of PVR
less effect on venous capacitance, cardiac preload (cardiac filling pressure) and Cardiac output
has some effect of natriuresis
CCB such as Diltiazem and Verapamil
significant effect on heart
decrease heart rate
decrease Cardiac output
CCB of dihydropyridine class
amlodipine
felodipine
isradipine
nicardipine
nifedipine
Dihydropyridine vs (Diltiazem and verapamil)
less effect on cardiac tissue
evoke/ stimulate reflex tachycardia
CCB
first line treatment of HTN
combination with diuretics/ angiotensin system inhibitors
protection against stroke, coronary heart disease, kidney disease
verapamil & diltiazem
decrease protein excretion in patients with kidney disease
combination with angiotensin receptor inhibitor and ACE inhibitor
adverse effect- no/ free
benefits
do not alter serum glucose
do not alter serum lipids
do not alter uric acid
do not alter electrolytes
HTN in asthma/ african
24-h BP control in HTN
amlodipine (long acting)
nifedipine (sustained release), gastrointestinal system
Vasodilators
Hydralazine
Minoxidil
to treat moderate to severe HTN
adverse drug reactions when used alone
Evoke reflex tachycardia
Cause fluid retention
Exacerbate Angina
*counteract adverse drug reactions by drug combinations*
diuretics+ B-adrenoreceptor antagonist/ sympatholytic agent
S/E hydralazine
lupus-like syndrome
S/E minoxidil
hypertrichosis (excessive hair growth in women)
minoxidil
topical
indicates for alopecia in men and women (Rogaine)
DRUG Reservation to overcome resistant anti HTN drug
hydralazine
minoxidil
Nitroprusside
sodium nitroprusside (HTN emergency)
IV administration
Short-half life
Rapid metabolization to cyanide in RBC (erythrocytes)
cyanide can be converted to thiocyanate
accumulation of thiocyanate & cyanide gradually (monitor BP and thiocyanate levels every 3 days to prevent potential toxicity
duration of therapy limited to a few days
Fenoldopam
Rapid-acting
IV administration
HTN emergency
activates vascular dopamine D1 receptors
promote vasodilation in coronary, renal (vasodilation of afferent and efferent arterioles- increased renal blood flow) and mesenteric vascular bed
short half-life
5minutes half-life
decrease serum potassium
monitor every 6 h
single-drug therapy
preferred for initial treatment of mild HTN
eg: angiotensin inhibitor (preferred)
OR
CCB (Preferred)
thiazide diuretics (less favored)
b-blocker reservation for patient (with heart disease eg: angina pectoris)
benefit of combined drug treatment
lower doses
associated with less s/e
most common combined drug
CCB + Angiotensin blocker (amlodipine, valsartan) thiazide diuretic + ACE inhibitor/ CCB
HTN >65 years Initial treatment
dihydropyridine (CCB)
or
2. Angiotensin inhibitor
>70years
beta blocker decrease Cardiac output significantly -cardioprotective effect of b-blocker if well tolerated will be given
black elderly
1)diuretic or 2) CCB with or without angiotensin inhibitor
patient with IHD, angina pectoris, MI
treat with B blocker + ACE inhibitor/ angiotensin receptor blocker
b blocker protect against sudden death
diabetes mellitus
blood pressure controlled at < OR at 130/80mmHg
DECREASE the risk of progression of diabetic nephropathy to end-stage renal disease
ACE inhibitors / ARBs- anti HTN- ability to reduce the progression of diabetic nephropathy
B blocker (drug effect)
sequestered signs of hypoglycemia
block glycogenolysis
but can be managed easily
(non-selective) b-blocker contraindication
asthma (due to potential bronchoconstriction resulted from the drug action) (drug binds to b2-adrenoreceptor)
Hypertensive emergency
severe elevated bp (greater than 180/120mmHg)
organ dysfunction (encephalopathy, intracranial hemorrhage)
upper level stage 2 HTN
severe headache
SOB
severe anxiety
case presentation
Woman, 56y
medical hx of 8y type 2 diabetes, 5y HTN
medications taken
1)metformin (decrease glucose absorption from GI tract and formation in the liver, enhance insulin sensitivity) 2) thiazide diuretic for blood pressure (decrease insulin sensitivity)
investigation
bp 138/86mmHg
microalbuminuria (proteinuria) (50 micro/min over 24h)
new prescriptions
valsartan
amlodipine
glipizide
discontinued thiazide diuretics
new management
dietitian exercise counselor
type 2 diabetes & HTN
increased risk of proteinuria
increased risk of chronic kidney disease
Metformin with
glipizide
incretin mimetics (sitagliptin) (stimulate decrease in plasma glucose)
excess blood pressure reduction can
precipitate renal ischemia
precipitate cerebral ischemia
precipitate coronary ischemia
short-acting nifedipine no longer used in emergency setting
Blood pressure control in more systematic manner
bp no more than 25% in 1 h
target to 160/100mmHg next 2-6h
gradual BP reduction 24 to 48h
eclampsia
1)seizure not due to altered brain electrical activity
2) causes may be from Blood vessels, brain , nervous system, diet ,genes
3) induced by hydralazine
drugs used in emergency setting
fenoldopam
nicardipine
labetalol
sodium nitroprusside
acute coronary ischemia + HTN emergency
nitroglycerin
acute left ventricular failure
enalaprilat
aortic dissection + perioperative HTN
esmolol
pheochromocytoma
non malignant
tumor release catecholamine
tumor of the adrenal medulla
highly vascularized
hypertensive crisis
sudden (paroxysmal) /continuous release of epinephrine or norepinephrine
surgical removal of pheochromocytoma
pre-operative treatment with phenoxybenzamine (to induce long-lasting alpha adrenoreceptor blockade + b-blockers)
tyrosine hydroxylase
rate limiting enzyme involving catecholamine biosynthesis
metyrosine- tyrosine hydroxylase inhibitor
antiHTN
Diuretics
Vasodilator
Angiotensin-inhibitor
sympatholytic drug
thiazide diuretic :short-term effects
decrease blood volume
decrease cardiac output
thiazide diuretic :long-term effects
reduce total peripheral vascular resistance
sympatholytic drugs
alpha-adrenoreceptor antagonists (reduce peripheral vascular resistance)
b-adrenoreceptor antagonists (reduce cardiac output)
centrally-acting drug(reduce peripheral vascular resistance)
angiotensin inhibitors
ACE inhibitors (lisinopril)
Angiotensin receptor blocker (losartan)
direct renin inhibitor (aliskiren)
main functions
decrease PVR
decrease aldosterone levels
fewer effect on blood volume (for patient with no heart failure)
fewer effect on Cardiac output (for patient with no heart failure)
vasodilators
Calcium channel blocker
hydralazine (provoke fluid retention and reflex tachycardia)
minoxidil (provoke fluid retention and reflex tachycardia)
nitroprusside
Main drug functions
decrease PVR
#b-blocker &angiotensin system inhibitor : beneficial for patient with heart disease
#angiotensin receptor blocker protective effect on stroke
angiotensin system inhibitor : beneficial for patient with kidney disease
#GINGIVA enlargement caused by calcium channel blocker, phenytoin (for seizures)
, ciclosporin (immunosupressant- for transplant rejection and psoriasis)
2. irbesartan (angiotensin II inhibitor)
3. metoprolol (b-blocker)
doxazosin (alpha-blocker)
grape fruit increase the dose of the ccb (causing severe hypotension)
inhibit cytochrome p450 3a4 (in the gut and liver)
cytochrome p450 3a4 metabolise ccb
amlodipine and doxazosin do not affect insulin sensitivity
-thiazide diuretic cause a small decrease in insulin sensitivity
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