hypertension Flashcards
1
Q
physiology of RAAS
A
liver synthesises angiotensinogen
angiotensinogen circulating in blood
less blood to brain –> stimulates sympathetic system –> stimulates beta 1 receptors in kidney –> renin is secreted –> converts angiotensinogen into angiotensin 1 –> ACE by endothelial cells of lungs converts angiotensin 1 to angiotensin 2
Angiotensin 2 acts on AT1 receptors present on various organs and increases Bp
2
Q
angiotensin 2 receptor
A
acts on AT1 receptors on various organs and increases BP
1. adrenal cortex -> increases aldosterone secretion (Na+ reabsorption - increases BP, K+ loss - hypokalaemia)
- blood vessels - arteries and veins - constriction
- heart - cardiac hypertrophy - oxygen demands increase - leads to chronic heart failure
3
Q
RAAS inhibitors
A
- direct renin inhibitors (-iren)
- ACE inhibitors (-pril)
- AT1 receptor inhibitors (-sartan)
4
Q
MoA of RAAS inhibitors
A
- reduce aldosterone secretion - Na+ loss in urine - diuretic
(SE - hyperkalemia) - Artery and vein - dilator
- Heart - reduce cardiac hypertrophy (cardioprotective effect - given in chronic heart failure)
5
Q
RAAS inhibitors should be avoided with which diuretic
A
K+ sparing diuretics
Both produce hyperkalemia
6
Q
drugs which reduce renin secretion from kidney
A
beta blockers
central sympatholytics - Clonidine, alpha methyl dopa
Also produce hyperkalemia
7
Q
drugs causing hyperkalemia
A
ABC CNS
alpha methyl dopa
beta blocker
clonidine
cyclosporine /tacrolimus - immunosuppressive agents
NSAID
spironolactone (K+ sparing diuretic)
RAAS inhibitors
8
Q
direct renin inhibitors
A
Aliskiren (only approved drug) - binds to renin and renin can no longer work
Remikiren, Enalkiren (under trial)
9
Q
Aliskiren
A
oral
use - as an anti hypertensive
SE & CI - same as ACE inhibitors
adv - does not increase bradykinin level (done by ACE inhibitors)
10
Q
ACE inhibitors
A
location - endothelial cells of blood vessels in lungs
non specific carboxypeptidase enzyme
increases bradykinin level -
adv: bradykinin is a vasodilator and decreases blood pressure -> thus, ACE inhibitors have additional antihypertensive effect
disadvantage: causes allergy (DARU)
dry cough
angioedema
rhinitis
urticaria
11
Q
functions of ACE
A
- breaks down angiotensin 1 (10 amino acids) into angiotensin 2 (8 amino acids)
- degrades bradykinin
12
Q
SE of ACE inhibitors
A
dry cough is the most common SE of ACE inhibitors (incidence - 15%)
angioedema
rhinitis
urticaria
13
Q
treatment of ACE inhibitor in diced dry cough
A
stop ACE inhibitors and change to sartans which do not increase bradykinin (best treatment)
aspirin + iron is found to be effective to control dry cough
14
Q
ACE inhibitor drugs
A
CRPF BELT QM
Captopril - 1st discovered
Ramipril
Perindopril
Fosinopril
Benazepril
Enalapril
Lisinopril
Trandalopril
Quinapril
Moxepril
15
Q
Captopril disadvantage
A
sulpha drug - bone marrow depression
shortest drug - twice/day
food reduces absorption
thus, rarely used now
other drugs -
no sulpha
long acting - once/day
no food interaction
16
Q
longest ACE inhibitor
A
Perindopril > Ramipril
17
Q
ACE inhibitor which does not require dose reduction in renal failure
A
Fosinopril (excreted in bile also)
18
Q
ACE inhibitor which is pro drug
A
All ACE inhibitors are pro drugs except
Captopril
Lisinopril
Enalaprilat (active form of Enalapril)
19
Q
active form of Enalapril
A
Enalapril (oral) ——-> Enalaprilat (iv drug) - used in hypertensive emergencies
20
Q
uses of ACE inhibitors
A
- DOC hypertension (essential hypertension)
- DOC hypertension + DM - does not interfere with blood glucose, HTN + CKD (nephropathy) - renoprotective effect, HTN + retinopathy - retinoprotective effect, HTN + stroke - neuroprotective effect, HTN + scleroderma - reduces collagen deposition
- DOC CHF - reduces cardiac hypertrophy
21
Q
renoprotective effect of ACE inhibitors in CKD
A
here, CKD - albuminuria (because usually kidney cannot filter albumin)
hyper filtration of living nephrons (increased GFR) –> albumin is filtered –> damage nephrons –> vicious cycle –> end stage renal disease
ACE inhibitors dilate efferent arterioles –> slightly reduce GFR –> reduce hyperalbuminuria –> reduce albuminuria –> reduce damage of nephrons
22
Q
CI of ACE inhibitors
A
bilateral afferent renal artery stenosis
GFR become extremely low and will lead to oliguria and ARF
should not be combined with NSAIDs (constricts afferent arterioles)
also CI in pregnancy (Category X drug) - renal agenesis in foetus - oliguhydramnios –> pulmonary hypoplasia (Potter sequence)
23
Q
Summary of ACE inhibitor
A
CAPTOPRIl
Cough - bradykinin
Angioedema - bradykinin
Pregnancy (no) - X category
Taste disturbance - dysguesia - seen with Captopril (sulpha)
Orthostatic hypotension
Prodrugs (except Captopril and Lisinopril)
Renal afferent artery stenosis CI
Increase K+ - hyperkalemia
Low blood count - bone marrow suppression (mainly seen with Captopril)
24
Q
Angiotensin receptors
A
AT1 - AT5 (All are GPCR)
AT1 - Gq type-excitatory - increases BP
AT2-Gi type - decreases BP
Block AT1 to decrease BP
25
AT1 receptor blockers
Losartan (lowest affinity for AT1)
Olmesartan
Valsartan
Elprosartan
Telmisartan
Irbesartan
Candesartan (highest affinity for AT1)
All are oral drugs only
All are competitive blockers of AT1 receptor but their effect is non surmountable because sartans bind irreversibly with very high affinity
26
uses, SE, CI of ARBs
same as ACE inhibitor
except tartans do not interfere with ACE enzyme, thus, they do not increase bradykinin level, and do not produce DARU SE
27
Unique properties of Sartans
Losartan has anti platelet effect as it blocks thromboxane receptor on platelets & has uricosuric action (excretes uric acid in urine) and thus, is good for gout
Telmisartan is PPAR gamma agonist (like Pioglutazone used in DM) so is good for DM
28
unique SE of sartan
causes sprue (diarrhoea) because increases Angiotensin 2 levels
max seen with Olmesartan > other drugs
29
MoA of calcium channel blockers
Blocks L (long) type of calcium channel
present in muscles like cardiac muscle and smooth muscle in blood vessels
30
types of calcium channels
L type (long) - CCB blocks
T type - neurons - seizures - ethosuximide, valproate
N type - neurons (pain) - Ziconotide (conotoxin) - painkiller
31
CCB types
1. DHP types (di hydro pyridine): (-dipine)
2. non DHP type - Diltiazem (Benzothiazepine grp) , Verapamil (Phenyl alkyl amine group)
32
Dipines
Artery dilators - blood vessels only
do not act on heart
SE: reflex tachycardia because of sympathetic stimulation
to treat this reflex tachycardia, dipines are routinely combined with beta blockers
33
Diltiazem
acts on heart and blood vessels
blocks SAN (bradycardia) & AV (heart block)
CI in sick sinus syndrome and 2nd degree and 3rd degree heart block
never combined with beta blocker - will lead to marked bradycardia & cause complete heart block
34
Verapamil
acts on heart>> blood vessels
blocks SAN (bradycardia) & AV (heart block)
CI in sick sinus syndrome and 2nd degree and 3rd degree heart block
never combined with beta blocker - will lead to marked bradycardia & cause complete heart block
35
Verapamil
most cardioprotective CCB (heart > BV)
SVT (arrhythmia) > angina (blocks SA node --> decreases HR --> decreases oxygen demand) > HTN (artery dilator)
also blocks N type calcium channel - treatment of pain in migraine headache
inhibits CYP 3A4
inhibits P glycoprotein
most common SE - vasodilatory headache
ventricular tachycardia and supra ventricular tachycardia
VT is more dangerous - ineffective contraction - blood decreases to aorta and brain - sudden death
SVT is of two types - atrial flutter and atrial fibrillation
SVT can lead to VT
therefore, we should SVT ---> VT so we have to block AVN
most effective for blocking AVN is Verapamil
36
CCBs approved in migraine headaches
Verapamil
Flunarizine (only for migraines)
37
Diltiazem
most preferred CCB in angina > HTN > SVT
also CYP3A4 inhibitor and P glycoprotein inhibitor
most common SE - headache
adv: less risk of bradycardia as compared to Verapamil
38
most preferred CCB
SVT : Verapamil
Angina : Diltiazem
HTN : Dipines
39
Dipines
DOC: HTN > Angina
DOC for peripheral vascular disease (Raynaud's diseases, pulmonary artery HTN, vasospastic angina - constriction off coronary artery) as divines are artery dilators [in PVD, beta blockers are CI]
CI: SVT (arrhythmia) - themselves cause reflex tachycardia - thus, combine with beta blockers
40
Nifedipine
short acting
sudden erratic absorption - sudden vasodilation - max risk of reflex tachycardia - increases oxygen demand of the heart - precipitate risk of angina and MI
can itself cause paradoxical angina
therefore, oral Nifedipine is not used
thus, sustained release oral preparation of Nifedipine is used - long acting - gradual vasodilation - less risk of reflex tachycardia, this, used in HTN
iv Nifedipine and sl Nifedipine is used ion the treatment of hypertensive emergencies (SE - hypotension)
41
Amlodipine
longest acting oral CCB - least risk pod reflex tachycardia
liver and renal safe
large volume of distribution (t1/2 is directly proportion to Vd) thus, long acting
least drug interaction ( does not interfere with CYP enzymes)
overall Doc for HTN
42
Nicardipine
longest acting iv CCB
Doc for hypertensive emergencies
43
Clevidipine
shortest acting iv CCB - rapidly metabolised by plasm,a esterases (like Esmolol)
used in hypertensive emergencies along with beta blockers like Esmolol, Labetalol (because short acting drug - may lead to reflex tachycardia)
44
Nimodipine
crosses BBB --> cerebral artery dilation --> thus, cerebroselective CCB
DOC for arachnoid hemorrhage to prevent cerebral vasospasm that occurs after sub arachnoid hemmorrhage
perianeurysm in meningeal arteries due to damage to arteries caused by HTN - rupture of artery - thunder clap headache/ "worst headache of my life" - bleeding isn't the problem because you can perform craniotomy (intraventricukar drain) and take out the blood - but after 3 days, digital substitution angiography - vasospasm as body tries to start protective mechanism - ischemic stroke - death)
45
Other dipines
Felodipine
Nitredipine - increases NO production and has anti atherosclerotic action)
Benidipine
Isradipine
46
Side effects of CCBs
Hypertensives Usually FORGeT CCB
m/c: Headache - cerebral VD --> sensory nerves wrapped around BV- one of the organs in brain that can carry pain is BV - VD - pulsatile headache
Urinary retention (detrusor muscle relaxation)
Flushing ( arteries of face dilate)
Oedema in ankle (plasma leakage)
Reduce BP (Hypotension)
Gerd (due to relaxation of LES)
Tocolytic effect (relaxation of uterus)
Constipation (relaxation of intestinal muscles)
47
antidote of CCB toxicity
iv calcium gluconate
48
adv of CCB over beta blocker
CCB are safe in asthma and COPD (beta blocker can precipitate asthma/ COPD
CCB safe in PVD (beta blocker can precipitate PVD)
CCB safe in diabetes and dyslipidemia (beta blockers bad for diabetes and dyslipidemia)
49
DOc for hyperthyroidism/thyroid storm to control arrhythmia or tachycardia
beta blocker
but if patient is asthmatic - DOC: Verapamil or Diltiazem
50
vasodilators
directly dilates BV
artery dilator - K+ channel opener (Minoxidil, Diazoxide, Hydralazine, Nicorandil)
veins dilator - nitrates
combined dilator - nitroprusside
51
other classes of antihypertensives which have vasodilatory effect
artery dilators - CCB, Fenoldapam (D1 agonist)
combined dilator - ACE inhibitors, alpha blockers
52
common SE of vasodilator
same as CCB
flushing
oedema
reflex tachycardia
postural hypotension
53
artery dilators
K+ channel blockers
cell outside more sodium and cell inside more potassium
potassium channel opener will lead to efflux of K+ which will lead to decreases positive charge inside cells - hyperpolarisation of muscles - muscles relax - muscles in BV relax - vasodilation
54
Minoxidil
pro drug
active form is Minoxidil sulphate
converted by phase 2 conjugation reaction (most drugs because active by phase 1 reactions except minoxidil and morphine)
uses-
1. hypertension
2. hair growth (cutaneous vasodilator) - topical creams applied on scalp for treatment of alopecia & oral Minoxidil (SE: hirsutism)
55
Alopecia
best - hair transplant
drugs - Minoxidil, Finasteride/Dutasteride (5 alpha reductase inhibitor) ---- 5% for males, 2% for females
New drug approved - Baricitinib (JAK inhibitor )- increases chance of Tb
56
Diazoxide
Also opens K+ channel on beta cells of pancreas
betray cells become hyperpolarised
insulin secretion inhibited
thus, Diazoxide treatment of insulinoma & CI in DM (will lead to hypoglycaemia)
57
Insulinoma
best Tx: surgical removal
when unfit for surgery
1. reduce insulin secretion - Octreotide (somatostatin), Diazoxide
2. kill beta cells of pancreas - Streptozotocin (anticancer drug) - overall DOC for insulinoma
58
Hydralazine
MoA: K+ channel opener, antioxidant action, Nitric oxide donor
Uses:
1. HTN
2. heart failure - cardioprotective effect [SHIP drugs - undergoes acetylation; common SE of SHIP drugs - DLE(drug induced lupus erythramatosus)]
59
Nicorandil
K+ channel opener - used as an antianginal drug
60
Nitric Oxide donors
1. nitroprusside - direct NO donor
2. nitrates - enzyme (MAD - mitochondrial aldehyde dehydrogenase) dependent NO donor
inside smooth muscle of BV, these drugs donate NO --> activates soluble guanylyl cyclase --> increases cGMP (degraded by phosphodiesterase) --> relaxes muscle/VD
61
nitroprusside vs nitrates
nitroprusside direct No donor while nitrates MAD enzyme dependent NO donor (MAD enzyme only in veins - not in arteries) thus, nitrates are o only ventilators and nitroprusside is combined dilator
nitroprussides have no tolerance while nitrates show tolerance (with time, the effect off the drug reduces - since MAD enzyme stops functioning due to down regulation and leads to loss of effect of nitrate)
nitroprussides are used in hypertensive emergencies while nitrates are used in HTN, angina/MI, CHF
62
PDE inhibitors
Sildenafil (used in impotence) - gap of 24 hrs with nitrate
Avanafil - gap of 24 hrs with nitrate
Vardenafil - gap of 24 hrs with nitrate
Tadalafil - gap of 72 hrs with nitrate
inhibit degradation of cGMP --> massive increase in cGMP --> massive VD --> hypotension and sudden death
63
Nitroprusside
direct NO donor and a combined vasodilator
iv drug
fastest acting antiHTN drug - thus, used in hypertensive emergencies
SE:
1. nitroprusside goes to the liver and is converted into cyanide - cyanide toxicity
2. thiocyanide toxicity - inhibits iodine entry into thyroid and causes hypothyroidism
3. should be protected from light since nitroprusside is photo volatile (thus, stored in amber coloured/black coloured bottles)
64
Cyanide toxicity
cyanide inhibits cytochrome c (mitochondrial enzyme) --> thus leading to histotoxic hypoxia
cytochrome c helps in ETC (which helps utilise oxygen into ATP)
treatment: (cyanide kit)
1. Hydroxycobalamine iv - vit B12 (DOC/ antidote for cyanide poisoning) - cobalt chelates with cyanide and does not let it enter the cell
2. Nitrites - inhalational Amyl nitrite & iv sodium nitrite - direct NO donor --> converts Hb into meth HB which chelates with cyanide
3. Sodium thiosulphate - increases urinary excretion of cyanide
65
HTN
sustained elevation of BP d/t which there is risk of organ damage (increases mortality)
66
Pathophysiology of HTN
increased sympathetic discharge in brain --> adrenergic nerves to heart, BV, kidney --> rerelease of epinephrine, norepinephrine -->
acts on beta receptor of heart --> leads to calcium entry --> increases HR -- increases SBP
acts on alpha receptors of BV --> calcium entry --> vasoconstriction --> increases DBP
acts on beta 1 receptor of kidney --> stimulate renin release --> activation of RAAS --> inhibition of diuresis --> increases blood volume --> increased BP
note: there is an alpha 2A receptor in our brain which reduces sympathetic discharge
67
antiHTN classes of drugs
1. sympatholytics
2. diuretics
3. RAAS inhibitors
4. CCB
5. vasodilators
68
Sympatholytics
1. central sympatholytics which act in brain and stimulate alpha 2A receptor and thus, decrease sympathetic discharge
Clonidine, alpha methyl dopa
in heart- decreases SBP (decreases cardiac output)
in BV - vasodilation
in kidney - decreases renin release
69
Adrenergic neuron blockers
inhibits releases of epinephrine, norepinephrine from nerves
Guanethidine (not used as it causes severe postural hypotension), Reserpine (increases risk of suicide)
70
Alpha blockers
Phentolamine
acts on BV and produces vasodilation
71
Beta blockers
Propranolol
acts on heart (decreases cardiac output) and kidney (decreases renin)
72
Diuretics
DOC thiazides but not used in severe HTN (over 160/100) in which case loop diuretics is given
Spironolactone is DOC for resistant HTN
73
Types of HTN
primary HTN / Essential HTN - idiopathic - most common cause
Secondary HTN - associated with some comorbidity (identifiable cause) - eg - hyperthyroidism, pheochromocytoma, CKD
74
Risk factors for HTN
strongest risk - high sodium diet
obesity
DM
genetic causes
75
lifestyle modification in Tx of diabetes
low salt diet (<5g/day)
76
BP guidelines (AHA)
normal BP : <120/80
stage 1 HTN: >130/80
stage 2 HTN: >140/90
HTN crisis: >180/120
77
BP guidelines ( JNC 8 by WHO)
no stages
patient age> 60 (old age) target BP < 150/90
patient age<60 (young age) target BP <140/90
race - black - C, D (avoid ACE inhibitors); white - A,C,D
DM (irrespective of age) target BP <140/90
DOC - ACE inhibitors, CCB, diuretics - thiazide
CKD (irrespective of age) target BP <140/90 - DOC - ACE inhibitors
78
1st line drugs for essential HTN
Ace inhibitors > ARBs
CCBs - dipines
Diuretics - thiazides
rest are all 2nd line drugs of essential HTN(eg; beta blockers)
79
uncontrolled HTN
BP not controlled with 2 classes of anti-HTN drugs at maximum dose
treatment - add 3rd drug
80
Resistant / persistent HTN
BP not controlled with 3 drugs at maximum dose
Tx: Add 4th drug - DOC Spironolactone
81
Refractory HTN
BP not controlled with 5 drugs
Tx: not defined
role of surgery - renal sympathectomy
82
beta blocker is DOC for HTN with which comorbidities
HTN with
stable angina
HOCM
aortic dissection
atrial fibrillation
migraine
hyperthyroidism
83
ACE inhibitors (or ARBs) is DOC for HTN with which comorbidities
CKD
microalbuminaria
ESRD
diabetes
metabolic syndrome
stroke
retinopathy
scleroderma
84
CCB (DHP type) is DOC for HTN with which comorbidities
peripheral vascular disease
renal artery stenosis
atherosclerosis
isolated systolic HTN
85
alpha 1 blocker is DOC for HTN with which comorbidities
Prazosin, Doxazosin (also opens internal urethral sphincter)
86
DOC for HTN with osteoporosis
diuretics - thiazide ( preserve calcium - increases bone density)
87
DOC for HTN with post menopausal hot flushes
Clonidine (acts on brain and inhibits VMC)
88
DOC for HTN with hyperaldosteronism
Spironolactone/ Eplerenone (blocks aldosterone receptors)
89
DOC for HTN with pheochromocytoma
Phenoxybenzamine
90
DOC for HTN with cheese reaction and clonidine sudden withdrawal
Phentolamine
91
antiHTN CI in gout
thiazide/loop diuretic (increases uric acid)
92
antiHTN CI hyperkalemia, renal artery stenosis, pregnancy, angioneurotic edema
ACE inhibitors
93
antiHTN CI in hyperkalemia, serum creatinine> 2.5mg/dl
Spironolactone
94
antiHTN CI asthma, COPD
beta blockers
95
antiHTN CI bradycardia, AV node block
Beta blockers and Verapamil, Diltiazem
96
antiHTN CI heart failure
Verapamil, Diltiazem
97
antiHTN CI depression
alpha methyl dopa
98
antiHTN safe in pregnancy
Safe -
Mother - Methyl dopa
Cares - Clonidine
Baby - beta + alpha blocker (Labetalol)
During - divines (Nifedipine)
Her - Hydralazine
Pregnancy - Phentolamine
99
antiHTN unsafe in pregnancy
Spironolactone
ACE inhibitor / ARB - absolutely CI (category X)
Atenolol (only beta blocker not given as it causes VC)
Nitroprusside (cyanide toxicity)
Diuretics (less blood delivered to foetus through placenta)
100
chronic HTN in pregnancy
DOC - alpha methyl dopa (safest)
add Labetalol
101
pregnancy induced HTN/ preeclampsia
normal female becomes pregnant ---> after 20 weeks of gestation --> increase in BP
Tx: Labetalol --> add Hydralazine --> add Nifedipine
102
overall DOC for HTN in pregnancy
Labetalol
103
safest antiHTN in pregnancy
alpha methyl dopa
104
hypertensive crisis
>180/120
HTN urgency - no organ damage - DOC: Clonidine
Han emergency - end organ damage (eg; stroke, MI, aortic dissection , ARF) DOC: Nicardipine
105
Malignant HTN
rapid increase in BP that requires an iv drug for treatment
106
drugs for hypertensive emergency
Now Nobody CAN HELP U Finally
Nicardipine (Overall DOC)
Nitroprusside (HTN encephalopathy/stroke)
Clonidine
ACE inhibitor - Enalaprilat
Nitrates
Hydralazine
Esmolol/Labetalol
loop diuretics
Phentolamine
Urapidil, Indoramine (alpha 1 blocker)
Fenoldapam (D1 agonist)
107
drugs not used in HTN crisis
thiazides not given but loop diuretics given
At1 receptors/ sartans not given but ACE inhibitors given
108
