Hypolipidemics and vasodilators Flashcards
(74 cards)
1
Q
Receptor which absorbs cholesterol into the intestinal cell
Drug which inhibits it
A
NPC1L1 receptor
Niemann Pick C1 like1 receptor
Exetimibe inhibits this receptor
2
Q
MTP of lipid metabolism
Inhibited by
A
Microsomal Transport Protein
Transports lipids into the RER of liver to be combined with proteins (to form VLDL)
Inhibited by Lomitapide (used along with Icosapent)
3
Q
Avasimibe
A
Inhibitor of ACAT (Acyl CoA transferase) which esterifies cholesterol
Under trial
4
Q
Icosapent
A
Blocks secretion of VLDL from liver
Used along with Lomitapide against genetic condition called familial hypertriglyceridemia.
5
Q
Fibrates
A
Derivatives of fibric acid
Increases activity of LPL (lipoprotein lipase) ➡️
increased removal of TAG from lipoproteins ➡️
decrease in TAG, VLDL and chylomicron
Side effect: increases LDL
6
Q
Mipomersen sodium
A
Blocks synthesis of apo B-100 ➡️ decreases LDL
7
Q
LDL receptor are increased by
A
- Statins
- Ezetimibe: decreased extrinsic cholesterol
- Bile acid binding resins
- PESK-9 inhibitors:
Evolocumab, Alivocumab
PESK-9 facilitates degradation of LDL receptor
8
Q
Statins
Decreases LDL receptor by which mechanism
A
Competitive inhibitor of HMG CoA reductase inhibitors ➡️ intrinsic cholesterol decreases ➡️ increased demand for extrinsic cholesterol
9
Q
Statins examples
A
Rosavastatin Atorvastatin Pravastatin Fluvastatin Simvastatin Pitavastatin
10
Q
Mechanism of action of statins
A
Competitive inhibition of HMG CoA reductase activity (activity increases at night)
- ➡️ Decreased cholesterol synthesis ➡️ LDL receptor increases ➡️ decreased plasma LDL
- Inhibits VLDL synthesis ➡️ decreased TAG
- Increases HDL
11
Q
Pleiotrophic effects of statins
A
Non lipidemic beneficial effects:
- Anti aggregant effect
- Anti coagulant effect
- Anti inflammatory effect (decreased CRP)
- Vasodilation (increased NO)
- Plaque stabilising effect
12
Q
Uses of statins
A
- DoC for treatment of dyslipidemia (eg., type II hyperlipoproteinemia)
- 1°and 2° prophylaxis of atherosclerotic cardiovascular disease (stable angina, MI, stroke)
13
Q
Absorption of statins
A
Good oral absorption
Maximum with prodrugs like lovastatin and simvastatin (which are highly lipid soluble) which can cross BBB
14
Q
First pass metabolism of statins
A
High first pass metabolism of statins
(But they have high plasma protein binding)
Reflux pump called OAT P1B1 (organic anionic transporter)
This is inhibited by gemfibrozil ➡️ increased bioavailability of statins
15
Q
Metabolism of statins
A
Phase-1:
By CYP3A4, except fluvastatin, pravastatin, rosuvastatin
Phase-2:
By glucuronidation
t1/2 maximum: rosuvastatin > atorvostatin
16
Q
Most potent statins
A
Pitavastatin > Rosuvastatin
17
Q
Bile acid binding resins
Mechanism and examples
A
Block enterohepatic circulation of bile acids ➡️ Decreases bile acid in liver ➡️ decreases cholesterol ➡️ increases LDL receptors ➡️ decreases plasma LDL Examples: 1. Cholestyramine 2. Cholesevelam 3. Colestipol
18
Q
Side effects of statins
A
- Myopathy:
don’t monitor CPK since myopathy can be delayed by years - Hepatotoxicity:
Monitor ALT/AST every 3-6 months - Insulin resistance
- Pravastatin decreases fibrinogen levels
19
Q
CI of statins
A
- Pregnant women
- Children <10 years
Except pravastatin, which is CI for children <8 years
20
Q
Uses of bile acid binding resins
A
- Add on to statins
- Dyslipidemia with increased LDL
- DoC in pregnant women and children instead of statins
- Treatment of biliary gastritis and diarrhoea
- Colesevelam is used for treatment of type II DM
21
Q
Side effects of bile acid binding resins
A
- Increased VLDL➡️ hypertriglyceridemia (used only if TAG <300 mg/dl)
- Bloating
- Constipation
- Dyspepsia
22
Q
Niacin mechanism of action
A
- Stimulates Gi receptors of adipocytes
➡️ decreases cAMP
➡️ inhibits HSL
➡️ decreases FFA, TAG, VLDL, IDL and LDL - Increases HDL (maximum among hypolipidemics)
- Only drug that decreases Lp(a)
23
Q
Uses of niacin
A
- Add on to statins
- Dyslipidemia to increase HDL
Not preferred nowadays
24
Q
Side effects of niacin
A
- Increases PG ➡️ niacin induced flushing (DoC: aspirin)
- Hepatotoxic: ALT/AST monitoring required
- Insulin resistance: blood glucose monitoring
- Increased uric acid level
25
Examples of fibrates
| Uses
Clofibrate
Bezafibrate
Fenofibrate
Gemfibrozil
Uses:
1. DoC for type III hyperlipoproteinemia
2. DoC for hypertriglyceridemia and chylomicronemia syndrome
3. Fenofibrate: decrease uric acid, so used in gout with hypertriglyceridemia
26
Dosage, side effects and CI of fibrates
Dose: 30 minutes before food (food increases absorption)
Side effects:
1. Myopathy except bezafibrate
2. Choledocholithiasis: maximum with clofibrate
CI: renal failure
27
Mechanism of action of fibrates
Stimulates PPAR (paraoxysmal proliferation of activated receptor-α) ➡️ stimulates lipoprotein lipase:
1. Decreases TAG, VLDL and chylomicron
2. Increases LDL, IDL and HDL (maximum with gemfibrozil)
28
Classification of vasodilators
```
1. Arterial dilators:
decrease after load
2. Venodilators and mixed dilator:
decreases preload
S/E: postural hypotension
```
29
Examples of arterial vasodilators
1. Calcium channel blockers like amlodipine
2. Hydralazine
3. Minoxidil
4. Diazoxide
5. Fenoldopam
30
Classification of CCB
```
1. Non-DHP:
•Verapamil (most potent)
•Diltiazem
2. DHP (dihydropyridines):
•Amlodipine
•Clevidipine
•Nifedipine
•Nicardipine
•Nimodipine
All are racemic mixture of enantiomers except diltiazem and nifedipine
```
31
Special features of amlodipine
A DHP CCB like clevidipine
Longest acting CCB
Has maximum oral bioavailability
32
Special features of clevidipine
A DHP CCB like nicardipine
| Shortest acting CCB since it is metabolised by plasma esterase
33
Uses of CCBs
1. HTN (mild/moderate): 1st line drugs
2. HTN urgency: oral nifedipine
3. HTN emergency: IV nicardipine (DoC) > IV clevidipine
4. DoC in Raynaud’s disease
5. Cerebral vasospasm (2° to SAH)
34
Special features of nimodipine
| Special use
A DHP CCB like amlodipine
Has high lipid solubility and high affinity for cerebral blood vessel
DoC for cerebral vasospasm (2° to subarachnoid haemorrhage SAH)
35
Side effects of calcium channel blockers CCBs
1. Head ache: M/C
2. Ankle edema:
Cause by pre-capillary dilation
Prevented by ACEi/ARB (via post-capillary dilation)
For verapamil:
3. Constipation
4. AV node block
Hence verapamil is CI with β-blocker (both causes AV node inhibition)
36
Hydralazine
```
Arterial vasodilator Mechanisms:
1. IP3 induced Ca release
2. Opens K+ channel
3. Release of NO
Uses (IV route):
HTN emergency in pregnancy (DoC labetolol IV)
```
37
Side effects of hydralazine
```
Arterial dilator
1. Head ache
2. Hypotension
3. SLE: M/C in females
Within 6 months of drug use
4. Sweet’s syndrome:
Neutrophilic dermatosis
```
38
Minoxidil
```
Potent vasodilator (arterial)
Mechanism:
Opens K+ channel
Uses:
1. Severe/resistant HTN
2. Androgenic alopecia (topically):
DoC finasteride
(S/E: decreased libido)
```
39
Side effect of minoxidil
Arterial dilator
S/E:
1. Hirsutism (via systemic route)
2. Na+/H2O retention- some very potent vasodilator
40
Classes of vasodilator drugs which act via increasing NO release
1. Hydralazine
2. Nitrates
3. Nitroprusside
41
Diazoxide
```
Arterial dilator
Mechanism:
Opens K+ channel ➡️ potent vasodilator
Uses:
1. DoC for insulinoma
2. Was used for HTN emergency via IV (S/E- severe hypotension)
```
42
Examples of venodilators
1. Nitroglycerin
| 2. Isosorbide dinitrate and mononitrate
43
Nitroglycerin mechanism of venous dilation (immediate)
It is metabolised by aldehyde dehydrogenase to NO
NO stimulates Guanylate cyclase ➡️ increases CGMP ➡️
Inhibits MLCK myosin light chain kinase ➡️:
1. In blood vessel:
Vasodilation
Uses in angina/MI
2. In GIT:
Relaxation
Oesophageal/biliary spasm
44
Effects of continuous nitroglycerin exposure
```
Continuous nitroglycerin exposure ➡️
ADH down-regulation ➡️
nitrate tolerance
Prevention:
8 hours of nitrate free period every day, especially at night time ➡️ decreased risk of acute angina
```
45
Nitroglycerin drug interactions with PDE-5 inhibitors
PDE-5 which metabolises cGMP is inhibited by Sildenafil and Tadalafil
These cause vasodilation and are used against pulmonary HTN and erectile dysfunction
Combination of these is CI as it causes severe hypotension
46
Drug interaction of guanyl cyclase simulator with nitroglycerin
Both produce vasodilation using similar effect
Examples of guanyl cyclase simulator:
1. Cinaciguat
2. Riociguat (used for pulmonary HTN)
47
Uses of nitroglycerin
High first pass metabolism do not preferred orally
1. Sublingual- DoC for:
•acute attack of angina
•acute prophylaxis is angina
2. IV: HTN emergency, pulmonary oedema
3. Transdermal, buccal: long term prophylaxis of angina (slow absorption)
48
Isosorbide dinitrate IDN
```
Venodilators
In liver it is denitrated to IMN (active form)
Uses:
Orally
1. Long term prophylaxis of angina
2. Chronic CHF (IDN + hydralazine)
Via sublingual route
3. Acute attack of angina
```
49
Isosorbide mononitrate IMN
Venodilator
Active form of IDN
No first pass metabolism
Use: orally for long term prophylaxis of angina
50
Side effects of nitrates (venodilators)
1. Hypotension
2. Head ache
3. Dizziness
4. Monday disease (workers of nitrate industry)
51
Mixed dilators
1. α blockers
| 2. Nitroprusside
52
Nitroprusside
Mixed dilator
Metabolised in endothelium
Mechanism similar to nitroglycerin
Gets metabolised to 2° product cyanide which is metabolised by rhodonase to thiocyanate
Thiocyanate effects:
1. Hypothyroidism (anti thyroid substance)
2. Neuropsychiatric effects
53
Uses of nitroprusside
1. HTN emergency (2nd line)
2. Pulmonary oedema
3. Aortic dissection always with β blocker (to inhibit reflex tachycardia due to vasodilation)
54
Functions of Angiotensin II and AT III
1. Blood vessels:
Acts on AT-I receptor causing vasoconstriction
2. Increases aldosterone:
Na+ / H2O retention and K+ loss
3. Glomerulus:
AT-II receptors of efferent arteriole constriction and
PGs cause afferent arteriole dilation
55
Angiotensin IV
In CNS
Increases cognition
AT IV analogue under trial for treatment against Alzheimer’s disease
56
RAAS inhibitors types
1. DRI: direct renin inhibitor
2. ACEi:
angiotensin converting enzyme inhibitor
Increases renin and AT-I
3. ARB:
angiotensin receptor blockers
Blocks AT-I
57
Effects of RAAS inhibitor
1. Blocks kininase
2. Blood vessel
3. Decreases aldosterone
4. Efferent arteriole dilation
58
Effects of RAAS inhibitor wrt kininase
ACEi blocks kininase
➡️ increases bradykinin, substance P, PGs
Side effects:
1. Angioedema
2. Dry cough (due to medullary cough centre irritation)
59
Effect of RAAS inhibitors on blood vessels and aldosterone levels
```
1. Causes vasodilation and loss of Na+/H2O ➡️ decreases bp:
S/E postural hypotension
1st line drug in HTN
2. K+ retention:
S/E hyperkalemia
Should not conbine ACEi with ARB
```
60
Effect of RAAS inhibitor in glomerulus
```
1. Efferent arteriole dilation ➡️ decreased GFR
CI:
• Renal failure
• B/L renal artery stenosis
2. Decreases proteinuria
Used in:
• DM
• CKD
• Nephrotic syndrome
DoC of HTN with proteinuria
```
61
Examples of ACEi
```
C. Captopril
L. Lisinopril
E. Enalapril
R. Ramipril
Q. Quinapril
f. Fosinopril
b. Benzapril
The above Clerq fb are given orally
Enalaprilat is given IV due to poor absorption
```
62
ACEi which are not prodrugs
Captopril and Lisinopril
63
Elimination of ACEi
```
1. Uniphasic: shortest acting and least potent
Clearance from plasma
Captopril
2. Biphasic:
+ high affinity for ACE
most ACEi
3. Triphasic: longest acting
biphasic + high AVd
Ramipril
```
64
Uses of ACEi
1. Hyperreninemic HTN: first line drug
2. HTN+ proteinuria: DoC
3. HTN urgency: oral captopril
4. HTN emergency: IV enalapril
5. History of MI or chronic CHF: to reduce mortality
6. Captopril test
65
Captopril test
Differential diagnosis b/w renovascular or essential HTN
In RV HTN the increase in renin is much more than in essential HTN
Confirmatory test is renal angiography
Captopril preferred as shortest acting
66
Specific side effects of ACEi
1. Angioedema
2. Dry cough M/C
3. Dysgeusia
4. Rash with itch
The last 2 are maximum with captopril
67
Examples of ARB angiotensin receptor blockers
```
T. Telmisartan
E. Eprosartan
C. Candesartan
I. Irbesartan
L. Losartan
O. Olmesartan
In tequila, the prodrugs are Ca and Ol
Telmisartan has maximum PPAR γ agonist
```
68
Losartan
```
Angiotensin receptor blocker ARB
Non specific
1. Blocks thromboxane A2:
Anti aggregant
2. Uricosuric effect:
2° use for chronic gout
3. PPAR γ agonist
Decreases insulin resistance
```
69
Pharmacokinetics of Angiotensin Receptor Blockers
```
Poor oral bioavailability
Increased plasma protein binding
t1/2:
max in Telmisartan
min in Eprosartan
```
70
Uses of ARBs angiotensin receptor blockers
Uses are similar to ACEi
1. Preferred in case of ACEi intolerance and ineffectiveness
2. Losartan- portal HTN
3. Irbesartan - rhythm control on atrial fibrillation
71
Side effects of ARBs
1. Alopecia
2. Agranulocytosis
3. Vasculitis
4. Olmesartan can cause sprue like syndrome (with characteristics of weight loss and abdominal pain)
72
Direct renin inhibitor DRI
```
Aliskiren - only FDA approved drug
Use: 2nd line for HTN
S/E:
hyperuricemia
diarrhoea, GERD
```
73
Common side effects of all RAAS inhibitors
Postural hypotension
| Hyperkalemia
74
Common contraindications of all RAAS inhibitors
1. Renal failure
2. B/L renal artery stenosis
3. Pregnancy:
In 1st trimester- CNS defects
In 2nd/3rd trimester- renal defects
