1. No category

ACE Inhibitors
Angiotensinogen
bradykinin
renin
Angiotensin I
ACE
ACE
inactive kinin
Angiotensin II
Na+/H2O retention
O retention
TPR
ACE Inhibitors
Angiotensinogen
renin
bradykinin
Angiotensin I
ACE
ACE--I
ACE
angiotensin II
aldosterone
Na+/H2O retention
kininase
inactive kinin
TPR
ACE Inhibitors
laryngeal itch
y
bradykinin
ACE I
ACE‐I
cough
ACE
ACE
kininase
inactive kinin
ACE Inhibitors
renal glomerular filtration
renal glomerular filtration
efferent arteriolar resistance
proteinuria
 microalbuminuria
microalb min ria
diabetes
ACE Inhibitors
captopriil prototype t ½ ±
1 5 hrs tissue 12hrs
1.5 hrs tissue 12hrs
lisinopril lisinopril t ½ t ½ ± 12 hrs
12 hrs
ramipril ‐
p
high risk g
pts
p
Angiotensin Converting Enzyme
Inhibitors (ACE
(ACE‐‐I)
Adverse effects
bradykinin produced –
bradykinin produced cough (30%)
cough (30%)
bradykinin bradykinin – angioneurotic oedema
angioneurotic oedema
CI ‐ pregnancy
CI – bilateral renal stenosis
hyperkalaemia
Angiotensin Receptor Blockers (ARB)
Angiotensinogen
renin
Angiotensin I
ACE
angiotensin II
angiotensin II
Naa+//H2O
O retention
ete t o
aldosterone
AT--1
AT
TPR
vasoconstriction
Angiotensin Receptor Blockers (ARB)
Angiotensinogen
renin
Angiotensin I
ACE
angiotensin II
ARB
AT--1
AT
Naa+//H2O
O retention
ete t o
aldosterone
TPR
vasodilation
Angiotensin Receptor Blockers (ARB)
Angiotensinogen
renin
Angiotensin I
ACE
Angiotensin II
bradykinin
ACE
I
Inactive kinin
i ki i
ARB
AT--1
AT
No co gh!!!
No cough!!!
Angiotensin Receptor Blockers (ARB)
losartan (Cozaar)
valsartan (Diovan)
(Di
)
No bradykinin produced (dilation)
y
p
(
)
ACE inhibitors without the cough
Expensive
Adverse effects = ACE‐I
hyperkalaemia
ACE / ARB
Diabetes = previous MI / stroke
Diabetics 4-5 fold higher risk of CVD
ACE are compelling
lli iindication
di ti
Targets
g
lower = 130/85
/
Role of thiazide?
Law et al 2003; Value of low dose combination treatment with blood pressure lowering drugs: analysis
of 354 randomized trials. BMJ.com; 29 June 2003 326; 1-8
Calcium Channel Blockers
Ca 2+
Ca 2+ + CaM
CaCaM
MLCK
Myosin LC - P
Actin
MLCK
Myosin - LC
Contraction
Calcium Channel Blockers
block voltage gated calcium L‐type channel
h
l
 vascular tone TPR
vascular tone
TPR
No renin release
Na+/H2O retention
postural hypotension
t lh
t i
Calcium Channel blockers
nifedipine
if di i
amlodipine
No effect
heart
neutral
-ve
HR & SV
VSM
TPR
+ve
Calcium Channel Blockers
verapamil
diltiazem
inhibit
heart
-ve
-ve
HR & SV
VSM
TPR
+ve reflex
Therapeutic
p
uses – co morbid
Angina
g
CVS
hypertension
arrhythmia (V+D)
arrhythmia h th i (V+D)
Calcium Channel Blockers (CCB)
Adverse effects nifed /amlod
Pedal oedema (dose related (30%)
Not true oedema (thiazides??)
Reflex tachycardia
Reflex tachycardia
Few direct cardiac effects
Calcium Channel Blockers (CCB)
Adverse effects (non-dihydropyridines)
Pedal oedema (dose related (30%)
Not true oedema (thiazides??)
N tt
d
(thi id ??)
 tachycardia – rare
direct cardiac ‐ bradycardia, negative inotrope
negative inotrope
AV nodal block
S
Synergistic
i ti combinations
bi ti
Thiazide
ACE-I
Vasodilatation
R i release
Renin
l
Enhance action of ACE
S
Synergistic
i ti combinations
bi ti
CCB
Vascular smooth
Muscle relaxation
ACE-I
Prevention of Angiotensin
g
II
formation (RAAS System)
ACE-II + CCB ttargets
ACE
t 2 separate
t
vasodilatoryy mechanisms
ACE / CCB combination
bi ti
in type I diabetes with proteinuria
type II diabetes with proteinuria
Isolated systolic hypertension
 transplant patients
Law et al 2003; Value of low dose combination treatment with blood pressure lowering drugs: analysis
of 354 randomized trials. BMJ.com; 29 June 2003 326; 1-8
ABCD off BP controll
Diuretics
AT1-receptor
p
blockers
ß bl k
ß-blockers
Calcium
antagonists
1-blockers
Possible Combinations of Different
Classes of Antihypertensive
A
Agents.
t Th
The mostt rational
ti
l
combinations are represented as
thick lines 2
ACE iinhibitors
hibit
2. 2003 WHO/ISH statement on management of
hypertension. J Hypertension, 2003, Nov; 21
(11): 1983 – 92.
Wh high
Why
hi h cholesterol?
h l t l?
Cholesterol
Physiology
off cholesterol
h l t l
+ CVD
HPETE
treatment
PGH
Place of statins
Cholesterol
HMG Co A reductase = key enzyme
HMG Co A reductase = key enzyme
not soluble in water
Transported by Apo lipoproteins
synthesized from fats
synthesized from fats
Acetyl‐
Acetyl
y ‐Co A in Liver
for membranes and hormones
Cholesterol - Risk Factor
Cholesterol
Thrombus
formation
Atherosclerosis
Angina Vascular
Lesions
Stroke
MI
Good and bad cholesterol
The Role Of LDL “Bad”
low LDL receptors Coronary Vascular
VLDL
Chylomicrons
LDL
LDL
LDL
LDL
IDL
Lipoprotein lipase
LDL
Remnants
LDL
liver
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
The Role Of high LDL receptors
VLDL
Chylomicrons
Lipoprotein lipase
Coronary Vascular
LDL
LDL
IDL
LDL
Remnants
LDL
LDL
LDL
LDL
LDL
LDL
liver
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL
LDL LDL
LDL
LDL
The Role Of HDL “Good”
Good
Tissues CE
LCAT
LIVER
HDL
CETP
VLDL
HDL apo A ‐ 1
HDL apo A LDL
Statins
Simvastatin
Pravastatin
Fluvastatin
- Prava
- Lescol
Atorvastatin – Lipitor
Rosuvastatin ‐ Crestor
Rosuvastatin Inhibit HMG CoA
Reductase Activity
Statins
 Increase Synthesis
S
h i off LDL
Receptors
 LDL 25 - 50%
 Trigs 10-40%
10 40%
 HDL
3 – 8%
Potency
 atorvastatin
 simvastatin
 rosuvastatin
10mg
20mg
5mg
g
Statins – Rule of 6
Doubling of statin
dose
Cholesterol lower
6%
Statins - Adverse
 Well Tolerated
 Rhabdomyolisis
y
fatal
 Myalgia
 Liver Problems – transient
 diabetes onset
GIT cholesterol blockers
Ezetemibe (Ezetrol)
Blocks cholesterol uptake gut
Liver
Li
S
Synthesizes
th i
LDL R
Receptor
t
Decrease LDL 20%
Well tolerated
Add on th
therapy to statins
Fibrates
Bezafibrate (Bezalip)
Gemfibrozil (Lopid)
Lipoprotein Lipase
A ti it
Activity
 PPAR – gamma
ago
agonist
Fibrates






Decrease VLDL
Use in mixed dyslipidaemia
Useful in type II diabetes?
dec eases LDL 10%
decreases
decreases TG
TG’s
s 40%
Increases HDL
10%
Fibrates - Adverse
 Well Tolerated
 Rhabdomyolisis
y
fatal drug
g
interaction
 Myalgia
 Liver Problems – transient
 CNS
Angina

Coronary arteries
narrowed
 cannot supply oxygen
 damaged endothelium
 cannot vasodilator
 decrease demand
Angina
 pain in chest
 ischaemia
i h
i anaerobic
bi
metabolism
 atherosclerosis > 50%
 stable
 demand
Types Of Angina
Angina of exertion
((exercise induced))
Unstable angina
g
(ACS)
(
)
(nocturnal) - MI risk acute coronary syndrome
 Variant - Prinzmetals angina
Coronary artery spasm
Mechanism
Coronary obstruction - plaque
Arteries cannot vasodilate
Oxygen delivery
Ischaemia
Catecholamines
O2 demand
LV function
Myocardial O2
Consumption
Heart rate
Contractility
y
LV Wall Stress
EDP
Intraventricular
pressure
TPR
Afterload
Anti-anginal
Anti
anginal Therapy
Reduce MVO2
EDV
HR
Increase coronary blood
flow to subendocardial
Anti-anginal
Anti
anginal Therapy



The Nitrates
Glyceryl trinitrate
Isosorbide dinitrate
I
Isosorbide
bid mononitrate
it t
(active of dinitrate)