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Evaluation of Anti-anginal drugs
Dr. Nitin Shinde.
Second Year Resident
Department of Pharmacology LTMMC & GH
Sion Mumbai-22. Date: 05-07-2014 1
CONTENTS
• Introduction- Pathophysiology of angina and
management
• Classification Of Drugs & their limitations.
In – Vivo methods:
1) Coronary artery occlusion
2. Microspheres-induced acute
ischemia
3. Isoproterenol-induced myocardial
necrosis
4. Stenosis-induced coronary
thrombosis model
5. Electrical stimulation-induced
coronary thrombosis
6. Myocardial ischemic
preconditioning model
In-Vitro Methods:
1. Isolated heart (Langendorff)
technique.
2.Isolated heart-lung
preparation
3.Calcium antagonism in
isolated rabbit aorta
4.Relaxation of bovine
coronary artery
5.Coronary artery ligation in
isolated rat heart
6.Plastic casts from coronary
vasculature in dogs
2
CONTENTS
Clinical evaluation.
Conclusion.
Coronary flow measurement
models.
1.Coronary in flow measurement.
2.Coronary outflow measurement.
3.Thermodilution technique.
4.Inert gas technique.
5.Radioactive microsphere
technique.
6.Coronary arteriography.
3 3
DO WE REALIZE? “Average heart beats 2.5-3.0 billion times in a life,
starting even before birth and ending with life”
4
Angina pectoris
• Introduction:
 Disease burden: >6 million
 400 000 new patients each year
 Obesity, insulin resistance, and type 2 diabetes mellitus
are increasing and are powerful risk factors for IHD
 South Asian population, especially India
 IHD is likely to become the most common cause of
death worldwide by 2020
5
Pathophysiology
Myocardial O2
demand exceeds
the supply
O2 demand
determinants:
-Heart rate,
-Systolic wall
tension,
-Contractility
-Cellular K loss,
-lactate
accumulation,
-ECG abnormalities,
-Ventricular
dysfunction.
-LVDP increase
-Pulmonary
congestion
-Dyspnea.
6
Angina
Episodic clinical syndrome due to transient myocardial
ischemia.
 Stable - is characterized by chest or arm discomfort
associated with physical exertion or stress and is
relieved within 5–10 min by rest and/or sublingual
nitroglycerin.
 Unstable - at least one of the features:
occurs at rest lasting >10 min
severe and of new onset (i.e., within the prior 4–6
weeks)
it occurs with a crescendo pattern (distinctly more
severe, prolonged, or frequent than previously).
 Prinzmetal's - a syndrome of ischemic pain that occurs
at rest but not usually with exertion and is associated
with transient ST-segment elevation.
7
Treatment
1. Reduce oxygen demand – by decreasing work
2. Increasing blood supply – by dilating coronaries
Acute Angina Chronic Stable Angina
Rest
Sublingual nitroglycerine
Single drug or combination
1. Long acting nitrates
2. Beta blockers
3. CCBs
4. K+
channel opener
5. pFOX inhibitors
(Trimetazidine, Ranolazine)
8
Nitrates
• Prodrugs
• Vasodilation of capacitance vessels, decreases preload,
lowers myocardial O2 requirement, improves
subendocardial blood flow
• Dilates epicardial arteries including stenotic segments
• Do not dilate coronary resistance vessels.
• Side effects : Headache, postural hypotension,
dizziness, weakness.
• Limitations: Development of tolerance.
• Nitrate free period associated with increased angina
9
Beta blockers
• Reduction in heart rate, blood pressure and contractility
• Redistribution of coronary flow
• Lengthening of diastole
• Antiadrenergic action during exercise.
• Side effects: Bradyarrhythmia, Raynaud’s phenomenon,
exacerbation of bronchial asthma , fatigue, depression,
blunting effect of hypoglycemia.
• Limitations: cannot be used in unstable angina, abrupt
discontinuation after chronic use precipitate severe
attacks.
• E.g. Propranolol , Atenolol , Metoprolol.
10
Calcium channel blockers
• Verapamil
• Diltiazem
• S.E: Nausea, constipation, bradycardia
• Dihydropyridines: Arteriolar dilatation, decrease TPR,
increase coronary flow.
• S.E: hypotension, palpitation, ankle edema, headache
Negative inotropic, chronotropic
and dromotropic effect, arteriolar
dilatation, increases coronary flow
11
K channel openers
• Nicorandil :
• Arteriolar and venodilatation.
• Increased coronary flow: dilatation of epicardial vessels
and resistance vessels.
• No significant effect on contractility and conduction
• S.E: flushing, palpitation, weakness, headache
12
Recent antianginals
• Trimetazidine: no effect on HR or BP or contractility of
heart
• Decreases fatty acid oxidation and increase glucose
metabolism, decrease intracellular acidosis, free radical
scavenging effect
• frequency of angina .
• increases exercise capacity.
13
Ranolazine:
• inhibits late Na+
current
Indirectly inhibit calcium uptake by myocardium
Inhibit sustained contraction of myocardium
Decrease oxygen consumption
• Negligible effect on HR and BP.
• Side effects – Constipation , Dizziness , constipation
,Headache.
14
Limitations of present drugs
1. Non selectivity
2. Affect hemodynamic parameters
3. Do not protect heart from stress induced
adrenergic effects
4. Beneficial effect is short-lived
5. Tolerance
15
Preclinical evaluation
16
In Vitro Models
1. Isolated heart (Langendorff) technique.
2. Isolated heart-lung preparation
3. Calcium antagonism in isolated rabbit aorta
4. Relaxation of bovine coronary artery
5. Coronary artery ligation in isolated rat heart
6. Plastic casts from coronary vasculature in dogs
17
In Vivo Models
1. Occlusion of coronary artery
2. Microspheres-induced acute ischemia
3. Isoproterenol-induced myocardial necrosis
4. Stenosis-induced coronary thrombosis model
5. Electrical stimulation-induced coronary thrombosis
6. Myocardial ischemic preconditioning model
18
Coronary flow measurement
• 1.Coronary in flow measurement.
• 2.Coronary outflow measurement.
• 3.Thermodilution technique.
• 4.Inert gas technique.
• 5.Radioactive microsphere technique.
• 6.Coronary arteriography.
19
20
1) Isolated heart (Langendorff)
preparation
• Estabished in1897 by Oscar Langendorff.
21
• PRINCIPLE: Heart is perfused in a retrograde direction from
aorta either at constant pressure or at constant flow with
oxygenated saline soln.
• Retrograde perfusion closes the aortic valve , just as in situ
heart during diastole .
• The perfusate is displaced through the coronary artery using a
canula inserted in the ascending aorta following of the
coronary sinus and opened right atrium and flows out via the
right ventricle and pulmonary artery.
22
Guinea pigs (300-500g) sacrificed
Heart removed quickly- placed in Ringer’s solution at 370
c
A glass or plastic cannula is introduced
into the aorta, tied with two threads and
perfusion is started with oxygenated Ringer’s solution
or Krebs-Henseleit buffer.
The heart is transferred to a
double walled plexi-glass perfusion apparatus .
Oxygenated Ringer’s solution is perfused at a constant
pressure of 40 mm Hg and at a temperature of 37 °C by
thermostat.
A small steel hook with a string is attached to the apex of
the heart
Drugs are injected into the
perfusion medium just above the aortic cannula
23
24
Evaluation
• Heart rate by chronometer – attached to polygraph.
• Contractile force is measured isometrically by a force
transducer
• Coronary flow measurements can be performed using a
mechanic-electronic flow meter consisting of a vertical
pipe and a magnetic valve.
• LVP (left ventricular pressure) with Statham pressure
transducer P 23 DB, which on differentiation
yielded LV dp/dtmax .
• Cardiac output is determined by electromagnetic flow
probes in the outflow system.
25
Myocardial oxygen consumption
(MVO2) (ml/min/gwt)
• MVO2= CF × (Pa – Pv) × (c/760) × 100.
• CF -is the coronary flow [ml/min/g]
• Pa -is the oxygen partial pressure of arterial
perfusate .
• Pv -is the oxygen partial pressure of the venous
effluent perfusate [mm Hg]
• C -is the 0.0227 representing the Bunsen
solubility coefficient of oxygen dissolved in
perfusate at 37 °C
26
Positive inotropic effects
• Evaluation of a positive inotropic compound usually
requires that cardiac force is first reduced.
• Acute experimental heart failure can be induced by an
overdose of barbiturates,such as sodium thiopental.
• This kind of cardiac failure can be reversed by β-
sympathomimetic drugs, cardiac glycosides
• β-Sympathomimetic drugs restore LVP and dp/dt max
and keep coronary blood flow elevated.
• Cardiac glycosides increase LVP and dp/dtmax and
leave coronary flow unchanged.
27
Calcium-antagonism Evaluation
• 1 to 5 mg BaCl2 are injected which induce a pronounced
spasm of the coronary arteries thereby reducing the
coronary flow.
• Five min later, the test drug is injected.
• After this effect has weaned, BaCl2 is injected
again and the test drug or a standard drug injected.
• The increase of coronary flow is expressed as
percentage of flow during BaCl2 spasm and compared
with the effect of the standard.
e.g.Nifedipine, is tested.
28
Gradual determination of hypoxic
damage
• Lindner and Grötsch (1973) measured the enzymes
creatine phosphokinase (CPK), lactate dehydrogenase
(LDH), α-hydroxy-butyrate dehydrogenase (α-HBDH),
and glutamic-oxalacetic transaminase (GOT) in the
effluent of a guinea pig heart preparation under varying
degrees of hypoxia.
• Metabolic studies : with nuclear magnetic
resonance Using 31P,
studies on metabolism of nucleotides and phosphorylated
intermediates of carbohydrates in isolated hearts have
been performed
29
EDRF release from the coronary
vascular bed
• Lamontagne et al. (1992) isolated platelets from
blood of healthy human donors and injected
platelets boluses into the perfusion line of the
Langendorff preparation of a rabbit heart.
• In the effluent cyclic GMP was determined as
an index for EDRF release
30
Advantages
 Highly reproducible, low cost and large numbers can be
studied
 Broad spectrum parameters can be measured
 Absence of confounding factors (neurohormonal)
 Allows induction of regional or global ischemia
 Hypoxia can be imposed
 Ischemia-reperfusion and arrhythmia studies can also be
done.
31
Disadvantage
 Does not represent in vivo settings. Endogenous factors
are not considered
 Constantly deteriorating preparation.
32
2)Isolated heart lung preparation
• Wistar rats of 300-350 grams are anaesthetized.
Artificial respiration is established. Chest cavity is
opened and ice-cold saline is injected to arrest
the heart.
SVC, IVC and aorta are cannulated and perfused with
Krebs-Ringer bicarbonate buffer containing rat RBC
Perfusate from aorta is passed through pnuematic
resistance and collected in a reservoir maintained at 37o
C.
It is then returned to IVC.
33
Test drug is administered into the perfusate
After 5 minutes
Parameters:
C.O is recorded with electromagnetic blood flow meter and
Mean arterial pressure from pneumatic resistance,
Heart rate is recorded using chronometer.
34
Evaluation
• Hemodynamic data of test drug group and
control group is compared using ANOVA.
• Recovery time is measured by kruskel wallis
test.
35
Modification in model
• Beaconsfield et al. (1974) used the heart-lung
preparation of guinea pigs to study the cardiac effect
of delta-9-tetrahydrocannabinol.
• Ishikawa et al. (1983) in the dog heart-lung preparation –
effects of norepinephrine and 5-hydroxytryptamine
• Hausknecht et al. (1986) to investigate the effects
of lung inflation on blood flow during cardiopulmonary
resuscitation,
• Fessler et al. (1988) to investigate the mechanism
• of reduced LV afterload by systolic and diastolic positive
• pleural pressure,
36
3)Calcium antagonism in isolated
rabbit aorta
• Rationale: KCl or norepinephrine induces
contraction of aorta rings. Test drugs with
calcium channel blocking have relaxing effect
KCl+
Rabbit
descending
thoracic
aorta
Cut into rings
of 4-5mm
width
Mounted in tissue bath
containing Krebs HCO3 buffer
20 minutes later, test drug is added. Percentage relaxation reading is
taken every 30 minutes after additions of test drug 37
KREB’S BUFFER
38
Evaluation
 Active tension is defined as the difference between the
generated tension and the baseline tension (1 gm).
 Active tension is calculated for the tissue at the time
point just prior to the addition of the test compound and
also at the point 30 min after the addition of each
concentration of test compound.
 The percent relaxation from the predrug, precontracted
level is calculated for each concentration of test
compound.
 A number of 5 experiments constitutes a dose range.
 An ID50 is calculated by linear regression analysis.
39
4)Relaxation of bovine coronary
artery
• Principle: Relaxation caused by test compounds can be
assayed using spiral strips from bovine CA
Bovine left descending CA is cut into spiral strips(20 mm long and
2-3 mm wide).suspended in a 4 ml organ bath at tension of 2 g
Oxygenated Krebs HCO3 solution at
37o
C. Krebs solution contains
antagonists to inhibit action of
endogenous Ach, 5HT, Hist. CAs
Isometric contractions are recorded with force-displacement
transducers on a grass polygraph. Relaxation caused by
test compounds are expressed as % of maximal response to 100 ng/ml
PGI2
Test compounds are compared
against standard compounds
PGE2 (contraction) and PGI2
(relaxation)
40
5)Coronary artery ligation
• Principle: left coronary artery ligation induces
ischemia, after removal of clip reperfusion
changes occur. Prevention of these changes is
an indicator of the efficacy.
Heart of Wistar rats of either sex weighing 280 – 300g
Langendorff technique
Silicon balloon is fitted into left ventricular cavity
Fluid volume pressed from the balloon corresponds to
stroke volume of heart
41
Stroke volume can be recorded by flowmeter probe
Isolated working hearts are perfused for 20 min with
krebs buffer at 65 mmHg
Ischemia is induced by clamping the LCA for 15 min
Clip is then opened ,Reperfusion changes
are monitored for 30 min
Test drug is given into perfusion medium before
occlusion or 5 min before reperfusion
42
Evaluation
• Parameters measured: LVP, LV dP/dt max, coronary
flow
• Myocardial LDH, CK, glycogen, ATP, lactate .
43
6) Plastic casts
• Principle: Prolonged administration of coronary drugs increase the
number and size of interarterial collaterals of dogs after coronary
occlusion, which can be seen by filling the coronary bed with plastic.
Dogs (10-15kg)- anesthesized- artificial respiration- heart exposed.
Ameroid cuffs are placed around major coronary branches.
Gradual swelling of the plastic material occludes the lumen
within 3–4 weeks
Animals sacrificed- the heart removed- coronary bed flushed
with saline.
Liquid araldite is filled in bulbous aorta & coronary tree
Evaluation: Plastic casts from the drug treated animals are
compared with casts from the sham group ( dogs subjected to
same procedure without drug treatment).
Dogs treated for 6 weeks
Tissue digested with 35% KOH
44
In vivo models
45
In Vivo models
1. Coronary artery occlusion
2. Microspheres-induced acute ischemia
3. Isoproterenol-induced myocardial necrosis
4. Stenosis-induced coronary thrombosis model
5. Electrical stimulation-induced coronary thrombosis
6. Myocardial ischemic preconditioning model
46
1.Coronary artery occlusion
• Principle: Compounds potentially reducing infarct-
size are tested by studying the size of the infarct
after proximal occlusion of the left anterior
descending coronary artery dogs.
METHOD: Dogs anaesthetized- pentobarbitone(35mg/kg
i.p.)- Artificial respiration started
Cannulation of vessels
LAD coronary artery is exposed and ligated for 360 min
Test substance is administered i.v. bolus
Hemodynamic parameters are measured 47
Coronary artery occlusion
Animals are sacrificed
Coronary arteriograms are made after injection of BaSO4 gelatin
mass into LCA
LV cut into Transverse section
Using X ray tube infarcted area is measured (defect opacity)
Slices are then incubated with p-nitro-blue-tetrazolium to visualize
infarct tissue (histology)
EVALUATION: Mortality,Hemodynamic changes and Infarct
size are determined in drug treated animals and compared
to vehicle control
48
2.Microspheres-induced acute
ischemia
Dog is anesthetized
Artificial respiration is established
Cannulation of – brachial vein, saphenous vein
for administration of drug
femoral artery connected to pressure transducer
49
Embolisation is terminated when
LVEDP increased to 16-18 mmHg,
PAP – 20 mmHg, HR, 200 /min
Test compound administered I.V.
Parameters measured: Systolic and Diastolic pressure,
LVEDP, HR, Pulmonary capillary pressure, PAP, COP and
then compared with control group.
A miller microtip catheter is inserted via
the LCA for determination of LVP &
LVEDP(Left ventricular end diastolic pressure)
Microspheres are injected through the catheter
initially as 10 ml later as 5 ml IV bolus
5 min apart
50
3.Isoproterenol-induced
myocardial necrosis
• Principle:
-Synthetic catecholamines like isoproterenol when
injected at high dose produce cardiac necrosis.
-Drugs such as sympatholytics or calcium
antagonists can totally or partially prevent these
lesions.
• Groups of 10 male wistar rats weighing 150-200 gms are
pretreated with test or standard drug for 7 days
51
Isoproterenol-induced myocardial
necrosis
Isoproterenol 8.5mg/kg S.C.
Test drug adm.
Day 0 Day 8Day -7
Day 9
Parameters measured: SBP, DBP, HR,
LVEDP, dP/dt
Rat is sacrificed, heart is removed,
weighed, preserved for HP,
and biochemical parameters
52
EVALUATION
GRADE HISTOLOGICAL CHANGES
GRADE 0 No change.
GRADE 1 Focal interstitial response.
GRADE 2 Focal lesions in many sections , mottled staining and
fragmentation of muscle fibre.
GRADE 3 Confluent retrogressive lesions with hyaline
necrosis and fragmentation of muscle fibre.
GRADE 4 Massive infarct with occasionally acute aneurysm
and mural thrombi
Histological grading:
The test has been used for evaluation
of coronary active drugs, such as calcium-antagonists
and other cardioprotective drugs like nitroglycerin.
53
4.Stenosis-induced coronary
thrombosis model
Dogs anaesthetized - pentobarbitone sodium( 40mg/kg
ip) and LCA exposed
Electromagnetic flowprobe placed on proximal part of
LCA to measure Blood Flow
Vessel is squeezed with haemostatic clamp
for 5 seconds
Principle: Clamping induces thrombosis in coronary
artery . An alteration in coronary blood flow with
transient platelet aggregation at the site of coronary
constriction is assessed using this model.
54
Test compound is administered IV & the cyclic flow
variations are registered for 2-5 hrs and compared
with pretreatment values
Plastic constrictor placed around artery at the
site of damage- changed several times till
desired constriction is achieved.
• Dogs with repeated cyclic flow variations of same
intensity are used for experimental purpose
55
5.Electrical stimulation induced coronary
thrombosis
Electrode is placed in the vessel with the intimal lining and
connected with the teflon coated wire of 9 volt battery,
potentiometer and amperometer
Intima is stimulated with 150 µA for 6 hours- occluding thrombosis occurs
Test drug – (s.c.) either,simultaneously or
30 mins following electrical stimulation
Time interval until thrombotic occlusion , thrombus size,
hemodynamic parameters are measured by canulating to
femoral artery. & connecting it to pressure transducer.
Principle: Electrical stimulation induces thrombosis
in coronary artery
German Landrace pigs (40 kg)- anesthesized with Ketamine (2
mg/kg) – Heart exposed- Electromagnetic flowmeter placed on
proximal part of LCA
56
6.Ischemia preconditioning model
• Rationale: Preconditioning(brief duration of ischemia and
reperfusion) can reduce damage produced by prolonged
ischemia and reperfusion
Rabbits are anaesthetized with ketamine
Artificial respiration is established and vessels
cannulated
4-0 suture is looped around marginal branch of
LCA .Loop is tighten for 5 min, loosened for 10 min
Tighten for 30 min followed by 120 min of
reperfusion
Test drug
administered
57
Evaluation
• The animals are sacrificed after the reperfusion
duration.
• Comparisons between systemic hemodynamic data
and infarct size studies are analyzed by ANOVA
using statistical software.
58
Coronary flow measurement
models
• 1.Coronary in flow measurement.
• 2.Coronary outflow measurement.
• 3.Thermodilution technique.
• 4.Inert gas technique.
• 5.Radioactive microsphere technique.
• 6.Coronary arteriography.
59
1.Coronary in flow measurement
• Dogs (15-20 Kg) are anaesthetized, maintained
on artificial respiration.
• Through left thoracotomy, heart is exposed and
pericardium removed
• Catheter is inserted through jugular vein to
cannulate coronary sinus to measure coronary
flow
• Femoral artery is cannulated to measure SBP,
DBP, mean BP, HR
• Test drug is administered through other jugular
vein 60
Coronary inflow measurement
• Evaluation: Changes in coronary flow and
hemodynamic parameters after test drug administration
is compared with values before administration
Advantage: approximately 95% coronary venous
flow can be measured
Disadvantage: only 60 % of coronary flow returns
through coronary sinus. No constant relation
between coronary venous outflow and coronary
sinus flow
61
2.Coronary outflow measurement
Electromagnetic flowmeter:
Principle: magnetic field perpendicular to blood
flow generates voltage in the conductor which
is picked up by electrode, amplified and
recorded.
Two poles of electromagnet are placed in
opposite sides of the coronary vessel. Distally
two chromium-vanadium electrodes are placed
adhering to the coronary artery
62
3.Thermodilution technique:
• A catheter ( webster) is passed to the beginning of
coronory sinus.
• A temperature sensor is placed further down the
coronory sinus.
• Ice cold saline of known temperature is injected into
coronary sinus.
• Modified temperature is measured.The temperature
difference obtained is proportional to blood flow.
Advantage: only right heart catheterization is required,
Resistance to infused saline and saline-blood mixture
is recorded by two thermistors
63
4.Inert gas technique
• Mainly helium and Nitrous oxide are used.
• A mixture of Air and inert gas of known quantity is
inhaled.
• A series of blood samples are withdrawn from a
peripheral artery (using needle) and coronory sinus/
cardiac vein ( using catheter).
Blood flow through Amount of substance taken
the organ = A – V difference
It can measure only mean flow and not
regional flow
64
Radioactive technique
• The radio-isotopes mainly used are - 121
I , 3
H & rubidium.
• Isotopes are inhaled / Injected and change in rate over
chest wall is measured by giega counter.
• By apropriate calculations measure of coronory flow can
be determined.
• It is fast and simple technique.
65
5.Radioactive microsphere
technique
• Determines regional blood flow including distribution of
coronory flow across the ventricular wall.
• A batch of radioactive microspheres (9-15 µ Diameter)
are suspended in saline detergent solution and injected
into the left atrium.
• The number of spheres trapped per unit myocardial
tissue is directly proportional to myocardial blood flow.
66
6.Coronary arteriography
• Most direct, reliable and advanced method.
• Thin, flexible tube called a catheter is put into a blood
vessel in your arm, groin (upper thigh), or neck.
• The tube is threaded into your coronary arteries, and the
dye is released into your bloodstream.
• X-ray pictures are taken while the dye is flowing through
the coronary arteries.
67
Parameter Studied Model Animal used
HR , Force of
contraction
MV02
Isolated Heart
Isolated Heart lung
Guinea Pig
Wistar Rat.
Ca - Antagonism Isolated Rabbit Aorta
Bovine coronary artery
Relaxation
Rabbit
Beef
LDH,CPK,Glucose
metabolism
Isolated Heart
(Langendorff)
Guinea Pig.
Histology Isopretenerol Induced
myocardial Necrosi
Wistar Rats
Thrombosis Electrical stimulation-
induced coronary
thrombosis
German Landrace Pig.
Embolism Microspheres-induced
acute ischemia
Dog
68
Clinical evaluation
69
Need of clinical evaluation
• Caution while interpreting preclinical data…
• Difficult to create animal models with coronary lesions as
in humans
• Extremely variable pain syndrome
• No direct relation between degree of pain and coronary
insufficiency
• All antianginal drugs must not be assumed to be
coronary vasodilators and vice versa
• In vitro preparations have a limited life span and not
exposed to endogenous neurohormonal factors
70
INTRODUCTION
• The treatment of stable angina pectoris has two major
aspects.
• The first is to reduce the risk of mortality by preventing
myocardial infarction (MI) and death.
• The second is to reduce symptoms of angina and
occurrence of ischemia, thereby improving the quality of
life.
• Patients with ischemic heart disease are the preferred
test subjects for the assessment of an antianginal effect.
However Information derived from healthy volunteers
can only be used for safety or pharmacokinetic
purposes.
71
Early phase (I )
• Objectives:
1. Exploratory clinical pharmacology
2. Dose determination: exercise test protocols
72
Strategy - design
Pharmacodynamics
• Haemodynamic effects at rest and during exercise.
• Drug with a novel mechanism of action, data showing
the antischemic action (e.g. myocardial perfusion
imaging or MRI)
• Additional exercise variables testing.
• Myocardial perfusion/left ventricular performance
• Coronary blood flow/ Diameter of normal and stenosed
coronary arteries 73
Titration studies -Early dose finding
• Start with low doses.
• Most common titration design: each patient is
titrated up to a certain point according to
specified rules.
• Minimum 4 dose levels
• Advantage : few healthy volunteers required.
• Disadvantage : Possible carry over effects
• Control group is mandatory
74
Confirmatory dose finding
• Parallel group design.
• Placebo controlled studies using 3 or 4 doses
• Duration: 2-4 weeks
• 40 – 80 patients per group
• Only sublingual nitroglycerin allowed
• Monotherapy
• Combination therapy
75
Factors assessed:
• Effects on heart rate, rhythm, conduction times and, if
necessary, refractory period
• Effects on renal function and electrolytes
• Effects on the pulmonary function
• Effects on the metabolism, particularly of glucose and
lipids
• Neurohormonal effects
• Platelet aggregation and other rheological effects
• Vital and laboratory parameters .
76
Phase ( II & III)- Selection of patients
• The patients included in the studies must suffer from
stable angina pectoris .
• To study the efficacy of antianginal drugs and safety
aspects of their indications.Mostly placebo controlled
parallel designs single or in combinations.
• With regard to dose-finding studies the documentation of
unequivocal coronary heart disease is mandatory.
77
Inclusion criteria
 H/o chronic angina pectoris on effort for > 3 months
before study entry.
 Percutaneous Coronary Angioplasty > 6months or
Coronary Angioplasty bypass > 3months.
 Coronary angiography >50% diameter stenosis of one or
more major coronary arteries.
 Positive scintigraphic test showing exercise induced
reversible myocardial ischaemia or a Positive stress
echocardiography.
78
Inclusion criteria
 Sinus rhythm.
 Subject experiencing pain within 3-7 min of Bruce
protocol on exercise testing.
 Reproducibility of results of exercise test should be
shown by patient.
 Resting ECG should not interfere with interpretation of
ST segment changes.
79
Exclusion criteria
 H.R. <60.
 Significant heart disease other than CAD.
 Unstable angina pectoris ,Prinzmetal angina.
 Severe heart failure symptoms (NYHA class lll / IV).
 Symptomatic hypotension or uncontrolled hypertension.
 AF/AFL.
 Pacemaker / implanted defibrillator.
 Any other condition that interferes with the ability to
perform or interpret Exercise Stress test.
80
Efficacy evaluation
• Primary:
• Occurrence of anginal pain during exercise
“ an antianginal agent cannot be considered
antianginal unless it increases the amount of
exercise that a patient can perform prior to the
development of angina after drug
administration ”
81
Exercise tests
• Two Types : Isometric or Dynamic.
• Isometric exercise : constant muscular contraction without
movement (e.g., handgrip).
• Dynamic exercises: preferred
• Maximal exercise test
• A)Treadmill Test.
• B)Upright bicycle ergometer
• A maximal exercise test brings an individual to a level of
intensity where fatigue or symptoms prohibit further exercise
or when maximal oxygen consumption (VO2max) is
achieved and no further increase in heart rate occurs.
82
A)Treadmill exercise tests
• Leads of the ECG are placed on the chest wall. The
treadmill is started at 2.74 km/hr (1.7 mph) and at a
gradient (or incline) of 10%.
• At three minute intervals the incline of the treadmill
increases by 2%, and the speed increased as in the
Bruce protocol
83
A)Treadmill test
84
Bruce Protocol
Stage Speed (km/hr)
Speed
(mph)
Gradient
(inclination)
1 2.74 1.7 10
2 4.02 2.5 12
3 5.47 3.4 14
4 6.76 4.2 16
5 8.05 5.0 18
6 8.85 5.5 20
7 9.65 6.0 22
8 10.46 6.5 24
9 11.26 7.0 26
10 12.07 7.5 28
MODIFIED BRUCE PROTOCOL:
Starts at a lower workload than the standard test- for elderly or sedentary
patients. First two stages of the Modified Bruce Test are performed at a 1.7
mph and 0% grade and 1.7 mph and 5% grade, and the third stage
corresponds to the first stage of the Standard Bruce Test protocol as
listed above.
85
Contraindications to Exercise
Testing
 Recent acute myocardial infarction (less than 2 days).
 High-risk unstable angina pectoris
 Symptomatic severe aortic stenosis
 Uncontrolled cardiac dysrhythmia
 Acute myocarditis or pericarditis
 Severe hypertension
 Decompensated congestive heart failure
 Intracardiac conduction block greater than first degree
 Suspected or known dissecting aneurysm
 Thrombophlebitis or pulmonary embolus
 Acute systemic illness
86
Treadmill test
• Advantage:
Permits 10-15% higher oxygen consumption rate
Excellent reproducibility
Minimum subject co-operation
• Disadvantage:
Difficulty to record exact BP and ECG
Not suitable for studies requiring relatively immobile
thorax e.g. echocardiography or scintigraphy.
87
B)Upright bicycle ergometer
Advantage: Stable ECG and BP recording
Intravascular catheters, expired air easily collected
Scintigraphic observations may be made
Disadvantage: Person should be accustomed to cycling
88
Evaluation of ECG Data
• 12 Lead ECG is preferred.
• The classic criteria for visual interpretation of positive
stress test findings are J-point (the junction of the point
of onset of the ST-T wave)
• ST80 :The standard criterion for this type of abnormal
response is horizontal or downsloping ST-segment
depression of 0.1 mV (1 mm) or more for 80 msec the
point that is 80 ms from the J point) in 3 consecutive
beats.
89
Efficacy evaluation
• Primary:
• Occurrence of anginal pain during exercise
“ an antianginal agent cannot be considered
antianginal unless it increases the amount of
exercise that a patient can perform prior to the
development of angina after drug
administration ”
90
1. Exercise Capacity
• Interpretation should include Total exercise capacity
and clinical, hemodynamic, and ECG response.
• The translation of total exercise capacity into METs
(metabolic equivalents of exercise) provides a
standard measure of performance
A MET: refers to the resting volume oxygen
consumption per minute (VO2) for a 70-kg, 40-year-
old man. One MET is equivalent to 3.5 mL/min/kg of
body weight.
91
2.Anginal pain
• The patient's experience of anginal pain should be
recorded in a patient diary as well as the concomitant
use of short-acting nitrates.
• The daily frequency, severity and duration, of anginal
pain should whenever possible be registered by patients
using available log books.
• The CCS Angina Grading System or other
questionnaires may be used for assessing changes in
symptoms or physical
function.
92
Canadian Cardiovascular Society
Classification of angina
Modification of
CCS
93
• 3) Time to the onset of angina
• Limitation :
1) subjective.
2) A significant amount of treated patients might have
no limiting angina after treatment or might be limited in
their exercise capacity by reasons other than angina.
• 4) Time to ST segment depression
• Time to 1 mm ST segment depression - more objective
variable and is indicative of an anti-ischemic effect
which is an important factor in antianginal drug
assessment.
• Nevertheless, although its prognostic value is
recognised, at present, its extrapolation in terms of
clinical benefit for the patient is unknown.
94
5)Measurement of Health-Related
Quality of Life (HRQoL)
• The evaluation of treatment effect on patient’s quality of
life provides relevant supportive information
on the overall treatment benefit.
• Validated questionnaires should be shown to be
clinically responsive and capable of differentiating:
-clinically important improvement or deterioration.
-provide relevant supportive information on the overall
treatment benefit.
95
6) Morbidity and mortality
• Since the target of antianginal therapy is essentially
symptoms control, at present, there is no requirement to
prove beneficial effect on these variables in order to
obtain a marketing authorisation, unless specifically
claimed.
• However, effects on cardiovascular and total morbidity
and mortality should be evaluated as a relevant safety
parameter.
• This should be done in particular if there is a reasoned
suspicion that a new drug might have detrimental effects
on these parameters
96
Endpoints for evaluating anti-
ischemic interventions
1. ‘Patients perception of chest pain’ usually is the primary
efficacy parameter
2. ST-segment depression during identical workloads pre-
and post- intervention
3. Maximal exercise tolerance
4. Rate-pressure product (RPP) at identical workload and
maximal exertion
5. Angina free exercise tolerance
6. Exercise tolerance at 0.1 mV ST-segment depression
7. Longevity of life (increased disease free survival)
8. Increased quality of life
9. Minimize complication rates
97
Some clinical trial designs
Title Drugs Phase
Metabolic Efficiency
With Ranolazine for
Less Ischemia in Non-
ST Elevation Acute
Coronary Syndromes
(MERLIN-)
Ranolazine
Placebo
Phase – 3 (2009)
Double-blind,
Randomized, Placebo-
controlled Study of the
Safety and Efficacy of
TAK-442
TAK-442
Placebo
Phase – 2(2010)
To compare the
pharmacokinetic
characteristics and
safety of dilatrend SR
capsule 32mg in
healthy male subjects.
dilatrend SR Phase – 1 (2013)
98
Some clinical trial designs-Phase 4
Title Drugs Phase
A Study on the Effects of
Ranolazine on Exercise
Duration in Subjects With
Chronic Stable Angina and
Coronary Artery Disease
(CAD) With Type 2 Diabetes
Mellitus (T2DM)
Ranolazine Phase 4 (2011)
An Open-label, Multi-center
Study Evaluating the Validity,
Reliability, and
Responsiveness of a New
Female-specific Angina
Questionnaire in Women
With Chronic Angina Treated
With Ranolazine Extended-
release Tablets (CVT 3041)
Ranolazine Phase 4 (2012)
99
To summarize…
• In the early evaluation of antianginal drugs, exercise test
protocols performed in a selected population of patients
are the only means to accurately determine appropriate
doses and dosing intervals.
• However, despite great attention to detail, the
assessment of a drug with a real antianginal effect
could remain inconclusive during exercise testing.
It is, therefore, important to follow the recommendations
made to optimize exercise testing for pharmacological
investigations.
100
To summarize…
• Other pharmacodynamic measurements may provide
insights into the mechanism of drug action but cannot be
selected as surrogates for dose-ranging or regulatory
purposes.
• Although exercise capacity currently remains the primary
efficacy variable for antianginal agents in therapeutic
confirmatory trials, outcome variables (e.g.,
mortality/survival data) may also be required for
regulatory purposes in the future……….
101
REFERENCES•
• Vogel WH, Schölkens BA. Drug Discovery and Evaluation [Internet]. Vogel HG,
Vogel WH, Schölkens BA, Sandow J, Müller G, Vogel WF, editors. Berlin,
Heidelberg: Springer Berlin Heidelberg; 2002. P.208-29.
• Mor M, Shalev A, Dror S, Pikovsky O, Beharier O, Moran A, et al. INO-8875, a
new trend in evaluation of chronic stable angina J. Pharmacol. Exp. Ther.
[Internet]. 2013 Jan;344(1):59–67.
• Lucia H. Lee, Chi-Jen Lee.CLINICAL TRIALS OF DRUGS AND
BIOPHARMACEUTICALS: Taylor & Francis Group, LLC 2006 p.146-57.
• L. Forslund, P. Hjemdahl:Prognostic implications of results from exercise testing
in patients with chronic stable angina pectoris treated with metoprolol or
verapamil The European Society of Cardiology 2000 p.347-53.
• Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener H-C, et al. Outcome
parameters for trials in Chronic stable angina: executive summary. Eur. Heart J.
[Internet]. 2007 Nov ;28(22):2803–17.
102
Live a healthy lifestyle
and keep your Heart pumping
forever and ever…….
103
104

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Evaluation of antianginal drugs

  • 1. Evaluation of Anti-anginal drugs Dr. Nitin Shinde. Second Year Resident Department of Pharmacology LTMMC & GH Sion Mumbai-22. Date: 05-07-2014 1
  • 2. CONTENTS • Introduction- Pathophysiology of angina and management • Classification Of Drugs & their limitations. In – Vivo methods: 1) Coronary artery occlusion 2. Microspheres-induced acute ischemia 3. Isoproterenol-induced myocardial necrosis 4. Stenosis-induced coronary thrombosis model 5. Electrical stimulation-induced coronary thrombosis 6. Myocardial ischemic preconditioning model In-Vitro Methods: 1. Isolated heart (Langendorff) technique. 2.Isolated heart-lung preparation 3.Calcium antagonism in isolated rabbit aorta 4.Relaxation of bovine coronary artery 5.Coronary artery ligation in isolated rat heart 6.Plastic casts from coronary vasculature in dogs 2
  • 3. CONTENTS Clinical evaluation. Conclusion. Coronary flow measurement models. 1.Coronary in flow measurement. 2.Coronary outflow measurement. 3.Thermodilution technique. 4.Inert gas technique. 5.Radioactive microsphere technique. 6.Coronary arteriography. 3 3
  • 4. DO WE REALIZE? “Average heart beats 2.5-3.0 billion times in a life, starting even before birth and ending with life” 4
  • 5. Angina pectoris • Introduction:  Disease burden: >6 million  400 000 new patients each year  Obesity, insulin resistance, and type 2 diabetes mellitus are increasing and are powerful risk factors for IHD  South Asian population, especially India  IHD is likely to become the most common cause of death worldwide by 2020 5
  • 6. Pathophysiology Myocardial O2 demand exceeds the supply O2 demand determinants: -Heart rate, -Systolic wall tension, -Contractility -Cellular K loss, -lactate accumulation, -ECG abnormalities, -Ventricular dysfunction. -LVDP increase -Pulmonary congestion -Dyspnea. 6
  • 7. Angina Episodic clinical syndrome due to transient myocardial ischemia.  Stable - is characterized by chest or arm discomfort associated with physical exertion or stress and is relieved within 5–10 min by rest and/or sublingual nitroglycerin.  Unstable - at least one of the features: occurs at rest lasting >10 min severe and of new onset (i.e., within the prior 4–6 weeks) it occurs with a crescendo pattern (distinctly more severe, prolonged, or frequent than previously).  Prinzmetal's - a syndrome of ischemic pain that occurs at rest but not usually with exertion and is associated with transient ST-segment elevation. 7
  • 8. Treatment 1. Reduce oxygen demand – by decreasing work 2. Increasing blood supply – by dilating coronaries Acute Angina Chronic Stable Angina Rest Sublingual nitroglycerine Single drug or combination 1. Long acting nitrates 2. Beta blockers 3. CCBs 4. K+ channel opener 5. pFOX inhibitors (Trimetazidine, Ranolazine) 8
  • 9. Nitrates • Prodrugs • Vasodilation of capacitance vessels, decreases preload, lowers myocardial O2 requirement, improves subendocardial blood flow • Dilates epicardial arteries including stenotic segments • Do not dilate coronary resistance vessels. • Side effects : Headache, postural hypotension, dizziness, weakness. • Limitations: Development of tolerance. • Nitrate free period associated with increased angina 9
  • 10. Beta blockers • Reduction in heart rate, blood pressure and contractility • Redistribution of coronary flow • Lengthening of diastole • Antiadrenergic action during exercise. • Side effects: Bradyarrhythmia, Raynaud’s phenomenon, exacerbation of bronchial asthma , fatigue, depression, blunting effect of hypoglycemia. • Limitations: cannot be used in unstable angina, abrupt discontinuation after chronic use precipitate severe attacks. • E.g. Propranolol , Atenolol , Metoprolol. 10
  • 11. Calcium channel blockers • Verapamil • Diltiazem • S.E: Nausea, constipation, bradycardia • Dihydropyridines: Arteriolar dilatation, decrease TPR, increase coronary flow. • S.E: hypotension, palpitation, ankle edema, headache Negative inotropic, chronotropic and dromotropic effect, arteriolar dilatation, increases coronary flow 11
  • 12. K channel openers • Nicorandil : • Arteriolar and venodilatation. • Increased coronary flow: dilatation of epicardial vessels and resistance vessels. • No significant effect on contractility and conduction • S.E: flushing, palpitation, weakness, headache 12
  • 13. Recent antianginals • Trimetazidine: no effect on HR or BP or contractility of heart • Decreases fatty acid oxidation and increase glucose metabolism, decrease intracellular acidosis, free radical scavenging effect • frequency of angina . • increases exercise capacity. 13
  • 14. Ranolazine: • inhibits late Na+ current Indirectly inhibit calcium uptake by myocardium Inhibit sustained contraction of myocardium Decrease oxygen consumption • Negligible effect on HR and BP. • Side effects – Constipation , Dizziness , constipation ,Headache. 14
  • 15. Limitations of present drugs 1. Non selectivity 2. Affect hemodynamic parameters 3. Do not protect heart from stress induced adrenergic effects 4. Beneficial effect is short-lived 5. Tolerance 15
  • 17. In Vitro Models 1. Isolated heart (Langendorff) technique. 2. Isolated heart-lung preparation 3. Calcium antagonism in isolated rabbit aorta 4. Relaxation of bovine coronary artery 5. Coronary artery ligation in isolated rat heart 6. Plastic casts from coronary vasculature in dogs 17
  • 18. In Vivo Models 1. Occlusion of coronary artery 2. Microspheres-induced acute ischemia 3. Isoproterenol-induced myocardial necrosis 4. Stenosis-induced coronary thrombosis model 5. Electrical stimulation-induced coronary thrombosis 6. Myocardial ischemic preconditioning model 18
  • 19. Coronary flow measurement • 1.Coronary in flow measurement. • 2.Coronary outflow measurement. • 3.Thermodilution technique. • 4.Inert gas technique. • 5.Radioactive microsphere technique. • 6.Coronary arteriography. 19
  • 20. 20
  • 21. 1) Isolated heart (Langendorff) preparation • Estabished in1897 by Oscar Langendorff. 21
  • 22. • PRINCIPLE: Heart is perfused in a retrograde direction from aorta either at constant pressure or at constant flow with oxygenated saline soln. • Retrograde perfusion closes the aortic valve , just as in situ heart during diastole . • The perfusate is displaced through the coronary artery using a canula inserted in the ascending aorta following of the coronary sinus and opened right atrium and flows out via the right ventricle and pulmonary artery. 22
  • 23. Guinea pigs (300-500g) sacrificed Heart removed quickly- placed in Ringer’s solution at 370 c A glass or plastic cannula is introduced into the aorta, tied with two threads and perfusion is started with oxygenated Ringer’s solution or Krebs-Henseleit buffer. The heart is transferred to a double walled plexi-glass perfusion apparatus . Oxygenated Ringer’s solution is perfused at a constant pressure of 40 mm Hg and at a temperature of 37 °C by thermostat. A small steel hook with a string is attached to the apex of the heart Drugs are injected into the perfusion medium just above the aortic cannula 23
  • 24. 24
  • 25. Evaluation • Heart rate by chronometer – attached to polygraph. • Contractile force is measured isometrically by a force transducer • Coronary flow measurements can be performed using a mechanic-electronic flow meter consisting of a vertical pipe and a magnetic valve. • LVP (left ventricular pressure) with Statham pressure transducer P 23 DB, which on differentiation yielded LV dp/dtmax . • Cardiac output is determined by electromagnetic flow probes in the outflow system. 25
  • 26. Myocardial oxygen consumption (MVO2) (ml/min/gwt) • MVO2= CF × (Pa – Pv) × (c/760) × 100. • CF -is the coronary flow [ml/min/g] • Pa -is the oxygen partial pressure of arterial perfusate . • Pv -is the oxygen partial pressure of the venous effluent perfusate [mm Hg] • C -is the 0.0227 representing the Bunsen solubility coefficient of oxygen dissolved in perfusate at 37 °C 26
  • 27. Positive inotropic effects • Evaluation of a positive inotropic compound usually requires that cardiac force is first reduced. • Acute experimental heart failure can be induced by an overdose of barbiturates,such as sodium thiopental. • This kind of cardiac failure can be reversed by β- sympathomimetic drugs, cardiac glycosides • β-Sympathomimetic drugs restore LVP and dp/dt max and keep coronary blood flow elevated. • Cardiac glycosides increase LVP and dp/dtmax and leave coronary flow unchanged. 27
  • 28. Calcium-antagonism Evaluation • 1 to 5 mg BaCl2 are injected which induce a pronounced spasm of the coronary arteries thereby reducing the coronary flow. • Five min later, the test drug is injected. • After this effect has weaned, BaCl2 is injected again and the test drug or a standard drug injected. • The increase of coronary flow is expressed as percentage of flow during BaCl2 spasm and compared with the effect of the standard. e.g.Nifedipine, is tested. 28
  • 29. Gradual determination of hypoxic damage • Lindner and Grötsch (1973) measured the enzymes creatine phosphokinase (CPK), lactate dehydrogenase (LDH), α-hydroxy-butyrate dehydrogenase (α-HBDH), and glutamic-oxalacetic transaminase (GOT) in the effluent of a guinea pig heart preparation under varying degrees of hypoxia. • Metabolic studies : with nuclear magnetic resonance Using 31P, studies on metabolism of nucleotides and phosphorylated intermediates of carbohydrates in isolated hearts have been performed 29
  • 30. EDRF release from the coronary vascular bed • Lamontagne et al. (1992) isolated platelets from blood of healthy human donors and injected platelets boluses into the perfusion line of the Langendorff preparation of a rabbit heart. • In the effluent cyclic GMP was determined as an index for EDRF release 30
  • 31. Advantages  Highly reproducible, low cost and large numbers can be studied  Broad spectrum parameters can be measured  Absence of confounding factors (neurohormonal)  Allows induction of regional or global ischemia  Hypoxia can be imposed  Ischemia-reperfusion and arrhythmia studies can also be done. 31
  • 32. Disadvantage  Does not represent in vivo settings. Endogenous factors are not considered  Constantly deteriorating preparation. 32
  • 33. 2)Isolated heart lung preparation • Wistar rats of 300-350 grams are anaesthetized. Artificial respiration is established. Chest cavity is opened and ice-cold saline is injected to arrest the heart. SVC, IVC and aorta are cannulated and perfused with Krebs-Ringer bicarbonate buffer containing rat RBC Perfusate from aorta is passed through pnuematic resistance and collected in a reservoir maintained at 37o C. It is then returned to IVC. 33
  • 34. Test drug is administered into the perfusate After 5 minutes Parameters: C.O is recorded with electromagnetic blood flow meter and Mean arterial pressure from pneumatic resistance, Heart rate is recorded using chronometer. 34
  • 35. Evaluation • Hemodynamic data of test drug group and control group is compared using ANOVA. • Recovery time is measured by kruskel wallis test. 35
  • 36. Modification in model • Beaconsfield et al. (1974) used the heart-lung preparation of guinea pigs to study the cardiac effect of delta-9-tetrahydrocannabinol. • Ishikawa et al. (1983) in the dog heart-lung preparation – effects of norepinephrine and 5-hydroxytryptamine • Hausknecht et al. (1986) to investigate the effects of lung inflation on blood flow during cardiopulmonary resuscitation, • Fessler et al. (1988) to investigate the mechanism • of reduced LV afterload by systolic and diastolic positive • pleural pressure, 36
  • 37. 3)Calcium antagonism in isolated rabbit aorta • Rationale: KCl or norepinephrine induces contraction of aorta rings. Test drugs with calcium channel blocking have relaxing effect KCl+ Rabbit descending thoracic aorta Cut into rings of 4-5mm width Mounted in tissue bath containing Krebs HCO3 buffer 20 minutes later, test drug is added. Percentage relaxation reading is taken every 30 minutes after additions of test drug 37
  • 39. Evaluation  Active tension is defined as the difference between the generated tension and the baseline tension (1 gm).  Active tension is calculated for the tissue at the time point just prior to the addition of the test compound and also at the point 30 min after the addition of each concentration of test compound.  The percent relaxation from the predrug, precontracted level is calculated for each concentration of test compound.  A number of 5 experiments constitutes a dose range.  An ID50 is calculated by linear regression analysis. 39
  • 40. 4)Relaxation of bovine coronary artery • Principle: Relaxation caused by test compounds can be assayed using spiral strips from bovine CA Bovine left descending CA is cut into spiral strips(20 mm long and 2-3 mm wide).suspended in a 4 ml organ bath at tension of 2 g Oxygenated Krebs HCO3 solution at 37o C. Krebs solution contains antagonists to inhibit action of endogenous Ach, 5HT, Hist. CAs Isometric contractions are recorded with force-displacement transducers on a grass polygraph. Relaxation caused by test compounds are expressed as % of maximal response to 100 ng/ml PGI2 Test compounds are compared against standard compounds PGE2 (contraction) and PGI2 (relaxation) 40
  • 41. 5)Coronary artery ligation • Principle: left coronary artery ligation induces ischemia, after removal of clip reperfusion changes occur. Prevention of these changes is an indicator of the efficacy. Heart of Wistar rats of either sex weighing 280 – 300g Langendorff technique Silicon balloon is fitted into left ventricular cavity Fluid volume pressed from the balloon corresponds to stroke volume of heart 41
  • 42. Stroke volume can be recorded by flowmeter probe Isolated working hearts are perfused for 20 min with krebs buffer at 65 mmHg Ischemia is induced by clamping the LCA for 15 min Clip is then opened ,Reperfusion changes are monitored for 30 min Test drug is given into perfusion medium before occlusion or 5 min before reperfusion 42
  • 43. Evaluation • Parameters measured: LVP, LV dP/dt max, coronary flow • Myocardial LDH, CK, glycogen, ATP, lactate . 43
  • 44. 6) Plastic casts • Principle: Prolonged administration of coronary drugs increase the number and size of interarterial collaterals of dogs after coronary occlusion, which can be seen by filling the coronary bed with plastic. Dogs (10-15kg)- anesthesized- artificial respiration- heart exposed. Ameroid cuffs are placed around major coronary branches. Gradual swelling of the plastic material occludes the lumen within 3–4 weeks Animals sacrificed- the heart removed- coronary bed flushed with saline. Liquid araldite is filled in bulbous aorta & coronary tree Evaluation: Plastic casts from the drug treated animals are compared with casts from the sham group ( dogs subjected to same procedure without drug treatment). Dogs treated for 6 weeks Tissue digested with 35% KOH 44
  • 46. In Vivo models 1. Coronary artery occlusion 2. Microspheres-induced acute ischemia 3. Isoproterenol-induced myocardial necrosis 4. Stenosis-induced coronary thrombosis model 5. Electrical stimulation-induced coronary thrombosis 6. Myocardial ischemic preconditioning model 46
  • 47. 1.Coronary artery occlusion • Principle: Compounds potentially reducing infarct- size are tested by studying the size of the infarct after proximal occlusion of the left anterior descending coronary artery dogs. METHOD: Dogs anaesthetized- pentobarbitone(35mg/kg i.p.)- Artificial respiration started Cannulation of vessels LAD coronary artery is exposed and ligated for 360 min Test substance is administered i.v. bolus Hemodynamic parameters are measured 47
  • 48. Coronary artery occlusion Animals are sacrificed Coronary arteriograms are made after injection of BaSO4 gelatin mass into LCA LV cut into Transverse section Using X ray tube infarcted area is measured (defect opacity) Slices are then incubated with p-nitro-blue-tetrazolium to visualize infarct tissue (histology) EVALUATION: Mortality,Hemodynamic changes and Infarct size are determined in drug treated animals and compared to vehicle control 48
  • 49. 2.Microspheres-induced acute ischemia Dog is anesthetized Artificial respiration is established Cannulation of – brachial vein, saphenous vein for administration of drug femoral artery connected to pressure transducer 49
  • 50. Embolisation is terminated when LVEDP increased to 16-18 mmHg, PAP – 20 mmHg, HR, 200 /min Test compound administered I.V. Parameters measured: Systolic and Diastolic pressure, LVEDP, HR, Pulmonary capillary pressure, PAP, COP and then compared with control group. A miller microtip catheter is inserted via the LCA for determination of LVP & LVEDP(Left ventricular end diastolic pressure) Microspheres are injected through the catheter initially as 10 ml later as 5 ml IV bolus 5 min apart 50
  • 51. 3.Isoproterenol-induced myocardial necrosis • Principle: -Synthetic catecholamines like isoproterenol when injected at high dose produce cardiac necrosis. -Drugs such as sympatholytics or calcium antagonists can totally or partially prevent these lesions. • Groups of 10 male wistar rats weighing 150-200 gms are pretreated with test or standard drug for 7 days 51
  • 52. Isoproterenol-induced myocardial necrosis Isoproterenol 8.5mg/kg S.C. Test drug adm. Day 0 Day 8Day -7 Day 9 Parameters measured: SBP, DBP, HR, LVEDP, dP/dt Rat is sacrificed, heart is removed, weighed, preserved for HP, and biochemical parameters 52
  • 53. EVALUATION GRADE HISTOLOGICAL CHANGES GRADE 0 No change. GRADE 1 Focal interstitial response. GRADE 2 Focal lesions in many sections , mottled staining and fragmentation of muscle fibre. GRADE 3 Confluent retrogressive lesions with hyaline necrosis and fragmentation of muscle fibre. GRADE 4 Massive infarct with occasionally acute aneurysm and mural thrombi Histological grading: The test has been used for evaluation of coronary active drugs, such as calcium-antagonists and other cardioprotective drugs like nitroglycerin. 53
  • 54. 4.Stenosis-induced coronary thrombosis model Dogs anaesthetized - pentobarbitone sodium( 40mg/kg ip) and LCA exposed Electromagnetic flowprobe placed on proximal part of LCA to measure Blood Flow Vessel is squeezed with haemostatic clamp for 5 seconds Principle: Clamping induces thrombosis in coronary artery . An alteration in coronary blood flow with transient platelet aggregation at the site of coronary constriction is assessed using this model. 54
  • 55. Test compound is administered IV & the cyclic flow variations are registered for 2-5 hrs and compared with pretreatment values Plastic constrictor placed around artery at the site of damage- changed several times till desired constriction is achieved. • Dogs with repeated cyclic flow variations of same intensity are used for experimental purpose 55
  • 56. 5.Electrical stimulation induced coronary thrombosis Electrode is placed in the vessel with the intimal lining and connected with the teflon coated wire of 9 volt battery, potentiometer and amperometer Intima is stimulated with 150 µA for 6 hours- occluding thrombosis occurs Test drug – (s.c.) either,simultaneously or 30 mins following electrical stimulation Time interval until thrombotic occlusion , thrombus size, hemodynamic parameters are measured by canulating to femoral artery. & connecting it to pressure transducer. Principle: Electrical stimulation induces thrombosis in coronary artery German Landrace pigs (40 kg)- anesthesized with Ketamine (2 mg/kg) – Heart exposed- Electromagnetic flowmeter placed on proximal part of LCA 56
  • 57. 6.Ischemia preconditioning model • Rationale: Preconditioning(brief duration of ischemia and reperfusion) can reduce damage produced by prolonged ischemia and reperfusion Rabbits are anaesthetized with ketamine Artificial respiration is established and vessels cannulated 4-0 suture is looped around marginal branch of LCA .Loop is tighten for 5 min, loosened for 10 min Tighten for 30 min followed by 120 min of reperfusion Test drug administered 57
  • 58. Evaluation • The animals are sacrificed after the reperfusion duration. • Comparisons between systemic hemodynamic data and infarct size studies are analyzed by ANOVA using statistical software. 58
  • 59. Coronary flow measurement models • 1.Coronary in flow measurement. • 2.Coronary outflow measurement. • 3.Thermodilution technique. • 4.Inert gas technique. • 5.Radioactive microsphere technique. • 6.Coronary arteriography. 59
  • 60. 1.Coronary in flow measurement • Dogs (15-20 Kg) are anaesthetized, maintained on artificial respiration. • Through left thoracotomy, heart is exposed and pericardium removed • Catheter is inserted through jugular vein to cannulate coronary sinus to measure coronary flow • Femoral artery is cannulated to measure SBP, DBP, mean BP, HR • Test drug is administered through other jugular vein 60
  • 61. Coronary inflow measurement • Evaluation: Changes in coronary flow and hemodynamic parameters after test drug administration is compared with values before administration Advantage: approximately 95% coronary venous flow can be measured Disadvantage: only 60 % of coronary flow returns through coronary sinus. No constant relation between coronary venous outflow and coronary sinus flow 61
  • 62. 2.Coronary outflow measurement Electromagnetic flowmeter: Principle: magnetic field perpendicular to blood flow generates voltage in the conductor which is picked up by electrode, amplified and recorded. Two poles of electromagnet are placed in opposite sides of the coronary vessel. Distally two chromium-vanadium electrodes are placed adhering to the coronary artery 62
  • 63. 3.Thermodilution technique: • A catheter ( webster) is passed to the beginning of coronory sinus. • A temperature sensor is placed further down the coronory sinus. • Ice cold saline of known temperature is injected into coronary sinus. • Modified temperature is measured.The temperature difference obtained is proportional to blood flow. Advantage: only right heart catheterization is required, Resistance to infused saline and saline-blood mixture is recorded by two thermistors 63
  • 64. 4.Inert gas technique • Mainly helium and Nitrous oxide are used. • A mixture of Air and inert gas of known quantity is inhaled. • A series of blood samples are withdrawn from a peripheral artery (using needle) and coronory sinus/ cardiac vein ( using catheter). Blood flow through Amount of substance taken the organ = A – V difference It can measure only mean flow and not regional flow 64
  • 65. Radioactive technique • The radio-isotopes mainly used are - 121 I , 3 H & rubidium. • Isotopes are inhaled / Injected and change in rate over chest wall is measured by giega counter. • By apropriate calculations measure of coronory flow can be determined. • It is fast and simple technique. 65
  • 66. 5.Radioactive microsphere technique • Determines regional blood flow including distribution of coronory flow across the ventricular wall. • A batch of radioactive microspheres (9-15 µ Diameter) are suspended in saline detergent solution and injected into the left atrium. • The number of spheres trapped per unit myocardial tissue is directly proportional to myocardial blood flow. 66
  • 67. 6.Coronary arteriography • Most direct, reliable and advanced method. • Thin, flexible tube called a catheter is put into a blood vessel in your arm, groin (upper thigh), or neck. • The tube is threaded into your coronary arteries, and the dye is released into your bloodstream. • X-ray pictures are taken while the dye is flowing through the coronary arteries. 67
  • 68. Parameter Studied Model Animal used HR , Force of contraction MV02 Isolated Heart Isolated Heart lung Guinea Pig Wistar Rat. Ca - Antagonism Isolated Rabbit Aorta Bovine coronary artery Relaxation Rabbit Beef LDH,CPK,Glucose metabolism Isolated Heart (Langendorff) Guinea Pig. Histology Isopretenerol Induced myocardial Necrosi Wistar Rats Thrombosis Electrical stimulation- induced coronary thrombosis German Landrace Pig. Embolism Microspheres-induced acute ischemia Dog 68
  • 70. Need of clinical evaluation • Caution while interpreting preclinical data… • Difficult to create animal models with coronary lesions as in humans • Extremely variable pain syndrome • No direct relation between degree of pain and coronary insufficiency • All antianginal drugs must not be assumed to be coronary vasodilators and vice versa • In vitro preparations have a limited life span and not exposed to endogenous neurohormonal factors 70
  • 71. INTRODUCTION • The treatment of stable angina pectoris has two major aspects. • The first is to reduce the risk of mortality by preventing myocardial infarction (MI) and death. • The second is to reduce symptoms of angina and occurrence of ischemia, thereby improving the quality of life. • Patients with ischemic heart disease are the preferred test subjects for the assessment of an antianginal effect. However Information derived from healthy volunteers can only be used for safety or pharmacokinetic purposes. 71
  • 72. Early phase (I ) • Objectives: 1. Exploratory clinical pharmacology 2. Dose determination: exercise test protocols 72
  • 73. Strategy - design Pharmacodynamics • Haemodynamic effects at rest and during exercise. • Drug with a novel mechanism of action, data showing the antischemic action (e.g. myocardial perfusion imaging or MRI) • Additional exercise variables testing. • Myocardial perfusion/left ventricular performance • Coronary blood flow/ Diameter of normal and stenosed coronary arteries 73
  • 74. Titration studies -Early dose finding • Start with low doses. • Most common titration design: each patient is titrated up to a certain point according to specified rules. • Minimum 4 dose levels • Advantage : few healthy volunteers required. • Disadvantage : Possible carry over effects • Control group is mandatory 74
  • 75. Confirmatory dose finding • Parallel group design. • Placebo controlled studies using 3 or 4 doses • Duration: 2-4 weeks • 40 – 80 patients per group • Only sublingual nitroglycerin allowed • Monotherapy • Combination therapy 75
  • 76. Factors assessed: • Effects on heart rate, rhythm, conduction times and, if necessary, refractory period • Effects on renal function and electrolytes • Effects on the pulmonary function • Effects on the metabolism, particularly of glucose and lipids • Neurohormonal effects • Platelet aggregation and other rheological effects • Vital and laboratory parameters . 76
  • 77. Phase ( II & III)- Selection of patients • The patients included in the studies must suffer from stable angina pectoris . • To study the efficacy of antianginal drugs and safety aspects of their indications.Mostly placebo controlled parallel designs single or in combinations. • With regard to dose-finding studies the documentation of unequivocal coronary heart disease is mandatory. 77
  • 78. Inclusion criteria  H/o chronic angina pectoris on effort for > 3 months before study entry.  Percutaneous Coronary Angioplasty > 6months or Coronary Angioplasty bypass > 3months.  Coronary angiography >50% diameter stenosis of one or more major coronary arteries.  Positive scintigraphic test showing exercise induced reversible myocardial ischaemia or a Positive stress echocardiography. 78
  • 79. Inclusion criteria  Sinus rhythm.  Subject experiencing pain within 3-7 min of Bruce protocol on exercise testing.  Reproducibility of results of exercise test should be shown by patient.  Resting ECG should not interfere with interpretation of ST segment changes. 79
  • 80. Exclusion criteria  H.R. <60.  Significant heart disease other than CAD.  Unstable angina pectoris ,Prinzmetal angina.  Severe heart failure symptoms (NYHA class lll / IV).  Symptomatic hypotension or uncontrolled hypertension.  AF/AFL.  Pacemaker / implanted defibrillator.  Any other condition that interferes with the ability to perform or interpret Exercise Stress test. 80
  • 81. Efficacy evaluation • Primary: • Occurrence of anginal pain during exercise “ an antianginal agent cannot be considered antianginal unless it increases the amount of exercise that a patient can perform prior to the development of angina after drug administration ” 81
  • 82. Exercise tests • Two Types : Isometric or Dynamic. • Isometric exercise : constant muscular contraction without movement (e.g., handgrip). • Dynamic exercises: preferred • Maximal exercise test • A)Treadmill Test. • B)Upright bicycle ergometer • A maximal exercise test brings an individual to a level of intensity where fatigue or symptoms prohibit further exercise or when maximal oxygen consumption (VO2max) is achieved and no further increase in heart rate occurs. 82
  • 83. A)Treadmill exercise tests • Leads of the ECG are placed on the chest wall. The treadmill is started at 2.74 km/hr (1.7 mph) and at a gradient (or incline) of 10%. • At three minute intervals the incline of the treadmill increases by 2%, and the speed increased as in the Bruce protocol 83
  • 85. Bruce Protocol Stage Speed (km/hr) Speed (mph) Gradient (inclination) 1 2.74 1.7 10 2 4.02 2.5 12 3 5.47 3.4 14 4 6.76 4.2 16 5 8.05 5.0 18 6 8.85 5.5 20 7 9.65 6.0 22 8 10.46 6.5 24 9 11.26 7.0 26 10 12.07 7.5 28 MODIFIED BRUCE PROTOCOL: Starts at a lower workload than the standard test- for elderly or sedentary patients. First two stages of the Modified Bruce Test are performed at a 1.7 mph and 0% grade and 1.7 mph and 5% grade, and the third stage corresponds to the first stage of the Standard Bruce Test protocol as listed above. 85
  • 86. Contraindications to Exercise Testing  Recent acute myocardial infarction (less than 2 days).  High-risk unstable angina pectoris  Symptomatic severe aortic stenosis  Uncontrolled cardiac dysrhythmia  Acute myocarditis or pericarditis  Severe hypertension  Decompensated congestive heart failure  Intracardiac conduction block greater than first degree  Suspected or known dissecting aneurysm  Thrombophlebitis or pulmonary embolus  Acute systemic illness 86
  • 87. Treadmill test • Advantage: Permits 10-15% higher oxygen consumption rate Excellent reproducibility Minimum subject co-operation • Disadvantage: Difficulty to record exact BP and ECG Not suitable for studies requiring relatively immobile thorax e.g. echocardiography or scintigraphy. 87
  • 88. B)Upright bicycle ergometer Advantage: Stable ECG and BP recording Intravascular catheters, expired air easily collected Scintigraphic observations may be made Disadvantage: Person should be accustomed to cycling 88
  • 89. Evaluation of ECG Data • 12 Lead ECG is preferred. • The classic criteria for visual interpretation of positive stress test findings are J-point (the junction of the point of onset of the ST-T wave) • ST80 :The standard criterion for this type of abnormal response is horizontal or downsloping ST-segment depression of 0.1 mV (1 mm) or more for 80 msec the point that is 80 ms from the J point) in 3 consecutive beats. 89
  • 90. Efficacy evaluation • Primary: • Occurrence of anginal pain during exercise “ an antianginal agent cannot be considered antianginal unless it increases the amount of exercise that a patient can perform prior to the development of angina after drug administration ” 90
  • 91. 1. Exercise Capacity • Interpretation should include Total exercise capacity and clinical, hemodynamic, and ECG response. • The translation of total exercise capacity into METs (metabolic equivalents of exercise) provides a standard measure of performance A MET: refers to the resting volume oxygen consumption per minute (VO2) for a 70-kg, 40-year- old man. One MET is equivalent to 3.5 mL/min/kg of body weight. 91
  • 92. 2.Anginal pain • The patient's experience of anginal pain should be recorded in a patient diary as well as the concomitant use of short-acting nitrates. • The daily frequency, severity and duration, of anginal pain should whenever possible be registered by patients using available log books. • The CCS Angina Grading System or other questionnaires may be used for assessing changes in symptoms or physical function. 92
  • 93. Canadian Cardiovascular Society Classification of angina Modification of CCS 93
  • 94. • 3) Time to the onset of angina • Limitation : 1) subjective. 2) A significant amount of treated patients might have no limiting angina after treatment or might be limited in their exercise capacity by reasons other than angina. • 4) Time to ST segment depression • Time to 1 mm ST segment depression - more objective variable and is indicative of an anti-ischemic effect which is an important factor in antianginal drug assessment. • Nevertheless, although its prognostic value is recognised, at present, its extrapolation in terms of clinical benefit for the patient is unknown. 94
  • 95. 5)Measurement of Health-Related Quality of Life (HRQoL) • The evaluation of treatment effect on patient’s quality of life provides relevant supportive information on the overall treatment benefit. • Validated questionnaires should be shown to be clinically responsive and capable of differentiating: -clinically important improvement or deterioration. -provide relevant supportive information on the overall treatment benefit. 95
  • 96. 6) Morbidity and mortality • Since the target of antianginal therapy is essentially symptoms control, at present, there is no requirement to prove beneficial effect on these variables in order to obtain a marketing authorisation, unless specifically claimed. • However, effects on cardiovascular and total morbidity and mortality should be evaluated as a relevant safety parameter. • This should be done in particular if there is a reasoned suspicion that a new drug might have detrimental effects on these parameters 96
  • 97. Endpoints for evaluating anti- ischemic interventions 1. ‘Patients perception of chest pain’ usually is the primary efficacy parameter 2. ST-segment depression during identical workloads pre- and post- intervention 3. Maximal exercise tolerance 4. Rate-pressure product (RPP) at identical workload and maximal exertion 5. Angina free exercise tolerance 6. Exercise tolerance at 0.1 mV ST-segment depression 7. Longevity of life (increased disease free survival) 8. Increased quality of life 9. Minimize complication rates 97
  • 98. Some clinical trial designs Title Drugs Phase Metabolic Efficiency With Ranolazine for Less Ischemia in Non- ST Elevation Acute Coronary Syndromes (MERLIN-) Ranolazine Placebo Phase – 3 (2009) Double-blind, Randomized, Placebo- controlled Study of the Safety and Efficacy of TAK-442 TAK-442 Placebo Phase – 2(2010) To compare the pharmacokinetic characteristics and safety of dilatrend SR capsule 32mg in healthy male subjects. dilatrend SR Phase – 1 (2013) 98
  • 99. Some clinical trial designs-Phase 4 Title Drugs Phase A Study on the Effects of Ranolazine on Exercise Duration in Subjects With Chronic Stable Angina and Coronary Artery Disease (CAD) With Type 2 Diabetes Mellitus (T2DM) Ranolazine Phase 4 (2011) An Open-label, Multi-center Study Evaluating the Validity, Reliability, and Responsiveness of a New Female-specific Angina Questionnaire in Women With Chronic Angina Treated With Ranolazine Extended- release Tablets (CVT 3041) Ranolazine Phase 4 (2012) 99
  • 100. To summarize… • In the early evaluation of antianginal drugs, exercise test protocols performed in a selected population of patients are the only means to accurately determine appropriate doses and dosing intervals. • However, despite great attention to detail, the assessment of a drug with a real antianginal effect could remain inconclusive during exercise testing. It is, therefore, important to follow the recommendations made to optimize exercise testing for pharmacological investigations. 100
  • 101. To summarize… • Other pharmacodynamic measurements may provide insights into the mechanism of drug action but cannot be selected as surrogates for dose-ranging or regulatory purposes. • Although exercise capacity currently remains the primary efficacy variable for antianginal agents in therapeutic confirmatory trials, outcome variables (e.g., mortality/survival data) may also be required for regulatory purposes in the future………. 101
  • 102. REFERENCES• • Vogel WH, Schölkens BA. Drug Discovery and Evaluation [Internet]. Vogel HG, Vogel WH, Schölkens BA, Sandow J, Müller G, Vogel WF, editors. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. P.208-29. • Mor M, Shalev A, Dror S, Pikovsky O, Beharier O, Moran A, et al. INO-8875, a new trend in evaluation of chronic stable angina J. Pharmacol. Exp. Ther. [Internet]. 2013 Jan;344(1):59–67. • Lucia H. Lee, Chi-Jen Lee.CLINICAL TRIALS OF DRUGS AND BIOPHARMACEUTICALS: Taylor & Francis Group, LLC 2006 p.146-57. • L. Forslund, P. Hjemdahl:Prognostic implications of results from exercise testing in patients with chronic stable angina pectoris treated with metoprolol or verapamil The European Society of Cardiology 2000 p.347-53. • Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener H-C, et al. Outcome parameters for trials in Chronic stable angina: executive summary. Eur. Heart J. [Internet]. 2007 Nov ;28(22):2803–17. 102
  • 103. Live a healthy lifestyle and keep your Heart pumping forever and ever……. 103
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Notas do Editor

  1. Heart- the most vital part of the body. It supplies blood to all the body parts right from head to toe. But do we ever realize that heart is constantly working at subconscious level. On an average, heart beats 2.5 – 3 billion times in life. First beats of the heart are seen around 3-4th month of intrauterine life. From there onwards it never takes live till the person dies. When do we realize that heart actually exists in our body. There are two conditions: one is this. And the other is this of which we are concerned today. THAT IS ANGINA. Means chest pain or in laymen word CRY OF THE HEART. It occurs when heart which supplies blood to all organs itself gets deprived of it i.e. when the blood supply to the heart is less than its requirement.
  2. Angina pectoris occurs when cardiac workload and resultant myocardial O2 demand exceed the ability of coronary arteries to supply an adequate amount of oxygenated blood myocardial O2 demand is determined mainly by heart rate, systolic wall tension, and contractility As the myocardium becomes ischemic, coronary sinus blood pH falls, cellular K is lost, lactate accumulates, ECG abnormalities appear, and ventricular function deteriorates. Left ventricular (LV) diastolic pressure usually increases during angina, sometimes inducing pulmonary congestion and dyspnea.
  3. Prinzmetal&amp;apos;s - a syndrome of ischemic pain that occurs at rest but not usually with exertion and is associated with transient ST-segment elevation. This syndrome is due to focal spasm of an epicardial coronary artery, leading to severe myocardial ischemia.
  4. The perfusate might be blood, Tyrode, Locke or Krebs- Henseleit bubbled with carbogen at physiological temperature.
  5. MODIFICATIONS OF THE METHOD Yang et al. (1996) reported a protective effect of human adrenomedullin
  6. Effects on heart rate, rhythm, conduction times and, if necessary, refractory period Effects on renal function and electrolytes Effects on the pulmonary function Effects on the metabolism, particularly of glucose and lipids Neurohormonal effects Platelet aggregation and other rheological effects Vital and laboratory parameters