Ischemic heart disease

11/7/2015
1
ISCHEMIC HEART DISEASE
(IHD, CAD)
Dr. Ahmed A. Elberry, MBBCH, MSc, MD
Associate Professor of Clinical Pharmacy
Faculty of pharmacy,
KAU
1
DEFINITION & EPIDEMIOLOGY
IHD:
•  O2 or blood supply to myocardium resulting from narrowing
or obstruction of the coronary artery.
Incidence:
• IHD is the 1st leading cause of death in USA (cancer is the 2nd
cause)
• 5 million patients present to ER /year with IHD and ~1.5
million are hospitalized for ACS
2
ECONOMICALLY:
• Direct cost of hospitalization > $15 billion yearly,
• With additional > $4.5 billion yearly in diagnostic
procedures.

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2
Types of IHD
IHD may Asymptomatic or present as:
1. Angina:
• Stable (exertional)
• Vasospastic (variant or Prinzmetal).
• Unstable angina (US) [preinfarction]
2. Myocardial infarction (MI):
• Non–ST-segment elevation MI (NSTEMI)
• ST-segment elevation MI (STEMI)
NB.: Acute coronary syndrome (ACS): US angina & MI
3
NB.: Angina decubitus
(nocturnal angina)
Def.: Angina occurs in the recumbent position only.
Mechanism: Gravitational forces shift fluids with a  in
ventricular volume, â O2 needs â angina .
Treatment: Diuretics alone or in combination to reduce
left ventricular volume.
4

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ETIOLOGY
(Imbalance between O2 supply & O2 demand)
1.  quantity of coronary blood:
Atherosclerosis, thrombosis, spasm
2.  quality of coronary flow:
Anemia
3. cardiac muscle demand that cannot be
compensated
Severe exercise, tachycardia, thyrotoxicosis
5
O2
demand
O2
supply O2
demand
O2
supply
Predisposing factors for
atherosclerosis
1.Increased smoking
2.Increased weight
3.Hereditary
4.HT
5.Dyslipidemia
6.DM
7. Age (> 45 for male/ > 55 for female)
8. Activity (lack of regular activity)
6

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ANGINA
7
MANIFISTATION
Chest pain:
• Site: Retrosternal chest pain on exertion (?????) or rest
(????).The pain may radiate to shoulder, left arm, or
jaw.
• Type: tightness, squeezing or burning
• Duration: 0.5 – 30 minutes.
• Associated symptoms: May be associated with
sweating, SOB or vomiting (common in females)
Signs :
• No specific signs.
8

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5
DIAGNOSIS
9
1. Laboratory tests:
1. Hb, fasting glucose & lipoprotein.
2. Biochemical markers of MI:
• Both troponins & CK-MB to exclude MI
2. ECG is normal in about 50% of patients with angina.
3. Stress ECG or Exercise tolerance testing (ETT)
4. Echocardiography
5. Pharmacologic stress echocardiography
(e.g., dobutamine, dipyridamole, or adenosine): In
patients unable to exercise.
6. Cardiac catheterization
& coronary angiography
Treatment of angina
Goal of treatment:
• Short term goal:
• Relieve symptoms
• Long term goal:
• prevents sequences & complications (MI,
arrhythmia, HF, Death)
10

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11
1- Treatment of stable angina
Risk factor &
life style
modification
1- Treat:
- Obesity
- Dyslipidemia
- DM
- HTN
2-  Physical activity
3-  Smoking
4- Diet:
 Vegetables &
fruits
 Saturated fats
Pharmacological
1) Antiplatelets
2) Antiischemic:
1. BB
2. CCB
3. Organic
nitrates
4. Ranolazine
5. Ivabradine
3) Adjuvants:
1- ACEIs
2- Statin
Revascularization
PCI
CABG
ANTIPLATELETS
 Indication:
• All patients with IHD with no contraindications as 1st line
therapy.
 Include:
• Aspirin Small Dose (75-162 mg):
• selective  of platelet thromboxane A2
• Clopidogrel & Ticlopidine
Block ADP receptors
- Clopidogrel (Plavix): 75 mg
- Used when aspirin is contraindicated
- May be added to aspirin for 1 year
(esp in patient undergoing PCI)
- Ticlopidine (Tilopin): not used now
due to severe neutropenia
12

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BETA BLOCKERS
Mechanism of action:
1. –ve inotropic & chronotropic   cardiac work & O2
consumption
2. –ve chronotropic (Bradycardia)   diastolic time  
coronary perfusion time
3. antihypertensive effect   after load
13
 Classification & Side effects: see before
 NB.:
 BB does not produce coronary V.D & non selective may cause
even V.C [contraindicated in varient]
 BB with ISA may be detrimental in patients with rest or severe
angina (??)
MyoBloodFlow.mpg
Indications of BB:
1. 1st line in “stable angina” requiring daily maintenance
therapy
2. Coexisting
1. HT,
2. Supraventricular arrhythmias,
3. Postmyocardial infarction angina
4. Anxiety
• NB: BB are contraindicated in IHD associated with severe HF
Treatment objectives (targets):
• resting HR to 50 - 60 beats/min
•  maximal exercise HR to 100 beats/min or less.
14

11/7/2015
8
Dosing of BB in IHD
15
Agent Metoprolol
Tartrate
(Lopressor)
Metoprolol
Succinate
(Toprol XL)
Atenolol
(Tenormin)
Carvedilol
Dose 12.5-200 mg
BID
50-400 mg
daily
25-100 mg
daily
6.25-50 mg
BID
CALCIUM CHANNEL BLOCKERS
Mechanism of action:
• VD of systemic arterioles & coronaries (nifedipine &
amlodipine)   arterial pressure & coronary vascular
resistance
• –ve intotropic (Verapamil & diltiazem)  contractility
& O2 consumption
NB.:
• Reflex adrenergic stimulation overcomes much of the
–ve inotropic effect,
• –ve inotropic effect becomes clinically apparent only
in:
• presence of LV dysfunction
• when other –ve inotropics are used concurrently
16
 Side effects & classification: see before

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Indications:
1. Concurrent hypertension
2. Patients with contraindications to β-blockers:
eg:
1. Prinzmetal angina (CCB is the 1st choice)
2. Concurrent:
1. PVD,
2. Severe ventricular dysfunction,
(Amlodipine is the agent of choice in severe ventricular
dysfunction & the other dihydropyridines should be used with
caution if the EF is ˂40%)
NB.: coexisting conduction system disease (HB)
excluding the use of verapamil & diltiazem
17
Organic nitrates
• Nitrates (in the presence of SH group of tissues)  NO  
GC  c.GMP  spasmolytic &  platelet aggregation
• It  Cardiac work & O2 consumption indirectly through:
• Powerful venodilator   preload
• Mild arteriodilator  afterload
18

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Indications:
1st line in acute attack
May be used in prophylaxis as maintenance
therapy, usually in combination with BB or CCB
19
Side effects
1. Allergy
2. Headache (the most common side effect & can be
prevented by acetaminophen 15 – 30 min. prior to
administration)
3. Hypotension  reflex tachycardia [add BB or CCB
(Verapamil)] (More profound with PDE-5 inhibitors)
4. Postural Hypotension  syncope
5. Tolerance  due to depletion of SH group & can be
avoided by:
• Less frequent dosing (Allow 8-10 hours nitrate free / day)
• Drugs containing SH (as ACEIs .., diuretics) may decrease that
effect
6. Dependence  never stop suddenly
7. Formation of met-hemoglobin
8. Formation of nitrosamine  carcinogenic 20

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Preparations:
21
Glyceryl trinitrate
(nitroglycerine)
Isosorbid
dinitrate
Isosorbid
mononitrate
1) Sublingual Dose
Onset
Duration
0.4-0.6 mg/15 min max. 3
dose
1-3 min
10-30 min
5 mg (Wesorbide)
1-3 min
1 hour
2) Buccal Dose
Duration
0.4 / metered dose
10-30 min
3) Oral Dose
Duration
6.5 -13 mg SR 2-4 times /d
4-8 h
10-40 mg t.d.s
4-6 h
-SR is available
(Isobid)
10-40 mg/ 12 h
6-10 h
-SR is available
(Imdur)
4) T.D.S (Nitroderm)
- Ointment 2%
- Patch
Dose
Duration
Dose
Duration
1-1½ inch/4h
3-6 h
One patch 25 mg /day
8-12 h
RANOLAZINE (Ranexa)
• may be related to  in Ca++ overload in ischemic
myocytes through inhibition of the late Na+ current.
22
 Indications:
 should be reserved for patients who have not achieved adequate
response to other antianginal drugs (because it prolongs QT interval)
 Should be used in combination with amlodipine, βB, or nitrates.
 Dosing:
 started at 500 mg twice daily & increased to 1 g twice daily if needed.
 Side effects:
 Headache, constipation & nausea.
 QT interval prolongation (baseline & follow up ECG
should be obtained)

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23
Ivabradine
Mechanism:
• Block the If channel in SA node causing bradycardia.
Indication:
• Similar in efficacy to CCB & BB & indicated when BB are
contraindicated
SE:
• dose-dependent retinal toxicity (resolve spontaneously during ttt or
after discontinuation.
24

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ACEI
Indications:
• Associated with
1. LVEF ˂ 40% ,
2. HT,
3. DM,
4. CKD
Postulated mechanisms:
• Plaque stabilization
•  load on the heart through VD   O2
consumption
25
STATIN
Benefits:
• Cholesterol lowering effect
• Non-cholesterol lowering effect:
1. Antithrombotic
2. Antiinflammatorty
3. Antiproliferative
4. Antioxidant
 what is the dose?????
26

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Recommendations
All patients with CAD should be
given the following unless
contraindications exist:
1. Aspirin (Clopidogrel may be used if
aspirin is contraindicated)
2. ACEI to patients with CKD,
diabetes or LV dysfunction
3. β-Blockers with prior MI
4. CCB or long-acting nitrates when
βB are contraindicated OR failed
5. Cholesterol (LDL) lowering therapy
if LDL >130 mg/dL
6. SL nitroglycerin for immediate relief
of angina
27
2- Treatment of variant angina
Acute attack:
• should be treated with nitrates
Prophylactic treatment for 6 -12 m :
• CCB (the drug of choice)
• Long acting Nitrates
• NB: Avoid BB
28

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Acute coronary syndrome
29
MANIFISTATION
Persistent chest pain > 20 mins.
 Associated symptoms: May be associated with
sweating, SOB or vomiting (common in females)
Signs :
• No specific signs.
• may present with:
• Signs of acute HF including jugular venous
distention & an S3 sound.
• Arrhythmias (tachycardia, bradycardia, or HB).
30

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DIAGNOSIS
31
As in angina esp biochemical markers of MI
• Both troponins & CK-MB are detectable within 6 h of MI.
• Troponins is more specific & remain elevated for up to 10
d, whereas CK-MB returns to normal within 48 h.
• Troponin may  in other conditions as HTN, Tachycardia,
severe asthma, renal failure
• CK-MB may be increased in muscle injury
Complications of MI
ACT RAPID
1. Arrhythmia
2. CHF
3. TED
4. Rupture
5. Aneurysm
6. Pericarditis
7. Infarction (2nry, Reinfarction)
8. Death
32

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Risk Stratification
STEMI:
• highest risk of mortality with 97% chance of having an MI
subsequently
NSTEMI:
• TIMI risk score: 1 point for each of the following
1. > 65 Age
2. > 3 risk factors for CAD (Smoking, DM, HTN, family history,
dyslipidemia)
3. > episodes of chest pain in last 24 hours
4. > 0.5 mm ST segment depression
5. prior history of CAD
6. aspirin use in past 7 days
7. +ve biochemical markers for MI
• Low risk: 0-2 (mortality rate 3%)
• moderate risk: 3-4 (mortality rate 5%)
• high risk: 5-7 (mortality rate 12-19%) 33
34
3- Treatment of acute coronary syndrome
General
treatment
1- Hospitalization & bed
rest
2- Monitoring: ST-
segment for
arrhythmias & ischemia
3- O2 (if saturation is ˂
90%)
4- Stools softeners to
avoid constipation &
Valsalva maneuver
5- Analgesics (morphine
&NTG)
Early
therapy
For
STEMI
For
UA/NSTEMI
2ry prevention
of MI

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EARLY THERAPY for STEMI
1. Reperfusion therapy: treatment of 1st choice:
• Thrombolytics or PCI
• The target time to initiate reperfusion:
• within 30 minutes of hospital presentation for thrombolytic
therapy and
• within 90 minutes from presentation for PCI.
2. Dual antiplatelet therapy (DAPT)(as aspirin & clopidogrel)
3. Anticoagulant (Fondaparinux, UFH, LMWH
[enoxaparin]).
4. β-blocker, ACEIs, eplerenone (or spironolactone), statin
35
Reperfusion strategies
36NB.: Angiography not earlier than 3 hours after fibrinolysis
Facilitated PCI

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PCI (Percutaneous coronary artery
intervention)
37
EARLY THERAPY for UA/NSTEMI
Low risk (Early conservative
strategy):
1. DAPT
2. Anticoagulant
(Fondaparinux, UFH,
LMWH [enoxaparin]).
3. β-blocker, ACEIs, Statin
NB.: PCI may be also
required if stress ECG or
echo showed +ve evidence of
ischemia
38
 High risk (Early invasive
strategy):
1. DAPT
2. Anticoagulant
(Fondaparinux, UFH,
LMWH [enoxaparin]).
3. Angiography (PCI,
CABG, Non)
4. β-blocker, ACEIs, Statin
RISK STRATIFICATION:

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2ry prevention after MI
1. SL NTG or lingual spray (PRN)
2. Antiplatelet therapy (Aspirin & Clopidogrel)
3. Anticoagulant therapy: warfarin for Selected
patients (TED or history of TED, chronic AF)
4. β- blocker,
5. Annual influenza vaccination.
6. ACE inhibitor.
7. Control of risk factors as HTN, dyslipidemia & DM
• Statins should be prescribed at or near
discharge in most patients.
• Fibrates or Niacin should be considered in
selected patients with low HDL-C (<40 mg/dL)
and/ high TG (>200 mg/dL).
39
8. Aldosterone blockers
• Post-STEMI patients only
• No significant renal failure (cr < 2.5 men or 2.0 for
women)
• No hyperkalemia > 5.0
• LVEF < 40%
• Symptomatic CHF or DM
40

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Thrombolytics
(fibrinlytics)
 Indications:
When there would be a delay in performing PCI > 2 hours.
 They include:
1. Streptokinase (from streptococci)
2. Urokinase (from cultured human kidney cells)
3. Tissue plasminogen activator (t-PA):
• Alteplase
4. t-PA analogue (long t1/2 allowing IV bolus).
• Reteplase
• Tenecteplase
 Side effects of thrompolytics:
1. Failure of reperfusion (50%)
2. Bleeding & hemorrhagic stroke (most important, 1% of patients)
3. Allergy (especially with Streptokinase)
4. Fever
41
42
Streptokinase
(Strptase)
Alteplase
(Activase)
Reteplase
(Retavase)
Tenecteplase
(TNKase)
Antigenicity
Yes
No
No
No
Fibrin
specificity
Minimal
Moderate
Moderate
High
Elimination
Hepatic
Hepatic
Renal
Hepatic
t1/2 Min.
18-23
3-8
15-18
20-28
Dosing
1 h infusion
Bolus + 90
min infusion
2 boluses
1 bolus

11/7/2015
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43
B: BLEEDING AND STROKE
R: REPERFUSION FAILURE
IG: Induce Generation of degradation products of
fibrin
H: HYPERSENSITIVITY
T: TEMPERATURE INCREASE
Contraindications
Absolute CI:
1. active internal bleeding
2. intracranial neoplasm
3. aortic dissection
4. previous ICH at any time
5. closed head trauma within 3
ms
6. ischemic stroke within 3 ms
Primary PCI is preferred in
these situations.
44
Relative CI:
1. severe, uncontrolled HTN (˃
180/110 mm Hg)
2. Current anticoagulant use;
3. bleeding tendency
4. pregnancy;
5. active peptic ulcer;
6. history of ischemic stroke
longer than 3 ms
7. major surgery within 3 ws;
8. internal bleeding within 2-4
ws
9. for streptokinase, prior
administration (6 m – 1
year) or prior allergy

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ANTIPLATELET THERAPY
1. Drugs acting on Arachidonic
acid metabolism:
1.  Thromboxane A2 synthesis:
Aspirin Small Dose (75-325 mg)
2. Prostacyclin analogue:
Epoprostenol but very short t ½
2. Drugs acting on platelet
receptors:
1. Block ADP receptors (P2Y12) As:
Clopidogrel, Ticlopidine, Prasugrel,
Ticagrelor
2. Block GP IIb /IIIa receptors:
Abciximab – Tirofiban - Eptifibatide
45
ASPIRIN
Indications:
1. All IHD patients without contraindications &
within the first 24 h of hospital admission.
2. For patients undergoing PCI
Dosing:
• 162 - 325 mg, chewed & swallowed as soon as
possible.
• Maintenance dose of 75 - 162 mg.
46

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Thienopyridines
1- Clopidogrel (Plavix)
• Indications:
1. patients with aspirin allergy.
2. with aspirin to reduce morbidity & mortality in
a) STEMI &
b) patient undergoing PCI (for 1 year)
• Dose: A 300- 600 mg loading dose on1st hospital day, followed by
a maintenance dose of 75 mgd.
• Side effects:
• nausea, vomiting, & diarrhea (5% of patients).
• Thrombotic thrombocytopenia purpura (rarely).
• Hemorrhage (MOST SERIOUS).
47
48
 NB.:
 Clopidogrel is a prodrug (metabolized by CYP 2C19).
 Genetic polymorphism of CYP 2C19 “poor, intermediate,
rapid & ultrarapid metabolizers”
 Avoid inhibitors of CYP 2C19, omeprazole &
esomeprazole (why?).
 Factors  effect of clopidogrel ( CV adverse effects):
1. Noncompliance
2. Inadequate dose
3. Variation in absorption
4. HMEIs
5. Genetic polymorphism
6.  platelet reactivity (as in DM)

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Thienopyridines (contin.)
2- Ticlopidine (Tilopin)
• SE.:
• Severe neutropenia, agranulocytosis,
thrombocytopenic purpura (not used now).
3- Prasugrel (Effient):
 Dose: LD 60 mg, MD 10 mg Once daily
 Prodrug as previous drugs
 Rapid onset & Better bioavailability than
clopidogril
 High incidence of bleeding (CI with history of
TIA)
49
Ticagrelor (Brilinta):
 Dose LD 180 mg, MD 80 mg BID
 Non- Thienopyridines
 The only active drug
 Rapid onset & more potent but short duration (given
twice/day) [disadvantage & advantage???]
 Diminished effectiveness with concomitant
use of aspirin doses above 100 mg.
50

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Glycoprotein IIb/IIIa Receptor
Inhibitors
Abciximab (ReoPro) is preferred over eptifibatide &
tirofiban because it is the most widely studied agent.
Benefit:
• Abciximab, in combination with aspirin, thienopyridine, & UFH
reduces mortality & reinfarction.
Dose:
• 0.25 mg/kg IV bolus given 10- 60 min before the start of PCI,
followed by 0.125 mcg/kg/min (maximum 10 mcg/ min) for 12
h.
Side effects:
• Bleeding
• Thrombocytopenia
51
ACCF/AHA PCI Guideline
Recommendations for Antiplatelet
Recommendation Dosing COR LEO
Aspirin
Non–enteric-coated aspirin to all patients
promptly after presentation
162 - 25 mg I A
Aspirin maintenance dose continued
indefinitely
81-162 mg/d I A
P2Y12 inhibitors
Clopidogrel LD followed by
daily MD in pts unable to take aspirin
75 mg I B
P2Y12 inhibitor, in addition to aspirin,
for up to 12 mo for patients treated
initially with either an early invasive
Clopidogrel: 300-600 mg
LD followed by 75 mg/d
Ticagrelor: 180 mg LD
then 90 mg BID
I B
Ticagrelor is preferred over clopidogrel in pts
treated with invasive strategy
IIa B
GP IIb/IIIa inhibitors
In patients treated with early invasive strategy Preferred options are
eptifibatide & tirofiban
IIb B
52

11/7/2015
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53
berry_ahmed@yahoo.com

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