CVS PHARMACOLOGY

Outlines
 Introduction CVS physiology.
 Antihypertensive Agents and anesthetic
implications.
 Anti-Angina Pectoris
 Drugs Used in Heart Failure
 Agents Used in Cardiac Arrhythmias
 Objectives
After this presentation the audience/participants
can get idea on
Rehearses highlight on cvs physiology
anti hypertensive drugs and their anesthetic
implication.
 vasodilators and anti angina drugs and their
anesthetic implication.
common anti arrhythmic and diuretics.
 INTRODUCTION
Cardiac blood flow
 The heart is a double pump in which the right side
operates as a low-pressure system delivering de-
oxygenated blood to the lungs, while the left side is a
high pressure system delivering oxygenated blood to
the rest of the body.
 The walls of the right ventricle are much thinner than
those of the left, because the work load is lower for the
right side of the heart.
 The ventricular muscle is relatively stiff, and it would
take some time to fill with venous blood during
diastole. The thin, flexible atria serve to buffer the
incoming venous supply, and their initial contraction at
the beginning of each cardiac cycle fills the ventricles
efficiently in a short space of time.
 Coronary circulation
Carry blood to myocardium
 Heart depends strongly on aerobic metabolism
 Brief period of low oxygen : damage to
myocardium.
 Coronary arteries (2) open out of aorta just above
aortic valve
 -Left coronary artery supply : posterior part
 -Right coronary artery supply : right part
 Coronary veins return blood to coronary sinus
located near RA
Regulation of cardiac output
~ 5L /minute; dependent on:
Heart rate
Stroke volume
Preload
Afterload
Venous return depends
 Systemic filling pressure
 Auxiliary muscle pump
 Resistance to flow between peripheral vessels and right
atrium
 Right atrial pressure - elevation
Regulation of Arterial Pressure
 Arterial pressure affected by:
1. the autonomic nervous system (fast)
2. the renin-angiotensin system (hours or days)
3. the kidneys (days or weeks)
Cardiac Cycle
Cardiac electrical activity
 Cardiac muscle does not require any nervous stimulation to contract.
 Each beat is initiated by the spontaneous depolarization of pacemaker
cells in the sino-atrial (SA) node. These cells trigger the neighboring
atrial cells by direct electrical contacts and a wave of depolarization
spreads out over the atria, eventually exciting the atrio-ventricular (AV)
node.
 Contraction of the atria precedes that of the ventricles, forcing extra
blood into the ventricles and eliciting the Starling response.
 The electrical signal from the AV node is carried to the ventricles by a
specialized bundle of conducting tissue (the bundle of His)
 The conducting tissues are derived from modified cardiac muscle cells,
the Purkinje fibers.
 The conducting bundles divide repeatedly through the myocardium to
coordinate electrical and contractile activity across the heart.
 Although each cardiac muscle cell is in electrical contact with most of its
neighbours, the message normally arrives first via the Purkinje system.
 Antihypertensive agents
How to Diagnosis hypertension?
 based on repeated, reproducible measurements
of elevated blood pressure
 Usually symptom-free
What is the cause of HTN
 Known ethology for only 10-15% of the pt
(secondary hypertension).
 About 90-85% of HTN unknown cause (essential
or primary hypertension)
Anatomic sites of blood pressure
control
Consequences: Heart failure, kidney damage,
stroke, blindness ……..
Potential drug targets:
CNS, ANS: decrease sympathetic tone
Heart: decrease cardiac output
Veins: dilate => decrease preload
Arterioles: dilate => decrease afterload
Kidneys: increase diuresis; inhibit RAA system
Four major drug categories
Sympathetic nervous system suppressors:
– α1 and β1 antagonists
– α2 agonists
Direct vasodilators:
– Calcium channel antagonists
– Potassium channel agonists
Renin-angiotensin system targeting drugs:
– ACE inhibitors
– Angiotensin II receptor antagonists
Diuretics:
– Thiazides
– Loop diuretics
– K+ - sparing diuretics
 β Blockers
Advantages:
• No postural hypotension
• No salt and water retention
• Low incidence of side effects
• Low cost
• Once a day regime
• Preferred in young non-obese patients, prevention of sudden
• cardiac death in post infarction patients and progression of CHF
Drawbacks (side effects):
• Fatigue, lethargy – decreased work capacity
• Loss of libido – impotence
• Cognitive defects – forgetfulness
• Rebound hypertension
• Therefore cardio-selective drugs are preferred now
 Beta adrenergic blockers

Non selective: Propranolol, nadolol, timolol

Cardio selective: Metoprolol, atenolol, esmolol, betaxolol
 All beta-blockers have similar antihypertensive effects
 Reduction in CO but no change in BP initially
 Resistance vessels adapt to chronically reduced CO –
antihypertensive action
 Other mechanisms – decreased renin release from kidney
(β1 mediated), Reduced NA release and central
sympathetic outflow reduction
 Non-selective ones – reduction in GFR
 Drugs with intrinsic sympathomimetic activity may cause
less reduction in HR and CO
 β blockers – Anesthetic implications
Anesthetic indications:
 Premedication in a patient of β blocker therapy
 intentional hypotensive anesthesia – better control of heart
rate
 blunt hypertensive response to laryngoscopy and
intubation
 Thyrotoxic crisis – Propranolol 0.01-0.1 mg/kg iv (max 2 mg)
 Antiarrhythmic
 Phaeochromocytoma – to counter tachycardia due to α
blocker
- Muscarinic effect of succinylcholine is exaggerated by β
blockade
- Reversal of neuromuscular blockade with neostigmine
should be avoided if intraoperative bradycardia cannot be
increased with atropine.
 Normal sympathetic response to blood loss, acute
hypovolemia may be obtunded
 They are associated with acute withdrawal syndromes
that can lead to adverse perioperative events. ∴ should
not be stopped abruptly.
 Withdrawal can also lead to accelerated angina,
myocardial infarction, or sudden death.
 It is recommended that patients with 3 or more risk
factor for mortality
 Esmolol is used in the short-term management of
tachycardia and hypertension in the perioperative
period, and for acute supraventricular tachycardia.
 α blockers
Non-selective – Phenoxybenzamine, Phentolamine
 used in hypertensive emergencies, phaeochromocytoma
Selective α1 blockers – Prazosin, Terazosin
 Used in chronic hypertension
 Reduction in TPR and mean BP, also reduction in venous
return & CO
 Do not produce tachycardia as presynaptic α2 receptors
are not inhibited – autoregulation of NA release remains
intact
 Postural hypotension, fluid retention
 Also used in management of severe CHF along with cardiac
glycosides and diuretics
 α + β blockers
Labetalol:
α1+ β blocker
used to treat hypertensive crises and to
facilitate hypotension during anesthesia
used to treat hypertension associated with
angina and during pregnancy
 Direct vasodilators
1. Calcium channel blockers (= Calcium antagonists):
– Inhibit calcium entry into cells of the arteries
=> decreased afterload
Dihydropyridines:
– Target specifically L-type channels on vascular smooth muscle cells
– No cardiac effects (“Vasoselective Ca++ antagonists”)
– Can cause peripheral edema
• Nifedipine
• Nicardipine
• Nimodipine
• Nisoldipine
• Amlodipine
2. Potassium channel agonists:
Minoxidil:
- Increases outward K+
current => membrane hyperpolarization, which
inhibits Ca ++ channel activity
– Used only for severe, treatment-resistant
hypertension
– Major side effect: Hirsutism=> used topically to
treat baldness (Rogaine®)
Sodium Nitroprusside:
– Very unstable (only iv)
– Metabolized by blood vessels into NO
=> activates cGMP production => vasodilation
– Rapid action(30 sec !), short duration (effect ends after
3 min) => blood pressure “titration”
_ it can be used on induced hypotension.
– Used only to treat hypertensive emergencies
Hydralazine: used in severe, refractory or malignant
hypertension, pregnancy induced hypertension, pre-
eclampsia, eclampsia
 RAAS-targeting drugs
AT II :
potent vasoconstriction and stimulation of
aldosterone → increased systemic vascular
resistance and increased afterload →
increased BP
Aldosterone:
stimulates water and sodium reabsorption →
increased blood volume, increased preload,
and increased BP
Cardiac hypertrophy and cardiac remodeling
Angiotensin II
 Constricts vessels thereby increasing vascular resistance
and arterial pressure
 Stimulates the adrenal cortex to release aldosterone,
which acts upon the kidneys to increase sodium and fluid
retention.
 Stimulates the release of vasopressin (antidiuretic
hormone, ADH) from the pituitary which acts upon the
kidneys to increase fluid retention.
 Facilitates norepinephrine release and inhibits reuptake
from nerve endings, thereby enhancing sympathetic
adrenergic function.
 Stimulates cardiac and vascular hypertrophy.
ACE – Inhibitors:
1st line antihypertensive
 Captopril – active drug, metabolized to active metabolites
 Enalapril, Ramipril – pro drugs, become active following hepatic
metabolism
 Lisinopril – active drug, not metabolized
 Control HTN in ~ 50% patients when used alone
 Other uses of ACEI:
a. Congestive Heart Failure
b. Myocardial Infarction
c. Prophylaxis of high CVS risk subjects
d. Diabetic Nephropathy
e. Scleroderma crisis
ACEI – Advantages
 No postural hypotension
 Safe in asthmatics and diabetics.
 Prevention of secondary hyperaldosteronism and K+ loss
due to diuretics.
 Reverse the left ventricular hypertrophy and increased
wall-to-lumen ratio of blood vessels that occurs in
hypertensive patients.
 No hyperuricaemia or deleterious effect on plasma lipid
profile.
 No rebound hypertension on withdrawal.
 Minimal worsening of quality of life parameters.
 DOC in hypertensive patients with CHF.
 Renal protective effects in patients with diabetes.
 AT1 Receptor Blockers (ARBs)
Losartan, Telmisartan, Olmesartan
 Most of the physiological actions of angiotensin II
are mediated via AT1 receptor
 Competitive antagonist and inverse agonist of
AT1 receptor
 Does not interfere with other receptors except
TXA2
 Blocks all the actions of Angiotensin II
vasoconstriction, sympathetic stimulation,
aldosterone release and renal actions of salt and
water reabsorption
 ACEI and ARB should not be given concurrently
 Superiority of ARB over ACEI
 Blockade of the AT1-receptor is the most specific
way of preventing the adverse effects of
angiotensin II seen in heart failure and
hypertension, especially as angiotensin II may be
synthesized by alternative non ACE pathways.
 The AT2 receptor is not blocked, which may
possess cardio-protective properties.
 There is a much lower incidence of cough and
angioedema (no ACE inhibition) and therefore
improved compliance.
 ACEI & ARB - Anesthetic Implications
 Can theoretically blunt the compensatory activation of the renin-
angiotensin system during surgery → prolonged hypotension.
 For patients undergoing procedures with major fluid shifts, or for
patients who have medical conditions in which hypotension is
particularly dangerous, it may be prudent to discontinue them
before surgery.
Studies: Angiotensin-Converting Enzyme Inhibitors and
Angiotensin II Receptor Blockers before Elective Non-cardiac
Surgery: meta-analyisis
 Multiple guidelines suggest that ACE-I/ARB drugs be omitted on the
morning of surgery. Due to profound hypotension after the routine
induction of anesthesia during non-cardiac surgery when ACE-I or
ARB drugs are continued.
 Recently, on An Ongoing Dilemma, Hollmann et al on their meta
analysis have got some studies which can criticize the guideline if
we continue ACE-I/ARB drugs on day of surgery the hypotension
can be treated with fluid and the definition of hypotension was not
correct intraoperatively,
 Diuretics
1. Thiazide Diuretics
1st line antihypertensive.
 Mild (average fall in MAP ~ 10 mm Hg)
 Potentiate other antihypertensive (except DHPs) and prevent tolerance to
them
 Antihypertensive action is attenuated by NSAIDS
 They act on the early segment of the DCT by inhibiting Na+ and Cl−
reabsorption causing net loss of Na+ and water in urine
 Have maximal antihypertensive effect at low dose i.e. increasing the dose
increases only diuretic effect
Chlorthalidone, Hydrochlorthiazide, Indapamide
 Mechanism of antihypertensive action:
 Initially: Diuresis → depletion of Na+ and body fluid volume → decrease in
cardiac output
 Subsequently after 4 - 6 weeks, Na+ balance and CO is regained by 95%,
but BP remains low!
 There is reduction in total peripheral resistance (TPR) due to deficit of
little amount of Na+ and water (Na+ causes vascular stiffness) similar to
that seen in diets with sodium restriction.
 Thiazide diuretics other effects
 Renal – decrease renal blood flow & GFR
Metabolic:
 Hypokalemia causing muscle pain & fatigue, dangerous
arrhythmias in those taking digoxin, sudden cardiac death.
 Hyperglycemia - ↓ K+→ ↓ Insulin release
 Hyperlipidemia - ↑ risk of stroke
 Hyperuricemia
 These metabolic side effects occur at higher doses (50-100
mg per day)
 Low dose (12.5-25 mg per day) is recommended for HTN
 K+ sparing diuretic (spironolactone, amiloride, eplerenone)
usually added in elderly to combat hypokalemia.
 Loop Diuretics
 inhibit Na+ and Cl−reabsorption in the thick ascending
limb of the loop of Henle and in the early part of the
DCT.
 Weaker antihypertensive.
 Na+ deficient state is temporary, not maintained round
the-clock and TPR is not reduced.
 antihypertensive efficacy does not parallel diuretic
potency.
 Used only when HTN complicated by CRF, CHF, marked
fluid retention.
Furosemide, Torsemide, Bumetanide
Diuretics – Anesthetic Implications
 Chronic diuretic therapy →hypokalemia (more
with thiazides) → potentiation of the effects of
muscle relaxants used during anesthesia, as well
as predisposition to cardiac arrhythmias and
paralytic ileus.
 Thiazides cause hyperuricemia → may precipitate
or worsen gout during anesthesia when uric acid
excretion is reduced
 Thiazide diuretics taken for hypertension should
be continued on the day of surgery.
PREPARATIONS AVAILABL E
 Anti-angina
 Angina is chest pain or discomfort that occurs if an area
of heart muscle doesn't get enough oxygen-rich blood.
 Angina may feel like pressure or squeezing in chest.
The pain also can occur in your shoulders, arms, neck,
jaw, or back. Angina pain may even feel like indigestion.
 Angina isn't a disease; it's a symptom of an underlying
heart problem. Angina usually is a symptom of
coronary heart disease (CHD).
 CHD is the most common type of heart disease in
adults. It occurs if a waxy substance called plaque
builds up on the inner walls of coronary arteries. These
arteries carry oxygen-rich blood to heart.
There are four types of angina
 Stable angina
 Unstable angina:
 Variant angina (Prinzmetal's): A spasm in a
coronary artery causes this type of angina
 Micro vascular angina: can be a symptom of
coronary microvascular disease (MVD)
An anti-anginal is any drug used in the treatment of
angina pectoris, a symptom of ischaemic heart
disease.
Classification Of Anti-Angina Drugs
1) Nitrates and nitrites
a) Nitrates:
e.g. Nitroglycerin, Erythritol tetranitrate,
Trolnitrate phosphate, Isosorbide dinitrate,
Pentaerythritol tetranitrate, Mannitol
hexanitrate.
b) Nitrites:
e.g. Amyl nitrite , Sodium nitrite . Nitroprusside
sodium
2) Calcium Channel Blockers
a) Aryl alkyl amine derivative:
e.g. Verapamil
b) Benzothiazepine:
e.g. Diltiazem
c) Dihydropyridine derivative:
e.g. Nifedipine , Nimodipine , Nitrendipine , Nicardipine, Amlodipine ,
Felodipine , Isradipine
d) Newer second generation alkyl amine derivative:
e.g. Bepridil
3) β-Adrenergic Antagonist:
e.g. Propranolol (antihypertensives)
4) Miscellaneous Coronary Vasodilators:
e.g. Dipyridamol 1, Cyclandelate , Papaverine
Mechanism of action of Organic
Nitrates and Nitrites
 Mechanism of action of calcium
channel blockers
Inhibit the influx of Calcium into CARDIAC &
VASCULAR cells → ↓MUSCLE TONE
Mechanism of action of β-Adrenergic
Antagonist
Isosorbide mononitrate
Mechanism of action
 Nitric oxide formed in smooth muscle from
nitro vasodilators or from endothelial cells.
It activates guanylate cyclase (GC*).
Guanylate cyclase (GC*) activates cGMP
dependent protein kinesis that phosphorylate
myosin light chain kinesis.
Causing its inactivation and subsequent muscle
relaxation.
Side Effects Uses
• Fullness in head • Treatment or prophylaxis of acute angina
attack
• Throbbing headache • CHF
• Flushing • Myocardial infarction
• Percutaneous coronary angioplasty,
• Weakness thrombolytic therapy of acute myocardial
infarction.
• Sweating • Cyanide poisoning
• Palpitation
• Dizziness
• fainting
 Anti-anginal anesthetic implication

 Ischemia during the perioperative period demands

immediate attention by the anesthesiologist. The
impact of ischemia may be both acute (impending
infarction, hemodynamic compromise) and chronic (a
marker of previously unknown cardiac disease, a
prognostic indicator of poor outcome).
 Nitroglycerin is indicated in nearly all conditions of
perioperative myocardial ischemia. Mechanisms of
action include coronary vasodilation and favorable
alterations in preload and afterload. Nitroglycerin is
contraindicated when hypotension is present.
 Cont…
 Perioperative β-blockade may reduce the incidence
of perioperative myocardial ischemia via a number of
mechanisms. Favorable hemodynamic changes
associated with β-blockade include a blunting of the
stress response and reduced heart rate, blood
pressure, and contractility. All of these conditions
improve myocardial oxygen supply/demand ratios.
 Calcium channel blockers reduce myocardial
oxygen demand by depression of contractility, heart
rate, and/or decreased arterial blood pressure. Calcium
channel blockers are often administered in the
perioperative period for longer-term antianginal
symptom control.
 DRUGS USED IN HEART FAILURE
Pathophysiology
•End stage of CVD that impair the ability of
ventricle
• To fill with blood ; or
• Eject blood into the circulation
Causes → IHD (m/c), HTN, valvular disorders,
arrhythmias, CMP, and constrictive pericarditis.
Less common → Severe anaemia, B1 deficiency , or
the use of certain anticancer drugs, such as
doxorubicin, Transtuzumab
Drug therapy goals
1. Improve symptoms
2. Slow / reverse deterioration in myocardial function.
3. Prolong survival
 Drugs can also be used to treat underlying conditions,
control arrhythmias, prevent thrombosis, and treat anemia.
 Acute HF →Hospitalization & i.v. vasodilators (NO3&
Nesiritide), diuretics, inotropic agents, & O2
 Once stabilized →Oral medications, dietary restrictions, &
exercise guidelines
 Bed rest →early course of therapy
 Incremental exercise program →After improving
Drugs used for heart failure
1. ↑ CO (+ve inotropic drugs & vasodilators)
2. ↓ pulmonary & systemic congestion (Diuretics)
3. Slow or reverse cardiac remodeling (Ang & sym.
Inh.)
 Most significant dev. →Ang. inhibitors, β blockers,
+ve inotropic drugs (Digoxin, dobutamine,
milrinone) [All 3 act by ↑ Calcium level in cardiac
myocytes]
Management of chronic HF
• Depends on
1. underlying cause
2. degree of cardiac dysfunction
3. Signs & symptoms exhibited by patient
Systolic HF →ACEi.+ BB + loop diur. + ald. Antag.(↑k+)
• Some patients benefit by addition of digoxin &/or
combination of hydralazine and a nitrate, whereas
anticoagulant and antiplatelet drugs may be needed by
some patients.
• ARBs →Cannot tolerate an ACE inhibitor.
 ANTI- ARRHYTHMIC DRUGS
Cardiac Arrhythmias:
- 25% treated with digitalis
- 50% anesthetized patients
- 80% patients with AMI
reduced cardiac output
drugs or non-pharmacologic:
- pacemaker, cardioversion, catheter ablation,
surgery
ELECTROPHYSIOLOGY OF NORMAL
CARDIAC RHYTHM
SA node

AV node

ATRIA

His-Purkinje System

VENTRICLES
Trans-membrane potential of cardiac cells is
determined by the concentrations of the ff.
ions:
– Sodium, Potassium, Calcium
The movement of these ions produces
currents that form the basis of the cardiac
action potential
MECHANISMS OF ARRHYTHMIA
 ARRHYTHMIA – absence of rhythm
 DYSRRHYTHMIA – abnormal rhythm
ARRHYTHMIAS result from:
1. Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction
 Block results from severely depressed
conduction
 Re-entry or circus movement / daughter impulse
FACTORS PRECIPITATING CARDIAC ARRHYTHMIAS:
1. Ischemia
 pH & electrolyte abnormalities
 80% – 90% asstd with MI
2. Excessive myocardial fiber stretch/ scarred/ diseased
cardiac tissue
3. Excessive discharge or sensitivity to autonomic transmitters
4. Excessive exposure to foreign chemicals & toxic substances
 20% - 50% asstd with General Anesthesia
 10% - 20% asstd with Digitalis toxicity
 CLASS I: Sodium Channel Blocking
Drugs
• IA - lengthen AP duration
- Intermediate interaction with Na+ channels
- Quinidine, Procainamide, Disopyramide
• IB - shorten AP duration
- rapid interaction with Na+ channels
- Lidocaine, Mexiletene, Tocainide, Phenytoin
• IC - no effect or minimal AP duration
- slow interaction with Na+ channels
- Flecainide, Propafenone, Moricizine
 CLASS II: BETA-BLOCKING AGENTS
Increase AV nodal conduction
Increase PR interval
Prolong AV refractoriness
Reduce adrenergic activity
Propranolol, Esmolol, Metoprolol, Sotalol
 CLASS III: POTASSIUM CHANNEL
BLOCKERS
Prolong effective refractory period by prolonging
Action Potential
– Amiodarone - Ibutilide
– Bretylium - Dofetilide
– Sotalol
 CLASS IV: CALCIUM CHANNEL
BLOCKERS
Blocks cardiac calcium currents
→ slow conduction
→ increase refractory period
*esp. in Ca++ dependent tissues (i.e. AV node)
• Verapamil, Diltiazem, Bepridil
Miscellaneous:
 ADENOSINE → inhibits AV conduction & increases AV
refractory period
 DIGITALIS → Indirectly alters autonomic outflow
 MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels
 POTASSIUM → normalize K+ gradients
 Anesthetic implication for anti
arrhythmia
 Amiodarone has become a popular intravenous
antiarrhythmic drug for use in the operating room and
critical care areas because it has a broad range of effects for
ventricular and supraventricular arrhythmias.
 β-Receptor antagonists are very effective but
underused antiarrhythmic agents in the perioperative
period because many arrhythmias are adrenergically
mediated due to the stress of surgery and critical illness.
 Managing electrolyte abnormalities and treating
underlying disease processes such as hypervolemia and
myocardial ischemia are critical treatment steps before
the administration of any antiarrhythmic agent.
Thanks
 ANTICOAGULANT, THROMBOLYTIC,
and ANTI-PLATELET DRUGS
THERAPEUTIC STRATEGIES
These drugs are used to treat strokes, myocardial
infarctions, pulmonary embolisms, disseminated
intravascular coagulation (DIC)and deep vein thrombosis
(DVT) --- all potentially life-threatening conditions.
 Degrade fibrinogen/fibrin (fibrinolytic agents)
GOAL: eliminate formed clots
 Inhibit clotting mechanism(anticoagulants)
GOAL: prevent progression of thrombosis
 Interfere either with platelet adhesion and/or
aggregation(antiplatelet drugs)
GOAL: prevent initial clot formation
 THROMBOLYTIC DRUGS
 tPAs (TISSUE PLASMINOGEN ACTIVATORS): ALTEPLASE, RETEPLASE,
TENECTEPLASE, ANISTREPLASE, STREPTOKINASE, UROKINASE
The effectiveness of thrombolytics is inversely related to the time elapsed
since the thrombic crisis began → these drugs are most effective within 6
hours of onset of symptoms
Common Features
 dissolve existing life threatening thrombi
 activate plasminogen to plasmin Æ hydrolysis of fibrin and several other
coagulation factors
 plasmin formed inside a thrombus is protected from plasma antiplasmins
 short activation times, and short half-lives
 recommended for patients with:
o recent acute MI (selection of patients is critical!!! Some can be harmed)
o extensive pulmonary emboli
o severe deep vein thrombosis
o thromboembolic stroke (tPAs only)