DRUGS ACTING ON CVS

Presented by

Dr. Sannithi Nagarjuna

Coordinator for RIPER-GPAT Cell,

Hyderabad Academy &

Online GPAT Academy

7899107907

9885784793

nagarjunaspharma@gmail.com

ATHEROSCLEROSIS

Atherosclerosis is characterized by deposition of lipids and lipid

related materials like cholesterol, triglycerides and lipoproteins in

blood vessels particularly in Coronary Blood Vessels.

As a result of this condition blood/oxygen supply decreases to

muscle of the heart (Myocardium).

This condition further leads to angina pectoris and finally results in

Myocardial Infaraction.

LIPOPROTEINS

Lipoprotein, any member of a group of substances containing

both lipid (fat) and protein.

Lipoproteins in blood plasma have been intensively studied

because they are the mode of transport for cholesterol through

the bloodstream and lymphatic fluid.

Cholesterol is insoluble in the blood, and so it must be bound

to lipoproteins in order to be transported.

Two types of lipoprotein are involved in this function: low-

density lipoproteins (LDLs) and high-density lipoproteins

(HDLs).

LDLs transport cholesterol from its site of synthesis in

the liver to the body’s cells, where the cholesterol is

separated from the LDL and is then used by the cells for

various purposes.

HDLs probably transport excess or unused cholesterol from

the body’s tissues back to the liver, where the cholesterol is

broken down to bile acids and is then excreted. About 70

percent of all cholesterol in the blood is carried by LDL

particles, and most of the remainder is carried by HDLs. LDL-

bound cholesterol is primarily responsible for the

atherosclerotic buildup of fatty deposits on the blood

vessel walls, while HDL particles may actually reduce or retard

such atherosclerotic buildups and are thus beneficial to health.

Source: Google

Source: Google

Atherosclerosis is a disorder which mainly occurs due to

disturbance in homeostasis (Balance) between synthesis

and metabolism of cholesterol.

↑ HMG-CoA Reducatse ǂ ↓ Lipoprotein Lipase

(Enzyme involved in the (Enzyme involved in the

synthesis of cholesterol) metabolism/breakdown of cholesterol)

Based on this, mechanisms used to treat atherosclerosis

include

1. HMG-CoA Reducatse Inhibitors

2. Lipoprotein Lipase Activators

HMG-COA REDUCATSE INHIBITORS

(STATINS)

Source: Google

Source: Google

Ex:

LOVASTATIN – first introduced drug obtained from

Aspergillus terreus

ATORVASTATIN - high potent drug

ROSUVASTATIN - high potent drug

FLUVASTATIN - least potent drug

CERIVASTATIN - withdrawn from the market due to severe

hepatotoxicity

Stains are advised at bedtime because synthesis of

cholesterol is maximum in the midnight.

Side effects include

Myopathy (Muscle weakness)

Myalgia ( Muscle pain)

Rhabdomyolysis (Breakdown of muscles)

FIBRATES

Which activate lipoprotein lipase and they promote lipolysis.

Ex:

Clofibrate

Fenofibrate

Gemfibrozil

The first two are prodrugs and in the body they converted to

clofibric acid and fenofibric acid.

Side effects:

GIT disturbances

NIACIN

Which is also known as Vitamin B3 or Nicotinic acid.

Which is chemically Pyridine-3-carboxylic acid.

Mechanism of action:

Which inhibits the transportation of free fatty acids from adipose to

liver, where free fatty acids are converted to cholesterol and

lipoproteins

Which also increases HDL levels.

Side effects:

Skin allergic reactions due to release of PGs which will be suppressed

by NSAIDs

BILE ACID SEQUESTRANTS

Usually cholesterol is converted to bile acids which are used for

the emulsification of fats.

These are drugs which form complex with bile acids that result

in the formation of large complexes which are having poor

absorption.

Unabsorbed complexes are eliminated through stools.

Further due to this mechanism cholesterol is converted to bile

acids.

These drugs act by increasing the excretion of bile acids by

which increase the conversion of cholesterol to bile acids as a

result the levels of cholesterol will be decreases.

Ex:

Cholestyramine

Colestipol

Colesevelam

DRUGS WHICH INHIBIT

CHOLESTEROL ABSORPTION

Ex:

Ezetemibe

Gum Guggul (Guggullipids)- Obtained form

Commiphora molmol

Commiphora mukul

Commiphora weightii

Dietary Fibres

ANGINA PECTORIS

Which is a pain syndrome characterized by the

development of pain in the chest due to insufficient

oxygen/blood supply to muscle of the heart

(Myocardium).

Hence it is otherwise called as Myocardial

Ischemia/Myocardial Hypoxia.

Further angina pectoris results in Myocardial infaraction

(Heart attack).

Angina pectoris is a disorder which mainly occurs due to

disturbance in homeostasis (Balance) between oxygen

demand and oxygen supply.

The two major reasons for angina pectoris include

↑ Oxygen Demand ǂ ↓ Oxygen Supply

↑ Oxygen Demand ǂ ↓ Oxygen Supply

Ex: During Exercise Coronary Artery Disease

Increase in heart rate a) Vasoconstriction

b) Deposition of lipids

(Atherosclerosis)

c) Deposition of clots

d) Platelet aggregation

Drugs used in angina pectoris should either decrease the oxygen demand or increase the oxygen supply

↑ Oxygen Demand ǂ ↓ Oxygen Supply

(Drugs ↓ Oxygen Demand) (Drugs ↑ Oxygen Supply)

Coronary Artery Disease

Increase in heart rate a) Vasoconstriction

(Calcium channel Blockers, (Vasodilators)

β blockers) b) Deposition of lipids

(Drugs used in Atherosclerosis specially statins)

c) Deposition of clots

(Anticoagulants, Thrombolytics)

d) Platelet aggregation

(Antiplatelet drugs)

Source: Google

Source: Google

Source: Google

VASODILATORS

These are drugs which dilate blood vessels specially

coronary blood vessels by which they improve blood

supply to myocardium.

Hence they are otherwise called as Coronary Vasodilators.

Best examples are Organic Nitrates.

ORGANIC NITRATES

Organic Nitrates Organic Nitrate Reducatse__>> NO

(Nitric Oxide, EDRF)

Stimulates Guanyl Cyclase

GTP cGMP

Smooth muscle

relaxation

NO otherwise called as EDRF which causes vasodilation

due to increased levels of cGMP.

EDRF means Endothelial Derived Relaxing factor causes

vasodilation and derived from endothelium.

Organic Nitrates also cause dilation of Cranial blood

vessels which results in cerebro vasodilaton lead to

headache.

They are classified into 2 types based upon duration of

action

1. Short Acting Ex: Nitroglycerine (Glyceryl Trinitrate)

which undergoes high first pass metabolism.

Not suitable for oral route and given by sublingual route.

Onset of action is within 2min and duration of action is

upto 30 min

2. Long Acting Ex: Isosorbide dinitrate

Isosorbide-2-mononitrate

Isosorbide-5-mononitrate

CALCIUM CHANNEL BLOCKERS

1. Phenyl Alkyl Amines Ex: Verapamil (Which blocks calcium

channels only in heart)

2. Benzothiazepines Ex: Diltiazem (Which blocks calcium channels

both in heart & blood vessels)

3. Dihydropyridines Ex: Amlodipine, Nifedipine, Nimodipine

Nicardipine, Nitrendipine

(Which blocks calcium channels only in

blood vessels)

They are classified into 2 types

1. Nonselective β blockers – Bronchoconstriction side effect

Ex: Propranolol, Pindolol, Timolol, Sotalol

2. Selective β1 blockers

Ex: Atenolol, Acebutalol, Bisoprolol, Nebivolol

β blockers

OTHER DRUGS

1. DIPYRIDAMOL – Antiplatelet as well as direct acting coronary

vasodilator

2. TRIMETAZIDINE – Antioxidant property

3. RANOLAZINE -- Direct acting coronary vasodilator

Stable angina

pectoris

Variant angina

pectoris

Unstable angina

All drugs used in

atherosclerosis

specially statins

Vasodilators

Vasodilators Statins

Anticoagulants

Vasodilators

Atherosclerosis

Coronary artery disease

Angina pectoris

Myocardial infaraction

Atherosclerosis Coronary artery

disease

Angina pectoris Myocardial

infaraction

Atherosclerosis Coronary artery

disease

Angina pectoris Myocardial

infaraction

Statins

Fibrates

Niacin

Bile acid

Sequesterants

All drugs used in

atherosclerosis

Anticoagulants

Thrombolytics

Antiplatelet

drugs

Vasodilators

All drugs used

in angina

pectoris

Calcium

Channel

blockers

β blockers

All drugs

used in

angina

pectoris

ANTIHYPERTENSIVE AGENTS

Which are used for the treatment of hypertension

Increase in blood pressure called as hypertension

Normal blood pressure is 120/80 mm of Hg

> 140/90 mm of Hg is considered as beginning stage of

hypertension

Blood Pressure -- It is the pressure exerted by circulating blood on the

walls of blood vessels.

Cardiac output -- It is the volume of blood pumped by the heart per one

minute. It is approximately 5L.

Heart Rate – It is the number of heart beats/min. It is approximately

72 beats/min.

Stroke Volume – It is the volume of blood pumped by the heart per one

heart beat. It is approximately 70 mL.

Cardiac Output → Heart rate * Stroke Volume

72 * 70

= 5040 mL Approximately 5L

Peripheral Vascular Resistance (PVR) -- It is the resistance offered by

peripheral blood vessels for blood flow.

Blood Pressure = Cardiac output * Peripheral Vascular Resistance

Heart rate * Stroke Volume

Hypertension= ↑ Blood Pressure = ↑ Cardiac output * ↑ PVR

↑ Heart rate * ↑ Stroke Volume

TYPES OF HYPERTENSION

1. Essential/ Primary hypertension

Which is idiopathic and primarily genetics

2. Nonessential/ Secondary hypertension

due to secondary reasons like renal defects, cushings

syndrome, renal artery stenosis

Gestational Hypertension

Hypertension during pregnancy

Malignant hypertension/Hypertensive emergency

It is extremely high blood pressure that develops rapidly

and causes some type of organ damage. A person

with malignant hypertension has a blood pressure that's

typically above 180/120.

Different reasons for hypertension include

1. Increase in Cardiac output

2. Increase in Heart rate

3. Increase in Stroke volume

4. Increase in force of contraction

5. Vasoconstriction

The proposed mechanisms involved in the development

of hypertension include:

1. Increased activity of Renin-Angiotensin-Aldosterone

System (RAAS)

2. Increased activity of Sympathetic Nervous System

3. Increased activity of L type Calcium Channels

4. Excessive Vasoconstriction

5. Increased fluid and sodium retention

Source: Google

The other action of ACE is involved in the inactivation of

bradykinin.

Bradykinin

ACE

Inactive

Angiotensin-I is converted into angiotensin –II by the action of

another enzyme Chymase

Angiotensin-I

Chymase

Angiotensin-II

DRUGS WHICH INHIBIT RAAS INCLUDE

1. Renin Release Blockers Ex: β1 Blockers

2. Renin Activity Inhibitors Ex: Enalkiren, Aliskiren

3. ACE inhibitors

4. Angiotensin- II antagonists

5. Aldosterone antagonists Ex: Spiranolactone

6. Vasodilators

7. Diuretics

Source: Google

ACE INHIBITORS

Source: Google

Side effects of ACE inhibitors include

1. Dry cough & Angioedema ( due to increased levels of

bradykinin)

2. Hyperkalaemia

3. Unable to stop the conversion mediated through

Chymase

ANGIOTENSIN-II ANTAGONISTS

Which block the actions of angiotensin-II mediated through AT1

receptors and they will not have any action on ACE.

Advantages over ACE inhibitors include

1. No dry cough, No angioedema

2. No chymase mediated problem but these agents are also having

Hyperkalaemia

Ex:

Azilsartan

Candesartan

Eprosartan

Irbesartan

Losartan

Olmesartan

Telmisartan

Valsartan

Both ACE inhibitors and angiotensin-II antagonists are

preferably used in diabetic patients because they reduce the

development of diabetic nephropathy.

Both ACE inhibitors and angiotensin-II antagonists are

contraindicated in pregnant women because they produce

kidney defects in the fetus.

Both ACE inhibitors and angiotensin-II antagonists are having

hyperkalaemia side effect.

SYMPATHETIC NERVOUS SYSTEM

Noradrenaline is the neurotransmitter in sympathetic

nervous system.

All actions of sympathetic nervous system are mediated

through Noradrenaline.

Noradrenaline acts through the receptors called as

adrenergic receptors which include α and β receptors.

Type of

receptor

Second

Messenger

Location Pharmacological actions

α1 Gq ❖ Blood vesselsVasoconstriction,

increase in blood

pressure

α2 Gi ❖ CNSNo Action

Type of

receptor

Second

Messenger

Location Pharmacological actions

β1 GS ❖ HeartIncrease in force of

contraction,

Increase in cardiac output,

Increase in blood

pressure,

Increase in heart rate

β2 GS ❖ Smooth muscles

❖ Bronchi

❖ Liver

❖ Smooth muscle

relaxation

❖ Bronchodilation

❖ Glycogenolysis

β3 GS ❖ Adipose tissue❖ Lipolysis

The overall activity of sympathetic nervous system

(Noradrenaline) is increase in blood pressure through α1 and

β1 receptors.

Sympathetic nervous system increases blood pressure as a

part of homeostasis in balance with parasympathetic nervous

system.

But hypertension occurs due to increased activity of

sympathetic nervous system hence we are using α1 and β1

receptor blockers.

α BLOCKERS

1. Nonselective α blockers

Ex: Phenoxybenzamine, Phentolamine

2. Selective α1 blockers

Ex: Prazosin, Terazosin, Doxazosin

Which are also used to treat prostatic hyperplasia

β BLOCKERS

1. Nonselective β blockers

Ex: Propranolol, Pindolol, Timolol, Sotalol

❖ Having bronchoconstriction side effect

❖ Propranolol is also used for migraine treatment

❖ Timolol is also used for glaucoma treatment

❖ Sotalol acts as both class II & class III antiarrhythmic agent

2. Selective β1 (Cardioselective β blockers) blockers

Ex: Atenolol, Acebutalol, Bisoprolol, Nebivolol

α and β receptor blockers

Ex: Labetalol, Carvedilol

❖Which block α1, β1, & β2 receptors but no affinity for α2

receptors

❖ Carvedilol has antioxidant property

CENTRALLY ACTING ANTIHYPERTENSIVES

❖ Which act through α2 receptors located in CNS.

❖ α2 receptors are autoreceptors.

❖ Always stimulation of autoreceptors results in decrease of

further release of neurotransmitters.

❖ Stimulation of α2 receptors results in decrease of further

release of noradrenaline.

❖ Hence they are named as Centrally acting antihypertensives.

Ex:

Clonidine,

α- Methyldopa.

❖ α- Methyldopa in the body converted to α- Methyl

norepinephrine

❖ which stimulates α2 receptors located in CNS and

causes decrease in further release of noradrenaline.

❖ α- Methyl norepinephrine called as false transmitter

CALCIUM CHANNEL BLOCKERS

There are 3 types of calcium channels present

1. L (Longitudinal) located in CVS (Heart & Blood vessels)

2. T (Transient) located in CNS

3. N (Neuronal) located in neurons

ROLE OF CALCIUM

Heart

Influx of calcium

Interacts with troponin C

Increases phosphorylation between actin and myosin

Increases force of contraction

Increases cardiac output

Increases blood pressure

Blood Vessels

Influx of calcium

Interacts with Calmodulin

Increases phosphorylation between actin and myosin

Causes vasoconstriction

Increases peripheral vascular resistance

Increases blood pressure

Increased activity of L type Calcium channels results in

hypertension.

Hence we are using L type Calcium channel blockers.

They prevent the entry of calcium ions through L type Calcium

channels hence which are otherwise called as Calcium Entry

Blockers.

PHARMACOLOGICAL ACTIONS

1. Inotropic action (Force of contraction)

2. Dromotropic action (Impulse conduction)

3. Chronotropic action ( No of contractions/

No of heart beats)

PHARMACOLOGICAL ACTIONS

1. -Ve Inotropic action (↓ Force of contraction)

2. -Ve Dromotropic action ( ↓Impulse conduction)

3. - Ve Chronotropic action (↓ No of contractions/

↓ No of heart beats)

4. Vasodilation

THERAPEUTIC USES

1. As antihypertensive agents ( Due to -Ve Inotropic action ,

-Ve Dromotropic action, - Ve Chronotropic action & vasodilation)

2. As antiarrhythmics (due to -Ve Dromotropic action,

- Ve Chronotropic action)

3. As antianginals ( due to -Ve Dromotropic action,

- Ve Chronotropic action & vasodilation)

But they are contraindicated in CHF ( due to -Ve Inotropic action )

Ex:

1. Phenyl alkyl amines Ex: Verapamil – which block

calcium channels only in heart

2. Benzothiazepines Ex: Diltiazem- which block calcium

channels both in heart & blood vessels

3. Dihydropyridines Ex: Amlodipine, Nifedipine,

Nimodipine, Nitrendipine – which block calcium

channels only in blood vessels

VASODILATORS

Which dilate blood vessels specially peripheral blood

vessels and they decrease peripheral vascular

resistance and they decrease blood pressure.

They are classified into 2 types

ARTERIAL VASODILATORS

1. HYDRALAZINE - releases NO

- causes SLEs

( Systemic lupus erythematous syndrome)

2. MINOXIDIL - Potassium channel opener

- Causes Hypertrichosis (Excess hair growth)

- used to treat Alopecia

3. DIAZOXIDE - Potassium channel opener

- Causes Hyperuricemia and hyperglycemia

ARTERIAL & VENOUS VASODILATORS

Ex: SODIUM NITROPRUSSIDE

SODIUM NITROPRUSSIDE NO + CN

Rhodanese

Thiocyanates

Excreted through urine

Rhodanese enzyme is absent in infants hence contraindicated in

pregnancy and infants

Condition Indicated Drugs Contraindicated

drugs

Gestational

Hypertension

Centrally acting

antihypertensives,

Calcium channel

blockers

ACE Inhibitors,

Angiotensin-II

blockers,

Sodium

nitroprusside,

Diuretics

Hypertension with

diabetes

ACE Inhibitors,

Angiotensin-II

blockers

Diazoxide

Hypertension with

asthma

------- Nonselective β

blockers

Hypertension with

gout

------- Diazoxide

Hypertensive

emergencies

------- Sodium

nitroprusside

Presented by

Dr. Sannithi Nagarjuna

Coordinator for RIPER-GPAT Cell,

Hyderabad Academy &

Online GPAT Academy

7899107907

9885784793

nagarjunaspharma@gmail.com