PHARMACOLOGY II

Dr A.SHYAM SUNDAR.,M.Pharm.,Ph.D

Assistant professor in Pharmacology,

University of Nizwa,

Sultanate of Oman

What is Pharmacology?

• Pharmacology is the science that deals with

drugs.

• It explains what drugs do,and how they do

it.

• A knowledge of Pharmacology is essential

for using drugs effectively in treatment.

Drugs...

• Drug is a substance used to cure,diagnose or prevent the

disease.

• WHO defines drug as product that is used or intended to be

used to modify or explore physiological systems or

pathological states for the benefit of recipient.

• Drugs are intended to have a selective action,but this ideal

is seldom achieved

• There is always a risk of adverse effects as well as a

benefit connected with using any drug.

Pharmacokinetics...

• ‗Kinesis‘ means ‗movement‘,hence

pharmacokinetics means ―how drugs move

inside the body‖.

• It deals with Absorption, distribution and

metabolism and excretion of drugs.

• Simply it gives details regarding ―what the

body does to the drug.

Pharmacodynamics...

• ‗Dynamics‘ means ‗power‘,hence

Pharmacodynamics detail about the power

the drug.

• Pharmacodynamics is the study of drug

effects.

• Simply it deals with what the drug does to

the body.

Drug names...

• Chemical name explains the drug‘s chemical

composition and molecular structure. ex.( +/- ) – 2

– ( p-isobutylphenyl ) proponic acid.

• Generic Name ( Nonproprietary name ) name

given by the United States Adopted Name

Council.Universally accepted. ex.ibuprofen.

• Trade Name ( Brand name/ Proprietary name)

the drug has a registered trademark ; use of the

name restricted by the drug‘s owner ex. Motrin

Receptors

• Receptors are proteins in nature.

• They may be located inside the cell or on

the cell‘s surface.

• Most of the drugs and endogenous

substance binds with receptors and then

produce Biological actions.

Agonists and Antagonists...

• Agonists are the drugs that bind to receptors and stimulate/

enhance a response ex. Insulin, isoproterenol – stimulate

beta 1 receptor.

• Antagonists are the drugs that bind to receptors and block a

response ex. cimetidine – blocks H2 receptor.

• Agonists and Antagonists can preferably defined with the

terms Affinity and Intrinsic activity.

• Affinity is the tendency of the drug to bind with the receptor.

• Intrinsic activity is the capacity of the drug to produce

biological action after binding with the receptor.

Sources of drugs...

From plants (eg, morphine).

From animals (eg, insulin).

From minerals (eg, iron).

From synthetic chemical compounds manufactured in laboratories.

(Eg, adding, deleting, or altering a side-chain).

From micro organisms (eg, many antibiotics).

From biotechnology origin: this process involves manipulating

Deoxyribonucleic acid (dna) and ribonucleic acid (rna)

Types of drugs...

• Prescription drugs.

• Non-Prescription drugs.

• Controlled drugs

Prescription Drugs • Prescription drugs are drugs that the

government has designated to be

potentially harmful unless their use

is supervised by a licensed health

care provider.

• Although these drugs have been tested

for safety and therapeutic effect,

prescription drugs may cause different

reactions in some individuals.

• Prescription drugs, also called legend

drugs, are the largest category of drugs.

Prescription drugs are prescribed by a

licensed health care provider.

• The prescription (see Fig) contains the

name of the drug, the dosage, the method

and times of administration, and the

signature of the licensed health care

provider prescribing the drug.

Non-Prescription drugs

• Declared by the FDA to be safe (if

taken as directed) and obtained

without a prescription.

• These drugs are also referred to as

over-the-counter (OTC) drugs and

may be purchased in a variety of

settings, such as a pharmacy,

drugstore, or in the local

supermarket.

• OTC drugs include those given for

symptoms of the common cold,

headaches, constipation, diarrhea,

and upset stomach.

• These drugs are not without risk

and may produce adverse reactions.

For example, acetylsalicylic acid,

commonly known as aspirin, is

potentially harmful and can cause

gastrointestinal bleeding and

salicylism .

• Labeling requirements give the

consumer important information

regarding the drug, dosage,

contraindications,precautions, and

adverse reactions.

• Consumers are urged to read the

directions carefully before taking

OTC drugs.

Controlled Substances...

• Controlled substances are the

most carefully monitored of all

drugs.

• These drugs have a high

potential for abuse and may

cause physical or

psychological dependence.

• Prescriptions for controlled

substances must be written in ink

and include the name and address

of the patient and the Drug

Enforcement Agency number of

the primary health care provider.

Drug use in Pregnancy...

• Drugs administered to pregnant

women, particularly during the first

trimester (3 months), may cause

teratogenic effects.

• A teratogen is any substance that

causes abnormal development of

the fetus leading to a severely

deformed fetus. Drugs are one type

of teratogen.

• In an effort to prevent teratogenic

effects, the FDA has established

five categories suggesting the

potential of a drug for causing birth

defects.

PHARMACIST...

PHARMACIST...

CARDIOVASCULAR

PHARMACOLOGY

4 BASIC POINTS & 4 MAIN DISEASES

Heart Failure is a condition in which the heart is unable to meet the

metabolic demands of the body.

Hypertension is a condition in which the pressure at which heart ejects its

blood into the arteries persistently increases abnormally.

Cardiac Arrhythmias, a group of disorders in which there will be abnormality

either in the impulse generation or impulse conduction.

Angina is the hearts way of signaling that it doesn't receive sufficient blood supply

and Myocardial Infarction occurs when oxygen deprived myocardial cells start

dying.

ANS AND CVS When sympathetic nervous

system is stimulated...

When parasympathetic nervous

system is stimulated...

β1 receptors activated and causes

Increase in heart rate,

Increase in conduction velocity and

Increase in force of contraction

M2 receptors activated and causes

Decrease in heart rate,

Decrease in conduction velocity and

Decrease in force of contraction

α1 receptors activated and causes

vasoconstriction

Secretion of Catacholamines

and α1and β1 actions occur.

UNIT 1:

CONGESTIVE HEART FAILURE

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Differentiate the types of heart failure

• Explain compensatory mechanisms of heart failure

• Understand the physiology of cardiac contraction and

ionic movement during cardiac contraction

• List the classes of drugs used to treat cardiac failure and

their mechanism of action

• Recall vital information about the drugs used in CHF.

• Apply pharmacological knowledge gained in the clinical

scenario.

Types of heart failure...

• Low-output heart failure vs High-output heart failure.

• In LOHF,the metabolic demands of the body is normal and

heart will not be able to supply the normal demand.

• In HOHF,the metabolic demands may be very high (due to

anemia or hyperthyroidism),and the heart will not be able

to supply blood to meet this increase in demand.

• Left sided heart failure vs Right sided heart failure.

• LSHF leads to pulmonary edema and RSHF leads to

systemic edema

COMPENSATORY MECHANISMS OF HEART

FAILURE

• Increased sympathetic activity.

• Retention of sodium and water.

• Myocardial hypertrophy.

Increased force of contraction

and heart rate

Workload of the heart increases

Further decline in heart’s pumping

capacity

Myocardial

hypertrophy

Physiology of cardiac contraction

• Actin and myosin

• Tropomyosin

• Troponin complex

• Ca++ Ions

Classification of drugs

MOA OF CARDIAC GLYCOSIDES

MOA OF BETA ADRENERGIC AGONISTS

AND PHOSPHODIESTERASE INHIBITORS

DOPAMINE

PHOSPHODIESTERASE INHIBITORS

Direct acting Vasodilators

Nitrates

Hydralazine

• Vasodilators reduces both

preload and afterload.

• Venodilation reduces preload

and Arterial dilation reduces

afterload.

• Minoxidil is used to treat male

pattern bladness.

MOA OF ACE INHIBITORS

CONTRAINDICATED IN PREGNANCY

• β-blockers decrease sympathetic activity

by blocking the β-receptors on the

excitable cells in the myocardium and

blood vessels.

• A blockade of these receptors results in

decreased cardiac contractile activity

and heart rate, decreased blood pressure,

and decreased peripheral circulation.

• All these effects reduce the oxygen

demand of myocytes.

β-blockers such as bisoprolol,

carvedilol, metoprolol are used in

treatment of heart failure in addition to

the treatment of diuretics and ACE-

inhibitors

BETA-BLOCKERS IN CHF

• Diuretics increase excretion of Na+ ions

from the kidney.

• As a result water is excreted as well, which

lowers plasma volume, extra cellular fluid,

cardiac output and ultimately relieve edema

and dyspnea.

Two classes of diuretics are applied in the

treatment of the symptoms of heart failure.

• Loop diuretics act in the ascending loop of

Henle.

Example: Furosemide.

• Thiazide diuretics act in the distal tubule.

Example: Hydrochlorothiazide.

• Spiranolactone is also used in

maintenance of severe heart failure since it

slows down the remodeling of the heart by

antagonising the aldosterone receptors of

the heart.

DIURETICS IN CHF

CONGESTIVE HEART FAILURE - Summary

Therapeutic goals: 1)Reduce workload of the heart

2)Improve myocardial contractility

ANTIHYPERTENSIVE DRUGS

UNIT 2:

ANTIHYPERTENSIVE DRUGS

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Differentiate the types of hypertension

• Explain short and long term control of blood pressure

• List the classes of drugs used to treat hypertension and

their mechanism of action

• Recall vital information about the drugs used in

hypertension.

• Apply pharmacological knowledge gained in the clinical

scenario.

Filling Pressure: A measure of the average (arterial and venous) pressure necessary to cause

filling of the circulation with blood; it varies with blood volume and is directly proportional to

the rate of venous return and thus to cardiac output.

ANTI-HYPERTENSIVES

ACE INHIBITORS

CONTRAINDICATED IN PREGNANCY

Angiotensin antagonists

Losartan and Valsartan are examples

CONTRAINDICATED IN PREGNANCY

BETA ADRENERGIC BLOCKERS

• Beta-1 blockade in cardio myocyte

blocks tachycardia,hypertension and

force of contraction of heart.

• Beta-2 blockade in lungs causes

bronchoconstriction,poor peripheral

circulation.

• Selective beta-1 blockers are preferred

in patients with respiratory troubles as

the non selective blockers alters both

heart and lungs.

• Example for selective beta-1 blockers

and non selective blockers are

atenelol,metaprolol and propranolol

respectively.

MOA and ADR of beta blockers

CALCIUM CHANNEL BLOCKERS

Contraindicated in patients with CHF

Apart from Thiazide diuretics,Loop diuretics and

Spiranolactone also employed in treatment of hypertension.

All diuretics reduce BP by lowering blood volume

which eventually decrease cardiac output.

DIURETICS

ALPHA ADRENERGIC ANTAGONISTS

Both drugs are used to treat mild to moderate

hypertension.

Guanafacine has same ADR and MOA as that of

clonidine

Positive coomb’s test and rebound hypertension

are the respective ADR of methyl dopa and

clonidine respectively.

CENTRALLY ACTING ANTIHYPERTENSIVES

HYPERTENSION -Summary Therapeutic goals:

1)Reduce volume overload

2)Reduce sympathetic outflow

3)Block adrenergic receptors of the heart

4)Dilate blood vessels

HYPERTENSIVE EMERGENCY

Sodiumnitroprusside,Diazoxide and Labetalol are used in hypertensive

emergency.

Sodiumnitroprusside is the doc but cyanide toxicity is prodoced during its

metabolism which is treated with an enzyme called Rhodanase

Diazoxide is used in patients with coronary insufficiency.

Labetelol is also used to treat hypertensive emergency but carries the ADR of

nonselective beta blocker.

Hypertensive emergency is a rare, but life-threatening situation in which

the diastolic blood pressure is either over 150 mm Hg (with systolic

blood pressure greater than 210 mm Hg) in an otherwise healthy per-

son, or 130 mm Hg in an individual with preexisting complications, such

as encephalopathy, cerebral hemorrhage, left ventricular failure, or aor-

tic stenosis.

HYPERTENSION- Summary Therapeutic goals:

1)Reduce volume overload

2)Reduce sympathetic outflow

3)Block adrenergic receptors of the heart

4)Dilate blood vessels

ANTI-ARRHYTHMIC

AGENTS

UNIT 3:

ANTI-ARRHYTHMIC AGENTS

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Explain the processes of cardiac impulse generation and

conduction

• List arrhythmias arising from Atrium, AV node and

Ventricles.

• List the classes of drugs used to treat arrhythmias

• Recall vital information about the drugs used in

arrhythmias.

• Apply pharmacological knowledge gained in the clinical

scenario.

Classification of anti-arrhythmic agents

Cardiac Arrhythmia- Summarys

Therapeutic goals:

Restore normal rhythm of the heart

UNIT 4:

ANTI-ANGINAL AGENTS

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Classify types of angina

• Understand the concept of oxygen demand versus oxygen

supply.

• List the classes of drugs used to treat angina.

• Recall vital information about the drugs used in angina.

• Apply pharmacological knowledge gained in the clinical

scenario.

Anti anginal drugs

In angina, oxygen demand is more than

oxygen supply the treatment strategy

is to

1. Increase oxygen supply and

2.Decrease oxygen demand of heart.

Mechanism of action of Nitrates

• Beta blockers block the beta-1

receptors of the heart and reduces

heart rate,force of contraction and

blood pressure.So,the workload of

heart decreases.

• As the workload of the heart

decreases, the oxygen demand also

decreases and thus beta blockers are

indicated.

• Calcium channel blockers dilates

arteries and veins.

• Dilation of arteries reduce

afterload and dilation of veins

reduce preload of the heart.

• As the preload and afterload

decreases, the workload of the heart

also decreases and thus calcium

channel blockers are inicated in

angina.

Anti-anginal mechanisms of Beta blockers

and

Calcium channel blockers

ANGINAL TREATMENT IN THE PRESENCE OF OTHER DISEASES

ANGINA- Summary

Therapeutic goals:

Reduce work of heart and improve cardiac blood flow

Stable angina Unstable angina

DIURETICS

Dr A.Shyam Sundar,

Assistant professor in Pharmacology,

University of Nizwa,

Sultanate of Oman

UNIT 5:

DIURETICS

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Explain the processes of sodium and water reabsorption

at nephron.

• Classify diuretic drugs

• Recall vital information about the diuretics.

• Apply pharmacological knowledge gained in the clinical

scenario.

Diuretics are drugs that increase renal excretion of

water, sodium, and other electrolytes, thereby

increasing urine formation and output.

They are important therapeutic agents widely used in

the management of both edematous (e.g., heart failure,

renal and hepatic disease) and non edematous (e.g.,

hypertension, ophthalmic surgery) conditions.

Diuretics are also useful in preventing renal failure by

their ability to sustain urine flow.

ACETAZOLAMIDE

Therapeutic uses

Adverse reactions

Therapeutic uses

Adverse reactions

LOOP DIURETICS

THIAZIDE DIURETICS OSMATIC DIURETICS

Therapeutic uses Therapeutic uses

Adverse reactions

Adverse reactions

Potassium sparing Diuretics

Clinical uses Adverse reactions

Drugs used in anemia and other

blood cell deficiencies

Dr A.Shyam Sundar,

Assistant Professor in Pharmacology and Toxicology,

College of Pharmacy and Nursing,

University of Nizwa,

Sultanate of Oman

UNIT 6:

Drugs used in anemia and other blood cell

deficiencies UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• List different types of anemia

• List drugs used in the treatment of anemia and other

blood cell deficiencies

• Recall vital information about the drugs used in anemia

and other blood cell deficiencies.

• Apply pharmacological knowledge gained in the clinical

scenario.

Common Anemias 1. Microcytic Hypochromic Anemia:

Caused by iron deficiency. Hence called as iron deficiency anemia

Most common

2. Megaloblastic Anemia:

Caused by deficiency of Vit B12 / Folic acid ( Co-Factors required for maturation of RBC).

3. Perinicious Anemia:

Common type of Vit B 12 Deficiency anemia.

Caused by defect in the synthesis of IF, a protein required for absorption of dietary vit B12.

4. Hemolytic Anemia:

Due to destruction of RBC.

Iron stores are elevated, not decreased.

Other blood cell deficiencies

• By the manifestation of diseases or as a side

effect of radiation or cancer chemotherapy,

there may be deficiency in either erythrocytes

or neutrophils and platelets.

Drugs used in anemias and other blood

cell deficiencies Oral Iron Supplements:

Ferrous Sulfate, Ferrous Gluconate and Ferrous Fumarate.

Parenteral Iron:

Iron dextran.

Vitamin B12:

Cyanocobalamine.

Hydroxocobalamine.

Red Cell Factor:

Erythropoietin (Epoitin-alfa)

Myeloid Growth Factors:

Filgrastim (G-CSF).

Sargramostim (GM-CSF).

Megakaryocyte Factors:

Oprelvekin

Thrombopoietin

Iron

Essential metallic component of heme.

Present in Hb, transferrin, Ferritin

Deficiency of iron occurs in all woman, malnourished, inadequete and

Iron intake.

Children and pregnant woman need excess requirement of iron.

Used in microcytic anemia.

Ferrous ion supplementation ( Dietary) and in special cases parenteral iron

administration.

Should not be given in hemolytic anemia, because iron stores are elevated

not depressed in hemolytic anemia.

Parenteral defurroxime, is used to treat acute iron intoxication.

Vitamin-B12

• Vit-B12 deficiency and Folic acid deficiency first manifest

as anemia. Vit-B12 also cause neurologic damage/defect.

• Available as hydrocobalamine and Cyanocobalamine.

• Used in pernicious anemia.

• Vit-B12 deficiency anemia is mostly due to inadequate

absorption, therapy should be through parenteral

administration of Vit-B12.

Folic Acid

• Required for normal DNA synthesis.

• Deficiency may lead to either Megaloblastic

anemia or Neural tube defects in fetus.

• Rapidly dividing cells are highly sensitive to folic

acid deficiency. For this reason anti folate drugs

are useful in the treatment of various infections.

• Folic acid supplements will also correct the

anemia but not the neurologic defects of Vit-B12.

Hematopoietic Growth Factors

• Almost a dozen glycoprotein hormones regulate the differentiation and maturation of stem cells within the bone marrow have been discovered.

• Four r-DNA products are approved by US-FDA for the treatment of patient with blood cell deficiencies, such as

1. Erythropoietin.

2. Myeloid Growth Factors. [granulocytes ( basophil, neutrophil and Eosinophil), monocyte and platelets]

3. Megakaryocyte Growth Factors. (A giant cell in the bone marrow that is ancestor of blood platelets)

4. Other Hematopoietic Growth Factors.

Erythropoietin:

Used for anemias associated

with renal failure, bone marrow

disorders, anemias due to cancer

chemotherapy, Zidovudin therapy,

bone marrow transplantation,

AIDS and Cancer.

Myeloid Growth Factors:

Filgrastim(G-CSF) and

Sargramostin(GM-CSF).

stimulate the production of

neutrophils.

Accelerate the recovery of

neutrophils after

Chemotherapy,aplastic anemia

and congenital neutropenia.

Sargramostim causes fever,

arthralgia and capillary damage

with edema.

Megakaryocyte

Growth Factors:

Oprelvekin and

Thrombopoietin are used in

thrombocytopenia and

reduces the need for platelet

transfusion.

Both drugs cause fatigue,

headache and fluid

retention.

Other Hematopoietic

Growth Factors

M-CSF, stem cell

factors, IL-3,6,9 are other

HG factors.

SCF and IL-3 have the

broadest progenetor cell

line effect, producing red

cell, granulocyte,

monocyte, macrophage,

megakaryocyte, eosinophil

and basophil and basophil

cell lines.

Next lecture We will start Respiratory

Pharmacology…

So, revisit the physiology of

respiratory system in advance.

Drugs for Hyperlipidemias

Dr.A.Shyam Sundar. M.Pharm.,Ph.D,

Assistant Professor in Pharmacology And Toxicology

University Of Nizwa

Sultanate of Oman Source: Henry Hitner and Barbara Nagle

UNIT 7:

Drugs used in the treatment of Dyslipedemia

UNIT INSTRUCTIONAL OUTCOMES:

At the end of this unit, the student should be able to,

• Differentiate good and bad lipids

• List drugs used in the treatment of dyslipidemia

• Recall vital information about the drugs used in

dyslipidemia

• Apply pharmacological knowledge gained in the clinical

scenario.

Atherosclerosis

• Atherosclerosis is a

progressive condition

that leads to CAD and

PAD.

• Fat buildup inside the

arteries—plaque

• CAD—coronary

artery disease

• PAD—peripheral

artery disease

Hepatic Cholesterol Synthesis

Cholesterol and

Atherosaclerosis, Grundy)

Rate Limiting

Only pathway

for cholesterol

degradation

Energetically expensive;

prefer to conserve what is

already made/acquired – LDL

receptor pathway

Dyslipidemia The normal range of plasma total CHO concentration < 6.5 mmol/L.

There are smooth gradations of increased risk with

elevated LDL CHO conc, and with reduced HDL CHO conc.

Dyslipidemia can be primary or secondary.

The primary forms are genetically determined

Secondary forms are a consequence of other conditions

such as diabetes mellitus, alcoholism, nephrotic

syndrome,chronic renal failure, administration of

drugs

Lipoproteins

• There are several different lipoproteins:

– Low-density lipoprotein (LDL)

– Very-low-density lipoprotein (VLDL)

– High-density lipoprotein (HDL)

Triglycerides

• Main form of fat from diet

• Provide body with energy

• Chylomicrons:

– Very large lipoproteins that deliver

triglycerides to muscle and fat tissue

Monitoring the Disease • Risk factors for

atherosclerosis

– Age

– History of smoking

– Hypertension

– Premature menopause

– Obesity

– Diabetes mellitus

– Hyperthyroidism

Monitoring the Disease

• The goals of treatment are:

– Lowering LDL cholesterol

– Reducing total serum cholesterol and

triglycerides

– Increasing HDL cholesterol

Lipid-lowering drugs

• Several drugs are used to decrease plasma LDL-CHO

• Drug therapy to lower plasma lipids is only one approach to treatment

• and is used in addition to dietary management

and correction of other modifiable cardiovascular risk factors

Hypolipidemic Drugs

• There are five

groups of drugs

used in the

management of

hyperlipidemia:

– HMG-CoA reductase

inhibitors

– Cholesterol absorption

inhibitors

– Bile acid sequestrants

– Fibric acid derivatives

– Nicotinic acid

Hypolipidemic Drugs

HMG-CoA Reductase Inhibitors

• Also referred to as statins

• MOA—inhibit enzyme that causes

cholesterol synthesis

• IND—adjunct to dietary treatment to

decrease total serum and LDL cholesterol:

– Reduce LDL level up to 30%

– Raise HDL level up to 20%

HMG-CoA Reductase Inhibitors

• Adverse effects:

– Headache, dizziness, alteration of taste,

insomnia, abdominal cramping and

photosensitivity

• May cause myalgias, leg ache, and

muscle weakness

• Contraindicated during pregancy

Cholesterol Absorption Inhibitors

• Ezetimibe:

– MOA—blocks absorption of cholesterol

in the intestines

• Decreases VLDL

• Decreases circulating LDL cholesterol

– IND—treatment of hyperlipidemia in

conjunction with diet alteration

Cholesterol Absorption Inhibitors

• Ezetimibe:

– Modestly reduces total cholesterol, LDL,

and triglyceride blood levels

– Ideal to combine with other hypolipidemic

drugs

– Adverse effects—abdominal pain, fatigue,

coughing, diarrhea, back pain, and arthralgia

Bile Acid Sequestrants

• MOA—bind bile salts and cholesterol in the GI tract, preventing absorption of both

• IND—hyperlipidemia: – Increased elimination of bile salts, cholesterol, and

other fats in the feces.

– Adverse effects include GI disturbances, severe constipation, and fecal impaction.

– Most serious adverse effect is intestinal obstruction.

Nicotinic Acid

• MOA—affects cholesterol synthesis through a G proteinScoupled receptor: – Inhibits triglyceride lipase

– Stimulates lipoprotein lipase

– Decreases free fatty acid release and removes triglycerides

• IND—hyperlipidemia

• Adverse effects—flushing, nausea, vomiting, and diarrhea

Fibric Acid Derivatives

• Gemfibrozil:

– MOA—inhibits breakdown of fat into

triglycerides, and limits liver production

of triglycerides

– IND—to decrease triglycerides

– Adverse effects—nausea, vomiting,

diarrhea, and flatulence

Preferred Therapy

• All hypolipidemic drugs are indicated as

adjunctive therapy to reduce elevated

cholesterol levels.

• HMG-CoA reductase inhibitors are the most

prescribed.

• Cholestyramine can also be used in the

treatment of partial biliary obstruction.

Contraindications

• Systemic hypolipidemic drugs should not be

used in patients with liver dysfunction.

• Bile acid sequestrants should not be used in

patients with biliary obstruction.

• Statins should not be used in pregnant

women.

Drug Interactions

DRUGS AFFECTING

THE

RESPIRATORY SYSTEM

Dr A.Shyam Sundar,

Assistant Professor in Pharmacology,

University of Nizwa,

Sultanate of Oman

OVERVIEW

Asthma is a reversible obstructive disease of the lower airway.

With asthma, there is increasing airway obstruction caused by bronchoconstriction,

inflammation and edema of the lining of the bronchioles, and the production of thick mucus

that can plug the airway.

Chronic obstructive pulmonary disease (COPD) is the name given collectively to

emphysema and chronic bronchitis because the obstruction to the airflow is present most of

the time.

Emphysema is a lung disorder in which the terminal bronchioles or alveoli become enlarged

and plugged with mucus.

Chronic bronchitis is the chronic inflammation and possible infection of the bronchi.

Rhinitis is an inflammation of the mucous membranes of the nose, and is characterized by

sneezing, nasal itching, watery rhinorrhea and congestion.

Coughing is the forceful expulsion of air from the lungs.

A cough may be productive or nonproductive.

With a productive cough, secretions from the lower respiratory tract are expelled.

A nonproductive cough is a dry, hacking one that produces no secretions.

DRUGS USED IN RESPIRATORY DISORDERS

ASTHMA

There are three types of Asthma

1. Extrinsic Asthma (also referred to as

allergic asthma and caused in response to

an allergen such as pollen, dust, and animal

dander).

2. Intrinsic asthma (also called non-allergic

asthma and caused by chronic or recurrent

respiratory infections, emotional upset, and

exercise).

3. Mixed asthma (caused by both intrinsic

and extrinsic factors).

In asthma,there will be

Contraction of bronchial smooth muscle,

Inflammation of the bronchial wall,

Increased mucous secretion.

Drugs addressing bronchoconstriction and inflammatory issues

Leukotriene inhibitors

An antitussive is a drug used to relieve coughing.

A mucolytic is a drug that loosens respiratory secretions.

An expectorant is a drug that aids in raising thick, tenacious mucus from the respiratory

passages.

The mucolytic acetylcysteine may be used as part of the treatment of bronchopulmonary

diseases such as emphysema,as adjunctive therapy in chronic bronchopulmonary diseases,

such as chronic emphysema, emphysema with bronchitis, chronic asthma, tuberculosis,

and bronchiectasis, pneumonia and tracheobronchitis,cystic fibrosis,in acetaminophen

overdosage.

Expectorants are used to help raise respiratory secretions.

An expectorant may also be included along with one or more additional drugs, such as an

antihistamine, decongestant, or antitussive, in some prescription and nonprescription

cough medicines.

Antitussives,Mucolytics and Expectorants

AUTOCOIDS

Dr A. Shyam Sundar,

Assistant Professor in Pharmacology,

University of Nizwa,

Sultanate of Oman

Overview Autocoids are local hormones which are produced locally, exert their

actions locally and degraded locally.

They can be derivatives of

1. Amines (Histamine and Serotonin).

2. Peptides (Bradykinin,Angiotensin).

3. Lipids (Prostaglandins, Leukotrienes and Platelet activating factor)

Histamine , Serotonin will be discussed in detail in this lecture.

We have already discussed the actions of Angiotensin in the chapter

anti-hypertensive drugs and Leukotrienes were discussed during

anti asthmatic lectures.

HISTAMINE- RECEPTORS LOCATION AND

ACTIONS

HISTAMINE RECEPTOR BLOCKERS AND THEIR

CLINICAL USES

H1 receptor blockers:

First generation:

Azelastine

Chlorpheniramine

cyproheptadine

Diphenhydramine

Hydroxyzine

Phenindamine

Promethazine

Tripelenamine

Second generation :

Cetirizine

Desoratadine

Fexofenadine

Loratadine

Clinical uses of H1 receptor blockers

Urticaria

Hypersensitivity reactions

ADRs of

H1 antagonists

HISTAMINE RECEPTOR BLOCKERS AND THEIR

CLINICAL USES

Clinical uses:

Peptic Ulcer

Zollinger-Ellison Syndrome

Acute Stress ulcers

Gastroesophagal reflex disease

SEROTONIN

Serotonin is an indole ethylamine found in both plant and animal tissues.

90% of serotonin is present in GI tract and 10% present in CNS.

Serotonin exert its action through seven major 5-HT cell membrane receptor

subtypes.

Physiological actions of Serotonin:

PROSTAGLANDINS

Impotence

Therapeutic Uses of Prostaglandins:

Several of the naturally occurring prostaglandins, such

as dinoprost , dinoprostone , and carboprost , find use as

abortifacients . Misoprostol in combination with methotrexate is

particularly effective in terminating pregancy in the first trimester.

Misoprostol is a synthetic prostaglandin E1 analog used to inhibit

the secretion of hydrochloric acid in the stomach. It produces

inhibition of gastric acid and pepsin secretion and enhances

mucosal resistance to injury. Misoprostol is particularly useful in

patients with gastric ulcer who are chronically taking nonsteroidal

anti-inflammatory agents

Alprostadil injected into the corpus cavernosum of

the penis provides effective treatment of some forms

of male impotence.

ANTI ULCER DRUGS

ANTIULCER DRUGS DR A SHYAM SUNDAR., A peptic ulcer is an open sore or raw area on the lining of the stomach

(gastric ulcers), or on the duodenum (duodenal ulcers). Define ulcer and compare and contrast Gastric &duodenal Ulcer Identify the classification of drugs Used to treat PUD Describe treatment goals for PUD Know prototype drugs in each classification &their details Use Pharmaceutical process for the welfare of the clients receiving

drug therapy for PUD

Proglumide ACh

PGE2

Histamine Gastrin

Adenyl

cyclase

_ +

ATP cAMP

Protein Kinase (Activated)

Ca++

+

Ca++

Proton pump

K K+ H+

Gastric acid

Parietal cell

Lumen of stomach

Antacid Omeprazole

Ranitidine

H2 M3

Misoprostol

_

_

_

_

+

PGE receptor

+

+

Gastrin

receptor +

+

+

See Animation

Can you identify these people ?

Nobel prize

Medicine –

2005

Barry J Marshall J. Robin Warren

Discovery of

H.pylori &

its role in

ulcer

Antacids

• Weak bases that neutralise acid

• Also inhibit formation of pepsin

(As pepsinogen converted to pepsin at acidic pH)

• Present day antacids :

Aluminium Hydroxide

Magnesium Hydroxide

• OTC drug for symptomatic relief of dyspepsia

Duration of action :

30 min when taken in empty stomach

2 hrs when taken after a meal

Side effects :

Al3+ antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying)

Mg2+ antacids – Osmotic diarrhoea .

In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy

Antacids – Common additives & Interactions

Adsorb drugs and form

insoluble complexes that

are not absorbed .

Clinical importance :

Interactions can be

avoided by taking antacids

2 hrs before or after

ingestion of other drugs .

Simethicone – Decrease

surface tension ,thereby

reduce bubble formation

Added to prevent reflux .

Alginates- Form a layer of

foam on top of gastric

contents & reduce reflux

Oxethazaine – Surface

anaesthetic

Histamine H2 Receptor Antagonist

• Reversible competitive inhibitors of H2 receptor

• Highly selective, No action on H1 or H3 receptors

• Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine )

• Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)

H2 Blockers–Side effects &

Interactions

Extremely safe drugs

• Cimetidine causes gynecomastia, galactorrhea

(as it is antiandrogenic & increases prolactin level)

• Cimetidine inhibits CYP450 & increases conc. of Warfarin, Theophylline, Phenytoin, Ethanol.

Proton Pump Inhibitors

Most effective drugs in antiulcer therapy

Irreversible inhibitor of H+ K+ ATPase

Prodrugs requiring activation in acid environment

Weakly basic drugs & so accumulate in canaliculi

of parietal cell

Activated in canaliculi & binds covalently to

extracellular domain of H+ K+ ATPase

Acid secretion resumes only after synthesis of new

molecules

Half life is about 1.5 hrs

Proton Pump Inhibitors

Omeprazole 20 mg o.d.

Esomeprazole 20 - 40 mg o.d.

Lansoprazole 30 mg o.d.

Pantoprazole 40 mg o.d.

Rabeprazole 20 mg o.d.

Poton Pump Inhibitors – Kinetics

Given as enteric coated granules in capsule or

enteric coated tablets

Pantoprazole also given intravenously

Half life – 1.5 hrs

Since it requires acid for activation - given 1 hr

before meals

Other acid suppressing agents not coadministered

P.P.I. – Side effects & Interactions

Extremely safe drugs

Causes hypergastrinemia which leads to carcinod

tumor in rats

But no evidence of such tumors in man

Inhibit CYP 450 & hence metabolsim of warfarin,

phenytoin, etc

Pantoprazole & Rabeprazole have no significant

interactions

Mucosal Protective Agents

• Sucralfate

• Misoprostol

• Colloidal Bismuth compounds

Sucralfate • Salt of sucrose complexed to

sulfated aluminium hydroxide

• In acidic pH polymerises to viscous gel that adheres to ulcer crater

• Taken on empty stomach 1 hr. before meals

• Concurrent antacids, H2 antagonist avoided

( as it needs acid for activation )

Colloidal Bismuth Compounds

• Coats ulcer, stimulates mucus & bicarbonate secretion

• Direct antimicrobial activity against H.pylori

• May cause blackening of stools & tongue

• Not used for long periods – bismuth toxicity

Misoprostol • PGE1 analogue

• Modest acid inhibition

• Stimulate mucus & bicarbonate secretion

• Enhance mucusal blood flow

• Approved for prevention of NSAID induced ulcer

• Diarrhoea & cramping abd. pain – 20 %

• Not so popular as P.P.I are more effective & better tolerated

Triple Therapy

The BEST among all the Triple therapy regimen is

Omeprazole / Lansoprazole - 20 / 30 mg bd

Clarithromycin - 500 mg bd

Amoxycillin / Metronidazole - 1gm / 500 mg bd

Given for 14 days followed by P.P.I for 4 – 6 weeks

Short regimens for 7 – 10 days not very effective

Triple Therapy – cont …

Bismuth subsalicylate – 2 tab qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Some other Triple Therapy Regimens are

Ranitidine Bismuth citrate - 400 mg bd

Tetracycline - 500 mg bd

Clarithromycin / Metronidazole - 500 mg bd

Quadruple Therapy

Given when Triple Therapy fails

Omeprazole / Lansoprazole - 20 / 30 mg bd

Bismuth subsalycilate - 2 tabs qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Now you have learnt about drugs used for treating

peptic ulcer ? Are there any drugs that can cause peptic

ulcer ?

Drugs causing peptic ulcer

Non Steroidal Anti Inflammatory Drugs

(NSAIDs)

Glucocorticoids

Cytotoxic agents

Antiemetics

Vomiting

Centre

(medulla)

Cerebral cortex

Anticipatory

emesis

Smell

Sight

Thought

Vestibular

nuclei Motion

sickness

Pharynx &

GIT

Chemo & radio

therapy

Gastroenteritis

Chemoreceptor

Trigger Zone

(CTZ)

(Outside BBB)

Cancer chemotherapy

Opioids

Muscarinic, 5 HT3

& Histaminic H1

5 HT3

receptors

Dopamine D2

5 HT3,,Opioid Receptors

Muscarinic

Histaminic

H1

Pathophysiology of Emesis

Now answer this question

Which group of drugs can be used as

antiemetics ?

Serotonin 5 HT3 Antagonists

Dopamine D2 Antagonist

Anticholinergics

H1 Antihistaminics

Cannabinoids

Serotonin 5 HT3 Antagonist

Potent antiemetics

Even though 5 HT3 receptors are present in

vomiting centre & CTZ, the antiemetic action is

restricted to emesis caused by vagal

stimulation.

High first pass metabolism

Excreted by liver & kidney

No dose reduction in renal insufficiency but

needed in hepatic insufficiency

Given once or twice daily – orally or

intravenously.

Drugs Available

Ondansetron 32 mg / day

Granisetron 10 mg / kg / day

Dolasetron 1.8 mg / kg / day Indications Chemotherapy induced nausea & vomiting – given 30

min. before chemotherapy.

Postoperative & postradiation nausea & vomiting

Adverse Effects

Excellent safety profile

Headache & constipation

All three drugs cause prolongation of QT interval, but

more pronounced with dolasetron.

Dopamine D2 Antagonist

Antagonise D2 receptors in CTZ.

Drugs available

Metoclopramide 2.5 mg b.d

Domperidone 10 mg b.d

Both drugs are also prokinetic agents due to

their 5 HT4 agonist activity.

Domperidone – oral ; Metoclopramide – oral &

i.v

Metoclopramide crosses BBB but domperidone

cannot.

Phenothiazines & Butyrophenones

Phenothiazines

Prochlorperazine

Promethazine

Phenothiazines are antipsychotic with

potent antiemetic property due to D2

antagonism.

Butyrophenone

Droperidol

Droperidol used for postop. nausea &

vomiting, but cause QT prolongation.

H1 Antihistaminics

Most effective drugs for motion sickness

Drugs available

Meclizine

Cyclizine

Dimenhydrinate

Diphenydramine

Promethazine – Used in pregnancy, used by

NASA for space motion

sickness

Anticholinergics

Scopolamine (hyoscine) – used as

transdermal patch for motion sickness

Cannabinoids

Dronabinol – used as adjuvant in

chemotherapy induced vomiting.It is a

psychoactive substance

Nabilone

Summary

What’s Latest?

Aprepitant…(nk-1 receptor Blocker)

Rational Thinking:

a. Atropine

b. Scopolamine (TDP)