Principles of Clinical

Pharmacology

Ioan Magyar MD, PhD

Assoc. Professor of Basic & Clinical
Pharmacology
Senior Doctor in Clinical Pharmacology &
Emergency Medicine
Additional competence: Clinical
Toxicology
• Introduction to Clinical Pharmacology
• Clinical pharmacology can be defined as the
study of drugs in humans.
• Clinical pharmacology is a relatively new science.
• It is related to pharmacotherapy but is not the
same science.
• Clinical pharmacology is a science about drugs.
• It is closley linked to fundamental
pharmacology.
The fundamental problemes with which
pharmacology is concerned are following:
1. The relationship between dose and biological
effect.
2. The localization of the site of action of a drug.
3. The mechanism (s) of action of drug.
4. The absorption, distribution, metabolism,and
excretion of a drug (PK).
5. The relationship between chemical structure
and biological activity.
• Clinical pharmacology is the scientific discipline
that involves all aspects of the relationship
between drugs and humans.
• Its breadth include the discovery and
development of new drugs, the application of
drugs as therapeutic agents, the use of drugs, the
beneficial and harmful effects of drugs in
individuals and society, and the deliberate misuse
of drugs.
• Clinical pharmacology is a multidisciplinary team
science that encompasses professionals with a
variety of scientific skills including medicine,
pharmacology, pharmacy, biomedical science and
nursing.
• Clinical pharmacology has been termed a
bridging discipline because it links classical
pharmacology with clinical medicine.
The descriptor 'clinical pharmacologist' is normally used
in a professional sense to refer to physicians involved
in the medical care of patients who are specialists in
clinical pharmacology.
They have usually undertaken several years of
postgraduate training on important aspects of clinical
pharmacology including clinical trials, drug
evaluations, pharmacoepidemiology,
pharmacovigilance and clinical toxicology.
• Clinical pharmacologists are concerned both:
• 1). Optimal use of existing medications
• 2). Scientific study of drugs in humans.

• The latter area include both evaluation of:

• 1).The safety and efficacy of currently available
drugs;
• 2). Development of new and improved
pharmacotherapy.
A few personalities had an significantly influence on
clinical pharmacology development:
1). Rudolph Bucheim (1820-1879) has been
credited with establishing pharmacology as a
laboratory-based discipline.
• 2). In the United States, Harry Gold and Walter
Modell began in the 1930 s to provide the
foundation for the modern discipline of clinical
pharmacology.

• They inovated (invention) of the double-blind

design for clinical trials and the use of effect
kinetics to measure the absolute bioavailability of
digoxin.
• A great challange for the pharmacologists and
physicians was adverse drug reaction (ADR) to
thalidomide – an inofensive anxiolytic and
antivomiting drug

• Few drugs have focused as much public attention

on problem of ADRs as did thalidomide, which
was first linked in 1961 to catastrophic outbreaks
of phocomelia by Lenz in Germany and McBride
in Australia.
• The thalidomide tragedy provided an major
impetus for developing a number of NIH-funded
academic centers of excellence of clinical
pharmacology.
• NIH = National Institutes of Health
• FDA = Food and Drug Administration
• Serious ADRs (defined as those ADRs that require
or prolong hospitalization, are permanently
disabling, or result in death) have been
estimated to occur in 6.7% of hospitalized
patients.
• The incidence of ADRs probably is still higher
than is generally recognized.
• In addition, the majority of these ADRs continue
to be caused by drugs that have been in clinical
use for a substantial period of time.

• Evaluation and Development of Medicine

• Clinical pharmacologists have made noteworthy
contributions to the evaluation of existing
medicines and development of new drugs.
• In 1932, Paul Martini published a monograph:
Methodology of Therapeutic Investigation, that
summarized his experience in drug evaluation
and probably entitles him to be considered the
first clinical pharmacologist.
• Martini described the use of placebos, control
groups, stratification, rating scales, and the
n of 1 trial design, and emphasized the need to
estimate the adequacy of sample size and to
establish baseline conditions before beginning a
trial.
• He also introduced the term clinical
pharmacology.

• More recently, Sheiner outlined a number of

improvements that continue to be needed in the
use of statistical methods for drug evaluation,
and asserted that clinicians must regain control
over clinical trials – to ensure that the
important questions are being addressed.
• Contemporary drug development is a complex
process that is conventionally divided into
preclinical research and development and a
number of clinical development phases.

• A following figure illustrate these two main steps:

• I.Preclinical Development
• II.Clinical Development
 Less than 1/3 of the drugs tested in clinical
research – in the marketplace
 A good clinical trial – multidisciplinary
perssonel:
 1). Basic scientists
 2). Clinical pharmacologists
 3). Clinician specialists
 4). Statisticians
• To avoid some errors in clinical trials some
methods are used:

• 1. Crossover design – alternating of test drug

with placebo and standard drug
• Placebo response from Latin,I shall please
• Placebo respons is a positive way of
therapeutic result
• In clinical trials placebo = an inert form with
the same properties of the tested drug (odor,
consistency)
• To eliminate this phenomen (placebo
response) we can use:
• 2. Single-blind design or
• 3. Double –blind design
• In the last design – only a third person know
about testing drug (with the special code)
• CLINICAL TRIALS.IND & NDA
• Once a drug is judget ready to be studied in
humans, a Notice of Claimed Investigational
Exemption for a New Drug (IND) must be filed
with the FDA.
• The IND includes:
• 1).Information on the composition and
source of the drug;
• 2). Manufacturing information;
• 3). All data from animal studies;
• 4). Clinical plans and protocols;
• 5). The names and credentials of physicians
who will conduct the clinical trials.
• Its often requires 4-6 years of clinical testing
• The volunteers or patients must be informed
• Phase 1
• The drug is studied in 20-80 healthy
volunteers;
• In this phase the trial is open – investigators
and subjects know what is being given;
• Its evaluated toxicity, PK profile of the drug;
• Phase 1 studies its performed by the clinical
pharmacologists – in research centres;
• Phase 2
• In this phase testing drug is evaluated in
patients
• The goal – to determine efficacy of the drug
• A small number (100-200) of patients – is
evaluated in great detail
• A single-blind design is used with placebo and
an older active drug (to compare)
• The ADRs (drug toxicity) might also detected
in this phase
• Phase 2 of trials are done in clinical centres
(university hospitals)
• Phase 3
• The drug is evaluated in much larger numbers
of patients (thousands) to further establish
safety and efficacy.
• Using information gathered in phases 1 and 2,
phase 3 trials are designed to minimize errors
caused by placebo effects, variable course of
disease, etc.
• Therefore, double-blind and crossover
techniques are frequently used.
• Phase 3 studies can be difficult to design and
execute
• Are usually expensive because a large
numbers of patients involved and the masses
of data that must be collected and analyzed.
• The investigators are usually specialists in the
disease being treated.
• Certain toxic effects (caused by immunologic
processes) may be first become apparent in
phase 3.
• If phase 3 results meet expectations,
application will be made for permission to
market the new agent;
• The process of applying for marketing
approval requires submission of a New Drug
Application (NDA) to the FDA;
• The FDA review this material and a decision
on approval may take 3 years or longer;
• In cases where an urgent need is percieved
(eg, cancer chemotherapy), the process of
preclinical and clinical testing and FDA review
may be greatly accelerated.
• For serious diseases, the FDA may permit
extensive but controlled marketing of a new
drug before phase 3 studies are completed;
• Phase 4
• Once approval to market a drug has been
obtained, phase 4 begin.
• This constitutes monitoring the safety of the
new drug under actual conditions of use in
large number of patients.
• PHARMACOVIGILANCE
• ADVERSE DRUG EVENT SURVEILLANCE
• Pharmacovigilance is the last phase in drug
development.
• It is the postmarketing surveillance and study
of ADRs, with the ultimate goal of preventing
or minimizing their occurence
• New prescription drugs are only marketed
after carefully controlled clinical trials have
shown them to be safe and effective.
• The conduct of pharmacovigilance - by both
industry and health authorities
• The costs (billions of dollars annually) includes
collection, compilation, quality control, and
analysis of the spontaneus reports.
• Pharmacovigilance is a necessary interface
between therapeutics and clinical
epidemiology.
• Although it is the poor relative of
pharmacology and the bogeyman of the
sellers of new drugs, pharmacovigilance is,
neverthless, very important component for
the rational use of drugs
• Modern pharmacovigilance was heralded in
the 1960s by the thalidomide disaster, a
devastating and obvious fetal abnormality
produced by us of drug in pregnancy.
• Pharmacovigilance is the fourth steps (the last
phase) in clinical development of the drugs,
after the drug is marketed.
• New prescription drugs are only marketed
after carefully controlled clinical trials have
shown them to be safe and effective.
• When a new drug enters the market, it has
been tested in only 3-5000 patients.
• Its most common adverse efects should be
known and in particular those that are
predictable from their basic pharmacological
properties.
• However, at marketing, serious or even lethal
but very rare adverse drug reactions (ADRs)
that cannot be explained by the basic
pharmacology of the drug and that occur in,
say, 1 out of 10,000 patients or even less
commonly, may not have occurred or been
recognized.
• Farmacovigilance is the postmarketing
surveillance and study of ADRs, with the
ultimate goal of preventing or minimizing their
occurrence.
• Pharmacoepidemiology. Epidemiology of
ADRs
• Pharmacoepidemiology can be defined simply
as application of epidemiological methodes to
the effects of medicines, including vaccines
and cell-based or biological treatments.
• Clinical pharmacology is closely related to
pharmacoepidemiology.
• The later area uses methodes from both clinical
pharmacology and epidemiology.
• Epidemiology of ADRs
• Although some ADRs are minor and resolve without
sequelae, others can cause permanent disability or
death;
• ADRs occur commonly, but estimates of incidence
vary considerably;
• This is due to substantial underreporting of ADRs and
differences in study methodology, populations
studies and ADR definitions;
• ADRs account for 2.9-15.4 of all hospitals admissions
in the U.S.
• The incidence may be highest in the elderly and
other compromised populations;
• Nearly 16% of nursing home residents are
hospitalized because of an ADR;
• A significant risk factor for hospitalization is the concomitant
use of seven or more medications;
• ADRs are believed to be fourth to sixth leading cause of death
among hospitalized patients;
• A recent study suggests that an estimated 6.7 of hospitalized
patients experience serious ADRs (defined as those that
require or prolonged hospitalization, are permanently
disabling, or result in death);
• ADRs increase lenght of hospital stay by 2.2 to 4.6 days; the
hospital costs are also increased (more that $ 2500/event);
ADVERSE EVENTS (AEs)
Hurwitz and Wade proposed four categories of AEs.
The first two – type A and the second two –type B
1.Side effect
2.Excess effect
3.Allergy (hypersensitivity)
4.Idiosyncrasy
DeSwarte ( ADRs into eight categories)
1.Overdose
2.Side effect
3.Secondary or indirect effect
4.Interaction
5.Intolerance
6.Idiosyncrasy (primary toxicity)
7.Allergy
8.Pseudoallergy (anaphylactoid)
• Type A adverse event
• Rawlins and Thompson have calssified AEs into type
A (augmented) and type B (bizare).
• They are also called predictable or anticipated
events.
• They are generally less severe and more frequent
than type B events.
• They are usually detected during the clinical trials
done before marketing.
• They are two subclasses:
• 1. Exaggerated desired effect
• The exaggeration of a desired pharmacologic effect
after a normal dose in a susceptibile subject or after
a higher than normal dose;
• Orthostatic hypotension with an antihypertensive
• Daytime somnolence after a sedative-hypnotic drug
• Hypoglycemic shock after insulin
• All effects are examples of this phenomen
• 2.Undesired effect
• The appearance of an undesired pharmacologic
effect can be seen after a normal dose or a higher
than normal dose in a susceptible subject.
• Constipation due to morphine
• Gastrointestinal irritation with NSAIDs
• Hair loss from chemotherapy
• Type B adverse event
• They are called pharmacologically unexpected,
unpredictable, or idiosyncratic adverse reactions.
They are two subclasses:
• 1.Immunologic
• An allergic or hypersensitivity reaction occurs as a
result of an immunologic mechanism.
• A pseudoallergy or anaphylactoid reaction is the
result of a mechanism involving the release of the
same mediators realesed during an immunologic
reaction due to IgE.
• Such reactions can occur with radiocontrast agents,
NSAIDs, dextrans etc.
2. Idiosyncratic
• This is also known as primary toxicity.
• The term of idiosyncratic is often used in a broad
sense
• The abnormal adverse reactions that occur in a given
individual and whose mechanism is not yet
understood.
• Congenital enzyme abnormalities may produce the
hemolytic anemia due to G6PD deficiency.
• Types C, D, and E are not mechanisms but
characteristics of their manifestations. They are not
reffered to frequently in the literature.
• The letter C refers to continuous, chronic
• Type D refers to delayed in appearance
• Type E refers to end of use
• DRUG THERAPY IN PREGNANCY
• Most drugs taken by pregnant women can
cross the placenta and expose the developing
embryo and fetus to their pharmacologic and
teratogenic effect.
• Drug passage across the placenta is
dependent on lipid solubility and the degree
of drug ionization.
• Lipophilic drugs tend to diffuse readily across
the placenta and enter the fetal circulation.
• Thiopental, a drug comonly used for cesarean
sections, crosses the placenta almost
immediately and can produce sedation or
apnea in the newborn infant.
• Highly ionized drugs such as succinylcholine
and tubocurarine, also used for cesarean
sections, cross the placenta slowly and
achieve very low concentrations in the fetus.
• The molecular weight of the drug also
influences the amount of drug trensferred
across the placenta.
• An important clinical application of this
property is the choice of heparin as an
anticoagulant in pregnant women.
• Because it is very large (and polar) molecule,
heparin is unable to cross the placenta.
• Unlike warfarin, which is teratogenic and
should be avoided during first trimester and
even beyond.
• Heparin may be safety given to pregnant
women who need anticoagulation.
• Phenobarbital, when given to pregnant
women near term, can induce fetal hepatic
enzymes responsible for the glucuronidation
of bilirubin,
• and the incidence of jaundice is lower in
newborns when mothers are given
phenobarbital than phenobarbital is not used.
• Administration of phenobarbital to the mother
was suggested recently as a means of
decreasing the risk of intracranial bleeding in
preterm infants.

• Predictable toxic drug actions in the fetus

• Chronic use of opioids by the mother may
produce dependence in the fetus and
newborn.
• This dependence may be manifested after
delivery as a neonatal withdrawal syndrome.
• A less well understood fetal drug toxicity is
caused by the use of ACEs during pregnancy.
• These drugs can result in significant and
irreversible renal damage in the fetus;
• ACEs are cid in pregnancy
• Adverse effects may also be delayed, as in the
case of female fetuses exposed to
diethylstilbestrol, who may be at increased
risk for adenocarcinoma of the vagina after
puberty.
• Teratogenic drug actions
• A single intrauterine exposure to a drug can
affect the fetal structures undergoing rapid
development.
• Thalidomide is an example of a drug that may
profoundly affect the development of the
limbs after only brief exposure.
• This exposure, however, must be at a critical
time in the development of the limbs.
• The thalidomide phocomelia risk occurs
during the fourth to seventh weeks of
gestation.
• The mechanisms by which different drugs
produce teratogenic effects are poorly
understood.
• Drugs may interfere with the passage of
oxygen or nutrients through the placenta and
therefore have effects on the most rapidly
metabolizing tissues of the fetus.
 FDA teratogenic risk categories

Ctegory Description
A Drug has been studied in humans. Evidence supports its safe use.
Remote possibillity of fetal harm. Can be appropriately administered
during pregnancy.
B Animal studies demonstrate no fetal risk. Inadequate studies in
pregnant women. Slightly increased fetal risk. Can be appropriately
administered during pregnancy.
C Teratogenic risk cannot be ruled out. Animal studies show potential
adverse fetal effects. Potential benefits may outwigh risks. Can be used
with caution.
D Drug demonstrates risk in humans. Potential benefits may outweigh
risks. Should be avoided.
X Drug demonstrates harm in mother or fetus. Risk clearly outweighs
benefit. Contraindicated.
• DRUG THERAPY IN INFANTS & CHILDREN
• Special attention must be paid to PK in the
first year of life, particularly during the first
few months.
• PD differences between pediatric and other
pateints have not been explored in great
detail.
• Drug absorbtion in infants and children folows
the same general principles as in adult.
• Drug distribution depend on percentage of
water in body wheight (70-75 % in neonates
versus 50-65 % in adult).
• In general, protein binding of drugs is reduced
in the neonate.
• Drug metabolism
• The neonatess decreased ability to
metabolize drugs, many drugs have slow
clearance and prolonged elimination half-
lives.
• The capacity of the liver to metabolize drugs is
lower at birth.
• Oxidative capacity is reduced at birth but
appears to develop over the days;
• An example: the half-life for ibuprofen is
greather than 30 hours in premature infants in
the first day of life compared with less than 2
hours in children and adults.
• Drug excretion
• Renal function is limited at birth because the
kidneys are anatomically and functionally
imature.
• The glomerular filtration rate is much lower in
newborns than in older infants, children, or
adults and limitation persist during the first
few days of life.
• Calculated on the basis of body surface area,
glomerular filtration in the neonate is only 30-
40 % of the adult value.
• GFR (glomerular filtration rate) is 10-15
mL/min/m2 and becomes double by 1 week of
age (because of a postnatal drop in renal
vascular resistance and increase in renal blood
flow) and reaches adult values by 1 year of
age.
• Renal clearance of drugs is delayed in
newborns and young infants, necessitating
dose reductions, but after 8-12 months of age,
renal excretion of drugs is comparable with
that of older children and may even exceed
that of adults.
• In young children, the ration of renal size
relative to BSA (body surface area) is larger
than in adults, and drug clearance normalized
to BSA can exceed that in adults.
• Because renal clearance is more efficient in
children, the dose of aminoglycosides
requiered to achieve effectiv antibiotic plasma
concentrations in children is usually 1.2-2-fold
higher than in adults.
• So, the dosing interval in cildren also may
need to be shorter than in adults.
• Drug therapy in the Elderly
• A cronological definition is often used regard to aging
population: young old (65-75 years), old (75-85
years) and old old (more than 85 years);
• Many old patients have 5 to 10 diagnosis; an
example: hypertension, coronary artery disease,
osteoarthritis,, osteoporosis, type 2 diabetes
mellitus, and treated prostate or breast cancer –
often coexist in an individual patient.
• In addition, treatable insomnia, depression and anxiety may
be present;
• The incidence of Alzheimer's disease is very high in patients
over 85 years old;
• Renal function (renal blood flow, GFR, tubular secretory
processes) decline with increasing age.
• Examples of drugs with decreased renal drug clearance in
elderly: NSAIDs, ACEIs and diuretics:
• Biotransformation in elderly is delayed compared with the
normal adults.
 DRUGS USED IN ASTHMA

• Astmul bronșic – astma (ασθμα) = respirație dificilă;

•Asthma means difficulty in breathing.
• The clinical expression varies from a mild
intermittent wheeze or cough to severe chronic
obstruction.
• Clinical of asthma:
• Cough
• Shortness of breath
• Chest tightness
• Wheezing
• Acute asthma attacks are triggered by:
• 1. Exposure to allergens or cold air
• 2. Exercise
• 3. Upper respiratory tract infections
• The most severe exacerbation of asthma is status
asthmaticus.
• It is a life-threatening condition that requires
hospitalization and must be treated
aggressively.
• Cardinal features of asthma are:
• 1.Airway obstruction
• 2.Inflammation
• 3.Hyperreactivity of the airway
• The airway obstruction associated with asthma is
reversible, in contrast to chronic obstructive
pulmonary disease (COPD, emphysema and
chronic bronchitis).
• Asthma can be devided in two forms:
• I. Extrinsic asthma (allergy-induced asthma)
• II. Intrinsec asthma (infectious asthma)
• I. Extrinsic asthma
• Allergy and aberrant immune respons appears to
underlie of this type of asthma;
• Children over 3 years and most young adults;
• II. Intrinsic asthma
• Airway inflammation is the main feature of this
form of asthma;
• Other patients may have both allergic and
nonallergic forms of asthma.
• Airway obstruction
• Three factors contribute to airway obstruction:
• 1.Contraction of the smooth muscle
• 2.Excessive secretion of mucus
• 3.Edema of the respiratory mucosa
• Antigens such as ragweed polen or house mite
dust sensitize individuals to produce antibodies
like immunoglobulin E (IgE=reagine).
• These antibodies attach themselves to the surface
of mast cells and basophils.
• Another exposure to the same antigen after days or
month leads to release of histamine and cysteinyl
leukotrienes (CysLTs) from lung mast cells.
• These mediators produce:
• Bronchoconstriction
• Mucus secretion
• Pulmonary edema
• Mast cells also release chemotatic mediators, such
as leukotriene B and cytokines.
• These mediators recruit and activate additional
inflammatory cells particularly eosinophils and
alveolar macraphages.
• Ultimately, repeated exposure to antigen establishes
a chronic inflammatory state in the asthmatic
airway.
• The inflammatory process in asthma is mediated
through the release of > 100 inflammatory
mediators.
• Complex cytokine networks, including chemokines
and growth factors, play important roles in
orchestrating the inflammatory process.
• Chronic inflammation may lead to structural changes
in the airways, including an increase in the number
and size of airway smooth muscle cells, blood
vessels, and mucus-secreting cells.
• A characteristic histological feature of asthma is
collagen deposition (fibrosis) below the basement
membrane of the airway epitelium.
• This appears to be result of eosinophilic
inflammation, even at the onset of asthmatic
symptoms.
• The complex inflammation of asthma is suppressed
by corticosteroids in most patients, but even if
asthma is well controlled, the inflammation and
symptoms return if corticosteroids are discontinued.
• Asthma usually starts in early childhood, then may
disappear during adolescence and reappear in
adulthood.
• It is characterized by variable airflow obstruction and
shows a good therapeutic response to
bronchodilators and corticosteroids.
• Airway inflammation
• The recognition that asthma is a disease of
airway inflammation has fundamentally
changed strategy of treatment of asthma.

• Treatment strategy
• The overall objectives of antiasthma therapy are:
• 1. Return lung function to normal
• 2. Prevent acute exacerbations of disease
• The primary classes of drugs used in asthma are:
• Bronchodilators and
• Antiinflammatory agents
• I. Bronchodilatators include:
• 1. Theophyline
• 2. Adrenomimetic amines
• 3. Ipratropium bromide (an anticholinergic
drug)
• II. Antiinf lammatory agents are
corticosteroids
• Another group are the leukotriene modulators,
such as cromolyn sodium, and nedocromil
sodium.
• Bronchodilators are used both in maintenance
therapy and to reverse acute attacks.
• Antiinflammatory therapy must be used in
conjunction with bronchodilatators in all but the
midlest asthmatics.
Adrenomimetic agents
1.Epinephrine (Suprarenyn, Primatene)
2.Isoproterenol (Isuprel)
3.Albuterol (Salbutamol,Ventolin, Proventil)
4.Terbutaline (Brethine, Brethaire)
5.Salmeterol (Serevent) and Formoterol
6.Bitolterol (Tornalate)
7.Pibuterol (Maxair)
8.Metaproterenol (Alupent)
• These adrenomimetic drugs are the mainstay of
• modern bronchodilatator therapy.
• These agents are used both to reverse acute
episodes of bronchospasm and prophylactic to
maintain airway patency over the long term.
• The most beneficial effect of these agents is
bronchodilation in patients with bronchospasm.
• Other effects (adverse) include tachycardia,
anxiety, and tremor.
• Epinephrine is agonist on both alfa- and beta-
adrenoceptors.
• Albuterol, terbutaline and salmeterol are beta
2-adrenoceptors agonist.
• These agents have a higher affinity for beta 2-
adrenoceptors (the predominant subtype in
airway).
• Epinephrine sc is used to reverse severe acute
episodes of bronchospasm and status
asthmaticus.
• Epinephrine is not the first choice drug in
treatment of asthma because its effectson the
cardiovascular system.
• Isoproterenol is given by inhalation from
metered-dose inhalers or from nebulization.
• Terbutaline and albuterol are administered
either orally or by inhalation.
• Salmeterol is given by inhalation only.
• These three compounds are relatively selective for
beta 2-adrenoceptors.
• Bronhodilatation is accompanied by the minimal
cardiac stimulation.
• Beta2-agonists produce tachycardia at large doses.
• Inhaled salmeterol has a half-life more than 12
hr, much longer than either albuterol or
terbutaline.
• Its long duration of action makes salmeterol
suitable for prophylactic use, such as in
preventing nocturnal symptoms of asthma.
• Because of its slow onset of action salmeterol
should not be used to treat acute symptoms.
• Bronhodilation efect of adrenomimetic drugs are
due to increased cAMP.
• Adrenomimetics enhance production of cAMP by
activating AC, which promotes conversion of ATP
into cAMP.
• Clinical uses
• Inhaled epinephrine is still used extensively for
the management of acute attacks, particularly in
children.
• Isoproterenol is used by inhalation for treatement
of bronchospasm.
• It is also used IV for asthma and as a stimulant in
cardiac arrest.
• Terbutaline and albuterol (salbutamol) have
very rapid onset of action and are indicated for
treatment of acute symptoms.
• Salmeterol has a slow onset of action but a long
duration of action.
• Salmeterol is used as prophylactic therapy only,
not to reverse acute symptoms.
• Adverse effects
• Tremor, anxiety, and palpitations – after
epinephrine in normal doses.
• Epinephrine is dangerous if the drug is used in
patients with coronary artery disease,
hypertension, or arrhythmias.
• The inappropriate use of epinephrine has resulted
in:
• 1). Extreme hypertension;
• 2). Cerebrovascular accidents;
• 3). Pulmonary edema;
• 4). Angina;
• 5). Ventricular fibrillation.
• Adverse effects from inhaled isoproterenol are not
serious – at normal dose.
• When excessive dosage are used, tachycardia,
dizziness, and nervousness may occur.
• Muscle tremor is an adverse effect of beta2-
adrenomimetic agents used orally.
• It is due to activation of beta 2-adrenoceptors in
skeletal muscle.
• Beta2-agonists also cause tachycardia and
palpitations in some patients.
• The over-use of beta-adrenoceptor agonists is
associated with a slight increase in asthma
mortality.
• Theophylline
• Theophylline continue to have an important place
in the therapy of asthma.
• It apeares to have antiinflammatory as well as
bronchodilator activity.
• The principal pharmacological effects are:
• Smooth muscle relaxation
• CNS excitation
• Cardiac stimulation

• Theophylline produces in the asthmatics:

• Resolution of obstruction
• Improvement in pulmonary function
• Other mechanisms that may contribute to
antiasthmatic action of theophylline:
• 1). Antagonism of adenosine
• 2). Inhibition of mediator release
• 3). Increased sympathetic activity
• 4). Alteration in immune cell function
• 5). Reduction in respiratory muscle fatigue
• Bronchodilation is due to inhibition of PDE and
increased cAMP and cGMP.
• Clinical uses
• Management of asthma
• COPD (chronic obstructive pulmonary disease)
• Adverse effects. Contraindications
• Theophylline has a narow therapeutic index
• The plasma therapeutic levels are between 10 and
20 mcg/mL.
• Nausea and vomiting
• At 40 mcg/ml (and more) – seizures
• In children – restlessness, agitation, diuresis and
fever.
• A rapid IV injection – arrhythmias, hypotension,
and cardiac arrest.
• Caution in patients with: myocardial disease, liver
disease and acute myocardial infarction.
• Ipratropim bromide(Atrovent)
• It is used via inhalation in COPD and to a lesser
extent in asthma.
• It may be more suitable for prophylactic use.
• Ipratropium and albuterol is a fixed combination
(Combivent) – used in COPD.
• Antiinflammatory drugs
• Asthma is not a simply disease marked by acute
bronchospasm but rather a complex chronic
inflammatory disorder of the airways.
• Inhaled corticosteroids, along with beta2-
adrenoceptor agonists, are front-line therapy of
chronic asthma.
• Inhaled corticosteroids are not effective for relief
of acute episodes of severe bronchospasm.
• A fixed combination of inhaled fluticasone and
salmeterol (Advair, Seretide) is available for
maintenance antiinflammatory and
bronchodilator treatment of asthma.
• Adverse effects
• After systemic administration: adrenal supression,
growth retardation, cataracts, osteoporosis, and
increased susceptibility to infection.
• Inhaled corticosteroids are generally well
tolerated.
• Oral candidiasis,dysphonia,throat irritation,and
coughing.
• Glucocorticosteroids are teratogenic (do not use
during pregnancy).
• Leukotriene modulators
• 1. Zafirlukast (Accolate) and Montelukast
(Singulaire) are cysteteinyl leukotriene receptor
antagonist.
• Cys LTs include leukotrienes C4, D4, and E4.
• 2. Zileuton (Zyflo) – leukotriene synthesis
inhibitor
• All three agents (montelukast, zafirlukast, and
zileuton) are indicated for the prophylaxis and
chronic treatment of asthma.
• They should not be used to treat acute asthmatic
episodes. All three agents are used orally.
• Cromolyn sodium (Intal) and nedocromil
sodium (Tilade) are used for the prophylaxis of
mild or moderate asthma.
• Both are administered by inhalation.
• They are particularly useful in children.
• They should not be used for the control of acute
bronchospasm.
• Immunomodulatory therapies in asthma
• OMALIZUMAB
• Is a humanized monoclonal antibody that blocks the
binding of IgE on IgE receptors (on the mast cells);
• Omalizumab prevents these interactions and the
resulting inflammation;
• Omalizumab is used for the treatment of patients
with severe asthma;
• Omalizumab reduces the requierements for oral and
inhaled corticosteroids and markedly reduces asthma
exacerbations.
 DRUG THERAPY OF ANGINA PECTORIS
• Angina pectoris is a clinical manifestation that
result from coronary atherosclerotic heart
disease (CAD).
• The name denotes chest pain caused by
accumulation of metabolites resulting from
myocardial ischemia.
• Ischemic heart disease is the most common
serious health problem in many countries.
• The most frequent cause of angina is
atheromatous obstruction of the large
coronary vesseles (classic angina,
secondary angina).
• Another cause of myocardial ischemia (and
pain) is coronary spasm (vasospastic or
variant angina).
• In certain patients angina may result from a
combination of coronary vasoconstriction,
platelet aggregation, plaque rupture, and an
increase in myocardial oxygen demand (unstable
or crescendo angina).
• The primary cause of angina pectoris is an
imbalance between the oxygen requirement of
the heart and the oxygen supplied to it via
coronary vesseles.
• The resulting ischemia usually leads to pain.
• Classic angina may also called angina of effort.
• Variant angina is also called Prinzmetals
angina.
• In some individuals, the ischemia is not always
accompanied by pain, resulting in
silentischemia.
• 1. Stable angina pectoris is characterized by a
deep, poorly localized chest or arm discomfort
(rarely described as pain) that is reproducibly
associated with physical exertion or emotional
stress and relieved within 5 to 15 minutes by rest
and/or sublingual nitroglycerin.

• 2. Unstable angina is definited as angina pectoris

(or equivalent type of ischemic discomfort) with
at least one of three features:
• 1)it occurs at rest (or with minimal exertion)
usually lasting more than 20 minutes (if not
interrupted by nitroglycerin);
• 2)it is severe and described as frank pain and of
new onset (ie.,within 1 month);
• 3)it occurs with a crescendo pattern (ie.,more
severe,prolonged,or frequent than previously).
• (E.Braunwald, Heart Disease, 6 th Edition, 2001.)
• There are three classes of antianginal drugs:
• I.ORGANIC NITRATES
• II.BETA BLOCKERS
• III.CALCIUM CHANNEL BLOCKERS
• I.ORGANIC NITRATES
• Organic nitrates have been used in the therapy
of angina pectoris routinely for more than 140
years.
• They use is increasingly in other cardiac
conditions, such as: decompensated congestive
heart failure (CHF) and acute myocardial
infarction (AMI).
• The prototype of these agents is nitroglycerin.
• Other common organic nitrates are isosorbide
mononitrate, isosorbide dinitrate (Maycor)
and pentaerythritol tetranitrate.
• All organic nitrates are very lipid soluble.
• Clinical uses
• Sublingual or buccal nitroglycerin is used either
to terminate an acute attack of angina or for
short-term prevention of angina.
• Nitroglycerin is also the mainstay of therapy for
relieving acute coronary vasospasm.
• For long-term therapy of angina pectoris is
recomended isosorbid dinitrate and
pentaerythritol tetratnitrate.
• For prophylactic therapy of angina pectoris is also
used nitroglycerin ointment, and transdermal
nitroglycerin.
• Mechanism of vasodilator action.
• Tolerance and dependence
• Repeated and frequent exposure to organic
nitrates is accompanied by the development of
tissue tolerance to the drugs vasodilating effects.
• When nitroglycerin formulations (e.g.,
transdermal patches, sustained-release oral
dosing, or ointments) are used, tolerance may
occur within 24 ore.
• Adverse effects
• Vascular headache, postural hypotension, and
reflex tachycardia are common side effects of
organic nitrate therapy.
• Postural hypotension and tachycardia can be
minimized by proper dosage adjustment and by
instructing the patient to sit down when taking
rapidly acting preparations.
• Since nitrite ions oxidize the iron atoms of
hemoglobin and convert it to methemoglobin,
there may be a loss in oxygen delivery to tissues.
• Cautions
• Chest pain that is not relieved by two or three
tablets within 30 minutes may be due to an acute
myocardial infarction (AMI).
• In addition, nitrate administration may result in
an increase in intracranial pressure, and
therefore, these drugs should be used cautiously
in patients with cerebral bleeding and head
trauma.
• II.BETA-BLOCKERS
• Beta-blockers are a very useful class of drugs in
angina pectoris because an acute anginal attack is
accompanied by an increase in sympathetic
nervous system activity.
• Based on their ability to reduce oxygen demand,
all beta-blockers shown to be effective in
treatment of secondary angina.
• Administration of these compounds results in a
decrease in frequency of anginal attacks, a
reduction in nitroglycerin consumption, an
increased exercise tolerance, and a decreased
magnitude of ST segment depression on the ECG
during exercise.
• Propranolol (Inderal) is the prototype of this
class of compounds.
• Other beta-blockers used in treatment of angina
pectoris are:
• Nadolol (Corgard), compound that block both 1-
and 2-adrenoceptors, and
• Atenolol (Tenormin) and
• Metoprolol (Lopressor), compounds which are
cardioselective 1-receptor antagonists.
• Propranolol is nonselective beta-blockers because
it is both 1- and 2-adrenoceptors antagonist.
• Propranolol and other -adrenoceptor blockers
antagonize the actions of catecholamines on the
heart and thereby attenuate the myocardial
response to stress or exercise.
• The resting heart rate is reduced by propranolol,
but not to the same extent as is the decrease in
exercise-induced tachycardia.
• Overall, propranolol reduces myocardial oxygen
consumption for a given degree of physical
activity.
• Arterial blood pressure (afterload) is also reduced
by propranolol.
• Although the mechanisms responsible for this
antihypertensive effect are not completely
understood, they are thought to involve:
• a reduction in cardiac output
• a decrease in plasma renin activity
• an action in central nervous system
• a resetting of the baroreceptors
• Thus, propranolol may exert a part of its
beneficial effects in secondary angina
(atherosclerotic angina) by decreasing three of
the major determinants of myocardial oxygen
demand that is, hart rate, contractility, and
systolic wall tension.
• Propranolol and other -blockers also have been
shown to produce an increase in oxygen supply
to the subendocardium of ischemic area.
• It is due to reduce in heart rate and increase
diastolic perfusion time.
• Because subendocardial blood flow and flow
distal to severe coronary artery stenosis occur
primarily during diastole, this increase in diastolic
perfusion time, due to bradycardic effect of
propranolol and other -blockers, would be
expected to increase subedocardial blood flow to
ischemic areas.
• Clinical uses
• Propranolol is particularly indicated in patients
whose angina attacks are frequent despite use of
organic nitrates.
• Propranolol may be combined with
nitroglycerin, the latter drug being used to
control acute attacks of angina.
• Propranolol and nadolol also have been used
successfully in combination with certain calcium
channel antagonists (nifedipine).
• Caution should be used in combination beta-
blockers with calcium-blockers, such as
verapamil or diltiazem, since the negative
inotropic and chronotropic effects of this
combination may lead to severe bradycardia,
atrioventricular nodal block, or decompensated
congestive heart failure (CHF).
• Adverse effects
• Abrupt interruption of propranolol in therapy of
angina pectoris has been associated with
reapearance of angina, AMI, or death due to a
sudden increase in sympathetic nervous tone to
heart.
• The mechanisms underlying this reactions are
unknown, but they may be the result of an
increase in the number of -receptors that occur
following chronic -adrenoceptor blockade.
• This fenomen is named up-regulation of
receptors.
• Nonselective beta-blockers like propranolol
should be avoided in patients with asthma or
chronic obstructive pulmonary desease (COPD)
because its ability to produce bronchospasm.
• III.CALCIUM CHANNEL BLOCKERS
• The calcium entry blockers or calcium channel
blockers are a group of orally active drugs that
have been approved for use in the treatment of
vasospastic and effort-induced angina.
• These compounds block L-type voltage-
dependent calcium channels in vascular muscle
and in the heart, block platelet aggregation, and
are particularly effective in the prophylaxis of
coronary vasospasm or variant angina.
• In addition, these compounds are used in the
chronic treatment of secondary angina.
• The main compounds of this group are verapamil
(Isoptin), nifedipine (Adalat), and diltiazem
(Cardizem).
• They posses the common property of selectively
antagonizing Ca2+ movements that underlie the
process of excitation-contraction coupling in the
cardiovascular system.
• The primary use of these agents is in the
treatment of angina, selected cardiac
arrhythmias, and hypertension.
• A number of second-generation analogues are
known, particularly in the nifedipine (1,4-
dihydropyridine) series, including nimodipine
(Nimotop), nicardipine (Cardene), felodipine
(Plendil), nisoldipine (Sular), and amlodipine
(Norvasc).
• These agents differ from nifedipine principally in
their potency, pharmacokinetic characteristics,
and selectivity of action.
• Pharmacological effects
• Drug-induced inhibition of calcium influx via
voltage channels results in widespread dilatation
and a decrease in contractile responses to
stimulatory agents.
• In general, arteries and arterioles are more
sensitive to the relaxant actions of these drugs
than are the veins, and some arterial beds (eg.,
coronary and cerebral vessels) show greater
sensitivity than others.
• Peripheral vasodilation and the consequent fall in
blood pressure are commonly accompanied by
reflex tachycardia when nifedipine and its
analogues are use.
• Characteristic cardiac effects include a variable
slowing of the heart rate, strong depression of
conduction at the A-V node, and inhibition of
contractility, especially in the presence of
preexisting heart failure.
• The latter effects are observed when verapamil
and diltiazem are used.
• Efficacy in angina is largely derived from their
hemodynamic effects, which influence the supply
and demand components of the ischemic balance:
• 1) by icreasing blood flow directly or by increasing
collateral blood flow;
• 2) by decreasing afterload and reducing oxygen
demand.
• Adverse effects
• Excessive inhibition of calcium influx can cause
serious cardiac depression, including cardiac
arrest, bradycardia, atrioventricular block, and
heart failure.
• These affects have been rare in clinical use.
• Retrospective case control studies reported that
immediate-acting nifedipine increased risk for
myocardial infarction in patients with
hypertension.
• Slow-release and long-acting vasoselective
calcium channel blockers are usually well
tolerated.
• Bepridil consistently prolongs the cardiac action
potential and may cause a dangerous torsades de
pointes arrhythmia in susceptible patients.
• It is cantraindicated in patients with a history of
serious arrhythmias or prolonged QT syndrome.
• Minor toxicity includes flushing, dizzness, nausea,
constipation, and peripheral edema.
• Clinical pharmacology of angina pectoris
• Before starting treatment of angina is very
important to reduce the risk factors for coronary
atherosclerosis such as smoking, hypertension
and hyperlipidemia.
• Treatment of angina and other manifestations of
myocardial ischemia is based on reduction of
myocardial oxygen demand and increase of
coronary blood flow to the potentially ischemic
myocardium.
• Pharmacologic therapy to prevent myocardial
infarction and death is with antiplatelet agents
(aspirin, clopidogrel) and lipid-lowering agents.
• In unstable angina and non-ST-elevation
myocardial infarction, aggressive therapy with
coronary stenting, antilipid drugs, heparin and
antiplatelet is recommended.
• 1.Angina of effort (stable /secondary angina)
• For maintenance therapy of chronic stable angina,
long-acting nitrates, calcium channel-blocking
agents or beta-blockers may be chosen;
• The best choice of drug will depend on the
individual patients response.
• In hypertensive patients, monotherapy with either
slow-release or long-acting cahannel Ca blockers
or beta-blockers may be adequate.
• In normotensive patients, long-acting nitrates
may be suitable.
• Some patients may require therapy with all three
drug groups.
• 2.Vasospastic angina (variant or primary
angina)
• Nitrates and the calcium channel blockers are
effective drugs for relieving and preventing
ischemic episodes in patients with variant angina.
• In approximately 70% of patients treated with
nitrates + calcium cahannel blockers, angina
attacks are completely abolished.
• Prevention of coronary artery spasm is the
principal goal of therapy.
• All presently available calcium channel blockers
appear to be equally effective.
• 3.Unstable angina & acute coronary
sindromes
• In patients with unstable angina with recurrent
ischemic episodes at rest, recurrent thrombotic
occlusions of the offending coronary artery occur
as the result of fissuring of atherosclerotic plaque
and platelet aggregation.
• Anticoagulant and antiplatelet drugs play a major
role in therapy.
• Aspirin has been shows to reduce the incidence of
cardiac events.
• I.V. heparin or s.c. low-molecular-weight heparin
(LMGH) is indicated in most patients.
• Antiplatelet agents like clopidogrel, ticlopidine,
and GP IIb/IIIa antagonists have been found to be
effective in decreasing risk in unstable angina.
• In addition, therapy with nitroglycerin and beta-
blockers should be considered;
• Calcium channel blockers should be added in
refractory cases.
 MANAGEMENT OF ACUTE MYOCARDIAL
INFARCTION (AMI)
• Annual in the USA about 1 million suffer an AMI.
• AMI a fatal event in  33 % of patients.
• 50 % of deaths occur within 1 hr of onset, mainly
due to ventricular fibrillation (VT).
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
• It is very important early use of:
• 1.Aspirin
• 2.Beta-blockers
• 3.Thrombolytic therapy
• 4.Angiotensin-converting enzyme inhibitor
• 5.Statins
• The four D
• 1.Door (early recognition of AMI - at the door)
• 2.Data (perform ECG)
• 3.Decision (rapid decision of thrombolysis)
• 4.Drug (choise of thrombolytic drug)
Thrombolytic therapy and survival
Time from onset Lives saved/1000 treated
Within 1 hr 65
2-3 hr 27
4-6 hr 25
7-12 hr 8
• Emergency of treatment of AMI
• Initiation of a IV line
• This strategy it also applies in emergency room
• 1.Morphine – the drug of choise for pain relieve
• Slowly IV
• 4-8 mg, initial dose
• Repeated 2-4 mg every 5-15 min until pain is
relieved;
• Beneficial effects of morphine: anxiolytic effect,
relieves pain and venodilatation (reduces preload)
• Caution: respiratory depression, nausea and
vomiting and bradycardia (inferior AMI).
• Nausea and vomiting can be suppressed by IV
metoclopramid 5-15 mg, before the second
injection of morphine.
• Other opioid analgetics are diamophine (2-5 mg iv
every 4 hr; it is preferred by physicians in UK),
and meperidine (25-50 mg slow IV).
• 2.Beta-blockers
• Metoprolol (IV 5 mg at a rate of 1 mg/min and 5
min later second 5-mg bolus);
• 3.Nitrates 5-200 mcg/kg IV with pump infusion
• 4.Oxygen 2-4 l/min
• 5.Continuous monitoring of cardiac rhythm and
HR. BP is measured at least every 15 min.
• 6.Diazepam 5-10 mg IV (for sedation)
• 7. IV Heparin is advisable in patients with:
• HF (herat failure)
• Cardiogenic shock
• LV aneurysm
• Systemic embolization
• Deep vein thrombophlebitis or pulmonary
embolism
• Administration of t-PA (tissue plasmin activator)
• 8.Atropine if bradycardia is present
• 10.Thrombolytic therapy
• 1.STREPTOKINASE (STREPTASE)
• Vials: 1.5 million IU; 750 000 IU; 250 000 IU; 100
000 IU
• Dosage: 1.5 million IU in 100 mL 0.9 % saline IV
over 30-60 min; 3 million IU is highly efficacious.
• 2.ALTEPLASE (ACTILYSE ACTIVASE)
• Tissue plasminogen activator (t-PA)
• Vial: 10, 20, 50 mg
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
• Dosage: 15-mg bolus; 0.75 mg/kg over 30 min (not
50mg), 0.50mg/k over 60 min (not 35 mg), total
dose  100 mg.
• Contraindications of thrombolysis
• 1.Existing or very recent hemorrhage.
• 2.History of cerebrovascular accident with any
residual disability, intracranial aneurysm, brain
tumor, or arteriovenous malformation.
• 3.Mjor surgery or serious trauma within the last 2
months.
• 4.Severe and poorly contolled hypertension (
220/110 mm Hg).
• 5.Sever liver or kidney disease.
• 6.Suspected aortic dissection.
• 7.Pregnancy.
• 8.Infective endocarditis.
• 9.Acute pancreatitis.
• 10.Severe anemia.
• 11.Recent prolonged or traumatic CPR
(cardiopulmonary resuscitation).
Braunwald Eugene: Heart Disease – A Textbook of Cardiovascular Medicine
 CLINICAL PHARMACOLOGY OF CHRONIC HEART FAILURE

• Chronic heart failure (CHF)

• It may be defined as the clinical condition in
which ejection fraction (EF) is  40%.
• The normal range of EF = 55 – 65 %.
• EF is the amount of blood expels from left
ventricle (LV)/heart-beat.
• A significant loss of cardiac pump function is
associated with symptoms, such as:
• Fatigue
• Dyspnea (shortness of breath)
• Chest pain
• Syncope (loss of conciousness)
• Death
• The most common cause of heart failure is
coronary artery heart disease (CAD).
• Heart failure occurs when the cardiac output is
inadequate to provide O2 needed by the body.
• CHF is highly lethal condition, mortality rate is
about 50 %.
• In systolic failure both, contractility and EF are
reduced.
• In diastolic failure EF may be normal.
• The primary defect in heart failure is considered
to be an altered excitation-contraction coupling
process.
• Many other systems and organs are involved:
sympathetic nervous system, kidney,
angiotensinII, aldosterone, and apoptosis of
cardiac cells.
• Clinical trials (and research) has shown a better
beneficial effect of non-cardiac therapy than
use of classical cardiac glycosides or digitalis.
• Inotropic drugs such as digoxin are very useful
in acute failure.
• Angiotensin-converting enzyme (ACE) inhibitors,
beta-blockers, aldosterone receptor antagonist,
and combined hydralazine-nitrate therapy are
proven to prolong life in patients with CHF.
• The challenge of the clinician – keep the CHF
patients out of hospital while reducing morbidity
and mortality in the high-risk population.
• Myocardial excitation-contraction coupling
• The physiological processes that begin with
cardiac sarcolemal membrane depolarization and
culminate in contraction are collectively defined
as myocardial excitation-contraction
coupling.
• Depolarization of the cardiac myocyte sarcolemal
membrane during the action potential results in
the intracellular entry of extracellular calcium.
•
• The major regulators of the transsarcolemal entry
of Ca2+ include L-type calcium channels and
autonomic receptors.
• These membrane-bound proteins all contribute to
the influx a minute quantity of calcium from
outside the cell into the myocite.
• The entry of this small quantity of calcium causes
the release of the large reservoir of calcium stored
in the sarcoplasmatic reticulum (SR) through the
SR calcium release channel (ryanodine receptor).
This large reservoir of calcium interacts with
tropomyosin to allow the actin and myosin
filaments to overlap, resulting in systolic
myocardial contraction.
Diastolic relaxation results from resequestration of
this large reservoir of calcium back into the the SR
through SR calcium adenosine triphosphatase
(ATPase).
• Calcium exits the cell through the Na+ - Ca2+
exchanger and sarcolemal Ca 2+ ATPase.
• Another mechanism that regulate calcium influx
is autonomic receptors.
• Beta-adrenergic stimulation lead to the
stimulationof AC (adenylyl ciclase) to convert ATP
to cAMP.
• Increasing cAMP results in phosphorylation of L-
type calcium channel and open state of the
channel.
• Alfa-adrenoceptor stimulation results in
stimulation of PLC (phospholipase-C)-mediated
breakdown of phosphatidylcholine to the IP3
(inositol triphsophate) and DG (diacyl glycerol).
• These second messengers further enhance
mobilization of both transsarcolemmal calcium
influx and SR calcium efflux.
• Binding of AG II to its myocyte receptor increase
Ca2+ influx through L-type calcium channels.
• Etiology of HF
• 1.Myocardial damage:
• Ischemic heart disease and its complications
• Myocarditis
• Cardiomyopathy
• 2.Ventricular overload
• a).Pressure overload
• Systemic hypertension
• Coarctation of the aorta
• Aortic stenosis
• Pulmonary stenosis
• b).Volume overload
• Mitral regurgitation
• Aortic regurgitation
• Ventricular septal defect
• Atrial-septal defect
• Patent ductus arteriosus
• 3.Restriction/obstruction to ventricular
filling
• Mitral stenosis
• Cardiac tamponade
• Constrictive pericarditis
• Restrictive cardiomyopathies
• Atrial mixoma
• 4.Cor pulmonale
• 5.Others:
• Arteriovenous fistula
• Thyrotoxicosis
• Myxedema
Pharmacological agents used in CHF
1.Cardiac glycosides
2.Diuretics
3.Vasodilators
4.ACE inhibitors
5.Beta-blockers
6.Phosphodiesterase inhibitors
• 1.Cardiac glycosides
• This agents are found in a family of plants
(Digitalis purpurea, Digitalis lanata).
• Cardiac glycosides (digoxin and digitoxin) are
used in medical practice more than 200 years ago.
• These agents have a very narow therapeutic
window or a small therapeutic index.
• Digoxin (Lanoxin) and digitoxin (Crystodigin) has
been widely accepted as a means a minimizing
toxicity for digitalization process.
• Digitalis has become the mainstay of therapy for
CHF.
• Clinical use
• Randomized clinical trials have been conducted to
explore the safety and efficacy of digitalis in the
management of CHF.
• The first major trial showed an improvement in
quality of life but no mortality benefit.
• A second major clinical trial revelead that digitalis
dminished end points of death and
hospitalizations but did not improve overal
survival.
• Thus, no studies have demonstrated that digitalis
therapy improves survival in CHF patients.
• However, digitalis does decrease morbidity by
diminishing the number of admissions to the
hospital for symptoms such as dyspnea and
fatigue.
• The consensus now is to prescribe a dose that
achieve a digitalis blood level of 0.8 to 1.2 ng/ml.
• Toxicity
• Digital toxicity includes nausea, vomiting,
anorexia, fatigue, and a characteristic visual
disturbance (green-yelow halos around bright
objects).
• Cardiac toxicities have included tachyarrhythmias
and bradyarrhythmias,including SV and V
tachycardia and AV block.
• The most classic (but not the most frequent)
manifestations of digitalis toxicity include atrial
tachycardia with A-V block.
• Treatment of digitalis toxicity
• Simply stopping the drug – in mild cases
• Anti-digitalis antibodies (Digoxin-specific
antibody, Digibind) – in life-threatening situation.
• The availability of RIA (radioimmunoassay) for
digitalis levels and antidigitalis antibodies, useful
in reversing digitaliss actions, have minimized
• the frequency of fatal toxicity.
• 2.Diuretics
• Furosemide (Lasix) is a loop
diuretics.Furosemide blocks the transporter (Na+-
K+ -2Cl symporter) in the ascending limb of the
loop of Henle.
• The effect is delivery of more Na+ to the distal
tubule and enhanced urinary loss of Na+ and
water.
• Furosemide was accepted as the standard of
therapy in clinical trials of patients with CHF.
• Spironolactone (Aldactone) is only diuretic that
has been shown to improve survival in CHF (in a
double-blind multicenter prospective trial).
• The addition of spironolactone to digitalis and an
ACE inhibitor significantly improved survival
among patients with severe CHF.
• Spironolactone inhibit binding of aldosterone to
its receptors on the cells of distal tubule and
collecting duct of the kidney.
• Aldosterone enhances salt and water retention at
the expense of enhanced renal K+ and H+
excretion.
• Spironolactone enhances diuresis by blocking
sodium and water retention while retain
potassium.
• 3.Vasodilators
• A major advance in the pharmacological
management of CHF has been the demonstration
that afterload reduction improved survival.
• Reduction of afterload was beneficial for clinical
condition such as mitral regurgitation.
• A decrease in SVR (systemic vascular resistance)
lead to lower arterial BP.
• The consequency of this reduction in arterial BP is
an increase amount of blood that floowed from
the LV to the aorta and decreased in mitral
regurgitation (in the left atrium).
• The decrease in back up of blood into the lungs
provided considerable symptomatic relief from
dyspnea,fatigue,and chest pain.
• A Cooperative Study in which vasodilators were
added to digitalis and furosemide was the first to
demonstrate a significant improvement in survival
in CHF.
• A combination of hydralazine and nitrates was
asociated with a reduced number of deaths in
patients with CHF.
• 4.ACE inhibitors
• Captopril was the original prototype product of
these agents.
• Prospective multicenter double-blind placebo-
controlled clinical trials have demonstrated an
early and persistent survival benefit with ACE
inhibitors in CHF patients.
• ACE inhibitors were found superior to hydralazine
and nitrates.
• ACE inhibitors are now clearly the agents of the
first choice in the pharmacologcal management
of CHF.
• ACE inhibitors not only block the conversion AG I
to AG II.
• They also block the breakdown of
bradykinin.Kinins are vasodilators.
• ACE inhibitors results in the elaboration more
kinins (vasodilators) and less AG II.
• 5.Beta-blockers
• For many years the prevailing view was that beta-
blockers are contraindicated in CHF.
• Several studies have led to the incorporation of
beta-blocker therapy, using carvedilol or
metoprolol, into the standard of care for CHF.
• Patients already taking digitalis, furosemide, and
ACE inhibitors were prescribed a beta-blocker in
these studies.
• Surprisingly, the long-term use of beta-blockers in
CHF improved ventricular function and prolonged
survival.
• Circulating plasma NE (norepinephrine) levels
correlate inversely with survival in CHF.
• That is, higher levels of NE are associated with a
decrease in survival.
• NE is actually directly toxic to cardiac myocytes, at
least in culture.
• The addition of either an alfa- or beta-blocker
confers partial protection from NE damage.
• These data from animal studies may be relevant to
human HF, since they suggest that both alfa- and
beta-blockade may be beneficial in the CHF.
• This rationale favors the use of the combined
nonselective beta- and alfa-blocker carvedilol over
beta 1-cardioselective metoprolol.
• 6.Phosphodiesterase inhibitors
• Milrinone (Corotrope) and amrinone (Inocor)
are cAMP-elevanting agents.
• Administration of either milrinone or amrinone
increases cAMP levels by preventing its
degradation by phosphodiesterases.
• These agents are helpful for the acute short-term
management of decompensated patients with
CHF.
• The long-term use of these agents has been
associated with an increase in mortality in CHF.
• Management of pulmonary edema
• Its cause is
• 1. Cardiogenic: usually due to LVF (left
ventricular failure), often due to complications of
ischemic heart disease, tachyarrhythmias,
hypertension, valvular heart disease, or congestive
dilated cardiomyopathy.
• Mitral stenosis, left atrial myxoma.
• 2.Noncardiac: ARDS (adult respiratory distress
syndrome) caused by pneumonia, toxins, alergens,
gastric aspiration, hemorrhagic pancreatitis.
• Other causes includes drugs, narcotic overdose,
uremia.
• Treatment of CPE (cardiogenic pulmonary
edema)
• 1). Oxigen to mantain adequate PO2;
• 2). Morphine 3-5 mg, repeated at 15-30 min; total
D = 10-15 mg. The beneficial effects of morphine
result from:
• Venous pooling and therefore preload reduction.
• The allaying of anxiety and reduction of
tachypnea.
• An increase in VF treshold.
• 3. Furosemide 40-80 mg iv slowly repeated in 30
min;
• 4. Nitroglycerin is givel sublingual 0.4-0.8 mg;
• NITROGLICERINA
• Fiole de 5 mg/1 ml sau, în cazul nostru, avem fiole de
10 mg/10 ml, adică 1 mg/1 ml.
• Se introduc 3 fiole (30 mg), adică 30 ml Nitroglicerină
într-o seringă de 50 ml.
• Plus cei 20 ml până la 50 ml în total.
• Decu, avem 30 mg nitroglicerină/50 ml sau 30 000
mcg/50 ml sau 600 mcg/ml.
• La o viteză de perfuzie de 1 ml/h administrăm 600
mcg/h sau 10 mcg/min (se împarte 600 la 60).
• Dozele sunt în limite largi, 5-200 mcg/min, în funcție
de răspunsul terapeutic și valorile tensionale.
• Reținem ca regulă generală: 1ml/h = 10 mcg/min.
• 20 mcg/min = 2 ml/h
• 15 mcg/min = 1,5 ml/h
• 5 mcg/min = 0,5 ml/h
• In severe pulmonary edema i.v. nitroglycerin is
indicated
• Dose: 5-200 mcg/min, infusion pump!
• Added therapy
• Ventricular tachycardia reversed by bolus of
lidocaine.
• Arrhythmias may quickly respond to electrical
conversion.
• If severe hypertension is present – nitroprusside
or ACE inhibitors is useful.
• If hypotension is present – dopamine 2-10
mcg/kg/min and nitrates are indicated.
• If atrial fibrillation or SV tachycardia is present –
digoxin is indicated.
• Endotracheal intubation and mechanical
ventilation are recommended if respiratory failure
is present (PO2  50 mmHg or PCO2  50 mm
Hg).
 Clasificarea funcțională a insuficienței cardiace (NYHA)

(1964) Clasa funcțională Apariția simptomelor

1). Fără simptome la activitățile obișnuite
2). La activitățile obișnuite
3). La activități mai mici decât cele obișnuite
4). În repaus
(1973) Statusul cardiac Prognostic
1). Necompromis Bun
2). Ușor compromis Bun cu tratament*
3). Moderat compromis Favorabil cu tratament*
4). Sever compromis Rezervat cu tot tratamentul
* Tratament complex, inclusiv chirurgical
• ACEI = angiotensin-converting enzyme inhibitor
• AF = atrial fibrillation
• ARB = AT1 angiotensin receptor blocker (antagonist)
• ARNI = angiotensin receptor/neprilysin inhibitor (Valsartan/Sacubitril)
• Valsartan = AT1 receptor blocker
• Sacubitril = neprilysin inhibitor (nepilysin is enzyme responsible for degradation of BNP and ANP)
• CAD = coronary artery desease
• DM = diabetes mellitus
• ICD = implantable cardioverter-defibrillator
• ISDN = isosorbide-2,5’-dinitrate
• CRT = cardiac resynchronization therapy
• HF = heart failure
• HRQL = health-related quality of life
• HTH = hypertension
• LV = left ventricular
• MI = myocardial infarction
 CLINICAL PHARMACOLOGY OF HYPERTENSION

 Hypertension is a serious concerns of

clinical practice.
 It is reffered as sustained increased arterial
BP more than 140/90 mm Hg.
 In USA is estimated – 60 million people are
hypertensive.
 In 2000 hypertension was found in 28% in
American adults.
• Sustained arterial hypertension damages blood
vessels in kidney, heart, and brain and leads to
an increased incidence of:
- Renal failure
- Coronary disease
- Cardiac failure
- Stroke
• Hypertension is an important contributing factor
to cardiovascular disease – cause of morbidity
and death in the US.
 The individuals with high BP may be
asymptomatic for many years.
 Hypertension stage I (mild)
 Diastolic BP is 90 to 99 mmHg and/or systolic BP
is 140 to 159 mmHg.
 Hypertension stage II (moderate)
 Diastolic BP=100-109 mmHG and/or systolic BP =
160-179 mmHg.
 Hypertension stage III (severe): Diastolic BP 
110 mmHg and/or systolic BP  180 mmHg.
 Hypertension can be divided in two types:

I.Primary hypertension or essential

hypertension – unknown etiology.
 More than 90 % of hypertensive patients.

II.Secondary hypertension – renovascular

disease or pheochromocytoma may be cause of
this type.
 The risk factors are:
 1.Smoking
 2.Hyperlipidemia
 3.Diabetes
 4.Family history of cardiovascular disease
 There are three general approaches to the
pharmacological treatment of primary
hypertension:
 1.The first – the use of diuretics to reduce blood
volume.
 The second – use of drugs that interfere with the
renin-angiotensin system such ACE inhibitors
 The third – use of drugs that decreased in
peripheral vascular resistance, cardiac output,
or both.
 I.DIURETICS
 Thiazide diuretics are the drug of choice for
treatment of primary hypertension (mild or
moderate) and normal renal and cardiac function.
 Chlorothiazide, hydrochlorothiazide
 They can be used alone or in combination with
other antihypertensive agents.
 In severe hypertension and renal insufficiency
(glomerular filtration rate is less than 30 ml/min)
the loop diuretics furosemide and bumetanide
are recommended.
They have greater natriuretic potency than
thiazides.
 In hypertension secondary renal disease, diuretics
should not be used because they elevate plasma
renin.
 The K+-sparing action of spironolactone,
triamteren, and amiloride can be used in
conjunction with other types of diuretics to help
alleviate the K+ loss caused by them.
II.DRUGS THAT IMPAIR SYMPATHETIC
NERVOUS SYSTEM FUNCTIONING
1.Alfa-blocking drugs
 The alfa 1-receptor-selective antagonists such as
prazosin (and its congeners) are useful for
management of primary hypertension.
 They can be used alone in mild hypertension.
 When hypertension is moderate or severe,
prazosin must be used in combination with a
thiazide and a beta-blocker.
 Prazosin have favorable effects on plasma lipids.
 Prazosin can be used in hypertensive patients
with diabetes mellitus.
 2.Beta-blocking drugs
 Beta-blockers are used in cardiac
arrhythmias,angina pectoris and also in the
treatment of hypertension.
 Beta-blockers have proved to be quite effective
antihypertensive agents.
 They are useful drugs in primary hypertension.
 Beta-blockers are quite popular antihypertensive
drugs.
 They are well tolerated, and serious side effects
are seldom.
 Beta-blockers (when used alone, several weeks)
produce a significant reduction in BP in 30% of
patients with mild to moderate hypertension.
 Thus, beta-blockers can be used as a first step in
treatment of high blood pressure.
 However, they are often used in conjunction with
a diuretic.
 The combination of a beta-blocker, thiazide
diuretic, and vasodilator – provides significant
control of moderate to severe hypertension in
approx. 80% of patients.
Propranolol is prototype of this class of drugs.
Metoprolol is a cardioselective beta1-antagonist.
D= 100-400 mg/d for antihypertensive efect.
Nadolol and carteolol are nonselective beta-
blockers.
 Atenolol, betaxolol and bisoprolol are beta 1-
selective blockers with antihypertensive effect.
 Labetalol is a particularly beta-blockers because
its additional alfa-blocking effect.
 Labetalol is useful in management of
hypertensive emergencies (repetead iv, 20-80 mg).
 Carvedilol is used for ordinary hypertension.
 Dose is 6.25 mg twice daily.

 Esmolol is a beta1-selective blockers with very
short duration of action.The half-life is 9 min.
 Esmolol is used for management of intraoperative
hypertension and hypertensive emergencies.
 It must given in continuous iv infusion ( starting
doses 50-150 mcg/kg/min, up to 300
mcg/kg/min).
3.Centrally acting drugs
Clonidine is used primarilly for the treatment of
moderate hypertension.
Clonidine activated central alfa2-receptors.
Moxonidine is similar.
The antihypertensive effect of clonidine is due to a
decrease in sympathetic activity transmitted from
the brain to the peripheral vasculature.
Adverse effects: drowsiness and drysness of
mouth.
 Other untoward effects include constipation,
nausea or gastric upset, and impotence.
A dangerous effect is rebuond hypertension,
which folows abrupt withdrawal of clonidine
therapy.
Alfa-methyldopa (Aldomet) is another drug with
CNS action.
It is suitable for monotherapy of primary
hypertension.
Methyldopa lewerss BP by reducing peripheral
vascular resistance.
Because methyldopa decrease BP without
compromising renal blood flow or glomerular
filtaration rate, it is useful in hypertension
complicated by renal disease.
4.Ganglionic blocking agents
Trimetaphan camsilat (Arfonat) is used
occasionally for hypertensive emergencies and
in surgical procedures (such as brain surgery) in
which hypotension is desirable to reduce
possibility of hemorrhage.
Adverse effects include marked postural
hypotension, blurred vision, urinary retention,
paralytic ileus and impotence.
It is rare used.

5.Adrenergic neuron-blocking drugs

 These drugs have an antihypertensive effect
because they prevent the release of transmitters
from peripheral postganglionic sympathetic
nerves.
 Guanethidine (Ismelin) is a powerful
antihypertensive agent (prototype of this class).
 It is most frequently used in the treatment of
severe hypertension that is resistant to other
drugs.
 The half-life is 5 days.
 Slow elimination contributes to the cumulative
and prolonged effects of the drug.
 Adverse effects include postural hypotension,
sexual impotence (difficulty ejaculating in male
patients), diarrhea and increased gastric secretion.

6.Drugs that interfere with NE storage

Reserpine (Serpasil) is the prototype drug.
It interfere with norepinephrine storage.
Reserpine is used in mild to moderate
hypertension.
 Adverse effects include sedation and depression
(CNS).
 Nightmares and thoughts of suicide also occur.
VASODILATORS
These drugs are effective in lowering BP,
regardless of etiology of hypertension.
1.Hydralazine
Hydralazine causes the release of nitric oxide
(NO);
 NO acts on vascular smooth muscle to cause
relaxation.
 Often is used in combination with a diuretic and
a beta-blocker (triple combination).
2.Minoxidil
The major indications are:
1.Severe hypertension that may be life threatening
2.Hypertension that is resistant to usual therapy
Minoxidil is more potent and longer acting than
Hydralazine.
3.Diazoxide (Hyperstat)
Chemically similar to the thiazide diuretics.
It is devoid of diuretic activity and causes Na+ and
water retention.
It is a very powerful vasodilator and is available
only for iv use in hypertensive emergencies such as
malignant hypertension, hypertensive
encephalopathy, and eclampsia.
 4.Sodium nitroprusside
 Is a potent vasodilator drug.
It is used only iv for hypertensive emergencies.
Sodium nitroprusside relaxes venules as well as
arterioles.
It is used in the management of hypertensive
crisis.
Adverse effect include nausea, vomiting, and
hadache.Thiocyanate intoxication also may occur
(delirium and psychosis).
ANGIOTENSIN-CONVERTING ENZYME (ACE)
INHIBITORS
1.Captopril
2.Enalapril
3.Lisionopril
4.Benazepril
5.Perindopril
6.Ramipril
7.Trandolapril
Angiotensin II inhibitors lower BP by decreasing
peripheral vascular resistance.
ACE inhibitors are widely used in treatment of
hypertension.
Adverse effect include hypotension,cough and
angioedema,and acute renal failure.
ACE inhibitors use is associated with an increased
teratogen risk.
Angiotensin receptor-blocking agents
1.Losartan
2.Valsartan
3.Candesartan
4.Irbesartan
5.Telmisartan
They also have antihypertensive effects and they
have no effect on bradykinin metabolism.
Cough and angioedema are less common (than
with ACE inhibitors).
A particularly antihypertensive drug is
Fenoldopam.
It is used for hypertensive emergencies by iv
infusion.
Fenoldopam is an agonist of D1 receptors,
resulting in dilatation of peripheral arteries and
natriuresis.
 • DRUG THERAPY OF CARDIAC
ARRHYTHMIAS
• Cardiac arrhythmias are a frequent problem in
clinical practice, occuring in up to
• 25 % of patients treated with digitalis
• 50 % of anesthetized patients
• and over 80 % of patients with acute myocardial
infarction (AMI).
• Cardiac arrhythmias result from alterations in the
orderly sequence of depolarization folowed
repolarization in the heart.
• Cardiac arrhythmias may result in alterations in
the heart rate or rhythm and arise from
alteration in impulse generation or conduction.
• The clinical implications of disordered cardiac
activation range from asymptomatic palpitations
to lethal arrhythmia.
• Cardiac arrhythmias may be classified according
to:
• I.The site of origin of abnormality
• 1.Atrial arrhythmias
• 2.Junctional/nodal arrhythmias
• 3.Ventricular arrhythmias
• II.Heart rate (increased or decreased)
• 1.Tachycardia (tachyarrhythmias)
• 2.Bradycardia (bradyarrhythmias)
• Electrophysiology of heart
• Physiological sinus rhythm is characterized by
impulses arising in the sinoatrial (SA) node and
conducted in sequence through the atria, the
atrioventricular (AV) node, bundle of His,
Purkinje fibres and ventricles.
The electrical impulse that triggers a normal cardiac
contraction originates at regular intervals in the
SA node, usually at a frequence of 60-100
beats/minute.
This impulse spreads rapidly through the atria and
enters the AV node, which is normally the only
pathway between the atria and ventricles.
• Conduction through the AV node is slow,requiring
about 0.15 s.
• The impulse then propagates over the His-
Purkinje system and invades all parts of the
ventricles.
• Ventricular activation is complete in less than 0.1
s;
• Therefore, contraction of all of ventricular muscle
is synchronous and hemodynamically effective.
• Arrhythmias consist of depolarization that
deviate from the above description in one or more
aspects;
• There is an abnormality in the site of origin of
the impulse, its rate or regularity, or its
conduction.
• The cells of heart posses two main types of
responses or action potentials:
• 1.Fast or rapid responses – sodium-dependent
channels, such as in Purkinje fibers and working
muscle (ventricular);
• 2.Slow responses – calcium-dependent channels,
such as in SA node and AV node;

• In addition, other types of channels are potassium

(K) and cloride (Cl) channels.
• The action potential (AP) of a cardiac muscle cell
is shown in above slides and it is diveded into five
phases:
• Rapid or fast depolarization (phase 0)
• Early or partial repolarization (phase 1)
• Plateau (phase 2)
• Rapid repolarization (phase 3)
• Slow diastolic depolarization (the resting phase
or pacemaker potential) (phase 4)
• Ionic mechanisms underlying these phases can be
summarized as follows:
• Phase o (rapid depolarization) occurs when the
membrane potential reaches a critical firing
thershold (about -60 mV);
• It is induced by opening of voltage-dependent
sodium channels.
• The sodium channels open rapidly in response to
membrane depolarization and close within 1 to 2
miliseconds (inactivation).
• Phase 1 (partial repolarization) occurs as the
Na current is inactivated.
• There may also be a transient voltage-sensitive
outward current.
• Phase 2 (the plateau) is characterized by a net
balance between inward (depolarizing) and
outward (repolarizing) ion currents maintaining
the myocyte in a depolarized state.
• During this phase, Ca2+ enters the cell, causing
Ca2+ release from intracellular stores and linking
electrical depolarization with mechanical
contraction.
• Phase 3 (repolarization) occurs as the Ca2+
current inactivates and a delayed outwardly
rectifying K+ current activates,causing outward
K+ current.
• These effects results in rapid repolarization with
return to the hyperpolarized resting membrane
potential.
• Phase 4 (slow diastolic depolarization) is a
gradual depolarization during diastole.
• Pacemaker activity is normally found only in
nodal and conducting tissue.
• In normal atrial and ventricular myocytes, phase 4
is electrically stable, with the resting membrane
potential held at approximatively – 90 mV.
• The pacemaker potential is caused by a
combination of increasing inward currents and
declining outward currents during diastole.
• It is usually most rapid in cells of the SA node,
which therefore acts as pacemaker for the whole
heart.
• Cells in the SA node have a greater background
conductance to Na+ than do atrial or ventricular
myocytes.
• In addition, inactivation of voltage-dependent
calcium channels wears off during diastole,
resulting in increasing inward Ca2+ current
during late diastole.
• Activation of T-type calcium channels during late
diastole contributes to pacemaker activity in the
SA node.
• The negative membrane potential early in diastole
activates a cation channel that is permeable to
Na+ and K+, giving rise to another inward current.
• Mechanisms of arrhythmias
• Disturbances in the orderly formation and
conduction of the cardiac impulse may result in
heart rate are either too fast (tachycardia) or to
slow (bradycardia).
• In general, bradyaarrhythmias result from the
failure of impulse generation within the SA node
or failure of excitatory wavefront to conduct from
the atrium to the ventricle through the AV node.
• Bradyarrhythmias do not respond to
pharmacologic therapy and may require
permanent cardiac pacing.

• Conversely, tachyarrhythmias may be manage

using antiarrhythmic drugs.
• The mechanisms underlying tachyarrhythmias are
calssified into three groups:
• 1) abnormal automaticity
• 2) triggered activity
• 3) re-entry
• 1.Enhanced automaticity (abnormal)
• Automaticity can be defined as the ability of a cell
to alter its resting membrane potential toward
excitation threshold without the influence of an
external stimulus.
• Automaticity may described as a cells ability to
raise spontaneously (depolarize) the resting
membrane potential above the threshold value to
initiate an action potential.

• Enhanced automaticity resulting in tachycardia

may result from an increase in the slope of phase 4
depolarization or a decrease (less negative) in the
resting membrane potential.
• Activation of beta-adrenoceptors, hypokalemia
and stretching of cardiac cell all increase the slope
of phase 4 depolarization and may serve as the
trigger for enhanced automaticity.

• It is also possible for tissue that normally does not

have pacemaker activity to develop inappropriate
spontaneous diastolic depolarization and serve as
ectopic focus for impulse generation.
• 2.Triggered activity
• Triggered activity occurs when after-
depolarization induced by a preceding action
potential raise the resting membrane potential
above the thereshold value, leading to an addition
action potential.
• After-depolarizations may be categorized as
early, occurring during phase III of the action
potential before achieving full repolarization, or
delayed, occurring after full repolarization of the
membrane.
• After-depolarizations may stimulate an isolated
extrapropagated impulse or lead to sustained
repetitive activity.
• The crucial difference between triggered
activity and abnormal automaticicty is that
triggered activity depends on preceding action
potential and cannot be self-induced.
• After-depolarization or triggered activity are often
associated with excessive increases in intracellular
Ca2+.
• The potential for development of triggered activity
is accentuated in the presence of an increase in
extracellular Ca2+, that would increase the
amount of ionized calcium entering the cell
during depolarization.
• Furthermore, conditions or pharmacological
interventions favoring prolongation of the plateau
(phase 2) of the action potential and prolongation
of the QT interval of the ECG would increase
intracellular Ca2+ and the potential for
proarrhythmia.
• Early after-depolarization are proposed to be
the mechanism given rise to torsades de pointes.
• Conditions or drugs known to prolong the action
potential, especially by interventions that
decrease the outward potassium currents,
facilitate development of torsades de pointes.
• Early after-depolarizations may develop in
association with hypokalemia, hypoxia,
acidosis, and a wide range of pharmacological
agents that interfere with outward currents or
enhance inward currents.
• Antiarrhythmic agents, in particular sotalol,
quinidine, and dofetilide, may give rise to after-
depolarizations and torsades de pointes
tachyarrhythmia in persons with underlying
cardiac abnormalities or alterantions in plasma
electrolytes.
• Conditions leading to bradychardia also may
facilitate development of torsades de pointes.
• Delayed after-depolarizations may occur in the
presence of a rapid heart rate, digitalis
glycoside, hypokalemia, hypercalcemia and
catecholamine.
• Each of these influences ultimately leads to an
increase in intracellular ionized calcium that is
known to activate an inward ionic current.
• 3.Rentry
• Reenty is an abnormality of impulse conduction
wherein an excitatory wave front circulates around
the inexcitable region. For reentry to occur, there
must be a region of unidirectional block and
slow conduction.
• The delay in conduction permits the tissue ahead
of the advancing wave front to regain its
excitablity, sustaining the reentry circuit.
• It is estimated that 80 to 90 % of clinical
arrhythmias have a reentry mechanism.
Antidysrhytmic drugs (unclassified Vaughan
Williams)
1.Atropina Sinus bradycardia
2.Isoprenaline Heart block
3.Digoxin Rapid atrial fibrilation
4.Adenosine Supraventricular Tachycardia
5.Calcium chloride Ventricular tachycardia due to
hyperkalaemia
6.Magnesium sulfate Torsades de pointes
MANAGEMENT OF ARRHYTHMIAS
1.Supraventricular paroxysmal tachycardia
SVT usually arises from reentry mechanism.
The heart rate (HR) varies from 140 to 240/min.
The rhythm is regular.
Treatment
1.Vagal maneuvers such as Valsalva maneuver
(expiration against closed glottis);
2.Carotid sinus massage;
• 1. Adenosine (Adenocard) 0.05-0.25 mg/kg given
iv;
• Adenosine is effective in up to 90% of cases;
• Usually iv bolus 6 mg over 2 sec, rapidly flushed
into a peripheral vein;
• Adverse effects: transient headache, facial
flushing, and dyspnea, but bronchospasm may
last more than half-hour in asthmatics.
• Adenosine is contraindicated in asthma.
• 2.Verapamil iv is effective in more than 90 % of
episodes of SVT.
• The drug has proved useful in patients with
normal hearts and without the following
complications:
• Hypotension;
• Known WPW syndrome or suspicion of WPW in
view of very fast ventricular response  220/min;
• Acute myocardial infarction (AMI), CHF, or
cardiomegaly;
• Left ventricular dysfunction,ejection fraction (EF)
below 40 %;
• Sinus or AV node disease;
• Wide QRS tachycardia ( 0.10 sec);
• Suspected digitalis toxicity;
• Beta-blockade present.
Verapamil is contraindicated in patients with these
consitions.
Dosage: 5-10 mg is given slowly over 1-2 min.
3.Propranolol 1 mg iv given slowly and repeated
every 5 min to a maximum of 5 mg.
Metoprolol is given in a dose of 5 mg at a rate of 1-2
mg/min.
2.Atrial flutter
The atrial rate is usually 240-340/min.
Atrial flutter is easily converted to sinus rhythm by
synchronized DC (direct current) shock at low
energies of 25-50 joules.
Propranolol may be used to slow the ventricular
response, if the patient is hemodynamically
stable.
3.Atrial fibrilation (AF)
AF is the most common sustained arrhythmia
observed in clinical practice.
In the majority of patients ,drugs action to control
(decrease) ventricular responses – adequate
therapy.
In some cases it may be necessary reversion to sinus
rhythm (with drugs or DC cardioversion).
Torsades de pointes
Is a life-threatening arrhythmia associated with
prolongation of QT interval.
The rate is usually 200-250/min.
Treatment
1. Atrial or ventricular pacing as soon as possible.
2. Magnesium sulfate bolus IV, 2 g (10 ml of a 20%
solution) over 1 min.
 DRUG USED IN ACID-PEPTIC DISEASES

• Acid peptic diseases include:

• 1.Peptic ulcer (gastric and duodenal)
• 2.Gastroesophageal reflux
• 3.Mucosal injury (due to stress)
• Secretion of gastric acid, mucus and
bicarbonate (physiology)
• Acid is secreted from gastric parietal cells by a
proton pump (K+/H+-ATPase).
• The three endogenous secretagogues for acid
are histamine, acetylcholine and gastrin.
• PGE2 and PGI2 inhibit acid, stimulate mucus and
bicarbonate secretion and dilate mucosal blood
vessels.
• The genesis of peptic ulcers involves:
• 1. Infection of the gastric mucosa with Helicobacter
pylori plus
• 2. Other factors such as inbalance between the
mucosal-damaging mechanisms (acid, pepsin), and
the mucosal-protecting mechanisms (mucus,
bicarbonate, local synthesis of PGE2 and PGI2 and
NO).
• The reason why peptic ulcers develop is not fully
understood.
• Infection of the stomach mucosa with Helicobacter
pylori (a Gram-negative bacillus that causes chronic
gastritis) is now generally considered to be a major
cause, especially of duodenal ulcer.
There are three pathological condition in which is
useful to reduce acid secretion:
1.The peptic ulceration (both duodenal and gastric).
2.The reflux oesophagitis (gastric juice causes damage
to the oesophagus).
3.The Zollinger-Ellison syndrome (a gastrin-produced
tumor).
Prostaglandins protect the stomach against damage.
• 1.Stimulate mucus and bicarbonate secretion
• 2.Decreased acid secretion
• 3.Vasodilatation
• This explains the ability of NSAID (inhibitors of PG
formation) to cause gastric bleeding and erosions.
• Therapy of peptic ulcer and reflux oesophagitis
involve decreasing the secretion of acid with H2-
receptor antagonist or proton-pump inhibitors and
/or neutralising secreted acid with antacids.
• These are often coupled to eradication of H.pylori.
• I.H2-receptor antagonists
• They inhibit histamine-, gastrin-, and acetylcholine-stimulated
acid secretion;
• Pepsin secretion also falls, volume of gatric juice is reduced.
• They are inhibitors of gastric acid secretion and promote
healing of duodenal ulcers.
• Cimetidine (Tagamet), ranitidine (Zantac), famotidine
(Pepcid), and nizatidine (Axid) are H2 blockers.
• 70-85 % of duodenal ulcers are healed during 4 to 6
weeks of therapy (with any of these agents);
• In gastric ulceration incidence of healing is 60-80 %.
• Cimetidine may cause diarrhea, nausea, vomiting, or
mental confusion.
• Gynecomastia after high-dose or long therapy with
cimetidine.
• The latter efect is due to a weak antiestrogen activity
of cimetidine.
• Cimetidine is the substrat for cytochrome P450
system and co-administration of some drugs such as
benzodiazepines, theophylline, and warfarin may
increase the free fraction of this agents.
• Ranitidine, famotidine, and nizatidine are used
more frequently than cimetidine.
• Famotidine is the most potent H2-blocker.
• Ranitidine,famotidine and nizatidine do not alter the
microsomal cytochrome P450 metabolism of other
drugs, nor do they cause gynecomastia.
II.Proton pump inhibitors
The proton pump inhibitors available:
Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Pantoprazole (Protonix)
Rabeprazole (Aciphex)
Esomeprazole (Nexium)
• These are substituted benzimidazole prodrugs, which
accumulate on the luminal side of the parietal cells
secretory canaliculi.
• They become activated by acid transport and then
bind covalently to H+-K+ ATP-ase enzymes (proton
pump).
• These drugs markedly inhibit gastric acid secretion.
• Peptic ulcers and erosive esophagitis are healed
after use of proton-pump inhibitors.
• They are also used to treat patients with Zollinger-
Ellison syndrome, which is due to a gastrin-
hypersecreting neuroendocrine tumor.
• The most side effects are diarrhea and headache.
• Hypergastrinemia has been noted as a reaction to
the marked reduction in acid secretion.
• III.Antacids
• Antacids have been used in patients with dyspepsia
and acid–peptic disorders.
• Antacids are weak bases that react with gastric
hydrochloric acid to form water and salt.
• In sufficient quantity for long enough they can
produce healing of duodenal ulcers but are less
effective for gastric ulcers.
• The antacids in common use are salts of magnesium
and aluminium.
• Mg salts cause diarrhea and Al salts constipation.
• To preserve normal bowel function these salts are
often used in the mixtures.
• Some preparations (Mg trisilicate mixture and
some Al preparations) contain high
concentrations of sodium and should not be given
to pateints on a sodium restricted diet.
• Sodium bicarbonate acts rapidly and raise the
pH of gastric juice to about 7.4.
• Sodium bicarbonate react with HCl to produce
CO2 (carbon dioxide) and NaCl (sodium
chloride).
• Carbon dioxide causes gastric distension and
belching.
• Carbon dioxide also stimulates gastrin secretion
(secondary rise in acid secretion).
• Some sodium bicarbonate is absorbed (after
large doses) in the intestine and can cause
metabolic alkalosis.
• This agent should not be prescribed for long-term
treatment, or patients with renal insufficiency
and/or a sodium-restricted diet.
• Magnesium hydroxide is an insoluble powder
that forms magnesium chloride in the stomach.
• Mg2+ is poorly absorbed from the gut and does
not produce systemic alkalosis.
• Magnesium trisilicate forms with gastric juice
magnesium chloride and colloidal silica.
• This agent has a prolonged antacid effect.
• Aluminium hydroxide gel forms aluminium
chloride in the stomach.
• Aluminium hydroxide raises the pH of the gastric
juice to about 4.
• Colloidal aluminium hydroxide combines with
phosphates in the gastrointestinal tract and the
increased excretion of phosphate in the faeces
that occurs result in decreased excretion of
phosphate in the kidney.
• This is important to management of chronic renal
failure.
• To minimize the impact to bowel function
(magnesium cause osmotic diarrhea and
aluminium cause constipation) these agents are
commonly administered toghether in
formulations such as Gelusil, Maalox.
• Calcium carbonate is less soluble and react more
slowly than sodium bicarbonate with HCl.
• Calcium carbonate in excessive doses and with
high calcium containing dietary may cause
hypercalcemia, renal insufficiency and metabolic
alkalosis (milk-alkali syndrome).
• IV.Miscellaneous agents
• 1. Misoprostol (Cytotec)
• It is an anlogue of PGE2 approved for use in
prevention of NSAID induce ulceration.
• Misoprostol is absorbed rapidly after oral
administration and is hydrolized to the active
compound.
• Adverse effects include crampy abdominaal pain,
dose-related diarrhea, and uterine contractions.
• Tha last effect may be beneficial to control of
postpartum bleeding.
• 2.Sucralfate (Carafate)
• It is an aluminium hydroxide-slfated sucrose
complex.
• After exposure to gastric acid,t he compound
becomes negatively charged, creating a viscous
adherent complex.
• This complex is believed to inhibit back-diffusion of
H+.
• Other effects are a direct reduction in pepsin activity
and a slight rise in tissue PG levels.
• These effects may be beneficial in cytoprotection
and mucosal healing.
• Sucralfate is used for prophylaxis of stress-induced
gastritis in patients in intensive care unit.
• Constipation is the main side effect after its oral use.
• 3.Octreotide (Sandostatin)
• Sandostatin is a synthetic somatostatin analogue.
• It is used in i.v. infusion in patients with bleeding
varices, because it decreases splanchnic circulation
and therefore reduces portal pressures.
• Another clinical indications are:
• 1. Treatment of severe diarrhea and flushing
associated with malignant carcinoid syndrome;
2.Profuse watery diarrhea associated with VIP
tumor.
V. Treatment of Helicobacter pylori infection
1.Omeprazole + Amoxicillin + Metronidazole
2.Omeprazole + Clarythromicyn + Tetracycline +
Metronidazole