Module 1 - Cardiovascular Agents

PHARMACOLOGY 2 NOTES BY ALBANIA, NGILAY, OCTAVIO, RASGO
NOTRE DAME OF DADIANGAS UNIVERSITY (NDDU)

College of Pharmacy
COURSE TITLE PHARMACOLOGY II COURSE CODE Pharm36
rd st
Course 3 yr, 1 SEM Contact Hours 3 hours/week, 54 hours/sem
Placement
Date for this SME: Melba M. Roma, RPh, MSPh
topic
MODULE 1: CARDIOVASCULAR AGENTS
Reading Assignment: Katzung , B.G., Basic Clinical Pharmacology, 14th ed. Chap 11-15
Jacob, L.S. Pharmacology , 3rd ed., 1987
Content Demonstrate knowledge regarding drugs acting on the cardiovascular, renal and
Standards hematologic systems
Functional o Review the pathophysiology and mechanism of cardiovascular system
Knowledge o Describe pharmacokinetic properties, mechanisms of action, clinical applications,
pharmacologic and toxic effects of Cardiovascular agents
Introduction to the Cardiovascular System

(Flip) Vid watch:https://www.youtube.com/watch?v=GF0FcPao3s8
Transcript:
The cardiovascular system consists of: ● The type that carries deoxygenated blood
● The heart or also known as the from the tissues to the heart, the veins and
myocardium the smaller veins are called venules (into
● The blood vessels the heart)
● and the last type that connects arterioles
Heart and venules, the capillaries
The heart is the muscular pump of the body it beats
nonstop for the entire lifetime to supply blood which
is loaded by oxygen and nutrients to all tissues of
the body.
Blood Vessels
The blood vessels are classified to: Let's use a simplified illustration
● The type that carries oxygenated blood from The heart is composed of four chambers: two atria
the heart to tissues and they are called and two ventricles
arteries and the smaller arteries are called ● Venous blood (deoxygenated blood) enters
arterioles and (away from the heart) the right atrium through two veins, the
superior and the inferior vena cava
1
● The blood passes from the right atrium to heart can beat spontaneously at a rate of 40 beats
the right ventricle through the tricuspid per minute. Beating of the heart is myogenic in
valve nature not neurogenic that means that it does not
● Then contracts to push the blood through need an intact nerve supply to beat and the
the pulmonary artery to the lungs where evidence is that the heart of the fetus during
exchange of oxygen and carbon dioxide pregnancy beats before the heart is innervated and
occurs (deoxygenated to oxygenated) also isolated frog's hearts can beat spontaneously.
● Then oxygenated blood returns to the heart
from the lungs through four pulmonary
veins that enter the left atrium
● 2 pulmonary arteries, 4 pulmonary veins
Although the rhythmic beating of the heart is

myogenic it's still under the influence of autonomic
nervous system (involuntary) by its two branches
(dili ni gikan sa video pero like mas detailed mani the heart receives impulses from sympathetic and
hehe gi google ko lang) vagus parasympathetic nerves.
and here we should notice these exceptions. The ● Sympathetic nerve as we know from the
pulmonary artery is the only artery that carries ans chapter releases norepinephrine,
deoxygenated blood and the pulmonary veins are increasing the heart rate and
the only veins that carry oxygenated blood. ● Vagus parasympathetic nerve releases
● Then blood passes from the left atrium to acetylcholine, decreasing the heart rate.
the left ventricle through mitral valve then In general neural control of the heart speeds a
contracts to push the blood through aorta pulse up to 70 beats per minute. Sympathetic and
which then distribute blood to all body vagus nerves are under the control of higher
tissues centers in the brain.
Summary: The Conducting System of the Heart

Blood flows through the heart in the following order:
1) body –> 2) inferior/superior vena cava –> 3)
right atrium –> 4) tricuspid valve –> 5) right
ventricle –> 6) pulmonary valve –> 7)
pulmonary arteries –> 8) lungs –> 9) pulmonary
veins –> 10) left atrium –> 11) mitral or bicuspid
valve –> 12) left ventricle –> 13) aortic valve –>
14) aorta –> 15) body.
Legend:
Deoxygenated - blue
Oxygenated - red
We should also know that the wall of the left

ventricle is thicker than the right ventricle and
the wall of the atria is thinner than the The heart beats rhythmically and this rhythm
ventricles. The heart is supplied with blood depends mostly on the Sinoatrial node or known
through the coronary arteries that surround it. The as SAN. SAN is called the pacemaker of the heart
2
as it is the most rapidly beating part of the heart. to have positive chronotropic effect or known as
So, SAN controls the heart rhythm and initiates the tachycardia and if a drug decreases the heart rate
contraction of the heart. it is said to have negative chronotropic effect or
In general the part discharging at the highest rate is known as bradycardia.
the pacemaker of the heart. First, impulse starts
from sinoatrial node then travels through atria The second is the stroke volume: it is the volume
producing contraction of the atria. Then it reaches of blood in milliliters ejected by the heart in each
atrioventricular node (AVN) then to beat in a normal adult, about 70 milliliters per
atrioventricular bundle then travels through the beat. It indicates the force contraction of the
ventricles producing contraction of the ventricles. heart. Increased stroke volume means increased
force of contraction which is known as positive
inotropic effect.
The third definition is cardiac output. It is the

volume of blood in liters pumped by the heart in
one minute. It depends on two variables: the heart
Finally, we'll talk about some important definitions rate and the stroke volume. By multiplying both
that will be extensively used in the next lectures variables we can get the cardiac output which
The first one is the heart rate: it is the number of equals to about 5 liters. Cardiac output is
beats in one minute normally it is 70 beats per connected to blood pressure.
minute. If a drug increases the heart rate it is said
—END OF TRANSCRIPT
The cardiovascular system (CVS) is sometimes called the blood-vascular, or simply the

circulatory system. It consists of the heart, which is a muscular pumping device, and a closed system
of vessels called (AVC) arteries, veins, and capillaries. As the name implies, blood contained in
the circulatory system is pumped by the heart around a closed circle or circuit of vessels as it passes
again and again through the various "circulations" of the body.
Capillaries - connecting vessels between the arterioles and venules. Responsible for the gas
exchange.
The vital role of the cardiovascular system in maintaining homeostasis depends on the continuous
and controlled movement of blood through the thousands of miles of capillaries that permeate
every tissue and reach every cell in the body. It is in the microscopic capillaries that blood performs
its ultimate transport function. Nutrients and other essential materials pass from capillary blood into
fluids surrounding the cells as waste products are removed.
Heart
The heart is a muscular pump that provides the force
necessary to circulate the blood to all the tissues in the
body. Its function is vital because, to survive, the tissues
need a continuous supply of oxygen and nutrients,
and metabolic waste (metabolic waste product like
carbon dioxide and product of metabolism) products
have to be removed. Deprived of these necessities, cells
soon undergo irreversible changes that lead to death.
While blood is the transport medium, the heart is
the organ that keeps the blood moving through the
vessels. The normal adult heart pumps about 5 liters of
blood every minute (cardiac output) throughout life. If
it loses its pumping effectiveness for even a few
minutes, the individual's life is jeopardized.
3
Structure of the Heart
The human heart is a four-chambered muscular organ, shaped and sized roughly like a man's
closed fist with two-thirds of the mass to the left of midline.
The heart is enclosed in a pericardial sac (parang nakabalot) that is lined with the parietal layers of
a serous membrane (may fluid siya). The visceral layer of the serous membrane forms
the epicardium.
Serous Membrane - it functions to allow the membrane to slide past each other without friction. It
secretes the thin watery serous fluid
Layers of the Heart Wall

Three layers of tissue form the heart wall. The outer layer of the heart wall is the epicardium, the
middle layer is the myocardium, and the inner layer is the endocardium.
Epi (Outer) Myo (Middle or the muscle part) Endo (Inner)
Epicardium → myocardium → endocardium (from outer to inner)
Chambers of the Heart

The internal cavity of the heart is divided into four chambers:
● Right atrium - receive deoxygenated blood from superior/inferior vena cava or systemic veins
● Right ventricle - pump deoxygenated blood to the pulmonary arteries
● Left atrium - receive oxygenated blood from the pulmonary veins
● Left ventricle - pump oxygenated blood to the aorta
The two atria are thin-walled chambers that receive blood from the veins. The two ventricles are
thick-walled (It is thicker because it contracts more) chambers that forcefully pump blood out of the
heart. Differences in thickness of the heart chamber walls are due to variations in the amount of
myocardium present, which reflects the amount of force each chamber is required to generate.
The right atrium receives deoxygenated blood from systemic veins; the left atrium receives oxygenated
blood from the pulmonary veins.
Classification & Structure of Blood Vessels

Blood vessels are the channels or conduits through which blood is distributed to body tissues. The
vessels make up two closed systems of tubes that begin and end at the heart. One system,
the pulmonary vessels, transports blood from the right ventricle to the lungs (pulmonary artery) and
back to the left atrium (pulmonary vein). The other system, the systemic vessels, carries blood from
the left ventricle to the tissues in all parts of the body (aorta) and then returns the blood to the right
atrium (superior and inferior vena cava). Based on their structure and function, blood vessels are
classified as either arteries, capillaries, or veins.
Arteries carry blood away from the heart. Pulmonary

arteries transport blood that has a low oxygen content
(deoxygenated blood) from the right ventricle to the lungs.
Systemic arteries transport high oxygen content
(oxygenated blood) from the left ventricle to the body
tissues. Blood is pumped from the ventricles into large
elastic arteries that branch repeatedly into smaller and
smaller arteries until the branching results
in microscopic arteries called arterioles. The arterioles play
a key role in regulating blood flow into the tissue capillaries.
4
Capillaries, the smallest and most numerous of the blood vessels,

form the connection between the vessels that carry blood away
from the heart (arteries) and the vessels that return blood to the
heart (veins). The primary function of capillaries is the exchange
of materials between the blood and tissue cells.
Veins carry blood toward the heart. After blood passes

through the capillaries, it enters the smallest veins,
called venules. From the venules, it flows into
progressively larger and larger veins until it reaches
the heart. In the pulmonary circuit, the pulmonary
veins transport blood from the lungs to the left atrium
of the heart. This blood has a high oxygen content
because it has just been oxygenated in the lungs.
Systemic veins transport blood from the body tissue
to the right atrium of the heart. This blood has a
reduced oxygen content because the oxygen has been
used for metabolic activities in the tissue cells.
Ref: https://training.seer.cancer.gov/anatomy/cardiovascular/blood/classification.html
I. DRUGS USED IN THE TREATMENT OF CONGESTIVE HEART FAILURE

(Flip )Vidwatch:https://www.youtube.com/watch?v=afrRNjsWn9s
The effects of CHF
Transcript:
If you have heart failure your heart has lost the ability to pump enough blood to meet your body's needs. You
may have weak or damaged ventricular walls that are not able to push enough blood out of your heart. You
may also have stiff and thickened ventricular walls that do not allow your heart to fill with enough blood. If you
have left-sided heart failure your left ventricle does not deliver enough oxygen-rich blood to your body
making you feel tired and out of breath. Your failing left ventricle also increases the blood pressure in the blood
vessels between your lungs and left ventricle. This increased pressure forces fluid out of your blood and into
your lung tissues which makes it difficult for you to breathe. If you have right-sided heart failure your right
ventricle is unable to contract with enough force to push blood to your lungs. The result is a buildup of blood in
your Veins which causes a buildup of fluid called edema throughout the tissues in your body. Over time heart
failure on either side of your heart results in weakened enlarged ventricles that deliver less blood to your
body. To make up for the decreased amount of blood your nervous system releases stress hormones that
increase the speed and force of your heartbeat. Unfortunately the continued release of these stress
hormones makes your heart failure worse because they damage the muscle cells in your ventricles.
Heart failure - need electrocardiogram (ECG) to know the diagnosis if right or left
A. Introduction
1. Definition. Congestive heart failure (CHF) is the inability of the heart to meet the metabolic
requirements (FAILURE OF THE CONTRACTILITY. UNABLE TO PUMP THE REQUIRED VOLUME
OF BLOOD) of the peripheral systems.
2. Pathophysiology
a. Myocardial cell loss due to regional ischemia or myopathy results in deterioration of
systolic and diastolic performance.
Regional ischemia- localized
5
Ischemia - restriction of blood supply to the tissues which causes reduce supply of oxygen
Myopathy - muscle weakness
Side notes:
The top number is the maximum pressure the heart exerts while beating (systolic pressure).
The bottom number is the amount of pressure in the arteries between beats (diastolic
pressure).
Cardiac cycle events can be divided into diastole and systole. Diastole represents ventricular
filling, and systole represents ventricular contraction/ejection. Systole and diastole occur in both
the right and left heart, though with very different pressures (see hemodynamics below).
Diastole begins with the closing of the aortic valve (or pulmonic) and ends with the closing of
the mitral valve (or tricuspid). This period encompasses the ventricular relaxation and filling.
Diastole represents when the blood vessels return blood to the heart in preparation for the next
ventricular contraction.
Systole begins when the mitral valve (or tricuspid) closes and concludes with the closure of the
aortic valve (or pulmonic). This stage of the cardiac cycle represents ventricular contraction,
forcing blood into the arteries. When a ventricle contracts, the pressure within the ventricles will
(barring pathology) become greater than adjacent blood vessels, and the valves will allow the
blood out.
b. When confronted by an increased load, the remaining normal heart hypertrophies to maintain
adequate cardiac performance.
1) Hypertrophy results in a fall in stroke volume index and a rise in left ventricular filling
pressure.
Stroke volume - Stroke volume x heart rate = cardiac output. Volume of blood pumped out
of the left ventricle during each systolic cardiac contraction.
Hypertrophy - Abnormal increase or enlargement of heart muscle.
2) Peripheral vascular release increases and pulmonary congestion develops
c. Vasoconstrictor compensatory mechanisms (to maintain the blood volume) develop to maintain
cerebral and coronary perfusion. These include:
1) Stimulation of the sympathetic nervous system
Chemical released by the SNS: functions to increase heart conduction
● Norepinephrine
● Cortisol
And etc
2) Stimulation of the renin-angiotensin system
renin-angiotensin-aldosterone system (RAAS) that is involved in the homeostasis but
when there is that mechanism na need mag perform nung compensatory mechanism
wherein ma stimulate si RAAS the more na mag lead into hypertension.
ENZYME INVOLVED:
● Ace Angiotensin converting enzyme - converts Angiotensinogen to angiotensin 1 and
angiotensin 2.
Gives a vasoconstriction effect para mas mapabilis ang pag conduct ng heart.
Release the Ace then aldosterone then eventually sodium.
3. Symptoms. Major symptoms include weakness, fatigue, and dyspnea (shortness of breath).
B. Cardiac glycosides
1. Chemistry
a. Cardiac glycosides are the combination of an aglycone ( Aglycone - walang sugar fragment),
or genin, and one to four sugars.
6
1) The aglycone is chemically similar to bile acids and to steroids. It is the pharmacologically
active portion of the glycosides.
2) The sugars modify the water-and lipid-solubility of the glycoside molecule and, thus affect
its potency and duration of action.
Glycoside as activated by the enzyme and through hydrolysis to form the aglycone
b. Glycosides are obtained from dried leaves of the foxglove, Digitalis purpurea (digitoxin) or
Digitalis lanata (digitoxin, digoxin) and from the seeds of Strophantus gratus (ouabain).
c. The term digitalis is frequently used to refer to the entire group of cardiac glycosides.
2. Pk.
a. Digoxin is the most commonly used digitalis glycoside.
1) The bioavailability varies widely for different proprietary preparations of digoxin; intestinal
absorption of the drug may be as low as 40%
2) The serum half-life is normally about 36 hrs and significantly prolonged by impaired renal
function.
3) Digoxin is not metabolized and is eliminated principally by the kidneys in almost
unchanged form.
MOA. Digoxin inhibits the Na+,K+-ATPase (sodium potassium pump) directly. The more
sodium that leaves the the heart, the more potassium that enters the heart and vice versa. It
stimulates the sodium-calcium pump, wherein when the sodium leaves the heart, the calcium
enters the heart, and vice versa.
b. Digitoxin
1) It is well absorbed 90%-100% from the GIT , the serum half-life is 5-7 days
2) It is metabolized by the liver, and drugs that increase the activity of hepatic microsomal
enzymes, such as phenobarbital and phenytoin, accelerate its metabolism.
3) In contrast to digoxin, digitoxin is about 97% bound to plasma albumin.
Transcript: Mechanism of Action of Digoxin
Digoxin increases the force of cardiac contraction by direct action independent of innervation. Digoxin acts
by inhibiting the sodium potassium pump. The sodium potassium pump transports three sodium ions out of
the cell and brings two potassium ions into the cell against the concentration gradient using ATP energy.
(Active transport)
Digoxin inhibits the pump by binding to the allosteric site. This inhibition causes a buildup of intracellular
sodium ions. Increased intracellular sodium activates the sodium calcium exchanger.
The sodium calcium exchanger removes three intracellular sodium ions in exchange for one extra cellular
calcium ion. This builds up concentration of intracellular calcium. The excess calcium is taken up by
sarcoplasmic reticulum which leads to increased cardiac contractility.
3. Pharmacologic effects
a. General consideration
1) The most important property of cardiac glycosides is the positive inotropic effect
(increased contraction) ; that is, their ability to increase the force of myocardial contraction.
The result is increased cardiac work at reduced metabolic cost.
2) Glycosides also have effects on the eletrophysiologic properties of the heart (conductivity,
refractory period, automaticity)
3) Glycosides have extracardiac effects on vascular smooth muscle, neural tissue and other
tissues.
4) Factors that influence the effects of cardiac glycosides on the heart include:
7
a) The dose of the agent

b) The interaction of direct cardiac effects with reflex changes in the autonomic
and hormonal regulation of cardiovascular function.
c) The underlying cardiovascular pathophysiology
b. Effects of digitalis glycosides on the heart

1) Myocardial contractility
a) Cardiac glycosides increase the contractility of cardiac muscle by increasing both
the velocity of muscle contraction and the maximum force that is developed.
Cardiac glycosides DO NOT prolong the duration of the contraction.
b) In the CHF patients, glycosides cause a shift in the ventricular function curve,
which increases cardiac output, decreases cardiac filling pressures,
decrease heart size, and decreases venous and capillary pressures.
c) Two mechanism by which cardiac glycosides exert their positive inotropic
effects:
i. Digitalis inhibits membrane-bound Na+ and K+-activated adenosine
triphosphatase (Na+,K+-ATPase), thus increasing intracellular Ca2+ levels.
ii. The movement of Ca 2+ into the cell causes an increase in the slow
inward Ca2+ current during the action potential.
(During normal condition, in pumping of atpase, there is an influx in
cations Magnesium and Potassium, and the Calcium and Sodium will be
transported out of the cell)
(During digitalization, Magnesium and Potassium are transported out of
the cell, whereas, there is influx of Calcium and Sodium, thus increasing
contractility)
2) Myocardial oxygen consumption (MVO2)

d) The digitalis-induced increase in myocardial contractility causes an increase in
MVO2 (myocardial volume O2)
e) Decreased ventricular volume, resulting from the digitalis-induced increase in
muscle tone and cardiac output, decrease MVO2.
3) Electrophysiologic activity. Cardiac glycosides indirectly increase the vagal tone of the
heart. They prolong the refractory period of the AV node and decrease conduction velocity
through the AV nodes.
4) Heart rate. In CHF patients, digitalis slows the HR (a (-) chronotropic effect) due to a
combination of vagal and sinoatrial (S-A ) nodes. Tachycardia is seen with excessive doses
of digitalis (a (+) chronotropic effect). It has little effects on the heart rate of normal
individuals.
c. Extracardiac effects. A diuretic effect occurs because the increased cardiac output and renal
blood flow combine to reduce the neurohumoral factors that inhibit the excretion of salt and water.
4. Therapeutic uses and contraindications

a. Cardiac glycosides are of greatest value for treating low-output cardiac failure.
b. They are also of great value in the control of atrial fibrillation and flutter because of the
ability to reduce the ventricular rate by prolonging the refractory period of conduction tissue.
Digitalis may convert atrial flutter to atrial fibrillation.
c. Paroxysmal atrial tachycardia frequently responds to digitalis therapy, presumably as a result
of reflex vagal stimulation.
d. Cardiac glycosides is contraindicated in cardiac tamponade, high-output CHF, constrictive
pericarditis, and idiopathic, hypertrophic subaortic stenosis with outlet obstruction.
5. Digitalization and maintenance dosage
8
a. General considerations. Since digitalis glycosides are used almost exclusively either to
restore adequate circulation in patients with CHF or to slow ventricular rate in patients with atrial
fibrillation or flutter, long-term therapy is frequently necessary to maintain therapeutic myocardial
concentrations. .the low margin of safety increases the critical nature of dosage and
administration.
b. Digoxin. When there is no urgency, an oral digitalizing dose is first administered, and then
the maintenance dose is adjusted on the basis of clinical and lab assessment. Usually, a
steady-state level is achieved in 5 half-lives (about 8 days - based on half life that is 36 hours).
When digitalization must be achieved rapidly, digoxin can be administered IV over a period of
several minutes. The onset of action is within 5-30 minutes; the maximal effect is reached
within 1-5 hours.
c. Digitoxin. The total oral loading dose of digitoxin is divided into doses given every 6 hours and
administered over the course of 36-48 hours. The maximal effect of a dose of digitoxin is
reached approx 9 hours after oral administration. Once optimal benefit has been achieved, the
maintenance dose usually is adjusted to 10% of the digitalizing dose. Digitoxin is given IV but its
long latency period precludes its use in emergency situations.
Difference between Digitoxin and Digoxin:

● Absorption: Lesser/limited absorption in the GIT for Digoxin (40%) while Digitoxin is highly absorbed in
the GIT
● Half-lives: Digoxin - fast (36 hours) while Digitoxin - takes days; around 5-7 days
● Elimination: Digoxin is eliminated in the kidney unchanged (note: once excreted through the kidneys
that is unchanged form). Digitoxin takes days because it still binds to the plasma protein or the plasma
albumin so it decreases the elimination rate of the drug because 97% of the drug is bound to plasma
albumin and thus, it increases half life (meaning matagal).
● MOA: Digoxin - direct effect is that it inhibits the sodium-potassium ATPase so that indirectly, it also
inhibits the sodium calcium exchanger so that more calcium will be inside the cell thus there will be
more contractility in the heart.
6. Adverse effects
a. Digitalis glycosides have a low margin of safety (meaning it can be dangerous because it can
cause toxicity), and intoxication from an excess of the drug is a common and a potentially fatal
problem (usual patient cause of death because heart failure = kidney failure and so the drug is
not eliminated anymore thus leading to intoxication). In most CHF patients, the lethal dose of a
digitalis glycosides is likely to be only 5-10 times the minimal effective dose (very sensitive).
b. Intoxication is most frequently precipitated by depletion of serum K+ due to diuretic therapy, but
it can also occur from accumulation of maintenance glycoside doses taken over a long period of
time. Intoxication due to hypokalemia (low potassium levels) may also occur as a result of:
1) Prolonged administration of corticosteroids
2) Protracted vomiting and diarrhea - lasts for a longer period of time than expected;
manifestation of intoxication and other side effects of the drugs
Notes:
..diuretic therapy - usually in the CHF, namamanas din siya (edema). For it to eliminate the edema
condition of the patient, we give diuretics. We let the patients pee para ilabas ang fluid. Together with
that, the potassium is pinapalabas niya rin. The level of potassium is depleted konti and so it affects
now the functioning of your heart. You know how important the potassium is for the heart. Potassium
plays a role in every heartbeat. A hundred thousand times a day, it helps trigger your heart to squeeze
blood through your body. It also helps your muscles to move, your nerves to work, and your kidneys to
filter blood. Very low levels of potassium in the body can lead to irregular heart rhythms, including sinus
bradycardia, ventricular tachycardia, and ventricular fibrillation.
Diuretics lead to decreased potassium and so it precipitates the intoxication of digitalis.
9
c. Decreased renal function and hypothyroidism predispose patients to digitalis glycoside toxicity
because they reduce the excretion or the metabolism of the glycoside, and hence, they result in
excessive accumulation of the glycoside.
d. When the concentrations of digoxin and digitoxin rise above 2ng/ml and 35ng/ml of blood ,
respectively, signs of systemic toxicity often appear, and therapy must be discontinued. Signs of
toxicity include:
1) Anorexia (often the earliest sign) - eating disorder characterized by loss of appetite
2) Nausea, vomiting, and diarrhea
3) Headache, fatigue, malaise, neuralgias, and delirium - if the patient is dehydrated, they also
experience delirium
4) Vision changes, including abnormal color perception
5) Cardiac effects: premature ventricular contractions (PVCs) and ventricular tachycardia and
fibrillation (fibrillation - there is an irregularity in the beating of the heart); A-V dissociation
and block; sinus arrhythmia and S-A block
7. Treatment of digitalis toxicity

First of all, discontinue the drugs and then give KCl (to add to the potassium levels) because it depletes
potassium.
a. Cardiac glycosides and K+- depleting diuretics are discontinued - especially if loop diuretics
because these are used in case of emergency where there is toxicity pero yun nga include niya
si potassium
b. KCl is administered orally or by slow, careful IV infusion if hypokalemia is present; K+ is NOT
given however, if severe A-V block is found or if serum K+ levels are high. - Monitoring is very
crucial here (how would you know the patient’s level of potassium).
c. Because hypomagnesemia may accompany hypokalemia, magnesium replacement may also
be necessary.
d. Phenytoin (antiepileptic; for seizures) can be given for ventricular and atrial arrhythmias -
Phenytoin is classified also a Class 1B antiarrhythmic drug properties.
e. Lidocaine and procainamide can be used to treat ventricular arrhythmias - Lidocaine is an
anesthetic which is also a Class 1B type of drug used in arrhythmia. The action of lidocaine is to
block the cardiac sodium channels and shortening the action potential.
f. cholestyramine binds to cardiac glycosides and has been used to hasten their elimination -
cholestyramine is a binding agent; it is a bile acid sequestrant given to sequester the toxic
substances such as digoxin or the digitalis in the bile to hasten its elimination.
Drugs used during toxic effects of digitalis:

- KCl or Magnesium sulfate
- Phenytoin
- Lidocaine
- Cholestyramine - bile acid sequestrant
C. Angiotensin-converting enzyme (ACE) inhibitors - one of the most important drugs that we use in
CHF
a. ACEIs (captopril, enalapril, lisinopril) produce beneficial hemodynamic effects by decreasing
the conversion of angiotensin I to angiotensin II. (Therefore, these drugs are the inhibitors of
the enzymes that convert angio I to angio II). They also inhibit the degradation of bradykinin.
Bradykinin is a vasodilator. It also has a diuretic effect so it decreases the blood pressure and
thus, it preserves the cardiovascular function in the CHF.
b. Hemodynamically, these agents increase cardiac output by reducing afterload and by
decreasing total peripheral resistance, pulmonary resistance, and preload.
2. Therapeutic uses
a. Recently, captopril and enalapril are being used as first-line agent for CHF
10
b. Adding ACEI to therapy with diuretics and digitalis has increased the survival rate among
patients with moderate to severe CHF.
c. After MI (myocardial infarction or heart attack), ACEI may lessen the progressive
enlargement of the left ventricle.
3. Adverse effects
Since it inhibits the degradation of bradykinin, usually the bradykinin is degraded by the ACE
only. Since these drugs inhibit the ACE, they also inhibit the bradykinin.
a. Severe persistent cough occasionally occurs - when the patient is in maintenance of ACE
inhibitor, they also have cough because bradykinin is a chemical that mediates the
development of cough. Hence, there is mucus production due to the stimulation of
prostaglandin. Bradykinin is a proinflammatory chemical that is supposedly destroyed by the
ACE. But when you use ACE inhibitors, you also inhibit the degradation of bradykinin which
gives rise to the formation of mucus because the prostaglandin is stimulated.
b. Hypotension and deterioration of renal function can occur with an ACEI-diuretic combination.
- Again, bradykinin is proinflammatory. Prostaglandin is stimulated by bradykinin. We know
that prostaglandin has bronchoconstricting effects. Therefore, it enhances cough reflex
sensitivity.
c. A/E associated with captopril such as rash, taste disturbances (metallic taste), proteinuria
(protein in the urine), and leukopenia, may be related to the sulfhydryl moiety (thiol group)
of captopril. - Captopril contains a thiol a group.
D. Other drugs used in CHF

FIRST LINE OF DRUGS USED IN CHF: DIGOXIN, DIURETICS, ACE INHIBITORS
1. Diuretic therapy and Na+ restriction play an important role in reducing extracellular fluid
volume. Diuretics relieve symptoms of heart failure more rapidly than any other oral agent and
along with digoxin are first-line drugs for the treatment of CHF.
Same with hypertensive crisis they are also given diuretics para ilabas lahat ng congestion of
ions in the blood.
Sodium - reducing the level of sodium levels through urination para mababa level ng sodium
that leads to decrease blood pressure
2. Alpha-adrenergic blocking agents may be used in CHF to improve cardiac function by
inducing vasodilation through both direct and reflex actions.
3. Other vasodilators may be used for patients not responding to digitalis glycosides and diuretics.
a. Arteriolar dilators decrease afterload , whereas venous vasodilators reduce preload
which serves to increase cardiac output while reducing pulmonary congestion.
b. Isosorbide dinitrate, hydralazine, prazosin have all been used in the treatment of CHF.
Increased survival rates have been demonstrated with isosorbide and hydralazine used
together.
4. Amrinone is a bipyridine derivative, which inhibits phosphodiesterase type III. When
phosphodiesterase III is inhibited, intracellular cAMP concentration increases. This increase
results in the same type of inotropic effect in the myocardium as is produced
by sympathomimetics. It is reserved for the short –term therapy of CHF that is refractory to
other agents. It exerts a positive inotropic effect and increases systemic vasodilation,
administered by IV. - not commonly used
Q: Can we use calcium channel blockers for patients with CHF?

- We need calcium for CHF but CCB blocks the calcium. So, we should not use CCB.
They should be generally avoided for patients with CHF.
II. DRUGS USED IN THE TREATMENT OF ARRHYTHMIA

Drugs used in arrhythmia usually act to depress automaticity of latin pacemaker
11
A. General considerations
1. Cardiac arrhythmias
a. Cardiac arrhythmias are abnormalities in the rate, regularity, or site of origin of the cardiac
impulse, or a disturbance in the conduction of the impulse such that the normal sequence of
activation of atria and ventricles are altered.
b. Arrhythmias may be due to :
1) Faulty impulse initiation
2) Faulty impulse conduction
3) Combination of the above
c. The change in the impulse upsets the normal relationship that exists between the duration of the
refractory period (REPOLARIZATION OR RELAXATION PERIOD) and the conduction velocity
in myocardial tissue. Changes in the normal relationship between refractoriness and conduction
velocity may be critical, considering the heterogeneity of physiologic and mechanical properties
of the heart.
NOTE: Heart has long refractory period so it can fill with blood for the next cycle, to prevent
the possibility of tetany.
Tetany - condition in which muscle remains involuntarily contracted, it would prevent the
heart from pumping blood.
2. Cardiac electrophysiology
(Flip) Vid watch: EKG https://www.youtube.com/watch?v=791ZsLSmCjo

Action potential in myocytes https://www.youtube.com/watch?v=tLt3ZTeVzEY
Transcript for EKG
Basic look at an EKG and then some common deflection. Then, you might see this little negative
abnormalities deflection right there that's your QRS-wave. This
last wave over here with this other positive
First, the EKG we have three distinguishable deflection is the T-wave.
waves: Now, let's talk about each one of these waves.
What they are designed to and what they specify.
● P - WAVE: ATRIAL DEPOLARIZATION So, first off let's go over here to P-wave. So, the
● QRS-WAVE: VENTRICULAR P-wave tells us that the atria are depolarizing. In
DEPOLARIZATION other words, whenever the atria, so you start off
ATRIAL REPOLARIZATION with the SA node and the SA node fires those
● T-WAVE: VENTRICULAR impulses throughout the entire internodal pathways
REPOLARIZATION and Bachmann's bundle and it reaches the AV
node. What happens is once it reaches the AV
node the atria depolarize and they contract the
undergoes systole but that electrical activity that
shows up on here on the EKG with this positive
deflection point is designed to tell us that there is
Atrial Depolarization.
Depolarization means that the inside of the cell is
becoming more positive. It's conducting action
potentials.
This first one right here we refer to this wave as the This next one over here is the QRS wave. The
P-wave. P-wave is this positive deflection. From QRS wave is obviously this big negative positive
that isoelectric point right so we have that positive
12
negative deflection and this represents ventricular

depolarization.
Ventricular depolarization means that whenever
those impulses from the AV node they reach the AV
node there's a point 1 second delay that we talked
about in the cardiac cycle. It sends those impulses
down through the ventricles, down the AV bundle So, if you look here we have a normal P-wave and
right and left bundle branches Purkinje fibers and normal QRS complex but if you notice here
as it's moving around those guys it's causing the compare this with this normal T wave this R right
ventricles to become depolarized. In other words, here we call this part right here the ST segment.
the inside of their membranes are becoming more
positive and then eventually that will trigger
ventricular contraction which we talked about in the
cardiac cycle.
Another interesting thing is cells need to go through
a relaxation period so they need to depolarize and
then they need to repolarize so they can be excited
again.
So, if you notice we didn't mention here where's the From this part here to this part here it's the ST
atrial repolarization. Well, atrial repolarization is segment
hidden or masked within this QRS complex.
So, we can technically say that within the QRS and then we refer to this from the beginning of the
wave there is a hidden or masked atrial P wave to that Q that's our PR interval
repolarization occurring.
So, let's write that down here atrial repolarization is
occurring there's atrial repolarization and ventricular
depolarization occurring within this QRS wave.
Again, you can't see the atrial repolarization
because it's masked by this positive negative
deflection points within the QRS wave. PR interval looks good but the ST segment looks
like it's elevated. So, we call this an ST segment
Next one is going to be the T wave. The T wave is elevation. Sometimes in hospitals, you'll hear
what signifies the ventricular, the ventricles referred to as a STEMI. STEMI is short for saying
repolarizing. So after they've all contracted, after ST segment elevation myocardial infarction.
going through the refractory period so that they can
actually get all the oxygen to the tissues because So you would see if someone has a ST segment
that's when the coronary circulation is filling and elevation and most likely is indicative of some type
once it starts doing that has to repolarize and then of myocardial infarction or a heart attack but
get ready to be excited again. The T-wave obviously you could do other diagnostic testing to
represents ventricular repolarization. prove that all right that's one of those differential
diagnoses
Now, we can take a look at some of these common
abnormalities within the ECGs.
13
Then over here you'll notice in this one that there's obviously stress anxiety certain things can actually
a normal P-wave normal and QRS complex but trigger this to happen but it's not a life-threatening
then the T-waves flipped, it's inverted. T-wave there's no need for a pacemaker or anything like
inversions are indicative there is ST segment that.
depression.
T-wave inversions are usually indicative of

ischemia. Ischemia just means that there is a
decreased oxygen supply or lack of a decreased
lack of blood flow to the myocardial tissue and it's
going to cause this and negative deflection. Next one, if you look over here we notice the PR
interval is long and then it actually locally was
getting a little longer and then eventually over here
you notice there goes T wave P wave and no QRS
wave. What happened there?
Now the only way we'll be able to determine why

this is abnormal is if you actually look at the ECG Let's say that this PR interval let's say it's 220
paper. If you look at the ECG paper there's little milliseconds then we come over here in this PR
blocks that identifies the amount of time it takes if interval let's say it's 240 milliseconds. So again we
the PR interval. Normally the PR interval is about have our T wave here then we got our P wave but
160 to 200 milliseconds, if it's greater than that then look guys no QRS complex and then we go back to
there's a prolong PR interval. a P wave this is referred to as a second-degree
heart block and you can actually say this is called
mobitz one or Lincoln block. How do you
describe that you say that the PR interval is getting
progressively longer and then you drop a QRS
wave.
So that is one thing to remember for a
What happens in this one and I'd obviously I need second-degree heart block mobitz one. Now,
an ECG paper to see that but there's actually going second-degree heart block mobitz one is more
to be a prolonged PR interval right here but it's common within some type of inference oh there's a
consistent. It's not varying, it's a consistent block we're usually within the AV node. Time a
prolonged PR interval. So, let's say it's greater than cause of it is usually an infra nodal block. Now
200 so it's 220 milliseconds here and then over second-degree mobitz one can progress into
here this PR interval even though it's not looking mobitz 2 and again mobitz 1 isn't super
like it it is two hundred and twenty milliseconds life-threatening but it's obviously you know it's a
also. partial heart block.
If someone has consistent PR prolongation, PR
interval prolongations but it's not progressively
getting longer, this is described to be what's called
a first degree heart block which are
physiologically normal.
Okay, there's nothing really designed to be you
know this is not life-threatening it's very common
14
If we go over here this is a little bit more you know and then we got QRS complex and there we go T
dangerous you got to be careful with these ones wave P wave P wave again
this is a second-degree heart block mobitz 2
This one is completely the worst one, this is a
Now, a second-degree heart block mobitz 2, the PR complete heart block as you would describe it.
interval is normal so it's normal PR interval it's not So, third-degree heart blocks are very very
it's not fluctuating obviously I didn't show it perfectly life-threatening very dangerous you're gonna need
there but the PR interval is normal that's not to give them a most likely an artificial pacemaker
changing it's not going from 220 to 240. It's a actually definitely need an artificial pacemaker.
normal PR interval but what you notice is we
dropped our QRS complex and then we go back to Here's what's different from the second-degree
a P-wave then we might have a QRS complex. So heart block:
it's kind of like grouping them. It might look these The ventricles and the atria beat on their own
are kind of sometimes hard to differentiate a little bit rate. So, none of the impulses within the mobitz II
but with this one the third-degree heart block which some of the impulses from the atria actually get
I'll talk about it does have a varying PR interval down to the ventricles. Within third degree heart
whereas within the second-degree heart block block, none of the impulses get through the AV
mobitz to the PR interval is usually normal it's not node and down to the ventricles.
changing it's not fluctuating but some of the
p-waves don't make it through it doesn't get through The ventricles action develop their own beating rate
the AV node it doesn't go down to the ventricles so and the atria beat at their own rate. So because of
the ventricles don't contract that is important to that there is no connection if you will between the
remember. atria and the ventricle functioning as well anymore.
The P waves are going but they're not making it
through the AV node, they're not getting into the Okay this is a third-degree heart block, so the P
ventricles and the ventricles are contracting so this and the QRS wave are not agreeing correctly and
is called second-degree heart block mobitz II. they're beating at their own rate.
Just remember, normal PR interval but it drops the
QRS complex in there because some of the P
waves don't get through and again second-degree
heart blocks
Some of the symptoms that you can see within
This is gonna be an EKG that is indicative of what's
these people are some syncopes and dizziness
called wolff-parkinson-white syndrome (WPW
and stuff like that
Syndrome).
Wolff-parkinson-white syndrome is a congenital
condition in which the individuals have an irregular
accessory pathway and that accessory pathway is
called the bundle of Kent and it's actually
bi-directional so impulses can go through it down
All right let's go on to the next one this is a and tear great and it can go up through a
third-degree heart block and the third-degree heart retrograde which can create what's called reentry
block I've already kind of given you a little bit of and it can lead to supraventricular tachycardia
information on that we already know that they're which is can be symptomatic and asymptomatic.
going to have sometimes you're gonna have this Stuff like that usually the way to treat this as they
again so P wave QRS complex. So again P, QRS, sometimes you can do what's called
T-wave, P-wave and then you go back to a P wave radiofrequency catheter ablation where they hit
this bundle of Kent with radio frequency waves
15
creating scar tissue so that doesn't conduct the the ventricles and then cause the ventricles to
electrical potentials through it. depolarize and then again you'll have your T wave
We can see here and this one they don't really and then you might have some more again reentry
have a distinguishable P wave. It actually kind of circuits and then eventually some of those circuits
just goes straight up it looks coming up straight up will hit the AV node and send action potentials
right there that's actually a distinct wave. down.
Atrial flutter is this condition again is not

life-threatening but it can progress and become
very serious.
This one we're having to draw in blue that's called a Usually atrial flutter could be due to myocardial
delta wave and again over here you'll see this one infarctions or thyrotoxicosis like elevated t3 and t4
this is called a delta wave. Again this is usually could be due to mitral valve prolapse or a whole
indicative of someone who has bunch of reasons that we will talk about in the
wolff-parkinson-white syndrome. future but atrial flutter obviously is not completely
serious but it can progress and sometimes it can
progress into this one below it which is called atrial
fibrillation
and again you'll notice the nature of fibrillation you

have these like don't even really see a P wave then
it doesn't there's not distinct P waves it's just kind of
like this little squiggly almost around baseline
activity to where there's no P waves present it's just
Let's come over here and let's look at some more this kind of like irregular rhythm here and that's one
EKGs. of the big things to notice here they're not F well
● F-wave: Atrial Flutter they're actually they do have names but it's here's
● f-wave: Atrial Fibrillation the biggest thing they're F waves but they're little F.
So we look here you're gonna see this one and

right away you see the sawtooth like structures
these are supposed to be a P wave but we don't
So, these are little f waves. So, they're both F
call them P waves. We actually call them F-waves.
waves except this one up here natura flutters
These sawtooth waves indicate that there are some
capital F-waves and these are lowercase
P-waves they're just kind of like doing through this
f-waves.
that they're going through this reentry and then
eventually some of those re entries will hit the AV
So, these lower case F waves are indicative of
node and then send the action potentials down to
atrial fibrillation. These could be due to metabolic
16
syndrome again thyrotoxicosis and obesity it can go

on and on and on and sometimes you might have
to deal with this depending upon the condition
again you might have to do radiofrequency catheter
ablation you might have to do cardioversion Over here this is obviously common to someone
whatever it might be we'll get into more detail on who uses nicotine or so you know they drink a lot
that in the future of caffeine or certain drugs and stuff like that
what can happen is they can have this little
So again, these are F-waves but remember they're ectopic focus where they could trigger a
lowercase f-waves and this condition is called atrial premature ventricular contraction. So, they might
fibrillation. develop some irritable foci within the ventricles and
it might contract before the P wave actually sends
Another danger with atrial fibrillation I just wanted to the impulses out.
mention really briefly is that they don't really have
functional contractions and so the blood pools up
a lot inside of the atria and if there's stagnant flow
according to virtue of triad when there's a stasis of
blood flow there can be an increased chance of
forming thrombi and so sometimes these can form
a little vegetations on the valves a mitral valve and So, you'll notice here we go P wave right so we
the tricuspid valve and get dislodged and go and have a P wave then we got our QRS wave then we
cause an embolism like a pulmonary or cerebral have our T wave but we don't see the P wave it
embolism. kind of goes and actually bypasses the P wave
because of a premature ventricular ectopic focus
and it triggers a premature ventricular contraction
so it's indicative of this part right here okay so this
is indicative of PVCs or premature ventricular
Next one right here you're going to notice contraction.
something weird and this is kind of more common
in individuals who are using drugs like drug Obviously this can be due to caffeine it could be
overdoses. due to possibly some type of nicotine it could be
due to exercise a lot of common causes of this.
You'll notice that the P wave changes it takes on
different morphological structures at least three so
right here it looks like it's kind of triangular shaped
over here it looks kind of like normal and over
here it kind of looks like a little squiggled right.
This is really a bad one. This is life-threatening
Whenever you notice three different morphological and it's actually called torsades de pointes.
p-waves in sequence it's referred to it's what's Torsades de pointes I think they even call it de
called a wandering atrial pacemaker. You'll notice Ponce refers to twisting of the points around the
that it's more common to like drug overdoses but isoelectric line. This one's really really
you'll notice that there's obviously three life-threatening obviously you're going to need to
distinguishable or morphological P waves okay it's treat this it's a medical emergency but with torsades
a wandering angel price maker. de pointes it's usually referred to as a prolonged
QT syndrome and the most common causes of
prolonged QT syndromes are actually metabolic
17
reason so in other words more specifically if even medications can lead to those. So this is a
someone has low magnesium levels within the really really bad one obviously this needs medical
blood or if they have hypokalemia or attention immediately.
hypomagnesemia those are common causes and
P wave - positive deflection, atrial depolarization (conducting action potential, inside of the cells
are becoming positive), thus,atrium contracts
QRS wave - positive negative deflection, ventricular depolarization, (conducting action
potential, inside of the cells are becoming positive), ventricle contracts. Atrial repolarization
(relaxation of atrium)
T-wave - positive deflection, ventricular repolarization (relaxation), the last cells to depolarize in
the ventricles are the first to repolarize.
STEMI - ST segment, elevation, myocardial infarction
a. Action potential phases

1) The action potential of cardiac cells is divided into phases
2) The voltage changes of the action potential are associated with changes in ionic
conductance across the cell membrane. The following list gives only the major ionic
currents.
a) Phase 0. Rapid depolarization: Na+ rapidly enters the cell through Na+-specific
channels (“fast” channels) in the cell membrane. - pacemaker potential; sodium influx, p
wave
b) Phase 1. Rapid repolarization: K+ briefly leaves the cell. - QRS wave; potassium efflux
(exit the cell); shortest phase; QRS is the efflux phase,
c) Phase 2. Sustained depolarization (plateau): Ca2+ enters the cell through Ca2+ -specific
channels (“slow” channels) in the cell membrane. - ST segment
d) Phase 3. Rapid repolarization: K+ leaves the cell. - T wave; ventricular repolarization
e) Phase 4. Slow depolarization (diastole): in cells capable of self-excitation (e.g.
His-Purkinje cells), several ionic currents flow into and out of the cell until an impulse is
fire off. Other cells remain resting until activated. - resting potential
(Flip) Heart conduction Vid Watch: https://www.youtube.com/watch?v=RYZ4daFwMa8
Transcript:
The cardiac conduction system consists of the following components:

● The sinoatrial node, or SA node, located in the right atrium near the entrance of the superior vena
cava. This is the natural pacemaker of the heart. It initiates all heartbeat and determines heart rate.
Electrical impulses from the SA node spread throughout both atria and stimulate them to contract. It
generates electrical impulses.
● The atrioventricular node, or AV node, located on the other side of the right atrium, near the AV valve.
The AV node serves as electrical gateway to the ventricles. It delays the passage of electrical
impulses to the ventricles. This delay is to ensure that the atria have ejected all the blood into the
ventricles before the ventricles contract. - The AV node receives signals from the SA node and passes
them onto the atrioventricular bundle
● AV bundle or bundle of His. - This bundle is divided into right and left bundle branches which conduct
the impulses toward the apex of the heart. The signals are then passed onto Purkinje fibers, turning
upward and spreading throughout the ventricular myocardium.
Electrical activities of the heart can be recorded in the form of electrocardiogram, ECG or EKG. An
ECG is a composite recording of all the action potentials produced by the nodes and the cells of the
18
myocardium. Each wave or segment of the ECG corresponds to a certain event of the cardiac
electrical cycle. When the atria are full of blood, the SA node fires, electrical signals spread throughout
the atria and cause them to depolarize.
This is represented by the P wave on the ECG. Atrial contraction, or atrial systole starts about 100
milliseconds after the P wave begins. The P-Q segment represents the time the signals travel from the
SA node to the AV node. The QRS complex marks the firing of the AV node and represents ventricular
depolarization:
● Q wave corresponds to depolarization of the interventricular septum.
● R wave is produced by depolarization of the main mass of the ventricles.
● S wave represents the last phase of ventricular depolarization at the base of the heart.
● Atrial repolarization also occurs during this time but the signal is obscured by the large QRS
complex.
● The S-T segment reflects the plateau in the myocardial action potential. This is when the
ventricles contract and pump blood.
● The T wave represents ventricular repolarization immediately before ventricular relaxation, or
ventricular diastole. The cycle repeats itself with every heartbeat.
(end of transcript)
b. Automaticity
1) Automaticity is the ability of a cardiac cell to reach threshold potential and generate
impulses spontaneously.
2) In the cardiac cells, the resting potential depolarizes during phase 4 until a threshold
potential is reached and an action potential is initiated.
3) In man, the S-A node is the normal pacemaker since it has the steepest slope of
phase 4 and the most rapid firing rate. However, specialized atrial conduction fibers,
distal cells and the A-V node, and His-Purkinje fibers are latent pacemakers.
4) Abnormalities in cardiac rhythms arise from alterations in the site of normal automaticity
and abnormal generation of impulses.
5) Most antiarrhythmic agents depress the automaticity (i.e. decrease the rate of phase 4
depolarization) of latent pacemakers more effectively than the S-A node.
6) Inhibition of automaticity may also be due to decreased threshold potential or decreased
excitability of pacemaker cells.
c. Conduction velocity
1) Conduction velocity is the speed at which an impulse is propagated.
2) It is a function of:
a) The maximum rate (Vmax) of depolarization of phase 0
b) The threshold potential
c) The resting membrane potential
3) Depolarization of the membrane is associated with a decrease in conduction velocity.
4) The effective refractory period (ERP) is the period of repolarization during which no
normal action potential can be elicited. Shortening of the ERP during tachycardia may
produce arrhythmia, and an effective antiarrhythmic agent increases the ERP/APD
(action potential duration) ratio.
The rate of repolarization closely regulate the amount of calcium ion entering the cell.??
When large quantity of calcium ion enters the cells, due to an extended repolarization
period, ERP, the neuron may die leading to development of stroke or seizures.
5) Disturbances in cardiac conductance may underlie supraventricular or ventricular

arrhythmias.
19
6) In areas of injured myocardium, conduction may be slow, or refractoriness shortened,

or both, resulting in the reentry of aberrant impulses (causing abnormalities) and,
hence, a cardiac arrhythmia.
3. Classes of antiarrhythmic drugs

(Flip) Vid watch: https://www.youtube.com/watch?v=OnLsLByuo0E
Transcript:
Antiarrhythmic agents are drugs used to suppress abnormal rhythms of the heart. They act to
either:
● interfere with the dynamics of cardiac action potentials by blocking a certain ion channel, or
● block the sympathetic effects of the autonomic nervous system on the heart, to slow down
heart rate.
There are 5 classes of antiarrhythmic drugs:
● Class I: Sodium-channel blockers: these drugs bind to and block the fast sodium channels
that are responsible for the depolarizing phase in contractile myocytes. The result is a slower
depolarization with a smaller amplitude. Slower influx of sodium results in a smaller flow of
positive ions through gap junctions to adjacent cells; the adjacent cells take longer to reach the
threshold required to generate a new action potential, ultimately resulting in a slower
propagation of action potentials through the myocardium. This reduced conduction velocity
helps to suppress formation of re-entrant circuits, hence the use of these drugs for treating
re-entrant tachycardias.
Class I agents are divided further into subclass IA, IB and IC. These subclasses differ in the
strength of sodium channel blockage, and in their effect on the duration of action potentials and
the effective refractory period, the ERP. While subclass IC has no effect on ERP, IA prolongs
and IB shortens ERP, respectively. Changes in ERP may have different outcomes for different
types of arrhythmias. A longer ERP generally reduces cardiac excitability, but prolonged
repolarizations may increase the risk of torsades de pointes, a type of tachycardia caused by
afterdepolarizations.
● Class II: Beta-blockers: these drugs bind to beta1-adrenergic receptors and block the
sympathetic influences that act through these receptors. Sympathetic nerves release
catecholamines which act to increase SA node firing rate and cardiac conductibility, especially
at the AV node. These activities may precipitate arrhythmias. Beta-blockers suppress
sympathetic effects, thereby decreasing heart rate and slowing down conduction through the AV
node. The latter is particularly useful in treatment of tachycardias that originate upstream of the
AV node, known as supraventricular tachycardias, or SVT. Note should be taken, however,
that beta-blocker treatment may cause AV blocks.
● Class III: Potassium-channel blockers: these agents block the potassium channels
responsible for the repolarizing phase. The result is a slowed repolarization, hence a prolonged
duration of action potentials and refractory period. This reduces the heart’s excitability and
suppresses re-entrant tachycardias. However, these drugs may also cause arrhythmias
because slow repolarizations are associated with longer QT intervals and increased risks of
torsades de pointes.
● Class IV: Calcium-channel blockers: these drugs block calcium channels that are responsible
for depolarization in SA and AV nodal cells. Blocking these channels results in a lower sinus rate
and slower conduction through the AV node. However, because calcium is also involved in
cardiac myocyte contraction, these agents also reduce contractility of the heart and should not
20
be used in case of systolic heart failures.
● Class V includes all drugs that act by other or unknown mechanisms.
(end of transcript)
How do we know which type of drug to be used? - through the ambot wala ko kadungog - yssa
a. Class I antiarrhythmics agents depress phase 0 of the action potential by blocking Na+
channels.
1) Class IA antiarrhythmics cause moderate phase 0 depression but prolong
repolarization. Class IA drugs include quinidine, procainamide, and disopyramide. -
prolong erp, decreases cardiac ____, torsade de pointes (tachycardia caused by after
repolarization?)
2) Class IB antiarrhythmics cause minimal phase 0 depression and shorten
repolarization. It includes lidocaine, phenytoin, mexiletine, and tocainide. - sodium
channel blockers
3) Class IC antiarrhythmics cause marked phase 0 depression but have little effect on
repolarization; includes flecainide and encainide.
b. Class II antiarrhythmic agents act by β-adrenergic blockade. Class II drugs include
propranolol, acebutolol, and esmolol. Beta blockers blocks adrenergic receptors thereby
blocks the sympathetic action of catecholamines example, epinephrine, norepinephrine,
dopamine.
c. Class III antiarrhythmic agents prolong repolarization (K+ channel blockade) and
lengthen phase 2 of the action potential. This includes amiodarone and bretyllium. -
potassium channel blockers; blocks potassium channels that are responsible for
repolarization thus, there is decreased heart repolarization and so it prolongs duration of
action potential and refractory period. Hence, there is a decrease in heart excitability but
increases torsade de pointes.
POTASSIUM - excites heart (heart excitability)
d. Class IV antiarrhythmic agents are Ca+ antagonists; include verapamil, diltiazem, and
others. Verapamil is currently approved as an arrhythmic agent, while diltiazem is currently
being evaluated for supraventricular arrhythmias. - CCB blockers; block the calcium channel
responsible for depolarization in SA node and AV node thus, decrease sinus rate and slow
the conduction
CALCIUM - contracts heart (heart contractility)
Based on vaughan williams classification
B. Class IA antiarrhythmic agents

21
1. Quinidine
a. Chemistry. Quinidine is an alkaloid isolated from cinchona bark, is the d-isomer of quinine. -
quinine is antimalarial agent
b. Pk. As sulfate or gluconate form, it is well absorbed after oral administration and exerts a
maximum effect within 1-2 hours after administration by this route. Given IM as gluconate; 80%
of the drug is bound to plasma albumin, it is metabolized in the liver and excreted by the
kidneys.
c. Pharmacologic effects.
1) Effects on the heart. At high concentrations, quinidine has direct effects on most cells of
the heart. At lower concentrations, indirect (anticholinergic) effects may significantly
contribute to the overall action of quinidine on the heart.
Anticholinergic - blocks the acetylcholine in the rest and digest mechanism.
2) Extracardial effects. Quinidine can depress vascular smooth muscle tone, in part by
α-receptor blockade, and thus contribute to a reduction in peripheral vascular resistance.
d. Therapeutic uses.
1) Supraventricular arrhythmias. It is primarily used chronically and prophylactically to
prevent recurrences of paroxysmal supraventricular tachycardia (abnormally fast heartbeat)
due to A-V nodal reciprocating tachycardia.
2) Ventricular arrhythmias. It is very useful for long-term treatment of ventricular premature
depolarization or to prevent recurrences of ventricular tachycardia after cardioversion of this
arrhythmia.
e. Route of administration. Quinidine is given orally TID or QID. For IV use, the dose must be
diluted in glucose solution and injected slowly, monitor patient’s ECG.
It can also be given as 5% dextrose, that is why we have D-5 water or Dextrose 5% in water na
mga IV fluid which can be used to incorporate with Quinidine parenteral to be infused or injected
slowly.
f. A/E. cardiotoxicity includes A-V block, ventricular tachyarrhythmias, and depression of

myocardial contractility.
1) Ventricular arrhythmias are life-threatening, treatment involves
a. Na+ lactate or NaHCO3 (sodium bicarbonate), catecholamines or glucagon -
Na+ lactate (sodium ion lactate) is used to reverse cardiotoxic
electrocardiographic effects of drug.
b. Removal of quinidine by dialysis
2) “Quinidine syncope” due to ventricular tachyarrhythmias of polymorphic form (“torsades
de pointes”) can occur, especially if Q-T interval is prolonged by the drug. - torsades de
pointes - when seen in the ECG, the Q-T interval tracing is twisted.
3) Diarrhea, vomiting, nausea, and anorexia are the most common S/E; discontinue
quinidine.
4) “Cinchonism” symptoms include tinnitus, hearing loss, headache, diplopia (double
vision), photophobia, confusion, psychosis.
5) When given IV can cause hypotension, drug should be stopped.
2. Procainamide
a. Chemistry. Procainamide differs from procaine only in that it contains an amide structure rather
than an ester linkage; this difference protects it from enzymatic hydrolysis and frees it from most
of the CNS effects of procaine.
b. PK. May be administered orally, IV, or IM. The half-life is approximately 3 hours, 15% of the
drug is bound to plasma proteins. It is eliminated by both hepatic metabolism and renal
excretion, renal failure can produce toxicity.
22
c. Pharmacologic effects.
1) Effects on the heart. The direct cardiac effects of procainamide are quite similar to those
of quinidine; it decreases automaticity and lengthens the APD (action potential duration) and
the ERP (effective refractory period) in the atria and ventricles. It slows conduction in the
atrium, A-V node, and ventricle. (in general, it slows down conduction in the heart)
2) Extracardial effects. When given IV, can cause drop in BP, probably from peripheral
vasodilation. Unlike quinidine, procainamide does not have α-adrenergic blocking
properties. - meaning it does not block the effects of sympathetic nerves in the blood
vessels.
d. Therapeutic uses.
1) Ventricular arrhythmias. Procainamide is particularly effective in promptly abolishing
ventricular premature depolarizations and paroxysmal ventricular tachycardia
2) Supraventricular arrhythmias. It is now believed to be as effective as quinidine for the
management of atrial arrhythmias; however, higher doses of procainamide than of quinidine
may be necessary.
e. Route of administration. May be given orally, both initially and for maintenance. The slow IV
dose is reserved for life-threatening situations. When the arrhythmia has been interrupted,
infusion is stopped.
f. Adverse effects. Acute procainamide toxicity can cause ventricular arrhythmia, ventricular
fibrillation, and cardiac depression. Nausea, vomiting, diarrhea, and anorexia can occur
frequently with oral admin. but much less than with quinidine therapy. A reversible lupus
erythematous-like syndrome is most likely associated with this antiarrhythmic drug. Hypotension
can occur following IV admin. Procainamide can precipitate acute glaucoma and urinary
retention.
3. Disopyramide (Norpase)
a. PK. Disopyramide is well absorbed (83%) following oral administration. Approx 50% of a
dose is excreted in the urine in unchanged form. The half-life is 5-7 hours but may be
prolonged in patients with renal disease.
b. Pharmacologic effects. It has both direct and indirect actions on the heart which
resembles those of quinidine. Extracardiac effects is mild atropine-like action.
c. Therapeutic uses. For oral administration in the treatment of ventricular arrhythmias as an
alternative to quinidine and procainamide.
d. Adverse effects. Include conduction disturbances, CHF, or hypotension. Disopyramide
has a negative inotropic action that can be especially troublesome in patients with
preexisting ventricular failure.
C. Class IB antiarrhythmic agent

1. Lidocaine . It is an amide local anesthetic (eg. suturing)
a. PK.
1) Lidocaine is rapidly metabolized by the hepatic microsomal enzymes system with 70% of
the amount that enters the liver being metabolized in a single pass (first-pass metabolism).
Reductions in hepatic blood flow or function will reduce lidocaine plasma clearance.
(meaning accumulation may occur)
2) Oral administration results in very low plasma concentration because of the high percentage
of the drug that is removed by hepatic metabolism before reaching the general circulation. -
NO ORALLY ADMINISTERED LIDOCAINE, MORE ON PARENTERAL
3) Always administered by IV because of significant first-pass effect
4) Approx 70% of the drug is bound to plasma albumin
b. Therapeutic uses. Its antiarrhythmic action is limited, even though it is very effective in
treating ventricular arrhythmias. Because of its rapid onset and short duration of action, the
23
drug is particularly useful in treating these arrhythmias when they arise in emergency situations,
such as: open heart surgery, digitalis intoxication, myocardial infarction.
c. Route of admin. Can be administered IV or IM. The usual IV dose is given until the arrhythmia
is abolished, can be given by continuous IV infusion. Because its half-life is short, a
steady-state plasma concentration can be reached quickly by this method, given by IM to
achieve rapid plasma levels during emergencies.
Other routes of administration: ointment, topical, spray, anesthesia /dental anesthesia; no oral
d. Adverse effects. CNS s/e can include drowsiness, paresthesias (abnormal sensation typically
tingling or pricking, burning or prickling sensation; like pins and needles caused by the pressure
on or damage of the peripheral nerves), decreased auditory function, convulsions, and
respiratory arrest. Circulatory collapse can occur in patients with an acute myocardial infarction
after a rapid, large IV injection. Propranolol (beta blocker) or cimetidine (H2 blocker) can
decrease the plasma clearance of lidocaine. The concurrent use of tocainamide and lidocaine
can cause seizures.
2. Mexiletine. It is an orally active congener of lidocaine. The prominent effects of mexiletine on the
heart are similar to the effects of lidocaine, most useful in suppressing symptomatic ventricular
arrhythmias.
a. Route of admin. Given orally, administration with food or antacid is recommended. A
minimum of 2-3 days between dose adjustments is recommended. Patients with liver disease
may require lower doses.
b. A/E. gastrointestinal or neurologic a/e. Hepatic enzyme inducers, e.g. phenobarbital, can lower
mexiletine plasma levels.
3. Tocainaide . A lidocaine analog is also an amide local anesthetic, given orally. Like lidocaine, it
can suppress ventricular arrhythmias. It shortens the ADP and the ERP. Other s/e include GI
distress, CNS disturbances, allergic reactions, most frequently a maculopapular rash.
4. Phenytoin. It is closely related in structure to phenobarbital and is effective in treating epileptic
seizures (anti-seizure drug). As an antiarrhythmic agent, phenytoin resembles lidocaine in many
aspects.
a. Effects on the heart. The prominent effects of phenytoin on the heart are very similar to the
effects of lidocaine. Its extracardiac effects is that it exerts a depressant action on the
sympathetic centers in the CNS that may contribute to its antiarrhythmic effects.
b. Therapeutic uses. Phenytoin is most useful in treating ventricular arrhythmias associated
with digitalis toxicity or acute MI.
c. Route of admin. Most often administered by intermittent IV, but with continuous monitoring,
until either a therapeutic effects is achieved or toxic effect results. Orally, therapy is initiated
with a loading dose , followed by maintenance oral therapy.
d. A/E. CNS side effects are the most common problems encountered with phenytoin and include
nystagmus (repetitive involuntary rhythmic side-to-side, up and down or circular motion of the
eyes), vertigo, and loss of mental acuity. Large IV doses can alter hemodynamic function and
produce both a fall in cardiac output and hypotension, resulting in death.
D. Class IC antiarrhythmic agents

1. Flecainide and encainide administered orally, are indicated for use in patients with
life-threatening arrhythmias; such as sustained ventricular tachycardia. These agents are no
longer indicated for less severe ventricular arrhythmias because they can precipitate cardiac
arrest. - not commonly used because of their possible side effects
E. Class II antiarrhythmic agents: Beta-adrenergic antagonists (β-blockers)

1. Propranolol (Inderal)
- is a nonselective beta blocker to both β1 (cardiac receptors) and β2 receptors (bronchial
receptors).
24
However, it can lead to unwanted B2 blocker effects such as airflow obstruction. If the patient is
asthmatic, you cannot use propranolol. Β1 selective blocker is approved for asthmatic patient.
If the patient has cardiovascular disease, we should choose the most selective type: B1
selective antagonists. Example: Acebutolol
Propranolol is also contraindicated in diabetes because it can cause low blood sugar or it
may mask the signs of low blood sugar such as high/increased heart rate, sweating and
shakiness. BB decrease heart rate thus in diabetes where SS is increased heart rate. If the
heart rate is low, you may not be able to rely on symptoms to tell that blood sugar is low which
can be dangerous.
It inhibits glycogenolysis (breakdown of glycogen into glucose where the body needs to
produce energy).
a. Pharmacologic effects. The antiarrhythmic effect is due primarily to β receptor blockade

but also result from a direct membrane effect. It causes a substantial increase in the ERP of
the A-V node due to B-blockade. The ERP of Purkinje fibers is shortened substantially &
prolongs the P-R interval by its action on the A-V node
b. Route of admin. It is given by IV slowly with additional doses usually given every 3-5
minutes. Oral medication usually is begun with relatively small divided doses. The total
amount may need to be increased significantly to produce a therapeutic effect.
c. Therapeutic uses. It is used to control supraventricular tachyarrhythmias, including atrial
fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. Propranolol is useful
in ventricular arrhythmias that are due to enhanced adrenergic stimulation (from emotional
stress, exercise).
d. A/E. because it decreases sympathetic activity, it can produce severe hypotension,
significantly worsen CHF, and cause cardiac arrest. Propranolol can induce significant
bronchospasm in asthmatic patients and can mask signs and symptoms of acute
hypoglycemia(heart palpitations and shakiness). Sudden withdrawal of the drug can
produce angina, arrhythmias, and infarction. When you want to stop propranolol treatment, it
shouldn't be a sudden withdrawal but instead a tapering of dose only (dahan dahan until
totally eliminated) because it may cause angina, arrhythmias and infarction.
2. Beta 1-selective (cardioselective ) adrenergic antagonists

a. Acebutolol is a B1-selective adrenergic receptor blocker with some sympathomimetic
(adrenergic) activity, used chiefly in controlling ventricular premature beats.
b. Esmolol is a cardioselective B-adrenergic blocking agent with a short duration of action.
Given IV infusion to provide rapid control of supraventricular arrhythmias. A/E is
dose-related hypotension and bradyarrhythmias can occur.
F. Class III antiarrhythmic agents

1. Bretylium . A quaternary ammonium salt, is an adrenergic neuronal blocking agent.
a. PK. oral absorption is poor; however it is well absorbed after IM administration, it is
excreted unchanged in the urine.
b. Therapeutic uses. Bretylium is reserved for life-threatening ventricular arrhythmias that are
refractory to other therapy. Its use is confined to intensive care units.
c. A/E. IV bretylium causes orthostatic hypotension (a form of low blood pressure that
happens when standing after sitting or lying down) and some degree of supine
hypotension (lying down or at rest). Nausea and vomiting can occur with rapid IV
administration.
25
2. Amiodarone is an iodinated benzofuran derivative. It is highly lipid-soluble; its half-life is 20-100

days.
a. Therap. Uses. Amiodarone suppresses premature ventricular contractions and ventricular

tachycardia. Its use is reserved for the treatment of life-threatening ventricular arrhythmias
refractory to other treatment.
b. A/E. Pulmonary fibrosis, which is usually reversible. Cardiac effects including sinus
bradycardia, A-V block, and paradoxical ventricular arrhythmias.
G. Class IV antiarrhythmic agents: calcium (Ca2+)-channel blockers.

1. Verapamil (Isoptin). A Ca2+ -channel blocker, is considered the drug of choice for
supraventricular tachycardia treated by the IV route. It significantly depresses A-V nodal
conduction. It is, therefore very effective in paroxysmal supraventricular tachycardia. It is less
useful than other agents for ventricular arrhythmias.
a. A/E. because of its effects on the A-V node, verapamil should not be used in patients
with A-V nodal dysfunction. It can depress myocardial contractility, therefore care should
be exercised when administering it to patients with CHF.
2. Other Ca2+ -channel blockers are not at present approved for use as antiarrhythmic agents.
III. DRUGS USED IN THE TREATMENT OF ANGINA AND OTHER VASODILATORS.

(Flip) Vid watch https://www.youtube.com/watch?v=-I-NN2PSAU8
Transcript:
Angina pectoris, or simply angina, refers to chest pain or discomfort caused by reduced blood flow to the
heart, in a condition known as myocardial ischemia. Angina is described as a squeezing pain or heaviness in
the chest, which may also spread to the neck, arms, shoulders and back; or in the stomach area, particularly
after meals. Women are more likely to experience a burning sensation or tenderness instead of squeezing
pain. Angina is not the same as heart attack. It is associated with transient ischemia of the heart without
permanent damage, while heart attack is when a patch of the heart muscle dies from lack of oxygen. But
26
having angina significantly increases the risks for heart attacks, especially when left untreated. Angina is most
commonly caused by the narrowing of one or more coronary arteries that supply the heart. This can result from
a fixed obstruction by cholesterol plaques, or a temporary constriction due to blood vessel spasms. Angina can
also be caused by anemia, when the flow is adequate, but the blood does not have enough red blood cells to
carry oxygen.
There are several types of angina.

● Stable angina, the most common form, is usually caused by a fixed obstruction, a plaque. Stable
angina is predictable, with familiar pain patterns, and typically prompted by physical exertion, when the
heart requires more oxygen than it can get from narrowed vessels. Factors that constrict blood vessels
or increase blood pressure, such as emotional stress, cold temperatures or heavy meals, may also
induce angina. Stable angina does not happen at rest, when the reduced flow is sufficient for the low
demand of the heart. It usually subsides when the inducer is removed and responds well to
medications.
● Unstable angina, on the other hand, may occur unexpectedly, even at rest, with a changed pattern
from the usual stable angina. It is more severe, lasts longer, does not respond to rest or medications,
and is often the sign that a plaque has ruptured or a clot has formed. Unstable angina is a medical
emergency as it often precedes a heart attack. Electrocardiograms of patients with obstructive angina
commonly show ST-segment depression during attacks. Diagnosis is confirmed with stress test, where
patients are monitored while exercising. The site of obstruction can be detected with imaging
techniques, such as angiography. It appears, however, that a significant number of patients with stable
angina symptoms have more or less normal coronary arteries on angiograms. These cases are now
recognized as microvascular angina (Cardiac syndrome X), where the problem lies not in the large
coronary arteries, but their tiny branches, and is therefore undetectable by angiography.
● Microvascular angina is much more common in women than in men.
● Variant angina (Prinzmetal angina), a less common type, is caused by vascular spasms of coronary
arteries. Variant angina can occur during rest, usually at certain times of the day, often at night.
Emotional stress, smoking and use of cocaine are known triggers. Variant angina is often severe, but
responds well to medications. Diagnosis is by presence of ST-segment elevation during attacks, and
provocative testing with drugs that induce coronary artery spasms (ergonovine, acetylcholine).
Treatment of angina aims to relieve symptoms, reduce frequency of future anginas, but most importantly,
reduce risks of heart attacks. Apart from lifestyle changes to modify risk factors, treatment options include a
number of medications and surgical procedures. Nitroglycerin, a potent vasodilator, is most effective for acute
anginal attacks. Long-lasting nitrates, antiplatelet drugs (aspirin…), beta-blockers, and calcium channel
blockers can be prescribed to prevent future anginas. Several revascularization procedures are available to
restore normal blood supply to the heart. Coronary angioplasty makes use of a balloon, and sometimes a
stent, to widen the affected artery. Coronary bypass uses a graft to create an alternative route for blood to flow
beyond the site of blockage.
Four E’s
- Exercise
- Eating
- Emotional stress
- Exposure to cold temperatures
(end of transcript)
27
The nitrates, the β-adrenergic antagonists, and the Ca2+ - channel blockers are drugs that are useful in treating
the pain resulting from ischemic heart disease. They provide symptomatic treatment of angina pectoris but do
not affect the course of the disorder. Several vasodilators that are not used in the treatment of angina are also
briefly discussed in this section.
Ischemia - reduced oxygenation due to reduced blood supply in the tissues
A. Nitrates
- Widens or relaxes the blood vessels (not only in the heart but elsewhere in the body)
1. Chemistry
a. The term Nitrates will be used in this section to encompass both nitrites (esters of nitrous
acids) and nitrates (polyol esters of nitric acid).
b. Glyceryl trinitrate (nitroglycerin) is the prototype of this group.
c. Nitroglycerin and amyl nitrite are volatile liquids at room temperature. Other nitrates
(isosorbide dinitrate (Isordil) , pentaerythritol tetranitrate, erythrityl tetranitrate) are solids.
2. MOA. The nitrates relax all smooth muscle, including vascular smooth muscle. The proposed
biochemical action involves the formation of free radical nitric oxide (NO), which stimulates
guanylate cyclase. The resultant guanosine 3’,5’-monophosphate (cyclic GMP) activates a
protein kinase, which mediates dephosphorylation of myosin. They reduce venous tone, thereby
increasing venous capacitance and decreasing venous return to the heart. They decrease
peripheral arteriolar resistance.
Guanylate cyclase - enzyme that converts guanosine triphosphate to cyclic GMP

cGMP (cyclic GMP) - activates a protein kinase, which mediates dephosphorylation of myosin
Myosin - motor proteins known for their role in muscle contraction;
- reduce pre-load and post-load, thereby decrease myocardial oxygen consumption
3. PK.
a. The nitrates are readily absorbed through the buccal mucous membranes (Isordil SL), the skin
(Isordil patch), the GIT (Isordil oral tablet; 5mg and 10mg), and the lungs. (also available for
injection and ointment)
1) Sublingual administration produces rapid onset (2-5 minutes) and short duration of
action (less than 30 minutes) and, thus, provides the best treatment for acute attacks of
angina.
2) Oral preparations, which often come in a sustained-release form (can be dosed once
daily only; good for 24-hour release), can provide more prolonged prophylaxis against
angina than sublingual forms.
b. The nitrates are broken down in the liver by a glutathione-dependent organic nitrate reductase
and are excreted in the form of various nitrites and nitrates.
a. The major effect of the nitrates on the heart is to reduce myocardial oxygen requirements
relative to myocardial oxygen delivery, dilating the large epicardial and collateral coronary
arteries selectively.
b. Extracardiac effects (outside heart) is vasodilation of cerebral vessels produced by nitrates,
results in increased intracerebral pressure and sometimes headache. The nitrates dilate
vessels in the skin resulting in flushing. They relax bronchial and biliary tract smooth muscle
with the latter action resulting in the reduction of biliary pressure.
5. Route of administration.
a. Nitroglycerin (glyceryl trinitrate) is usually given SL. However, for long-lasting effects,
nitroglycerin may be administered either orally or topically (transdermally) via ointment or
patch.
b. It may also be given IV in medical emergencies.
28
c. Nitroglycerin tablets quickly lose potency when stored in contact with cotton, paper, or plastic
and should be kept in a dark glass container. (However, since it is volatile, it maintains its
potency up to 5 months once the bottle is opened)
6. Therapeutic uses. It is primarily used to treat acute attacks of angina/angina pectoris and, in
anticipation of attacks, to prevent their occurrence. Paroxysmal nocturnal dyspnea can be
relieved with nitroglycerin by improving left ventricular pressure and reducing pulmonary pressure.
Angina/Angina pectoris - chest pain caused by reduced blood flow to the heart; symptom of
coronary artery disease.
Paroxysmal nocturnal dyspnea - sensation of shortness of breath that awakens the patient.
7. A/E. Headache is a common early s/e of nitrates that usually decreases after the first few days of
treatment (i.e. patient usually develop tolerance to headache). Temporarily discontinuing the drugs
for a few days causes a recurrence of susceptibility to a headache when the nitrates are
readministered. Decreasing the dose is sometimes beneficial for headache rather than
discontinuing. Dizziness and weakness, and cerebral ischemia associated with postural
hypotension occasionally occur. Nitrite ions, when present in large amount, can oxidize enough
hemoglobin to methemoglobin to result in hypoxia. Death can occur with acute nitrate poisoning
from circulatory collapse or respiratory failure.
Methemoglobin - there is presence of iron in ferric form, which is incapable of binding oxygen, in
contrast with ferrous form.
B. Propranolol
1. MOA. The β-adrenergic blocking action of propranolol decreases sympathetic stimulation of the
heart, thus reduces the heart rate, esp during exercise, and decreases myocardial contractility.
These effects in turn decrease the oxygen requirements of the myocardium, both during exercise
and at rest. It may also decrease arterial pressure.
It has to do with the action of sympathetic nervous system (fight or flight response) in which it
releases catecholamines. β-blocker blocks catecholamines, thus reduces the heart rate.
Catecholamines - Dopamine, Epinephrine (adrenaline), and Norepinephrine (noradrenaline).

2. Route of admin. It is usually administered orally for the treatment of angina.
3. Therap. Uses. Propranolol is used prophylactically to decrease the severity and frequency of
anginal attacks. It can be administered concomitantly with nitroglycerin, in which case it reduces
the amount of nitroglycerin needed to control angina. It should NOT be used for
Prinzmetal’s(variant) angina which is caused by coronary vasospasm.
4. A/E. As noted, propranolol can worsen CHF and can precipitate bronchospasm in patients with
bronchial asthma. Bradycardia and hypotension can occur. Renal plasma flow and glomerular
filtration rate may be reduced.
C. Ca2+ -channel blockers

1. Classification. Verapamil, nifedipine, diltiazem, and nicardipine belong to CCB, or Ca
antagonist, class of antianginal drugs. These drugs selectively inhibit Ca2+ influx into heart muscle
(i.e. they block the slow inward channel for Ca2+) and inhibit influx into vascular smooth muscle.
They DO NOT change the serum Ca2+ concentration, it only slows down the concentration.
2. Pk. These drugs are rapidly and almost fully absorbed after oral administration and they are highly
bound by serum proteins. Verapamil undergoes extensive first-pass biotransformation in the liver.
All four drugs are excreted as metabolites in the urine.
3. Pharmacologic effects. By their inhibition of Ca2+ influx into myocardial and vascular smooth
muscle cells, it has diverse effects on the CV system.
a. They dilate the main coronary arteries and arterioles, and by inhibiting coronary artery
spasm, they increase myocardial oxygen delivery in patients with Prinzmetal’s angina
(variant agina)
b. The drug dilate peripheral arterioles and reduce the total peripheral vascular resistance,
thereby reducing the oxygen requirements of the myocardium.
c. Nifedipine reduces cardiac preload and may actually increase the heart rate.
29
d. Nicardipine may be more vasoselective than other CCB.

e. These agents have shown to antagonize the aggregation of thrombocytes to inhibit the
release of thromboxane A2 (TXA2).
Thromboxane - has prothrombic properties, thus increasing formation of thrombus or clots,
which increases platelet aggregation.
f. Extracardiac effects. Verapamil produces nonspecific sympathetic antagonism and has a
local anesthetic effect.
CCB works by slowing the movement of calcium into the cells of the heart and the blood vessel
walls, thus the heart pumps easily and the blood vessels are widened.
4. Route of admin. CCB may be given orally; for use in medical emergencies, verapamil (Isoptin) is
also available in IV form.
5. Therapeutic uses. CCB are useful in the treatment of both Prinzmetal’s and classic exertional
angina. Nifedipine is most effective in Prinzmetal’s angina. Verapamil, diltiazem, and
nicardipine have been approved for use in hypertension. Verapamil is used to treat certain
arrhythmias. The CCB have demonstrated to be effective in the prophylactic treatment of migraine
(not FDA approved).
6. A/E. CCB especially when used in combi with BB, can produce or aggravate: hypotension, A-V
block, CHF, asystole. Most of their a/e are mild; dizziness and peripheral edema are among the
more common. Verapamil can increase serum levels of digitalis during the 1st week of therapy and
thus, can cause digitalis toxicity. Nicardipine can produce a negative effect on cardiac contractility
when administered IV to patients with CHF.
D. Other vasodilators. Dipyridamole (Persantine). By inhibiting the uptake of adenosine into
erythrocytes and other tissues, it allows metabolically released adenosine, which is a coronary
vasodilator, to accumulate in the plasma. The drug decreases coronary vascular resistance and
increases coronary blood flow and coronary sinus oxygen saturation.
Adenosine - modulates various physiological functions

Persantine - most commonly used before but it is not available now; can be used as antiplatelet drug
IV. DRUGS USED IN THE TREATMENT OF HYPERTENSION

Flip Vidwatch https://www.youtube.com/watch?v=NShRLLU0pMM
Transcript:
In this video, we'll discuss the essential pathophysiology of hypertension so we could have fun
discussing the categories of the drugs used for it in the upcoming lectures. The first thing we should
know is what is hypertension.
Hypertension is defined as either a sustained systolic blood pressure of greater than 140 millimeters
hg or a sustained diastolic blood pressure of greater than 90 millimeters hg. Hypertension results from
increased peripheral vascular arteriolar smooth muscle tone. In other words, hypertension is a state of
elevated blood pressure which is the pressure exerted on the walls of arteries.
Systolic blood pressure is the blood pressure during systole or myocardium contraction and diastolic
blood pressure is the blood pressure during diastole or myocardium relaxation that leads us to the
classification of the blood pressure.
● The normal blood pressure lesser than 120 for the systolic and lesser than 80 for the diastolic
and
● Pre-hypertension from 120 to 139 for the systolic or from 80 to 89 for the diastolic
● Stage 1 hypertension from 140 to 159 for the systolic or from 90 to 99 for the diastolic and
● Stage 2 hypertension equals to or greater than 160 for the systolic or equals to or greater than
100 for the diastolic
30
Although many patients have no symptoms, chronic hypertension can lead to heart disease and stroke.
It is also an important risk factor in the development of chronic kidney disease and heart failure.
Hypertension may occur secondary to other diseases but more than 90 of patients have essential
hypertension that happens with no identifiable cause.
There are some risk factors we should know:

● The family history of hypertension increases the chance to develop Hypertension
● Older ages
● Diabetes
● Obesity
● Smoking
● Alcohol consumption
● Stressful lifestyle and
● High dietary intake of sodium are also risk factors for hypertension
Now let's understand the mechanisms involved in the control of blood pressure in the body and that
definitely would help us in understanding how the drugs work.
There are multiple organs involved in the control of blood pressure:

● The heart
● Blood vessels
● Kidneys
● Liver and
● Lungs
There are two major processes that control these organs to work in harmony and controlling blood
pressure:
● The Baroreceptors/pressure receptors in the sympathetic nervous system and
● the arena angiotensin aldosterone system
So what happens when the blood pressure falls? Before we begin, you should know that three
processes increase the blood pressure:
● increasing cardiac output
● increasing peripheral resistance or
● increasing blood volume
A fall in blood pressure causes pressure sensitive neurons in the aortic arch and carotid sinuses that
are called Baroreceptors (or archaically, pressoreceptors) to send fewer impulses to cardiovascular
centers in the spinal cord. This prompts a reflex response of increased sympathetic and decreased
parasympathetic output to the heart and vasculature resulting in activation of beta-1 adrenoceptors in
the heart, increasing cardiac output and activation of alpha-1 adrenoceptors in the blood vessels
causing vasoconstriction leading to a compensatory rise in blood pressure. The kidneys control the
blood volume simply when blood pressure falls, the kidneys release the enzyme renin leading to a
series of events that increase blood pressure. Let's discuss more details. there are also Baroreceptors
in the kidneys. They respond to reduced arterial pressure and to sympathetic stimulation of beta-1
adrenoceptors in the kidneys by releasing the enzyme renin.
31
Low sodium intake and greater sodium loss also increase renin release. Renin converts
angiotensinogen which is synthesized in the liver and secreted in plasma to angiotensin 1 which is
converted to angiotensin 2 in the lungs.
In the presence of angiotensin converting enzyme (ACE), angiotensin II is a potent circulating

vasoconstrictor constricting both arterioles and veins increasing peripheral resistance and blood
pressure. Angiotensin II also stimulates aldosterone secretion leading to increased renal sodium
reabsorption and increased blood volume which contribute to a further increase in blood pressure.
These effects of angiotensin II are mediated by stimulation of angiotensin II type 1 AT1 receptors. So we
can conclude the categories of the drugs that are used for hypertension:
● either they work as sympatholytics to decrease the sympathetic activity
● interfere with renin-angiotensin system or
● diuretics to decrease blood volume
What is the action of renin?

- Renin is released when there is less sodium intake.
Angio II - acts a vasoconstrictor circulating in the circulation. With angio II, there is increased peripheral
resistance and stimulation of aldosterone secretion which in turn, increases sodium and water retention. ADH
is stimulated by this aldosterone. Categories of drugs that work on this is the drugs work as inhibitors of these
actions, first by acting on the sympathetic stimulation (sympatholytic or antisympathetic agents) meaning to
decrease sympathetic activity.
● We also have the ARB’s (angiotensin receptor blockers e.g. -sartan).

● We also have drugs as ACE inhibitors that work in the action of ACE.
● ARB and ACE inhibitors interfere with the RAAS mechanism (Renin angiotensin aldosterone system).
● We have also the third class to be used which are the diuretics. They are used to decrease blood
pressure by promoting cardiac volume reduction through stimulating urination.
Where to find baroreceptors?

- found in carotid sinus and aortic arch; they function to sense pressure changes by responding to
change in the arterial walls.
STAGES OF HYPERTENSION (based on New Guidelines by ACC/AHA 2020)
Normal Elevated Stage I Stage II
Less than 120/80 120-129/80 and 130-139/80-89 Above 140 /90mmHg

mmHg below mmHg
American College of Cardiology (ACC) and the American Heart Association (AHA)
What Is Hypertension?
Hypertension, or high blood pressure, is a common condition. The older you are, the more likely you are to get
it. Blood pressure is the force of blood pressing against the walls of your arteries. When it's too high, your heart
has to work harder. This can cause serious damage to your arteries. Over time, uncontrolled high blood
pressure makes you more likely to get heart disease, stroke, and kidney disease.
32
Hypertension Symptoms
High blood pressure is often called a silent killer because it doesn't always have outward symptoms. That
means you could have it for years and not know. It can quietly damage your heart, lungs, blood vessels, brain,
and kidneys if it isn't treated. It's a major cause of strokes and heart attacks in the U.S.
What Do the Numbers Mean?
Normal blood pressure readings will fall below 120/80. Higher results over time can indicate hypertension. The
top number (systolic) shows the pressure when your heart beats. The lower number (diastolic) measures
pressure at rest between heartbeats, when your heart refills with blood.
Korotkoff sounds are generated when a blood pressure cuff changes the flow of blood through the artery.
These sounds are heard through either a stethoscope or a doppler that is placed distal to the blood pressure
cuff.
Elevated Blood Pressure: A Warning Sign

Elevated blood pressure is consistently just above the normal level -- anywhere between 120 and 129 for
systolic pressure and less than 80 for diastolic pressure. People in this range are more likely to get heart
disease than those with a lower reading. Your doctor may suggest lifestyle changes to help get your numbers
down.
The Hypertension Danger Zone

You have stage 1 high blood pressure if your systolic reading is between 130 and 139 or your diastolic is
between 80 and 89. A reading of 140 or higher systolic or 90 or greater diastolic is stage 2 hypertension. You
may not have symptoms. If your systolic is over 180 or your diastolic is above over 120, you may be having a
hypertensive crisis, which can lead to a stroke, heart attack, or kidney damage. Rest for a few minutes and
take your blood pressure again. If it's still that high, call 911. Symptoms include a severe headache, anxiety,
and nosebleeds. You might feel short of breath or pass out.
(https://www.webmd.com/hypertension-high-blood-pressure/ss/slideshow-hypertension-overview)
Sequential therapy - maintenance or prophylaxis
DIURETICS IS ALWAYS PAIRED WITH ACE INHIBITORS OR ARBs
33
● Commonly we have drugs that in 1 tablet, it is already a combination of ARBs + ACE

inhibitor ex. Amlodipine, nifedipine, amlodipine + losartan
Coronary Artery Disease - also known as arrhythmia
Loop diuretics include also the potassium ions to be eliminated.
Drug of Choice during Hypertension:

● ACE inhibitor + Diuretic + BB + CCB
Always Diuretics + ACE inhibitor/BB/CCB but it doesn’t mean that diuretics are maintenance
drugs. Only added in cases with extremely high pressure.
1. Because the etiology of essential hypertension is still unknown, drug therapy for this condition is
empiric (based on the experience of the patient that shows efficiency) and often rather specific.
Essential hypertension - hypertension of unknown cause; occurs when you have

abnormally high blood pressure that's not the result of a medical condition. This form of high
blood pressure is often due to obesity, family history and an unhealthy diet. The condition is
reversible with medications and lifestyle changes.
- 90% more cases of essential hypertension whereas the rest is secondary hypertension
which means hypertension secondary to those disorders like diabetes, kidney failure etc.
2. Traditionally, the first choice for the initial treatment of chronic hypertension has been a
thiazide-type diuretic or a ß-adrenergic receptor blocker. More recently some physicians
prefer to start therapy with an ACE inhibitor or a CCB. If the first agent is ineffective or poorly
tolerated, another agent is substituted. If more than one agent is needed, a diuretic is added.
3. In hypertensive emergencies, parenteral therapy is indicated, usually with nitroprusside or
diazoxide; IV labetalol or SL nifedipine are also suitable. Oral therapy should be started as
soon as possible because parenteral therapy is not suitable for long-term management of
hypertension.
Labetalol is a cardiac specific beta blocker.

Nifedipine - brand name: Adalat which comes in a liquid gel; if used as sublingual, you prick the
soft gel capsule and then squeeze it under the tongue.
Diazoxide - direct rapid acting vasodilator; chemically related to thiazide diuretics
With regards with sublingual ACE inhibitors, we have the Captopril → fast onset 10-20minutes
onset
Nitroprusside - this are nitrates; its action is to release nitric oxide (NO) in which it stimulates
the guanylate cyclase to produce cGMP (?) → it is the mediator to decrease the venus tone
and so decrease peripheral arterial assistance
Renin - aka angiotensinogase; enzyme excreted by kidney in response to renal hypotension and
hypernatremia; blocking the renin relaxes the bv (blood vessel) thus decrease bp (blood pressure)
● Negative mechanism of homeostasis in which it is release when there is no blood pressure
Sympathetic receptors
- Alpha - increase intracellular calcium ion and muscle contraction, vasoconstriction effect
- Beta - increase intracellular cAMP, contract myocardium, relaxation of blood vessel
How do diuretics lower blood pressure?

34
- Reduce volume by promoting urination
B. Diuretic agents
- are useful antihypertensive drugs when employed alone, or in combination therapy, where they
potentiate the action of the other hypotensive drugs and it is believed to result from their ability to
produce a negative Na+ balance.
1. The thiazides are the most frequently used diuretics. Their early hypotensive effect is related to a
reduction in blood volume; their long-term effect is related to a reduction in peripheral vascular
resistance. Ex. generic names: chlorthalidone, chlorothiazides
2. Furosemide, ethacrynic acid, bumetanide produce greater diuresis than the thiazides, but they
have a weaker antihypertensive effect and can cause severe electrolyte imbalance. Because
they retain their effectiveness in the presence of impaired renal function, they are useful in cases
where renal function is so impaired that the thiazides can no longer promote sodium excretion.
● Can cause severe electrolyte imbalance → loop diuretics ginasali niya ang potassium
and lahat na nasa kanya ilabas niya rin (takes place in loop of henle)
● It also inhibits the sodium-potassium-chloride cotransporters in the loop of henle
3. Spironolactone (aldactone), triamterene, amiloride have modest hypotensive and diuretic
effects and are useful in combination with a thiazide diuretic, whose effects they potentiate and
where they minimize K+ loss. Spironolactone is useful in treating patients whose hypertension is
due to mineralocorticoid excess.
● Spironolactone is a potassium sparing
Aldosterone is a mineralocorticoid; it influences sodium and water balance. Remember your ADH
antidiuretic hormones
C. β -adrenergic blocking agents

- have become increasingly important as antihypertensive agents. These agents are useful both alone
and in combination antihypertensive therapy.
1. Their MOA in hypertension is not known, but several consequences of BB probably play a role;
BB reduce cardiac output. They also inhibit renin secretion.
● Mechanism: lower the blood pressure by increase the heart rate
2. Sympathetic selectivity. The various BB all appear to be equally effective for the treatment of
hypertension. However, they vary in their selectivity for adrenoreceptors
a. Propranolol, timolol, nadolol, pindolol, penbutolol, and carteolol are nonselective, while
metoprolol, acebutolol, and atenolol (in low doses) are cardioselective (I.e. they have a
greater effect on β1 adrenoceptors)
b. Labetalol is a nonselective BB but possesses intrinsic sympathomimetic activity and blocks
vascular postsynaptic α-adrenergic receptors.
3. Adverse effects. The BB antagonists can exacerbate CHF, asthma, and COPD. They can
mask symptoms of hypoglycemia in individuals with diabetes mellitus. They can increase serum
triglycerides and decrease HDL cholesterol (except BB with intrinsic sympathomimetic activity).
Labetalol, when used chronically, causes more frequent orthostatic hypotension and sexual
dysfunction than do other BB.
● What are the symptoms of hypoglycemia that can be mistakenly as symptoms of high
blood pressure
○ Symptoms of hypoglycemia are sweating, tiredness, dizziness, tingling,
sensations, trembling and palpitation.
D. Ca2+ channel blockers

- are rapidly becoming important antihypertensive agents by virtue of their vasodilating effects.
Verapamil and nicardipine have been approved for this therapeutic use.
1. Diltiazem, verapamil, nicardipine increase vasodilation and decrease peripheral resistance.
2. Verapamil and diltiazem cause little change in heart rate, while necardipine produces an initial
increase, which is reflex-mediated.
35
3. Diltiazem and verapamil depresses A-V conduction and should not be used with BB.
4. Diuretics may enhance the efficacy of CCB.
● Calcium decrease blood pressure by decreasing cardiac contractility or decreasing myocardial

contractility
Verapamil + BB results in additive negative inotropic, chronotropic effects on the heart; has to do with the force
and the rate (mechanism on the heart)
When calcium ion is blocked, it reduces electrical conduct within the heart, reduce force of contraction of
muscle cells (cardiac myocytes), dilates arteries, decrease BP (blood pressure).
E. Arteriolar vasodilators.
- Reduced arterial pressure by decreasing systemic vascular resistance
1. General considerations. This group of antihypertensive drugs directly relaxes arteriolar smooth
muscle, thus decreases peripheral vascular resistance and arterial blood pressure. These drugs
can increase plasma renin activity as a result of increased reflex sympathetic discharge, causing
a pressor effect. This group of drugs often causes salt and water retention, thus expansion of
the ECF and plasma volume. Arteriolar vasodilators should be used in conjunction with diuretic
and BB therapy.
2. Hydralazine (brand name: Apresoline). This phthalazine derivative has a greater effect on
arterioles than on veins (which minimizes the incidence of postural hypotention). It may reduce
diastolic more than systolic blood pressure.
a. Pk. Hydralazine is well absorbed orally. It is subject to extensive first-pass hepatic
metabolism after oral administration, some 85% is bound to plasma. Tolerance develops
after 24 months of therapy.
b. Route of admin. Can be given orally or IM.
c. Therap. Uses. Hydralazine is used to treat moderate to severe hypertension. It has also
been used in the treatment of acute and chronic CHF. For long-term therapy, it is
administered orally. It is combined with a diuretic agent to prevent salt and water retention.
d. A/E. headache, anorexia, nausea, dizziness, and sweating occur frequently but tend to
diminish as hydralazine is administered over a period of time. It can worsen coronary artery
disease because of the myocardial stimulation it produces. It can also cause reversible
lupus-like syndrome, especially when more than 400mg/day are administered to slow
acetylators of the drug (usually caucasians)
3. Minoxidil. It is at least 90% absorbed following oral administration and 90% of the drug is
excreted as metabolites in the urine. The duration of action may be significantly longer, since it is
affected by hepatic blood flow and function. It is used to treat baldness.
a. Pharmacologic effects. A piperidinopyrimidine derivative, directly relaxes arteriolar smooth
muscle. It decreases peripheral vascular resistance more than hydralazine does.
b. Route of admin. orally in single or divided doses.
c. Therap uses. Minoxidil is indicated for the treatment of severe hypertension that does not
respond adequately to more conventional antihypertensive therapy. It may be particularly
useful for severe hypertension coupled with renal functional impairment. It should be used in
combi with a BB and a diuretic to avert increased sympathetic activity and salt and water
retention.
d. A/E. like hydralazine, minoxidil can produce s/e related to increased reflex sympathetic
stimulation and to salt and water retention. Hirsutism (excessive growth of hair) can occur
for unknown reasons.
● Side effects: grows hair
● Thus, this is used topically as shampoo for its effect of hirsutism.
36
4. Diazoxide is chemically similar to thiazide diuretics, but it causes salt and water retention rather
than diuresis. It is used as antihypertensive in IV form only, it is extensively bound to serum proteins.
It exerts its vasodilator effect principally on arterioles It inhibits the release of insulin, thus produce
hyperglycemia. IV diazoxide is one of the two major drugs used for hypertensive emergencies. It is
also used orally to treat hypoglycemia that is caused by hyperinsulinemia.
● Diazoxide is used to treat hypoglycemia and it is not used as diuretic.
F. Arterial and venous vasodilators.

- These drugs reduce both arterial resistance and venous tone and markedly decrease arterial blood
pressure.
1. Sodium Nitroprusside. Onset of action occurs within 1 minute of IV administration, and effects cease
within 5 minutes of stopping an infusion. It is rapidly inactivated by hepatic enzymes , first to cyanide
and then to thiocyanate.
a. Pharmacologic effects. It acts directly on arterial and venous smooth muscle but has little effect
on other smooth muscle. It decreases BP on both the supine and upright positions. It causes a
slight increase in heart rate and decrease in cardiac output except when heart failure is present; in
the latter case, the heart rate may decrease and the cardiac output increase.
b. Route of admin. Na+ nitroprusside is administered only as an IV infusion with sterile 5% dextrose
in water. Once prepared, the solution must be protected from light and used within 4 hours. BP
must be monitored continuously while the drug is being given.
c. Therapeutic uses. Like diazoxide, it is used for short-term, rapid reduction of BP in hypertensive
emergencies. It can also be used to produce controlled hypotension to minimize bleeding during
surgery.
d. A/E. hypotension, nausea, diaphoresis , headache, restlessness, palpitations, and retrosternal pain
can occur secondary to excessive, rapid vasodilation. Rarely, when high doses of nitroprusside are
administered for a prolonged period and sulfur stores are low, cyanide toxicity can occur.
2. Prazosin. This quinazoline derivative is a selective postsynaptic α1-adrenergic receptor blocking

agent that causes vasodilation of both the arteries and veins.
a. Pk. Prazosin is highly bound to plasma protein. It is extensively metabolized, and it may undergo
significant first-pass metabolism, has a bioavailability of about 60%, and is probably excreted in the
feces and bile.
b. Pharmacologic effects. Prazosin reduces peripheral vascular resistance and lowers arterial blood
pressure in both supine and erect patients. It does not increase plasma renin activity. Fluid retention
occurs during long-term therapy. It is given orally, two or three times daily.
c. Therapeutic uses. Prazosin is used to treat mild to moderate hypertension . it may be more
effective in conjunction with a diuretic or an a-adrenergic blocking agent than when used alone. It
is also used in the treatment of acute CHF.
d. A/E. Dizziness, headache, drowsiness, and palpitations can occur.It is best to give the initial dose
at bedtime as it can induce postural hypotension and syncope.
3. Terazocin. This a-adrenergic receptor blocker has a longer half-life (12 hours) and longer duration
of action (24 hrs) than does prazosin but is otherwise similar to it.
G. Centrally acting sympatholytic agents.

- Clonidine and methyldopa act centrally on the vasomotor centers of the brain and are predominantly
α-receptor agonists.
- Opposite action of sympathomimetic
Sympathomimetic subclasses
- Alpha 2 receptors - receptors have sympatholytic properties meaning it decreases neurotransmitter
release; in the brain stem ___, and inhibit sympathetic activity thus decrease BP
- Alpha 2 agonists - because they inhibit sympathetic activation and thus decrease unsa daw skfjsdnfl
37
1. Clonidine. (Brand name: Catapres) This imidazoline derivative is thought to stimulate a-adrenergic
receptors in the vasomotor centers of the brain resulting in decreased sympathetic outflow of the
peripheral vessels. The antihypertensive effects develop within 30-60 minutes of oral administration,
peak in 2-4 hours, and last for approx 8hrs. Its metabolites are excreted primarily in the urine.
a. Route. Clonidine is given orally, often administered in two unequal doses with the larger one given
at bedtime to minimize problems resulting from its sedative effects. It is also available as a
transdermal patch, which is applied once weekly.
b. Therapeutic uses. Clonidine can be used to treat mild hypertension. It can be used as a single
agent or in combination with other antihypertensive agents. It cannot be administered to patients
taking TCA (tricyclic antidepressants) because these drugs block its hypotensive effects.
c. A/E. Dry mouth, drowsiness, and sedation are the most frequent problems and may require
discontinuation of clonidine. Rebound hypertensive crises can result from abrupt cessation of
clonidine tablets or patches when the drug is used as a single agent. Fluid retention often occurs,
requiring concurrent diuretic therapy. Clonidine can cause or worsen depression.
Why does it worsen depression? - works by affecting the activity of NE (norepinephrine) which normally
influences BP, heart rate and anxiety in the body, attention and arousal; this medication stabilizes certain areas
in the brain making them less excited; inhibits signals of Epinephrine and norepinephrine.
2. Methyldopa. (Brand name: Aldomet)

- alpha 2 agonist and sympatholytic agent
a. MOA.
1) Methyldopa is an effective inhibitor of dopa decarboxylase and was initially thought to act as
an antihypertensive agent by decreasing stores of NE in the SNS. However, its primary
MOA is via a central effect (in the brain).
- It stimulates the brain to decrease the activity of the SNS; decrease NE
- Reduces plasma renin activity due to negative feedback mechanism because increased
renin contributes to HTN (hypertension) due to increased sodium
- methyldopa acts in the renin
- Alpha receptors are located in the arteries, when stimulated by Epinephrine or
Norepinephrine, the arteries constrict thus increasing BP (blood pressure)
2) It is metabolized by decarboxylation and β-hydroxylation in adrenergic neurons of the CNS.
The metabolite α-methylnorepinephrine, stimulates a-adrenergic receptors in the brain,
inhibiting sympathetic outflow, and believed to be the principal mechanism by which
methyldopa exerts its antihypertensive effect.
b. PK. It is poorly absorbed following oral admin and is subject to first-pass intestinal metabolism.
Its peak effect is exerted 4-6 hrs after administration, its effect may last up to 24 hrs.
Methyldopa is excreted largely by the kidneys.
c. Route of admin. given orally or by slow IV infusion.
d. Therap.uses. Used orally to treat mild or moderate to severe hypertension, usually in combi
with a diuretic. Adverse effects limit its usefulness.
e. A/E. Sedation is common, and although it may decrease with continued administration of
methyldopa, mental acuity may remain decreased. It can produce “drug fever” that mimics
sepsis, with chills and high fever. Febrile episodes may be accompanied by alterations in liver
function, which in rare occasions terminate in hepatic necrosis. Edema caused by salt and
water retention can develop if a diuretic is not administered. Rebound hypertension can follow
the sudden withdrawal of methyldopa but occurs less frequently than with clonidine. Orthostatic
hypertension occurs frequently. Lactation can occur in any sex, impotence can occur in some
men. Mild GI disturbances can occur.
H. Agents that block postganglionic adrenergic neurons..
38
- This group of drugs selectively inhibits sympathetic neuron function through interference with chemical
mediation at ganglionic nerve endings.
1. Reserpine
a. MOA. Reserpine, a rauwolfia alkaloid, depletes catecholamine and serotonin stores in the
peripheral and central nervous systems and causes impaired sympathetic nerve discharge. It
interferes with intracellular storage of catecholamines by inhibiting the binding of NE to
neurosecretory vesicles, both centrally and peripherally. NE that diffuses from the storage site is
degraded intracellularly by MAO. Reserpine decreases the synthesis of NE and increase its
turnover rate.
- Lipid soluble therefore it penetrates the blood brain barrier
- Catecholamines - role is to respond to the fight and flight (Epinephrine and norepinephrine)
- Prevents further synthesis of EPI by the MAO??
b. Pharmacologic effects. Reserpine decreases BP, usually decreases heart rate and cardiac
output, and may decrease peripheral vascular resistance. Reserpine exerts central actions that
produce sedation.
c. Route of adm. Reserpine is usually given orally but is also available as parenteral admin.
d. Therap.uses. Used principally in low oral doses in combination with other antihypertensive agents
to control moderate hypertension.
e. A/E. Reserpine regularly causes sedation and can cause episodes of severe depression, which are
due to reduction of biogenic amine levels in subcortical areas of the brain. It should not be
administered to patients prone to depression. Because reserpine decreases sympathetic activity,
unopposed parasympathetic activity can result in bradycardia, nasal congestion, and increased GI
activity. It is contraindicated in patients with active peptic ulcers (because it increases acid
secretion by the reserpine).
- Depression - decrease in epi and norepinephrine
2. Guanethidine. Initially, guanethidine displaces and releases enough unchanged NE to cause mild,
transient hypertension and cardiac stimulation. Hypotension and bradycardia follow. Because
guanethidine depresses vasoconstrictor reflexes, BP are reduced significantly more when the patient is
erect than when lying down. Venous return and cardiac output are decreased. Guanethidine has a direct
inhibitory effect on skeletal muscle contraction. It increases the sensitivity of tissues to catecholamines.
It is given orally in the treatment of moderate to severe hypertension, usually in combination with thiazide
diuretic and a vasodilator. Significant orthostatic hypotension and syncope (tendency to pass out)
frequently occur, esp during exercise, when patient first arise in the morning, during hot weather, and when
patient ingest alcohol.
I. Drugs that interfere with the renin-angiotensin system.
- The kidneys synthesize renin, which acts on plasma globulin substrate to produce angiotensin I. This
in turn is converted (by peptidyl dipeptidase) to angiotensin II, a potent vasoconstrictor. Drugs in this
group exert an antihypertensive effect by interfering with either the formation or the utilization of
angiotensin II.
- RAAS decreases BP by controlling water and sodium by interfering with the formation or utilization of
angiotensin II
1. Captopril , enalapril, and lisinopril (CEL)
- Captopril is an inhibitor
- Action of angiotensin II is vasoconstriction
- Renin - primary function is to increase bp in maintaining homeostasis ?
- If patient is hypertensive, iwasan ang renin????
39
a. Chemistry. Enalapril is a prodrug that is hydrolyzed in the liver to the active compound enalaprilat.
It differs structurally from captopril in lacking a sulfhydryl (SH) group. Lisinopril is the lysine analog
of enalaprilat.
b. MOA. CEL are specific competitive inhibitors of peptidyl dipeptidase (an ACE), the enzyme that
converts angio1 to angio2; therefore termed as ACE inhibitors. Angio1 is a potent direct
vasoconstrictor, thus CEL inhibit vasoconstriction. Angio2 stimulates the secretion of aldosterone
(ADH), which promotes (increase) salt and water retention, thus. CEL inhibit salt and water
retention and slightly increase serum K+ levels.
- If di mainihibit si ACE, maggamit siya ng ARBs or pwede combination
Because peptidyl dipeptidase is necessary to catalyze the degradation of bradykinin, the ACEI
may increase the concentration of bradykinin, which is a potent vasodilator. ACEI also exert an
antihypertensive effect in low-renin hypertension.
c. PK. Captopril is rapidly absorbed following oral administration and reaches peak blood levels
within an hour. Approx 95% of a dose is eliminated by the kidneys within 24 hrs. Enalapril is more
potent than captopril, and its duration of action is more than 24 hrs, twice as long as that of
captopril. Lisinopril is more absorbed slowly than enalapril and has a slower onset of action.
- Active form of captopril is enalapril.
- Captopril → brand name of Capoten as sublingual
d. Route of admin. Captopril is given orally, 1 hour before meals. The initial dose can be increased
at 1- to 2-week intervals. It has been administered sublingually, in which case the onset of action
may occur within 10-20 minutes, with the maximal effect reached within 1 hour. Enalapril is given
once or twice a day orally. Lisinopril is once a day orally.
e. Therap. Uses.
1) ACEI are increasingly used for the treatment of mild to moderate hypertension because they
are without the side effects associated with adrenergic blockers. ACEI are effective for
low-renin, as well as high-renin, hypertension. They are effective when used alone but are
often administered with a thiazide diuretic, in which case the antihypertensive effects
appear to be additive. An ACEI can also be given with a BB, but in this case, the
antihypertensive effect appears to be less than additive.
2) ACEI also relieve chronic CHF by reducing both preload and afterload.
3) These agents may be less effective than a diuretic for hypertension in black patients.
f. A/E.
1) Proteinuria can occur, esp in patients with compromised renal function. Monitoring of
urinary protein levels is recommended.
2) ACEI are contraindicated in patients with bilateral renal artery stenosis because acute renal
failure may ensue because there is narrowing of arteries that carry blood to both kidneys
often in people with atherosclerosis.
3) Hypotension has followed the first dose of ACEI in Na + -depleted patients.
4) Headache, dizziness, and fatigue are the most common s/e associated with enalapril.
5) Cough and bronchospasm can occur.
ACE inhibitor - decrease peptidyl dipeptidase (convert angio 1 and angio2) therefore increasing bradykinin
● When peptidyl dipeptidase is depleted, there is an increase in bradykinin
Bradykinin - potent vasodilator; stimulates prostaglandin - proinflammatory chemical, stimulates mucus (when
there is inflammation, there is mucus production) (too much mucus results to coughing)
- Destroyed by peptidyl dipeptidase
- Use ace inhibitor, proliferate bradykinin
2. Drugs that block receptors for angiotensin. Salarasin is an angiotensin II analog, exemplifies the
drugs that interfere with the renin-angiotensin system by this mechanism. These drugs can be given
only by IV infusion, they are primarily used diagnostically to detect a renal cause of hypertension.
- ACTION: DECREASE BP similar to mechanism of ACE inhibitor; angiotensin II analog
40
Action of ARBs - blocks receptors for angiotensin II; prevent angiotensin II from binding to its receptors so that
blood vessels or BV dilates
- dilation of the blood vessel there is relaxation therefore blood pressure will decrease
V. DRUGS USED IN THE TREATMENT OF CORONARY ARTERY THROMBOSIS.
More than 80% of patients with acute transmural myocardial infarction demonstrate thrombotic coronary artery
occlusion within 6 hours of symptoms. Streptokinase, urokinase, and tissue-type plasminogen activator
(t-PA) are available for IV administration in the treatment of coronary artery thrombosis associated with
myocardial infarction.
a. MOA.
1. Streptokinase, urokinase, and t-PA all facilitate the conversion of plasminogen to plasmin. Plasmin is
fibrinolytic.
● Plasminogen - the inactive precursor of plasmin, the major enzyme that degrades fibrin clots
● Plasmin - major important enzymes that degrades fibrin clots; breaks down fibrin (fibrinolytic
agent)
● Fibrin - causes blood clots; is an insoluble protein formed from fibrinogen during the clotting of
blood; it impedes (delay/prevent/obstruct) the blood flow to stop bleeding
● Hemostan - antifibrinolytic agent; arrest bleeding to form clots; opposite effect; promote
formation of clot
● Fibrinolytics - also known as thrombolytics
● Fibrinogen - is a glycoprotein (GP) complex made in the liver that circulates in the blood
meaning it is soluble
2. Because t-PA is more selective than the kinases, it has a high affinity for fibrin and induces the
degradation of plasminogen to plasmin only in the presence of fibrin. Theoretically, it should be less
likely to have systemic effects on clotting.
b. PK. The plasma half-life of t-PA is 5 minutes, compare to 16 minutes of urokinase and 23 minutes for
streptokinase.
c. Therap. Uses. Both t-PA and streptokinase have comparable efficacy in the reduction of mortality and
improvement of left ventricular function. Streptokinase appears most effective when given less than 3
hours after the onset of symptoms. Thrombolytic therapy is begun as soon as possible after the onset
of symptoms of myocardial infarction. Streptokinase is given by IV or intracoronary infusion.
Urokinase is infused into the occluded coronary artery, while t-PA is given by IV admin only.
d. A.E and C/I. Serious bleeding can occur; most importantly GI and intracranial hemorrhage are
possible. Streptokinase can cause anaphylaxis. With any thrombolytic agent, cardiac arrhythmias can
occur upon reperfusion of the occluded vessels. Contraindications to the use of thrombolytic agents
include internal bleeding, cerebral vascular accident, recent intracranial or intraspinal trauma, or
surgery, known bleeding diathesis, or severe uncontrolled hypertension.
VI. DRUGS USED IN THE TREATMENT OF HYPERLIPIDEMIA
Assignment: Flipped classroom - prepare for a quiz on this on saturday potangina HAHAHAHA :’)
● vidwatch: https://www.youtube.com/watch?v=Of1Aewx-zRM (Pcol of hyperlip.)
AKA HYPERLIPOPROTEINEMIA
Too many lipids (fats) from food intake
● Types: glycerol and triglycerides
Hypercholesterolemia
- Too much LDL cholesterol in the blood
Transcript:
41
In this lecture we gonna cover drugs used for hyperlipidemia so let's get right into it
● Hyperlipidemia simply is a disorder in which there are abnormally elevated levels of fat particles in the
blood known as lipids
○ Lipids can adhere to the walls of the arteries and restrict blood flow which in turn creates
significant risk of heart attack and stroke
○ There are three major lipids in the blood namely
■ Cholesterol, Triglycerides and Phospholipids
● Cholesterol is necessary for the synthesis of bile acid, steroid hormones and to
maintain the integrity of cell membranes
● Triglycerides are composed of glycerol and three fatty acids which serve as an
important source of energy that can be stored throughout the body
● Phospholipids are a major component of all cell membranes and function as an
emulsifiers
○ Because these lipids are insoluble in blood plasma, they have to be transported throughout the
body in a protein capsule known as lipoprotein
■ Lipoproteins consist of a hydrophobic core made of cholesterol and triglycerides
surrounded by hydrophilic shell made of phospholipids and apolipoproteins
● Apolipoproteins are specialized proteins that can control enzymes in lipoprotein
metabolism and serve as ligands for lipoprotein receptors depending on the
variation in lipid and apolipoprotein composition as well as their density
■ lipoproteins can be divided into four major types
1. Chylomicrons - are produced in the gut from dietary lipids and are composed
mostly of triglycerides and relatively small amount of cholesterol
2. Very low-density lipoprotein - VLDL
3. Low-density lipoprotein - LDL (bad cholesterol)
4. High-density lipoprotein - HDL (good cholesterol)
Chylomicrons are produced in the gut from dietary function of LDL is simply to deliver this cholesterol
lipids and are composed primarily of triglycerides to cells where it's used for cell membrane and
and relatively small amount of cholesterol. synthesis of steroid hormones. However, more than
half of the circulating LDL is eventually taken up by
VLDLs are produced in the liver and are composed the liver which uses cholesterol to synthesize bile
primarily of triglycerides and some cholesterol in acids.
the amount relatively larger in comparison to
chylomicrons. Bile acids are necessary for normal digestion and
absorption of fats and fat soluble vitamins in the
The function of these two lipoproteins is to deliver small intestine. Lastly, excess cholesterol from the
energy-rich triglycerides to cells throughout the peripheral cells is transported back to the liver by
body. Once they are secreted into the bloodstream, HDL.
the enzyme located on the capillary walls called
lipoprotein lipase, releases the fatty acids which HDL is composed mainly of protein with small
are then taken up by the tissues. amount of lipids and it is produced in the liver and
small intestine. The problem arises when we have
As the triglyceride content decreases, the VLDL abnormally high levels of LDL cholesterol which
gets transformed into LDL which now contains can accumulate in the innermost layer of the artery
relatively higher percentage of cholesterol. The wall and lead to formation of atherosclerotic
42
lesions. This is why LDL is often referred to as bad

cholesterol.
HDL, on the other hand, prevents formation of

atherosclerotic lesions by removing cholesterol as
well as suppressing LDL oxidation and vascular
inflammation. This is why HDL is often referred to
as a good cholesterol. So abnormally low levels of
it can also contribute to atherosclerosis.
There are several major classes of lipid

lowering drugs.
Secondly, use of statins has been associated with
muscle related problems or myopathy and in rare
First, we have HMG-CoA reductase inhibitors
cases rhabdomyolysis that is destruction of
commonly known as statins. In order to better
skeletal muscle. The mechanism behind that is still
understand how these agents work, we need to
being investigated. However, it is thought to be
take a closer look at the liver cell. This is where
related to the inhibition of mevalonate production
HMG-CoA reductase enzyme converts HMG-CoA
which happens to be an essential precursor to
into mevalonic acid which is a cholesterol
other compounds that are important to maintain the
precursor. This is a rate limiting step, so by
integrity of muscle cells.
inhibiting this enzyme, statins effectively reduce
concentration of cholesterol within the liver cell.
Liver cells sense the reduced levels of cholesterol
production and begin to compensate by
synthesizing more LDL receptors which in turn bind
and internalize LDL that's circulating in the blood.
Additionally, low intracellular cholesterol levels lead
to decreased secretion of VLDL which also
contributes to lowering of triglyceride levels. Lastly,
statins may also increase HDL levels by few
different mechanisms that are still being
investigated.
Ex. 'of drugs that belong to this class are
Atorvastatin, Fluvastatin, Lovastatin,
Pravastatin, Rosuvastatin, and
Simvastatin.When it comes to side effects,
because statins are metabolized in the liver, they
may elevate liver enzymes and thus increase risk of The next group of lipid lowering drugs which
liver toxicity in susceptible patients. includes only one agent that is Nicotinic Acid
commonly known as Niacin. So unlike statins,
Niacin works in adipose tissue where it inhibits an
enzyme called hormone-sensitive lipase which is
responsible for breakdown of triglycerides to free
fatty acids. Normally, the liver uses these free
fatty acids to make its own triglycerides which then
become an important component of VLDL. So by
reducing levels of free fatty acids available for
43
transport to the liver, Niacin effectively decreases One of the main effects induced by fibrates is
hepatic VLDL synthesis which in turn leads to increased expression of lipoprotein lipase which
decreased levels of LDL. Furthermore, Niacin in turn increases the removal of triglycerides from
increases HDL levels by a few different circulation and their breakdown to fatty acids.
mechanisms that are still being investigated now. Furthermore, fibrates decrease expression of a
protein called Apo-CIII which inhibits lipoprotein
Side effects: lipase activity. Lastly, fibrates also increase
expression of proteins Apo-AI and Apo-AII which
are major component of HDL thus leading to
increase in its concentrations.
Drugs that belong to this class include:

Fenofibrate and Gemfibrozil
When it comes to side effects:

● When it comes to side effects, one of the ● The most common ones are GI
most common ones is flushing caused by disturbances
Niacin induced prostaglandin release which ● Additionally just like with statins, myopathy
results in cutaneous vasodilation. and rhabdomyolysis have been reported
● Next, Niacin can compete with uric acid for particularly in patients with impaired renal
excretion by the kidney which can increase function. The precise mechanism of
risk of hyperuricemia and gout. myotoxicity is still yet to be determined
● Lastly, at large enough doses, Niacin may however it is thought to be multifactorial
also cause liver toxicity. ● Lastly, because fibrates increase the
cholesterol content of bile they can
increase risk of gallstone formation
Another group of lipid lowering drugs is fibrates.

So, fibrates work primarily by activating nuclear
transcription receptor called peroxisome
proliferator-activated receptor alpha or The next group of lipid lowering drugs is bile acid
PPAR-alpha for short. PPAR-alpha is found in sequestrants. So, as you already know bile acids
metabolically active tissues such as liver and are produced in the liver stored in the gallbladder
adipose tissue. The binding of fibrates to and they're excreted into the gut where they
PPAR-alpha induces activation or inhibition of facilitate digestion and absorption of lipids. Bile
certain genes that code for proteins involved in lipid acids sequestrants basically serve as an ion
metabolism. exchange resins that bind negatively charged bile
44
acids and salts in the small intestine. The formation internalize the cholesterol cargo upon endocytosis.
of this insoluble complex prevents the reabsorption The cholesterol is released and the NPC1L1
of bile acids and thus leads to their excretion. This returns back to the plasma membrane. Now, the
increase in bile acid excretion in turn creates cholesterol absorption inhibitor simply binds to
increased demand for their production. Since bile NPC1L1 and inhibits its ability to interact with
acids are made from cholesterol, liver cells clathrin AP2 complex that is necessary for
increase their number of LDL receptors to bring in endocytosis. This leads to decreased delivery of
more LDL cholesterol. In order to meet this new intestinal cholesterol to the liver which in turn
demand the end result is decreased levels of causes decrease in hepatic cholesterol levels
circulating LDL. and ultimately increased clearance of LDL
cholesterol from the circulation.
Example of drugs that belong to this class are:
Colesevelam Colestipol and Cholestyramine
Side effects are limited to the GI tract. So, bloating,

indigestion, constipation and nausea are quite
common. Additionally, these agents may decrease
absorption of fat soluble vitamins and they also
have potential to form insoluble complexes with
other drugs thus interfering with their absorption.
Currently the only drug that belongs to this class is

Ezetimibe. The side effects of Ezetimibe are few
and mild which makes it a good choice for
patients intolerant or unresponsive to statins.
Now let's move on to the next group of lipid

lowering drugs that is PCSK9 inhibitors. So
PCSK9 is an abbreviated name of enzyme
circulating in the blood that binds to LDL receptors
on the surface of liver cells and promotes their
degradation. In other words the activity of PCSK9
reduces the removal of LDL from the
Another group of lipid lowering drugs is cholesterol circulation.
absorption inhibitors. In order to understand how
cholesterol absorption inhibitors work, it's important Now the PCSK9 inhibitors are monoclonal
to understand the basic mechanism of cholesterol antibodies that bind to and inactivate PCSK9. In the
absorption in the small intestine. absence of PCSK9, there's more LDL receptors
available to bind and clear LDL from the decreased
So free cholesterol that comes either from bile or levels of LDL cholesterol. Example of drugs that
dietary sources first binds to protein abbreviated belong to this group include Evolocumab and
NPC1L1 which is located in the plasma membrane Alirocumab. Some of the side effects that have
of cells known as enterocytes that line the been reported with these agents are injection site
intestinal walls. This binding then triggers reactions, flu-like symptoms and some
endocytosis which utilizes a protein complex called neurocognitive problems.
clathrin AP2 that works on the cell membrane to
45
Last major group of lipid lowering drugs is omega-3 fishy aftertaste with fish-derived omega-3s. Lastly
fatty acids. So, omega-3 fatty acids are used at high enough doses there appears to be some
primarily for their triglyceride lowering effects increased risk of bleeding.
which are thought to be caused by inhibition of
VLDL and triglyceride synthesis in the liver. The
agents that fall into this class are the components
of omega-3 fatty acids called docosahexaenoic
acid and eicosapentaenoic acid, DHA and EPA
for short as well as omega-3 derivative Icosapent
ethyl. The most common side effects associated
with these agents are GI disturbances such as
abdominal pain nausea and diarrhea as well as
● Vid watch:
https://www.youtube.com/watch?v=g_8UPKMovJI (MOA of
drugs)
Transcript:
Anti-hyperlepidemic drugs include the statins, niacin,

fibrates, bile acid-binding resins, a cholesterol absorption
inhibitor and omega-3 fatty acids. These agents may be
used alone or in combination and they should always be
accompanied by lifestyle modifications such as exercise and a
diet low in saturated fats.
HMG-CoA inhibitors are also known as statins. There are

seven agents in this category:
● Pitavastatin (Livalo)
● Rosuvastatin (Crestor)
● Atorvastatin (Lipitor)
● Simvastatin (Zocor)
● Pravastatin (Pravachol)
● Lovastatin (Mevacor)
● Fluvastatin (Leschol XL)
46
Mechanism of Action:
They are competitive inhibitors of HMG CoA reductase which is the rate limiting step in cholesterol
synthesis and this leads to inhibition of de novo cholesterol synthesis. So, they deplete the intracellular supply
of cholesterol then depletion of intracellular cholesterol causes the cell to increase the number of cell surface
LDL receptors and that promotes the uptake of LDL from the blood.
So, we can say that plasma cholesterol is reduced by both decreased cholesterol synthesis and increased LDL
catabolism. These agents also decrease triglyceride levels and may increase HDL cholesterol levels in some
patients.
Potency of these drugs differs. Pitavastatin, rosuvastatin and atorvastatin are the most potent LDL
cholesterol lowering statin drugs followed by simvastatin, pravastatin and then lovastatin and fluvastatin.
These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias. Reduction of
elevated total and LDL cholesterol levels to slow progression of coronary artery disease along with diet and
exercise so reduce the risk of stroke and myocardial infarction.
Side effects of these agents include:
● Elevated liver enzymes. So, liver functions should be evaluated before starting therapy and if a patient
has symptoms consistent with liver dysfunction.
● Myopathy and rhabdomyolysis. Disintegration of skeletal muscles have been rarely reported usually
in patients with renal insufficiency or taking drugs such as erythromycin, gemfibrozil or niacin. So
plasma-creatine kinase levels should be determined in patients with muscle complaints.
● These agents may also increase the effect of warfarin
47
● They are contraindicated during pregnancy and lactation.
(end of transcript)
1. Classes of lipoproteins and transport pathways
a. Exogenous pathways (exo -> from diet)
1) Chylomicrons are formed from dietary triglycerides and cholesterol
- Also known as ultra low density lipoprotein that consists of triglycerides, phospholipids,
cholesterol and proteins
- Function: they transport dietary lipids from the intestines to other locations in the body
- ULDL
2) In adipose tissue and muscle, the enzyme lipoprotein lipase removes the triglycerides, leaving
chylomicron remnants containing intact cholesterol esters.
3) When chylomicron remnants reach the liver, they are taken up by hepatocytes and then cleaved,
releasing free cholesterol.
Free cholesterol - increase the packing of phospholipids; serves to stabilize cell membranes
4) The cholesterol can be:

a) Stored in hepatocytes as cholesterol esters
b) Released in bile as cholesterol or as bile acids - excessive cholesterol results to
accumulation, then hardening which forms gallstones and then it is not permeable in the
area
c) Used to form membranes or endogenous lipoproteins
b. Endogenous pathways
1) Very low-density lipoprotein (VLDL) is formed in the liver from triglycerides and cholesterol,
generally as a result of high caloric intake.
- Test for VLDL - high ___ proves that there is something wrong with the gallbladder
2) VLDL is released into the plasma, where lipoprotein lipase cleaves the triglycerides from VLDL.
3) The hydrolysis of VLDL produces intermediate-density lipoprotein (IDL). The metabolic fate of
IDL is twofold:
a) Some IDL particles are taken up by the liver via endocytosis and then cleaved to produce
free cholesterol. This receptor-mediated action is via the low-density lipoprotein (LDL)
receptor.
b) Some IDL particles remain in the circulation where triglycerides are removed so that IDL is
eventually metabolized to LDL.
4) LDL is involved in the transport of endogenous cholesterol ester to the liver or to extrahepatic
tissues. LDL constitutes 60%-70% of plasma cholesterol levels. Metabolic demand for cholesterol
(for synthesis of bile acids, steroids, or membranes) is met by increased synthesis of LDL receptors,
which promote endocytosis and release of free cholesterol.
- Bad cholesterol
- L - lechon aka bad because it collects in the walls of blood
5) High-density lipoprotein (HDL) is involved in the transport of cholesterol from peripheral cells
back to the liver. HDL absorbs free cholesterol released during cell turnover. The cholesterol is
esterified by the enzyme lecithin: cholesterol acyltransferase (LCAT), and the cholesterol seters
are transferred to VLDL or IDL particles.
- Good cholesterol
- Mainly secreted by the liver; contains high amount of protein and low amount of lipids
Total Cholesterol - consists of free cholesterol and cholesterol esters; commonly in adrenal glands
Two types of lipids in the blood
48
1.) Triglycerides - stores unused calories and provide the body with energy;
2.) Cholesterol - used to build cells and certain hormones
- Hormones are cholesterol-based
c. Nonspecific pathways. When plasma lipoprotein concentrations are high, macrophages and other
scavenger cells take part in lipoprotein degradation. This leads to cholesterol deposits in macrophages or
arterial walls (atheromas) and of tendons and skin (xanthomas).
- Xanthomas - discoloration of the skin; Xanthomas are lesions on the skin containing cholesterol and
fats. They are often associated with inherited disorders of lipid metabolism (inherited problems with the
way that fats are broken down and used). Xanthomas are raised, waxy-appearing, frequently
yellowish-colored skin lesions.
- An atheroma (plaque) is a fatty material that builds up inside your arteries. It's made of cholesterol,
proteins and other substances that circulate in your blood. Atheromas grow over time and may lead to
coronary artery disease, peripheral artery disease, heart attack or stroke.
Classification of lipoproteins
Classification Composition Primary function
Chylomicrons Triglyceride TGs 99%, 1% protein Transport dietary TGs to adipose tissue &
(exogenous muscle (exogenous)
pathway from
the diet)
VLDL Newly synthesized TGs Lipid 90%, Transport endogenous TGs to adipose
10% protein tissue & muscle
IDL Intermediate between VLDL & LDL Not usually detectable in the blood
LDL Lipid 80%, 20% protein Transport endogenous cholesterol from

liver to tissues
HDL Lipid 60%, 40% protein Collect cholesterol from the body’s
tissues, and take it back to the liver
2. Hyperlipoproteinemias
- increased cholesterol in blood; also known as high cholesterol
a. Causes.
1) Primary hyperlipoproteinemias , may be single-gene congenital defects or polygenic
(multifactorial)
2) Secondary hyperlipoproteinemia may occur in diabetes, hypothyroidism, alcoholism, biliary
cirrhosis, or renal disease, or in women taking oral contraceptives.
b. Use of drug therapy
1) In persons with hyperlipoproteinemia, lowering the serum lipid concentration reduces the risk of
atherosclerosis and its consequences. Specifically, a reduction in plasma LDL can reduce the risk
of coronary heart disease (CHD).
2) Some types of hypertrigyceridemia can cause life-threatening pancreatitis.
3) Drug therapy is usually tried after dietary fat restriction, reduction of atherosclerosis risk factors, and
moderate exercise programs have failed to lower serum lipids to an acceptable level.
49
4) Bile acid sequestrants, niacin, β-hydroxy-β-methylglutaryl coenzyme A (HMGCoA) reductase

inhibitors, and fibric acid derivatives demonstrably lower the risk of coronary artery disease; only
niacin has been shown to reduce overall mortality.
B. Antihyperlipidemic agents
● Cholestyramine, colestipol: bile acid sequestrants

a. MOA and pharmacologic effects
1) Cholestyramine and colestipol are resins that bind bile acids in the intestine, forming insoluble
complexes, which are then excreted in the feces.
2) The loss of bile acids leads to an increased conversion of cholesterol into bile acids
3) There is also a compensatory increase in hepatic LDL receptors
4) The net effect is a reduction in serum LDL and cholesterol levels.
b. Therapeutic uses.
1) The earliest use of bile acid sequestrants was to control pruritus in patients with cholestasis and
elevated plasma bile acids.
2) These agents are now also used to reduce elevated LDL levels.
3) Patients with heterozygous familial hypercholesterolemia or polygenic hypercholesterolemia can
be expected to respond.
4) The bile acid sequestrants are not effective for treating patients with elevated chylomicrons,
VLDL, or IDL; in addition, these agents elevate triglyceride levels.
c. A/E.
1) Since bile acids sequestrants are not absorbed, they have no adverse systemic effects.
2) The most common untoward effects are gastrointestinal discomfort and constipation
3) The resin may cause or aggravate steatorrhea (feces contain fatty materials) and may impede
absorption of fat-soluble vitamins
4) These agents may bind to other drugs (e.g. chlorothiazide, anticoagulants, digitalis glycosides),
impeding their absorption.
● STATINS: HMG CoA reductase inhibitors

- E.g. atorvastatin, simvastatin etc. “statin” drugs
- HMG CoA - hydroxymethylglutaryl coenzyme reductase
a. MOA.
1) 3-HMG CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis.
2) Drugs that inhibit HMG CoA reductase are highly effective in lowering serum LDL-cholesterol
levels.
a) HMG CoA reductase inhib block the hepatic synthesis of cholesterol
b) This block leads to a compensatory reduction in serum LDL
c) There is also a compensatory increase in synthesis of HMG CoA reductase so that
inhibition of cholesterol synthesis is not complete.
3) These drugs reduce serum levels of LDL, LDL-Cholesterol, VLDL-cholesterol, and triglycerides.
They elevate HDL-cholesterol.
b. Therapeutic uses. Statin is indicated for patients with hypercholesterolemia who are at high risk of
MI. it is specifically indicated for types IIa and IIb hypercholesterolemia in which IDL and total chol
are elevated. It is also useful in secondary hyperlipoproteinemia due to diabetes mellitus or
nephrotic syndrome. The drug may be useful in patients with combined elevated chol and trig.
c. A/E. serum hepatic transaminases are elevated in 2% of patients receiving statin, and muscle
creatinine phosphokinase (CPK) levels are elevated in 11%. GI reactions include flatulence and
diarrhea. When combined with another lipid-lowering drug or with cyclosporine, can cause
myopathies, sometimes progressing to rhabdomyolysis and renal failure. Teratogenicity occurs in
animals.
3. Niacin (Nicotinic acid)

a. MOA. In large doses, niacin reduces serum trig by lowering VLDL, usually within 1-4 days. The
reduction of VLDL in turn reduces IDL and LDL. Niacin usually produces a mild to moderate
50
increase in HDL. The VLDL-reducing action of niacin is independent of its vitamin activity. The
mechanism may involve :
1) Inhibition of lipolysis in adipocytes
2) Inhibition of hepatic trig esterification
3) Increased activity of lipoprotein lipase
b. Therapeutic uses. Niacin is helpful in controlling a wide range of hyperlipidemias. It is particularly
useful for type V hyperlipoproteinemia, characterized by severe hypertriglyceridemia and elevated
chylomicrons. It is not useful in familial lipoprotein lipase deficiency.
c. A/E. these can be minimized by taking the drug with meals and increasing the dosage gradually.
Niacin produces prostaglandin-mediated intense flushing and itching. GI distress is common, peptic
ulceration has occurred. Hepatic dysfunction can occur with high-dose regimens. Glucose
intolerance and hyperuricemia can occur.
4. Fibric acid deivatives
a. MOA. The fibric acid derivatives lower serum VLDL levels, thus reducing serum triglycerides. With
clofibrate, the net effect on serum cholesterol is minimal. However, serum cholesterol is
significantly reduced in patients with familial type III hyperlipoproteinemia. Clofibrate has no effect
on chylomicron levels or on HDL levels. Gemfibrosil lowers plasma VLDL-chol levels, lowers
LDL-chol to a lesser degree, and raises HDLchol.
b. Therapeutic uses. FA deriv are indicated for patients with familial type III hyperlipoproteinemia, in
which VLDL and IDL levels are increased. Gemfibrosil is the 1st-choice drug for
hypertriglyceridemia.
c. A/E. These agents are generally well tolerated, most common unwanted effects are mild GI
reactions. Myositis with elevated CPK and serum glutamic oxaloacetic transaminase (SGOT) levels
can occur. Cardiac arrhythmias have been reported with clofibrate, it also displaces warfarin from
albumin, potentiating its anticoagulant effects.
5. Probucol: lipophilic antioxidant
a. MOA. Probucol reduces total serum cholesterol; it lowers HDL-chol more than LDL-chol. It has little or
no effect on VLDL or triglycerides. MOA involves synthesis of chol-poor HDL, inhibition of early stages
of cholesterol synthesis, and an increased rate of LDL degradation. Its effect of cholesterol deposits
has been found to induce marked regression of xanthomas, and marked reduction in atheromatous
deposits. It involve the antioxidant effects of probucol, inhibiting the oxidation of LDL, thereby
preventing the uptake by macrophages.
b. Therap.use. Probucol is generally combined with another type of lipid-lowering drug for the treatment
of general hypercholesterolemia.
c. A/E. GI reactions are most common, prolongation of Q-T interval has been reported. Probucol is
stored in body tissue for up to 6 months, safety has not been established in pregnancy.
Antihyperlipidemic agents (Summary MOA)

● HMG CoA reductase inhibitors: ↓ LDL
● Fibrates: ↓ LDL, ↓ VLDL, ↑ HDL
● Bile acid sequestrants : ↑ HDL, ↓ LDL
● Probucol: ↓ LDL, ↓HDL
● Niacin: ↓ LDL, ↓ VLDL, ↑ HDL
Reference: Jacob, L.S. Pharmacology, 3rd ed. 1992.
Quiz on lipids will be based on vidwatch
DIURETIC AGENTS
51
(Flip) Vid watch: https://www.youtube.com/watch?v=9OBvNpnS0h4
Transcript:
in this lecture I'm going to talk about diuretics so let's get right into it so
diuretics also known as water pills simply promote the elimination of water
from the body now in order to understand how diuretics work first we need to
review the basic physiology of nephron so as you may already know nephron is the
structural and functional unit found within the kidneys each nephron has five
distinct regions that has specific function first we have Bowman's capsule
surrounding a network of capillaries called glomerulus here blood comes into
the afferent arteriole where components of the blood get filtered out of the
capillaries into the capsule filtered blood is then carried away from the
glomerulus by efferent arteriole next glomerular filtrate which contains
mostly water amino acids glucose sodium bicarbonate and electrolytes flows
through proximal convoluted tubule in this region almost 100% of the amino
acids glucose and about 90% of bicarbonate get reabsorbed as well as
about 65% of electrolytes such as sodium and potassium along with
water as a side note here remember wherever sodium ions go chloride and
water tend to follow the next major region through which the filtrate travels is
the descending and ascending loop of Henle which passes into the medulla of
the kidney now the descending limb has walls permeable to water but impermeable
to sodium so as the filtrate travels down water leaves but sodium tends to stay
making the filtrate more concentrated on the other hand the opposite takes place
in the ascending limb particularly in the thick limb which is permeable to
sodium but impermeable to water so as the filtrate travels up about 25%
of sodium gets reabsorbed passively as well as via active reabsorption mediated by
the sodium-potassium-2-chloride cotransporter next the filtrate travels
through the distal convoluted tubule here about 5 to 10% of sodium
chloride gets reabsorbed mainly via sodium-chloride cotransporter this part
is also relatively impermeable to water so at this point the filtrate becomes
more diluted finally the filtrate travels through the late distal tubule
and collecting duct here we find two types of cells the principal cells and
the intercalated cells now the functions of the principal cells are regulated by
two hormones aldosterone which increases sodium reabsorption and increases
potassium secretion and antidiuretic hormone which increases water
permeability and thus increases water reabsorption now on the other hand the
intercalated cells are regulated by aldosterone but their primary function
is to secrete hydrogen ions and reabsorb potassium so now let's switch gears and
let's talk about diuretics diuretics simply increase the volume of produced
urine by acting on different parts of nephron so in other words diuretics help
us to remove salt and water from the body which makes them very useful for
treatment of hypertension and abnormal fluid retention referred to as edema.
Now based on their mechanism of action diuretics can be divided into five major
classes and these are
● carbonic anhydrase inhibitors
● loop diuretics
52
● Thiazide diuretics
● potassium sparing diuretics and
● osmotic diuretics.
So let's look at each class in more detail starting with carbonic anhydrase inhibitors carbonic
anhydrase inhibitors produce their diuretic effect mainly by
reducing reabsorption of bicarbonate in the proximal convoluted tubule now
let's zoom in on the epithelial cell of the proximal tubule to see how they
exactly do that so to the left of the epithelial cell
we have lumen where urine is being formed and to the right we have interstitium
which contains blood vessels now here bicarbonate reabsorption is
initiated by the action of sodium-hydrogen ion exchanger which allows
sodium to enter the cell in exchange for hydrogen ion next reabsorbed sodium is
pumped by sodium potassium ATPase out of the cell where the secreted hydrogen ion
combines with the luminal bicarbonate ion to form carbonic acid
carbonic acid is then rapidly dehydrated to carbon dioxide and water by an enzyme
carbonic anhydrase now carbon dioxide enters the epithelial cell by simple
diffusion and gets rehydrated back to carbonic acid by intracellular carbonic
anhydrase finally intracellular carbonic acid dissociates to form hydrogen ion
which can be transported by sodium-hydrogen exchanger to the lumen and
bicarbonate ion which is transported out of the cell
now when carbonic anhydrase inhibitor comes around it inhibits carbonic anhydrase
enzyme and as a result bicarbonate gets retained in the lumen
since bicarbonate reabsorption utilizes the sodium-hydrogen exchanger inhibition
of carbonic anhydrase leads to significant reduction in proximal
tubule sodium reabsorption which ultimately results in mild diuresis now
the reason why the diuretic effect is only mild is because the majority of
the sodium that doesn't get reabsorbed in proximal tubule still gets reabsorbed
by distal parts of the nephron however this late reabsorption also
leads to increase potassium secretion which is one of the side effects
associated with this class additionally because bicarbonate is a
major component of the acid-base buffering system in the circulation it's wasting
leads to increase in plasma acidity known as metabolic acidosis now one of
the most popular drugs that belongs to this class is a Acetazolamide however
due to its relatively weak diuretic effect Acetazolamide is commonly used for its
other pharmacologic actions now let's move on to loop diuretics so loop
diuretics just like their name suggests work in the loop of Henle specifically
in the ascending limb where they inhibit sodium-potassium-2-chloride
cotransporter out of all diuretics these agents produce the greatest
diuretic effect because as much as 25% of sodium gets reabsorbed in the ascending
limb and at this point other parts of nephron can no longer compensate for
increased levels of tubular sodium so now let's zoom in on the cell that lines
the thick ascending limb to see what exactly happens there so upon reaching
the thick ascending limb some of the filtered sodium potassium and chloride
get reabsorbed by sodium-potassium-2-chloride cotransporter this among other
things leads to accumulation of potassium within this cell however
potassium also tends to leak out through potassium channels back into the lumen
53
which contributes to a more positive charge there now this positivity in the
lumen produces electrical driving force for paracellular reabsorption of
cations such as magnesium and calcium so when loop diuretic comes around and
blocks sodium-potassium-2-chloride cotransporter we not only lose sodium and
water but also potassium calcium and magnesium now keep in mind that
potassium loss takes place mainly in the late distal tubule
where sodium rich fluid enhances sodium potassium exchange and I'll talk about
this more later drugs that belong to this class include Bumetanide Ethacrynic acid
Furosemide and Torsemide now when it comes to side effects besides causing
electrolytes imbalance loop diuretics can cause rapid and excessive reduction in
blood volume also known as acute hypovolemia this can lead to hypotension
shock and even cardiac arrhythmias next because loop diuretics inhibit
sodium-potassium-2-chloride cotransporter which also happen to exist in the inner ear
their use has been associated with the damage to the hearing also referred to
as ototoxicity lastly Ethacrynic acid and Furosemide in particular
compete with a transport of uric acid at the same site thus blocking its
secretion which ultimately can lead to hyperuricemia and thus worsening of gout
symptoms now let's move on to thiazide diuretics so thiazides are probably the
most commonly prescribed diuretics they work mainly in the early part of the
distal tubule where they increase sodium chloride excretion by inhibiting
sodium-chloride cotransporter however since over 90% of sodium is
reabsorbed before reaching the distal tubule in general thiazides produce
rather weak diuresis on the other hand thiazides are capable of causing
vasodilation which reduces peripheral vascular resistance by mechanism that
unfortunately is not clearly understood yet now let's zoom in on the epithelial
cell of the early distal tubules to see what exactly happens there so here
sodium and chloride enter the cell via sodium-chloride cotransporter once
inside the cell sodium gets transported to the blood via the sodium-potassium
ATPase while chloride diffuses out on the other side via chloride channel now
when thiazide diuretic comes around and inhibits this sodium-chloride
cotransporter the result is decreased sodium chloride reabsorption and
ultimately since water follows the salt we get increased urine output
drugs that belong to this class include Chlorothiazide and Hydrochlorothiazide which are
structurally similar sulfonamide derivatives and we also have Chlorthalidone
Metolazone and Indapamide which are often referred to as thiazide-like
drugs because they don't have true thiazide ring but share the same mechanism of
action now when it comes to side effects just like loop diuretics thiazides can
cause hypokalemia which results from increased delivery of sodium
to the distal parts of the tubule moreover similarly to loop diuretics thiazides
can also lead to hyperuricemia by interfering with uric acid transport
which in turn may exacerbate gout now while loop diuretics can cause calcium
excretion leading to hypocalcemia thiazides on the other hand can cause
the opposite that is hypercalcemia there are two mechanisms that are thought to
be responsible for this first takes place in the proximal tubule where thiazide
induced volume depletion leads to a compensatory increase in sodium
reabsorption which in turn produces electrical gradient which leads to
passive calcium reabsorption the second mechanism involves the sodium-calcium
54
exchanger located on the basolateral side of the distal tubule so because

thiazides block sodium-chloride cotransporter there will be decreased
concentration of sodium inside the cell which then in turn causes the sodium
calcium exchanger to bring in more sodium in exchange for calcium which is
then excreted into the bloodstream lastly thiazides may worsen glucose
control leading to hyperglycemia and they may also elevate cholesterol
leading to hyperlipidemia some of the mechanisms thought to be responsible for
these effects include decreased insulin secretion and insulin sensitivity as
well as increased hepatic glucose production now let's move on to
potassium-sparing diuretics so potassium-sparing diuretics work primarily in
the collecting tubule where they inhibit sodium reabsorption and
potassium excretion although these potassium-sparing agents are relatively
weak diuretics they are often used in combination with diuretics from the
other classes in order to enhance their effects
now let's zoom in on the collecting tubule principal cell to see what
exactly happens there so principal cell has separate channels for sodium and
potassium as well as sodium-potassium ATPase on the basolateral side under
normal conditions here sodium enters the cell through sodium channel and then is
transported by sodium-potassium ATPase into the bloodstream in exchange for
potassium now because this sodium entry predominates here the lumen negative
electrical potential is generated and chloride is driven into the bloodstream
through paracellular pathway this in turn drives potassium out of the
cell through potassium channel so as a side note here this illustration should
also help you understand how loop diuretics and thiazides lead to potassium
loss so increased sodium load caused by loops and thiazides enhances sodium
reabsorption which makes lumen more negative this in turn generates driving
force for increased potassium secretion and ultimately lower potassium levels in
the blood stream hence hypokalemia now going back to
potassium-sparing diuretics agents within this class can be separated into two
groups based on their distinct mechanisms of action so the first group
works simply by blocking sodium channel which results in decreased sodium
potassium exchange and thus retention of potassium drugs that belong to this
group include Amiloride and Triamterene now the
second group on the other hand works by antagonizing aldosterone aldosterone is
a hormone which gets into the cell binds to the intracellular receptor and
stimulates transcription of genes encoding sodium channel and sodium
potassium ATPase thus increasing their expression in other words
aldosterone leads to increased reabsorption of sodium and water and
increased secretion of potassium so because aldosterone antagonists compete
for binding to that intracellular receptor the result is reduced synthesis
of proteins that activate sodium channels and decreased number of sodium
potassium ATPases which ultimately leads to potassium retention drugs that
belong to this group include Spironolactone and Eplerenone now when it
comes to side effects as you may already guessed hyperkalemia is the biggest problem
especially when these diuretics are combined with other drugs that can also
increase potassium levels lastly due to its chemical structure that resembles
our natural steroid hormones Spironolactone can stimulate receptors for testosterone
55
and progesterone leading to effects such as menstrual irregularities in females

and gynecomastia in males now before we end I wanted to briefly
discuss the last class of diuretics namely osmotic diuretics which work by
interfering directly with osmosis as you may recall from your basic biology class
water has tendency to move across membrane from lower osmolarity or the
dilute side to a higher osmolarity or the concentrated side so these osmotic
agents are filtered from glomerulus they are very water soluble or hydrophilic
and they undergo very limited reabsorption
due to their large molecular size this leads to increased osmolarity of the
tubular fluid and thus decreased water reabsorption
now because osmotic diuretics increase water excretion rather than
sodium excretion they're not very effective for treating edema caused by
sodium retention instead they are mainly used for reduction of intracranial
pressure promotion of urinary excretion of toxic substances as well as promotion of
urine production in patients with acute kidney failure
examples of osmotic diuretics are Mannitol and Urea as for the
side effects use of osmotic diuretics can lead to significant fluid changes such
as volume overload or dehydration and thus electrolyte imbalances and with
that I wanted to thank you for watching I hope you enjoyed this lecture and as
always stay tuned for more
(end of transcript)
Task:
● List the distinct region and function of nephron
● Classify the drugs according to its MOA
From the glomerulus wherein the function is
Bowmans capsule is lsabflkjf
56
Proximal Convoluted Tubule (PCT) - reabsorbs sodium bicarbonate, amino acids and glucose in which your
drugs act to inhibit your carbonic anhydrase
Loop of Henle - concentration gradient is developed here; concentrated filtrate is here; wherein your drugs
here if you have the loop diuretics it acts on the loop of henle
- Loop diuretics
- Most commonly used: thiazide diuretics
- Side effects of loop diuretics: causes to lose potassium;
- Thiazides acts onthe dct
- Potassium sparing diuretics - acts on aldosterone; increase in aldoesterone, increased sodium
reabsorption and increased potassium secretion; act to block the sodium channela and also a sodium
- ADH - act to increase water reabsorption
-
DCT - moa: reabsorption; permeable to all the ions but not water
A. General considerations. Diuretics are any substance that increases urine flow and thereby water
excretion. Diuretics are among the most commonly used drugs and the majority act by reducing sodium
chloride reabsorption at different sites in the nephron, thereby increasing urinary sodium, and consequently,
water loss. Some drugs can increase renal flow by nonrenal mechanisms, but these drugs are not generally
regarded as diuretics.
A. Classification. Diuretics can be classified by structure and mechanism of action into eight groups. Agents in
the first four groups are seldom or no longer used but are discussed because their mode of action or their role
in the history of diuretics is important. (* - not commonly used)
1. Xanthine diuretics *
2. Mercurial diuretics*
3. Carbonic anhydrase inhibitors - reduce reabsorption of carbonic acid (HC03); retains bicarbonate in
the lumen
4. Acidifying salts *
5. Thiazide diuretics - produce weak diuresis and weak vasodilation
6. High-ceiling (loop) diuretics - produce greatest diuretic effect and inhibits sodium potassium chloride
cotransporters
7. Osmotic diuretics - very water soluble; mainly for intracranial pressure wala ko natapos aksfksdf
8. Potassium (K+)-sparing diuretics
B. Sites of action. Although an individual diuretic can act on several areas of the nephron, the major sites of
action for the diuretics may be summarized as follows:
1. Those acting on the proximal tubule:

a. Osmotic diuretic - ex. mannitol ; used when to their is intracranial pressure to decrease
swelling and pressure inside your brain and including around the eye and brain area
b. Xanthine diuretics - common: caffeine and tea
c. Carbonic anhydrase inhibitors - ex. Acetazolamide (also used in open angle glaucoma
d. Acidifying salts - common in products: calcium chloride
2. Those acting on the ascending limb of the loop of Henle:
a. High-ceiling (loop) diuretics - ex. Furosemide; S/E: increased potassium excretion and
produce ototoxicity and hyperuricemia
b. Thiazide diuretics - acts on DCT; Most commonly prescribed to treat a standard case of
hypertension
57
c. Mercurial diuretics - not available anymore because it contains mercury

3. Those acting on the distal tubule: K+-sparing diuretics; ex. Spironolactone (Aldactone)
C. Therapeutic uses.
1. Diuretics are frequently employed for the clinical management of disorders involving abnormal fluid
distribution, such as edema, or for hypertension. They are also used to reduce the toxicity of
ingested or administered substances. For example, mannitol, an osmotic diuretic, reduces the renal
toxicity of the antitumor agent cisplatin, and acetazolamide, a carbonic anhydrase inhibitor, is used
to alkalinize the urine and increase salicylate elimination.
2. The efficacy of the different classes of diuretics varies significantly, with the xanthine diuretics being
the least effective and the “high-ceiling”, or “loop” diuretics being the most effective. The
establishment of a net negative Na+ balance, particularly with the less efficacious diuretics, can also
depend upon limiting the Na intake.
D. Adverse Effects.
Thiazides used in HTN and HF that can decrease glucose tolerance, increase K (potassium) in high
doses, positive for gout (give uric acid) by interfering with uric acid, increase LDL
- Commonly used but has many side effects
1. Prolonged use of some diuretics (e.g. mercurials, carbonic anhydrase inhib) results in refractoriness
or a reduction in efficacy. These agents are “self-limiting” and not frequently used.
2. Reduction in serum K+ levels (hypokalemia) is one of the most important adverse effects of many,
but not all, diuretics.
Summary of adverse effects of diuretics
Diuretic Hyperglycemia Hyperuricemia Hypokalemia Ototoxicity Calcium

excretion
Thiazide + + + - Decrease
- Worsen
insulin
resistance
- Compete
for same
transporter
of uric acid
that’s why it
gives
hyperurice
mia
Ethacrynic acid + + + + Increase
Furosemide + + + + Increase
Bumetanide + + + + Increase
Mercurials - - - - No effect
Acetazolamide - - + - No effect
58
Indapamide + + + - Decrease
Note: Treatment of severe hyperglycemia (grabe ang diabetes) can lead to hypokalemia (muscle weakness);
eat many bananas but it affected the heart and muscles which caused arrhythmia and cardiac arrest
Diuretics in general involve worsening of insulin resistance, inhibit glucose uptake and decrease insulin
release; also competes with same transporter as uric acid
DRUGS USED IN DISORDERS OF COAGULATION
(Flip) Vid watch: https://www.youtube.com/watch?v=eZBtQ0rDnG4&vl=en
Transcript:
in this lecture we're going to cover anticoagulants and antiplatelet agents. So let's get right into it.
Anticoagulants and antiplatelet agents are used to treat thrombotic disorders or unwanted clot inside a
blood vessel which can lead to heart attack or stroke. But before we discuss their mechanism of action let's
quickly review the clotting process. So in the absence of injury, the endothelial cells that make up the inner
surface of blood vessels release chemical mediators such as nitric oxide and prostacyclin. Now nitric oxide job
is to dilate blood vessels while prostacyclin job is to bind to receptors located on platelets. This binding triggers
certain reactions which ultimately prevent platelet activation and aggregation. What happens when there is a
damaged blood vessel let's say due to skin cut? Well suddenly we have less nitric oxide and prostacyclin
around so blood vessels become constricted and platelets become activated. But first things first with the help
of von willebrand factors, platelets adhere to exposed collagen which in turn causes them to change shape.
Next, these activated differently shaped platelets begin to release granules containing chemical mediators such
as ADP thrombin thromboxane A2 serotonin and platelet activating factor which attract and activate even more
platelets that come to the site of injury. Now the final step involves activation of the glycoprotein 2b/3a
receptors which bind circulating fibrinogen. The fibrinogen simultaneously binds to these receptors on two
separate platelets thus cross-linking platelets to form aggregates. There are several drugs that can disrupt this
platelet plug formation. Collectively we call them platelet aggregation inhibitors or simply antiplatelet drugs.
One of the most widely known drugs that belongs to this class is Aspirin. In order to understand how Aspirin
works let's take a closer look at the inside of a platelet. When platelet it becomes activated
arachidonic acid is released from the membrane phospholipids then it gets
converted to prostaglandin H2 by cyclooxygenase-1 enzyme also known as
Cox-1 finally prostaglandin H2 is further metabolized to thromboxane A2
which is released from the platelet to stimulate activation of new platelets as
well promote their aggregation so what Aspirin does is it irreversibly
inactivates Cox-1 enzyme thus effectively disrupting clot formation
next we have platelet aggregation inhibitors that work by blocking the
action of ADP receptor specifically P2Y12 subtype drugs that belong to this
group include Clopidogrel Ticagrelor Ticlopidine and Prasugrel as I
mentioned before activated platelets release chemical mediators one of them is
ADP which binds to P2Y12 receptor leading to activation of the
glycoprotein 2b/3a receptors which are required for fibrin mediated platelet
cross-linking so by blocking P2Y12 ADP receptors these drugs effectively
inhibit platelet aggregation and thus clot formation
next we have glycoprotein 2b/3a receptor blockers namely Abciximab
59
Eptifibatide and Tirofiban these agents simply inhibit platelet

aggregation by binding to the glycoprotein 2b/3a receptors on
platelets thus preventing fibrinogen from binding to platelets and making
them unable to cross link unlike the other drugs that we discussed so far
glycoprotein 2b/3a inhibitors are administered only intravenously now the
last group of antiplatelet drugs that I wanted to briefly
discuss are phosphodiesterase inhibitors namely Dipyridamole and Cilostazol these
two agents inhibit enzyme called phosphodiesterase that is responsible
for breaking down cyclic AMP to AMP so by blocking this enzyme Dipyridamole
and Cilostazol increase intracellular levels of cyclic AMP which in turn leads
to decrease in intracellular calcium and ultimately inhibition of platelet
activation furthermore these agents inhibit phosphodiesterase in the
vascular wall as well as uptake of adenosine which promotes vasodilation
for that reason Cilostazol in particular is often used to treat symptoms of
peripheral artery disease such as narrowing of vessels that supply blood
to legs when it comes to side effects bleeding is a major risk associated with
all antiplatelet drugs additionally Dipyridamole and Cilostazol
due to their vasodilating properties can produce headaches now
let's go back to our review of clot formation so the aggregation of
platelets acting like a plug is usually not enough to secure the site of injury
in order to strengthen the platelet plug a clot must form the formation of clot
involves cascade of enzyme reactions that transform various
clotting factors to their active forms ultimately producing web-like fibrin
mesh now there are two pathways involved with a clotting cascade the intrinsic
pathway which is activated by damage directly to the blood vessel wall and
extrinsic pathway which is activated by trauma to the vascular wall as well as
surrounding tissue so the intrinsic pathway starts with clotting factor 12 which
is activated when blood comes into contact with a collagen in the damaged
vascular wall and here "a" next to the Roman numeral stands for "activated" this
sets a series of reactions that leads to activation of factor 11
which then activates factor 9 which then activates factor 10
activated factor 10 then converts prothrombin to thrombin and finally
thrombin converts fibrinogen to fibrin which forms mesh that strengthens the
platelet plug now let's take a look at the extrinsic pathway so extrinsic
pathway is triggered by tissue factor released from damaged cells outside the
circulating blood it starts with an activation of factor 7 which then
activates factor 10 so at this point the intrinsic and extrinsic pathway converge
into a common pathway which again results in formation of fibrin clot
and as a side note here keep in mind that this is just a simplified
description of coagulation cascade and many details were intentionally omitted
so now let's switch gears and let's talk about anticoagulants that is drugs that
work by disrupting this coagulation cascade let's begin by discussing one of
the most widely recognized and anticoagulants that is Heparin and low-
molecular-weight Heparin such as Enoxaparin and Dalteparin now
these agents bind to our natural anticoagulant circulating in blood called
antithrombin 3 the primary function of antithrombin is to inactivate factor 10a
and thrombin so what Heparin drugs do is they bind to antithrombin and by doing
60
so they accelerate its activity in case of Heparin its binding to antithrombin

results in rapid inactivation of both factor 10a and thrombin however unlike
Heparin low-molecular-weight Heparins have very little effect on inactivation of
thrombin and instead they selectively accelerate inactivation of factor 10a
another agent worth mentioning here that also selectively accelerate inactivation
of factor 10a is Fondaparinux however unlike low-molecular-weight Heparins
Fondaparinux doesn't bind to any other plasma proteins and has no direct effect
on thrombin when it comes to side effects bleeding is a major risk
fortunately there is a reversal agent called Protamine sulfate which can be
used to treat excessive bleeding caused by Heparin drugs Protamine sulfate
simply works by binding to Heparin or low-molecular-weight Heparins to form
stable inactive complex Fondaparinux on the other hand doesn't have any
specific antidote at this time another possible major side effect that is
particularly associated with the use of Heparin agents is Heparin induced
thrombocytopenia "HIT" for short HIT is a disorder caused by immune system
making antibodies to Heparin when it's bound to platelet-derived protein called
platelet factor-4 once the antibodies bind to these Heparin
platelet factor-4 complexes they begin to activate platelets which clump together
causing formation of unwanted clots and fall in platelet count now let's move on
to another group of anticoagulants that is direct inhibitors of factor 10a
agents that belong to this group are Apixaban and Rivaroxaban the
mechanism of action of these drugs is very simple they both bind directly to
the active side of factor 10a thus preventing it from converting
prothrombin to thrombin the biggest advantage of these agents over the other
anticoagulants that we discussed is that they are available in oral formulation
unfortunately bleeding is still a major risk and specific antidote is currently
not available now let's move on to the next group of anticoagulants that is
direct thrombin inhibitors now depending on how they interact with the thrombin
molecule agents in this group can be subdivided into two classes first we
have univalent direct thrombin inhibitors which bind only to the
active site example of drugs that belong to this class are Argatroban and Dabigatran
the second class are bivalent direct thrombin inhibitors which bind to both
the active site and the exosite-1 that is fibrinogen binding site this
bivalent binding contributes to their high affinity and high specificity for
thrombin example of drugs that belong to this class are Bivalirudin and Desirudin
now one of the biggest advantages of direct thrombin inhibitors over
indirect thrombin inhibitors such as Heparin is that they don't bind to
platelet factor-4 which makes them very useful in treatment of Heparin induced
thrombocytopenia however just like with other anticoagulants bleeding is a major
risk and there is no specific antidote available at this time now there is one
more anticoagulant that I wanted to discuss which is Warfarin
Warfarin is one
of the oldest anticoagulants that's still on the market and it has its own
unique mechanism of action now in order to understand how Warfarin works its
important to first understand the role of vitamin K in the coagulation cascade
so vitamin K is required for synthesis of factors 2 7 9 and 10 these
61
coagulation factors are biologically inactive until they are carboxylated by

vitamin K this carboxylation reaction proceeds when we have reduced form of
vitamin K available in this reaction reduced vitamin K is oxidized to the
vitamin K epoxide in the presence of oxygen and carbon dioxide yielding
carboxylated fully active clotting factors
in the
last step of this reaction oxidized vitamin K is recycled back to the
reduced form by enzyme called vitamin K epoxide reductase
this is where Warfarin comes into play as it inhibits this enzyme and thus
disrupts this vitamin K dependent synthesis of biologically active clotting
factors as well as some other regulatory factors now
one of the biggest disadvantages of Warfarin is that it has a narrow therapeutic window and has been
associated with many drug-drug and drug-food interactions for these reasons
clinicians need to closely monitor patients on Warfarin by using the
International normalized ratio measurement also known as INR and adjust
the dose when necessary to balance the risk of bleeding against the risk of
clotting fortunately in the event of bleeding anticoagulant effects of Warfarin
can be overcome by administration of vitamin K however reversal can take up
to 24 hours therefore in the event of emergency infusion of fresh frozen
plasma might be necessary now the last group of drugs that I wanted to discuss
in this lecture are thrombolytics while antiplatelets and anticoagulants prevent
the clot from getting formed in the first place thrombolytics act on the
existing clot causing it to dissolve and the way
they do this is by directly or indirectly activating circulating protein called plasminogen which then
turns into plasmin now plasmin is an enzyme that breaks cross-links between fibrin molecules thereby
dissolving the clot
examples of thrombolytics include Alteplase Reteplase and Tenecteplase which are produced by recombinant
DNA technology to mimic our naturally occurring tissue plasminogen activator. another example is an agent
called Urokinase which is a naturally occurring thrombolytic produced from cultured human kidney cells and
lastly we have an agent called Streptokinase which is derived from streptococcal bacteria now
one of the main differences between these agents is their selectivity for
fibrin-bound plasminogen versus free circulating plasminogen so while
tissue plasminogen activator such as Alteplase is more clot selective and
acts to dissolve the fibrin in the thrombus Streptokinase and
Urokinase are less clot selective and thus are more likely to cause internal
bleeding into any organ system these bleeding complications from thrombolytic
therapy can be managed by administration of Aminocaproic acid or
Tranexamic acid these two agents can stop fibrinolysis by inhibiting
binding of plasminogen to fibrin as well as conversion of plasminogen to
plasmin and with that i wanted to thank you for watching I hope you enjoyed this
lecture and as always stay tuned for more
(end of transcript)
62
Hemostasis refers to the finely regulated dynamic process of maintaining fluidity of the blood, repairing
vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion
of vital organs.
● Thrombosis is the most common abnormality of hemostasis. Thrombotic disorders include acute
myocardial infarction, deep vein thrombosis, pulmonary embolism, and acute ischemic stroke.
These are treated with drugs such as anticoagulants and fibrinolytics.
● Bleeding disorders involving the failure of hemostasis are less common than thromboembolic
diseases. These disorders include hemophilia, which is treated with transfusion of Factor VIII prepared
by recombinant DNA techniques, and vitamin K deficiency, which is treated with dietary supplements
of the vitamin.
Thrombus vs. embolus
A clot that adheres to a vessel wall is called a “thrombus,” whereas an intravascular clot that floats in the
blood is termed an “embolus.” Thus, a detached thrombus becomes an embolus. Both thrombi and emboli
are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients. Arterial
thrombosis usually consists of a platelet-rich clot. Venous thrombosis typically involves a clot that is rich in
fibrin, with fewer platelets.
Stages of Blood Coagulation
(Flip) Vid watch: https://www.youtube.com/watch?v=x8TLTTyyPfI
Transcript:
Hemostasis is the process that controls bleeding at the site of injury. Blood loss is stopped by formation of
blood clots that seal the breaks in blood vessels. Hemostatic mechanisms involve small cell fragments known
as platelets and a dozen of soluble clotting factors. These elements are always present in the blood in their
inactive form, ready to activate, typically within seconds of an injury. When blood vessels are damaged, blood
is exposed to components of the surrounding tissue. Some of these components bind to and activate platelets.
Activated platelets are involved in all stages of hemostasis:
● First, they secrete chemicals that induce blood vessels to constrict, thereby reducing blood loss. This is
known as vascular spasm, the most immediate response to tissue injury. Vascular spasm is also
triggered by local pain receptors, and by substances released by endothelial cells.
● Second, activated platelets become adhesive to each other and to the endothelium; they clump
together, forming a platelet plug. They also secrete substances that attract other nearby platelets,
activating them in a positive feedback loop, speeding up the formation and propagation of the plug.
● Third, the surface of activated platelets serves as the site for coagulation - the formation of blood clots.
A clot is essentially a platelet plug reinforced with strands of a protein called fibrin - the final product of
the coagulation cascade. Coagulation is a complex chain reaction where one clotting factor activates
the next in the multi-step pathway.
There are 2 activation pathways for coagulation:

● The extrinsic pathway starts with the exposure of blood clotting factors to the tissue factor, TF, in the
extravascular tissue. This pathway is induced by injuries to blood vessels.
● The intrinsic pathway, which involves only factors within blood vessels, is thought to serve as a positive
feedback loop, amplifying coagulation.
63
The 2 pathways converge into a common pathway producing thrombin and ultimately fibrin. Thrombin has the
central role in the coagulation cascade. It cleaves soluble fibrinogen to generate insoluble fibrin. Thrombin also
further activates platelets, and initiates a positive feedback loop that is essential for clot propagation.
Blood clots prevent blood loss during wound healing, but once the vessels are repaired, they must be
dissolved to restore blood flow. This process, called fibrinolysis, is a small cascade that produces the enzyme
plasmin. Plasmin cleaves fibrin and dissolves the clot. Because most clotting factors are produced in the liver
and their production requires vitamin-K, liver diseases such as cirrhosis, and vitamin-K deficiency may cause
excessive bleeding.
The main bleeding disorders, however, are inherited. These conditions are caused by gene mutations that lead
to deficiency of a certain clotting factor. They are usually treated with replacement therapy, using purified
factors produced by recombinant technology, or frozen platelets. While formation of blood clots is critical to
control bleeding, inappropriate coagulation can be dangerous.
In fact, far more people die from unwanted blood clotting than from clotting failure. Unwanted blood clot
formation, known as thrombosis, is the most common cause of blocked arteries in heart attacks, strokes and
pulmonary embolism.
Factors that prevent inappropriate coagulation include:

● Platelet-repellent property of the endothelium,
● Anticoagulant factors - enzymes that prevent clot formation,
● and the fibrinolysis cascade that dissolves blood clots after they are formed
● Fluidity of normal blood flow also helps dilute the small amount of thrombin that forms spontaneously.
● Decreased flow or stagnation of blood may increase risks for thrombosis.
● People with high risks of unwanted blood clotting are treated with drugs that inhibit platelet aggregation,
such as aspirin; or drugs that inhibit coagulation, such as heparin or warfarin.
(end of transcript)
Task: describe each stage and list down the drugs used in blood disorders.
i. Vasospasm - secretion of serotonin

ii. Platelet adhesion - platelet clot formation or propagation
iii. Platelet aggregation - formation of blood clot or coagulation that leads to formation of fibrin
iv. Viscous metamorphosis
v. Activation of coagulation factors
vi. Fibrin synthesis
Iv, v, vi - under coagulation cascade
Platelets have ff functions:

1. Secrete vasoconstrictors which constrict blood vessels (bv) causing vascular spasms in broken bv
2. Form temporary platelets clogs to stop bleeding
3. Secrete procoagulants (clotting factors) to promote blood clotting
4. Dissolve blood clots when they are no longer needed
ANTIPLATELETS - platelet aggregation inhibitor
64
1. ASPIRIN. It is the only antiplatelet agent that irreversibly inhibits platelet function. The recommended dose
of aspirin ranges from 50 to 325 mg. Complete inactivation of platelets occurs with 75 mg of aspirin given
daily.
- mostly prescribed antiplatelet

- Major S/E: increased risk of bleeding
2. Ticlopidine, clopidogrel, prasugrel, and ticagrelor. These drugs irreversibly inhibit the binding of ADP
to its receptors on platelets and, thereby, inhibit the activation of the GP IIb/IIIa receptors required for platelets
to bind to fibrinogen and to each other. The maximum inhibition of platelet aggregation is achieved in 1 to 3
hours with ticagrelor, 2 to 4 hours with prasugrel, 3 to 4 days with ticlopidine, and 3 to 5 days with
clopidogrel. Commonly used in patients undergoing placement of a coronary stent for prevention of
atherosclerotic events following recent myocardial infarction.
- ADP receptors thus inhibit?
3. Abciximab. It is a platelet GP IIb/IIIa receptor monoclonal antibody. By binding to GP IIb/IIIa, the antibody
blocks the binding of fibrinogen and von Willebrand factor, and, consequently, aggregation does not occur
Abciximab is given i.v. in percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic
complications. Abciximab is expensive, limiting its use in some settings.
4. Eptifibatide and tirofiban . These two antiplatelet drugs act similarly to abciximab, namely, by blocking
the GP IIb/IIIa receptor. These agents are given intravenously, along with heparin and aspirin, as an
adjunct to PCI for the prevention of cardiac ischemic complications. The major adverse effect of both drugs is
bleeding.
5. Dipyridamole. A coronary vasodilator, is used prophylactically to treat angina pectoris. It increases

intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased
thromboxane A2 synthesis. It may potentiate the effect of prostacyclin to antagonize platelet stickiness and,
therefore, decrease platelet adhesion to thrombogenic surfaces. It is usually given in combination with aspirin
or warfarin. Causes headache and can lead to orthostatic hypotension (especially if administered IV).
6. Cilostazol. A newer orally active phosphodiesterase inhibitor that promotes vasodilation and inhibition of
platelet aggregation. Used to treat intermittent claudication, vascular sclerosis complicating diabetes mellitus,
and the improvement of symptoms in patients with chronic cerebral ischemia. Causing a decrease in plasma
triglycerides and an increase in HDL. Headache and GI side effects are the most common adverse effects.
Contraindicated in patients with heart failure.
7. Pentoxifyllines. A Methylxanthine derivative that has been called a “rheologic modifier.” Increases
deformability of RBCs thus increases microcirculation, reduce fibrinogen levels and inhibits platelets
aggregation. This decreases total systemic vascular resistance, improves blood flow, and enhances tissue
oxygenation in patients with peripheral vascular disease.
Uses: CVAs esp.TIA(transient ischemic attacks), ischemic ulcers of legs, diabetic angiopathies, sickle cell
anemias. It is available in extended-release tablets and is taken three times a day with food. Adverse
reactions are mainly GI in nature and are lessened by administration with food.
BLOOD COAGULATION. /clotting cascade
● Two major pathways (1) Intrinsic pathway - activated by damage to the blood vessel wall (2)
Extrinsic pathway
- Starts with cf 12; if cf12 is activated it proceeds to cf 11; activated cf 11, then cf 9 then
back to 10; cf 7 converge in extrinsic pathway having the common pathway in clotting
factor 10 to form prothrombin to produce thrombin and then eventually fibrinogen to fibrin
- Fibrin is produced as a mesh that strengthen the platelets
- Antithrombin drugs - acts on the factor 10
65
- Factor 12 is activated when blood comes into contact with the damage vascular wall or
bv wall
● 13 soluble factors are involved in clotting
● Biosynthesis of these factors are dependent on Vitamin K1 and K2
● Most of these factors are proteases
● Normally inactive and sequentially activated
● Hereditary lack of clotting factors lead to hemophilia –A
Heparin - injection
- Overdose Antidote: protamine sulfate
Warfarin - woral
- Overdose Antidote: Vitamin K
Prothrombin Time/ Pro Time (PT) - blood test that measures how long it takes blood to clot; also known as
INR test
Can we combine Aspirin with heparin?

- No because it will cause increased bleeding
ANTICOAGULANTS . These are the drugs used to reduce coagulability of blood.
Classification:
A) Heparin (the thrombin inhibitor) -Low molecular weight Heparin -Danaparoid -Lepirudin -Heparin sulfate
B) Oral anticoagulants -Warfarin (vitamin K antagonist) -Bishydroxycoumarin (dicumarol) -Acenocoumarol
–Phenindione.
Heparin
1. Straight chain mucopolysaccharide extracted from porcine intestinal mucosa and bovine lung, very strong
acid with MW 20000.
2. LMWH isolated from standard heparin by gel filtration chromatography or partial depolymerization
(1000-10000 daltons).
MOA: Heparin binds to antithrombin III (ATIII) complex increases thrombin –antithrombin reaction 1000folds.
ATIII inhibits activated clotting factors of intrinsic and common pathway including thrombin, Xa and IXa.
Anticoagulant properties of Heparin:

1. Inhibits the thrombin-mediated conversion of fibrinogen to fibrin
2. Inhibits the aggregation of platelets by thrombin
3. Inhibits activation of fibrin stabilizing enzyme
4. Inhibits activated factors XII, XI, IX, X and II
Therapeutic uses.
1. Acute deep vein thrombosis
2. Pulmonary embolism
3. Prophylactically to prevent postoperative venous thrombosis in patients undergoing elective surgery
4. Acute phase of myocardial infarction
5. Anticoagulant of choice for treating pregnant women with prosthetic heart valves or venous
thromboembolism, because these agents do not cross the placenta.
Adverse effects. Bleeding complications: careful monitoring of the bleeding time, prothrombin time (PT) and
its international normalized ratio (INR) is required to minimize this problem. Minor bleeding may be managed
by ceasing administration of the drug while Excessive bleeding by treatment with antidote (protamine
sulfate).
66
Contraindications and Drug Interactions with Heparin

1. Heparin is contraindicated in patients who are bleeding, patients with hemophilia, thrombocytopenia
and hypertension.
2. Heparin is contraindicated before and after brain, spinal cord or eye surgery.
3. Heparin should not be administered with aspirin or other drugs that interfere with platelet aggregation.
4. Positively charged drugs and aminoglycosides can reduce the effectiveness of heparin therapy.
Drugs: LMWH, Enoxaparin, Dalteparin, Ardeparin, Nadroparin, Tinzaprin, Reviparin
Warfarin. A Coumarin derivative, is the most commonly used oral anticoagulant. It is a vitamin K antagonist -
Impairs the generation of active vitamin K, decreasing the amounts of vitamin K dependent coagulation factors.
Overdose is reversed by vitamin K infusion. Can cross placenta - do not use during late pregnancies.
Therapeutic uses:
1. Used to prevent the progression or recurrence of acute deep vein
2. Thrombosis or pulmonary embolism after initial heparin treatment.
3. Prevention of venous thromboembolism during orthopedic or gynecologic surgery.
4. Prophylactically, it is used in patients with acute myocardial infarction,
5. Prosthetic heart valves, and chronic atrial fibrillation.
New Anticoagulants
Parenteral FXa Inhibitors
1. Fondaparinux: Selectively inhibits only Factor Xa by binding to ATIII. Use in the treatment of DVT and
PE and for the prophylaxis of venous thromboembolism in the setting of orthopedic and abdominal
surgery. Well absorbed from the subcutaneous route with a predictable pharmacokinetic profile and,
therefore, requires less monitoring than heparin. It is contraindicated in patients with severe renal
impairment. Bleeding is the major side effect.
2. Danaparoid: Fast acting, generally predictable dose response Direct thrombin inhibitors (DTIs)
3. Hirudin: bind at both the catalytic or active site of thrombin as well as at a substrate recognition site.
4. Lepirudin: derived from medicinal leech saliva and produced in yeast cells by recombinant DNA
technology.
5. Bivalirudin: Synthetic polypeptide, used parenterally, short half life.
6. Argatroban: Synthetic parenteral anticoagulant derived from arginine, metabolized in the liver and has
a half-life of about 39 to 51minutes.
7. Ximelagatran: similar efficacy and bleeding risk to warfarin and does not need monitoring, taken orally
twice daily, and rapidly absorbed by the small intestine. May cause hepatic damage
THROMBOLYTIC DRUGS
THROMBOLYTIC DRUGS (FIBRINOLYTICS) Acute thromboembolic disease in selected patients may be

treated by the administration of agents that activate the conversion of plasminogen to plasmin, a serine
protease that hydrolyzes fibrin and, thus, dissolves clots
Plasminogen - inactive enzyme of plasmin

Plasmin - active
Fibrin - insoluble protein form from fibrinogen during the clotting of blood
1. Streptokinase. A protein (but not an enzyme in itself) synthesized by streptococci that combines with
the pro-activator plasminogen. This enzymatic complex catalyzes the conversion of inactive
plasminogen to active plasmin.
67
2. Urokinase. A human enzyme synthesized by the kidney that directly convert plasminogen to active
plasmin. Plasmin formed inside a thrombus by these activators is protected from plasma antiplasmins,
which allows it to lyse the thrombus from within.
Adverse effects: hemorrhage is a major side effect.
Fibrinolytic Inhibitors:
1. Aminocaproic Acid. Similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis.
Competitively inhibits plasminogen activation
2. Tranexamic acid is an analog of aminocaproic acid and has the same properties.
USES
● Adjunctive therapy in hemophilia

● Bleeding from fibrinolytic therapy
● Prophylaxis for re-bleeding from intracranial aneurysms.
● Postsurgical gastrointestinal bleeding, post prostatectomy bleeding, bladder hemorrhage secondary to
radiation and drug-induced cystitis.
Adverse effects.
● Intravascular thrombosis from inhibition of plasminogen activator

● Hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness
Hematopietic growth factors
Vid watch: https://www.youtube.com/watch?v=rF9enaNTuaE - wala transcript oh no
RBC - erythropoietin produced in kidney

WBC - G-CSF (Filgrastim and Pegfilgrastim) - granulocyte stimulator, GM-CSF (Sargramostim,
Molgrasmostim) - granulocyte monocyte stimulators
Platelets - IL-11 (thrombocytopenia; drug: oprelvekin) and Thrombopoetin
ITS - thrombopoietin receptor +

- Symptoms: easily bruising and bleeding
- Drug: romiplostim; eltrombopag
Task: Classify the growth factors in the blood cells, its pharmacological use and drug products.
ANEMIA
TYPES OF Anemia
(Flip) Vid watch : https://www.youtube.com/watch?v=mOrRJBqm744 - 36 minutes kaayo
Transcript:
Alright Ninja Nerds! In this video we're going to talk about the various types of anemia. So first off, what is
anemia?
What is meant by anemia? Anemia by definition is low oxygen carrying capacity.
So, we can also give it another definition, which is a low amount of red blood cells.
68
But again the overall concept is that anemia is low oxygen carrying capacity, whether it be do to a decrease
number of red blood cells or dysfunctional red blood cells.
Alright, so we would see that on hematocrit. We would see a lower than normal erythrocyte layer on the
hematocrit.
So a low PCV or a low HCV, less than 45%. Alright, so here we have a whole bunch of different types of
anemias listed.
We're going to go through each one systematically, mentioning whats going on with these. So lets start over
here with the first one being iron deficiency anemia.
So with iron deficiency anemia, what would you notice? What would be the first thing that you notice within
these individuals?
In general, the symptoms of anemia are pretty much straight forward across the board. But with this type right
here, you'll notice that probably going to develop symptoms.
And again these symptoms are pretty much going to be similar across the board, it might be a little bit different
for other types of anemia.
But generally, they're going to have a shortness of breath or dyspnea. So they'll have some shortness of breath
or SOB.
Not what you think it means, so again SOB is shortness of breath or dyspnea. Second thing that they might
have is probably some fatigue, because they are not going to
have a much oxygen being delivered to their tissues right? So they're going to have some fatigue.
Alright, another thing that they might also have is whenever you have a low amount of red blood cells it triggers
a change in the volume of your heart and increases the work
load of your heart. So, it can lead to increase work load on the heart.
And it can lead to what is called tachycardia. And it can lead to a bunch of other things, but in general you're
going to notice this.
They are going to have shortness of breath, they're going to be fatigue, they are going to have an increase
workload on the heart, tachycardia and they can even have some dizziness
too, because of not getting enough oxygen. So they might even have a bit of dizziness, maybe even some
syncope depending upon how
bad the anemia is. Alright, that in general is the symptoms of it. Alright, so with iron deficiency anemia.
What would you see here? So iron deficiency is simple, its a deficiency in iron. But what is iron needed for?
If you remember, we go iron from the GI tract, what do we need with iron? Iron is essential to be able to
incorporate into hemoglobin.
You know there is a pigment called protoporphyrin 9.
What happens with protoporphyrin 9, it reacts with the iron, through what is called ferrochelatase,
which converts the iron and the protoporphyrin into Heme. And what is heme essential for?
For making hemoglobin. So without the iron, can you make functional hemoglobin?
No. So with low iron levels, you have low amounts of heme. And with low amounts of heme, you are going to
have low amounts of hemoglobin, dysfunctional
hemoglobin. Right? Another thing is hemoglobin is what takes up most of the cell volume within this red
blood cell. So if you are decreasing in your hemoglobin, the cell will be smaller. And we can determine that
through a blood test, called a blood indices which is called
mean corpuscular volume (MCV). And all mean corpuscular volume is.
You just take hematocrit which is about 45, right?
And then you'll take that and multiply that by 10, and then divide that by the total number of red blood cells for
every one liter, which is about 5, but it would be a trillion.
And the multiply it by 100, which gives you about 90 femtoliters. And in these individuals, they are going to
have a mean corpuscular volume lower than
69
90 femtoliters. So this is called, whenever the MCV is less than 90 femtoliters, we give it a term and
its called microcytic or microcytosis.
So what does that mean? That means that the red blood cells are really small. They are not having enough
hemoglobin, they're not going to be able to deliver as much oxygen
to the tissues. And they'll produce symptoms such as shortness of breath, fatigue, increased workload on the
heart, tachycardia, dizziness and so on and so forth.
That's the overall concept here. What is the cause of iron deficiency?
The causes are usual pretty straight forward, usually its because of blood loss.
Causes are usually do to, blood loss. Maybe you have some type of ulcer, you could be losing blood that way.
A more common cause is usually with women, who actually have heavy menstruation, menorrhagia.
Due to heavy menstruation, okay. That's another one, so heavy menstruation.
And whats one more? One more could even be do to, think about it, not getting enough iron in your diet.
So not enough iron in the diet. So low iron diet.
Which is a little bit more common with individuals who are vegetarians, right? Okay, in summary what would
you notice with iron deficiency.
Symptoms such as shortness of breath, fatigue, increase workload of the heart, tachycardia, dizziness.
You would take the red blood cell indices and would be their mean corpuscular volume less than 90 femtoliters,
which is called microcytosis or microcytic anemia.
So they have these tiny little red blood cells and what would be the cause of this? It could be blood loss, could
be heavy menstruation, could be a low iron diet.
What would you do for this person? You probably want to give them more iron. So whats the treatment? Give
them more iron. Probably not going to do too many transfusions, but you could do transfusions also.
But that is pretty much that. So that settles our iron deficiency. Lets go onto the next one.
Pernicious anemia or B-12, maybe even folic acid deficiency. So what is B-12 important for?
Remember that from the erythropoiesis process. You take in B-12, you take in folic acid.
B-12 is usually coming from leafy vegetables, it can even come from certain types of meat
sources. Folic acid is from the leafy vegetables and meats sources right? So these guys are coming in here
right?
So here's the B-12, we are going to focus on this one first. It comes in, and it gets to the stomach.
Now here is what the problem is. Most people think, oh its just a deficiency in B-12, not taking enough in.
That's not really the main cause of it. The main cause that they have found is that it is an autoimmune
condition.
So you know that there are these cells within your stomach called the parietal cells. And your parietal cells
secrete a glycoprotein.
And that glycoprotein is called intrinsic factor. Here's this blue protein, and this blue protein is called intrinsic
factor.
Intrinsic factor. And what happens? B-12 naturally binds to intrinsic factor, that's what B-12 wants to do.
It wants to bind with the intrinsic factor. Well here's the problem. In some individuals, their immune system
some how produces antibodies that will actually
bind to the intrinsic factor. So it will produce these antibodies, and look what happens. These antibodies bind to
the intrinsic factor, blocking B-12 from be able to bind.
And if B-12 can't bind, can B-12 get absorbed. No, because we need the intrinsic factor for the receptor
mediated endocytosis mechanism,
to get the B-12 into the blood stream, where it can bind to transcobalamin 1 or 2, right?
So again we will just draw here, but I'm not going to list it but you know but it is transcobalamin 1 and 2. What
happens?
If these antibodies attacks the intrinsic factor and B-12 can't bind, will you be able to absorb B-12? No.
70
So there would be less B-12 within the blood stream. What is B-12 very important for again? B-12 was needed
in order for the red blood cells DNA to mature and condense.
And if the DNA doesn't mature and condense, then what is going to happen?
Your actual red blood cells are going to be huge. And again, what will happen with this person? They are going
to have a red blood cell that is really really big.
Okay, well we already talked about microcytic, what would be the problem here then? Well if you look here, you
do an MCV.
And again you already know what it is, you take there hematocrit over the total amount of the number of red
blood cells, multiply by 100 right?
And normally its 90 femtoliters. Well this person is actually going to have large red blood cells, so their MCV
will be
greater than 90 femtoliters. This term is called macrocytosis or macrocytic.
Okay, so macrocytosis or macrocytic. So they'll have very, very large red blood cells.
And these red blood cells, will they be able to deliver as much oxygen? No, because the DNA didn't mature
very well. So again, what does B-12 needed for?
It's needed for DNA maturation and even some synthesis and condensation of the DNA.
And without that, what's going to happen? Can the red blood cells completely mature? No. Will they make
enough functional hemoglobin?
Not necessarily and these cells are so big that they can actually get stuck inside the capillaries and they can
undergo hemolysis.
So, you can actually lose red blood cells that way. Okay, so that's one thing. Folic acid, same thing.
This has a different mechanism of absorption, but for whatever reason, if you aren't able to get enough folic
acid within the diet for whatever reason, folic acid is also needed.
Right? So folic acid is also needed in order for the DNA to mature.
So now, people with this, we already understand symptoms are pretty much going to be the same kind of
concept.
What would you do to treat them? Well, B-12 isn't getting adequately absorbed. So we have to get into the
blood stream a different way, a different route.
So what we can do is, we can intramuscular injections. So what is going to be the treatment for this person
usually?
Intramuscular injections of B-12.
Okay? That's probably what we are going to do, most likely. Now this can occur, not just sometimes with
autoimmune, but in some elderly individuals
as their stomach gets smaller, the intrinsic factor production decreases, okay? So again, treatment of this
would usually be intramuscular injections of B-12.
Alright, so that pretty much gives us everything we need to know about B-12 and folic acid. Aright next one,
hereditary spherocytosis, this is a genetic condition.
So its some type of hereditary condition, as it says in the name, where there is some type of mutation, right?
Remember when we talked about this, very briefly in the life span of red blood cells. It has these plasma
membrane proteins, right?
What were these proteins called again? What was this green webby protein called?
Spectrin. This little red protein here that is anchoring the spectrin to the membrane, its a trans
membrane protein is called ankyrin.
And then these transmembrane or blue proteins can be tons of different types, they can be Band 3, protein 4.1,
glycophorins, there are tons of these, right?
But, what was the most important ones I told you before? Spectrin and ankyrin, these are the ones if there is
some type of deficiency or there
71
is some type of mutation, where these proteins aren't produced or adequately produced, this
cell membrane is not going to be a as flexible. And it is not going to hold it into this biconcave shape. If it can't
hold it into this biconcave shape, it actually takes on a spherical form.
And look at this red blood cell, its spherical. And that is why we call it spherocytosis.
So this one because of that, it throws of it's actual MCV.
And sometimes the MCV can fluctuate, but it is usually considered to be what is called microcyctic, usually
microcytic.
But its hyperchromic, but there isn’t going to be as much at the edges now, its going
to be all over the place. So it is not going to be good at delivering the oxygen effectively. And this is commonly
captured and caught within those sinosuoidal capillaries within your
spleen or your liver or your bone marrow. So what is one of the symptoms that these people will develop.
If they have this, it can actually get stuck inside the spleen. So let's say here is the spleen right here, right?
And here is the actual blood vessels coming into the spleen, right here. So here's the actual blood vessels
coming into the spleen.
If that red blood cell gets stuck in those sinusoidal capillaries, macrophages will actually
phagocytosis, that we talked about before, break it down into its components. But what's another thing? If we
have enough of these guys getting stuck in there, what will be the symptoms then?
You'll notice the spleen getting bigger. And what is that called, splenomegaly.
Okay, so they might have an enlarged spleen maybe, depending on how severe this is. And then they're not
going to get enough oxygen to the tissue cells because there is going
to be hemolysis, so they will have similar symptoms right? And they might even have splenomegaly. So that
pretty much gives us hereditary spherocytosis.
So its a deficiency or a mutation within ankyrin or spectrin, which causes the red blood cells to become
spherical.
Which can cause then to get caught inside of the capillaries and undergo hemolysis and can lead to
splenomegaly. Alright, let's go to my personal favorite here, G6PDH deficiency.
So it stands for, what does it stand for? It stands for, glucose 6-phosphate dehydrogenase.
This right here is actually a deficiency, a deficiency in this enzyme.
And you're probably wondering, where the heck does glucose actually have to do anything with this? Well here
is where it's very interesting, there is a specific mechanism.
You know that red blood cells they can't do aerobic cellular respiration, they can only do glycolysis.
So they can only convert glucose into pyruvate. And they can make lactic acid, they can make 2,3 bpg.
And a whole bunch of other things. But another important thing is that there are other things that can happen.
Not just in these red blood cells, but it can happen in other cells. But, it can also do what is called a pentose
phosphate pathway, where it goes to make what
is called ribose-5-phosphate, I'm just going to be R-5P. But in order for it to do that, so let's come actually down
here.
So here's glucose. And it has to go through 3 series of steps, one is called 6-phosphoglucanolactone, and
then it'll actually go to what is called R-5P.
So it'll actually turn into ribulose.
And here's what's important, in these steps there's a molecule called NADP+, that gets
converted into what's called NADPH. And over here, NADP+ into NADPH.
Why is this NADPH so important? Well you know there are a lot of free radicals that your body produces all the
time?
Its producing these things all the time. Remember we have the super oxide anion, you can have the hydroxide
free radical, you can
have the specifically the hypochloric acid, hydrogen peroxide.
72
And these are your free radicals right? So these are reactive oxygen species. What is the danger of these?
The can damage all different stuff within our bodies. Well there's a molecule called glutothione.
Im just going to draw a big G here. It has these things sulf-hydro groups, these little thiols.
Its a thiol group. And what happens is, when these actual glutothiones, again what are these called?
It's called glutothione. These glutothiones will actually take some of these hydrogens and these electrons from
these reactive oxygen species, to make them less toxic, to be able to block their dangerous
effective. So then what it does is, it'll actually combine, maybe it'll donate some of these hydrogens onto this
oxygen here.
Right? So it can actually donate hydrogens onto the oxygen, some of these hydrogens onto the H2O2 and
make water.
How will it do that? When it does that it gets converted into what is called... so this is the reduced form of
glutothione.
But then it can get oxidized and when it does that reaction to be able to act as an antioxidant,
and then they are actually linked together. They are linked together through disulfide bonds.
How is that causing a problem? Well in order for them to go back and so that they can actually catch more free
radicals,
the depends upon NADPH. So they need NADPH for this step.
NADPH drops off those hydride ions and those electrons to make NADP+.
And that converts this guy back into its reduced form. And there's an enzyme that drives this step called
glutothionperoxidase and reductase
enzymes. But whats the important thing, we need him in order to get him back into the proper antioxidant
form, so that we can prevent these reactive oxygen species from accumulating. But what happens is, we don't
have this enzyme right here.
This is where that enzyme works, G6PDH, glucose-6-phophatedehydrogenase.
Can you make NADPH if you don't have him? No. If you have a deficiency or you don't have him, you have
less NADPH.
And if you have less NADPH, then what's going to happen? You're not going to be able to make as much
reduced form of glutothion.
Can you hold onto these reaction and can you prevent these reactive oxygen species from accumulating? No.
What will these reactive oxygen species do? They'll damage the hemoglobin. So what they will do, imagine
here.
I have a hemoglobin molecule right here, what it'll do is, the reactive oxygen species will
damage these guys, so it will damage the actual hemoglobin. And the hemoglobin will start precipitating , and
when it starts precipitating it actually
goes and binds on to the actual inner cell membrane, and now look at it. It binds onto this inner cell membrane,
and when it binds onto this inner cell membrane,
it causes the red blood cell membrane to become less flexible, less pliable, less ability
to be able to bend and squeeze through capillaries. What can that do? That can cause a hemolytic anemia.
Where it will actually destroy these red blood cells and our red blood cell will drop, and that's causes anemia.
Alright, so what are these here called?
They are called Heinz Bodies. So whenever you do the test, you actually look for this.
So you look for the heinz bodies. How would you be able to detect hereditary spherocytosis? There is a test
that is called a Coombs test.
Just wanted to give that to you right there, coombs test. Ok, do a coombs test for that.
Maybe we will talk about that in future videos. That's the whole problem with this, is that these heinz bodies
that decrease the flexibility
73
of the red blood cell and it can't squeeze through the capillaries and it causes hemolysis. Which is again, red
blood cells decrease and then what else decreases with it?
Oxygen and you have anemia. Sickle cell anemia also abbreviated HbS.
Alright, sickle cell hemoglobin, what happens here?
It's a point mutation or a specifically, do you know there a different types of point mutations? Whether its a
missense mutation and nonsense mutations, this is an example of what is called
as a missense mutation. So what do I mean by that? If you have a string of hemoglobin, here's an amino acid,
here's an amino acid, here's
an amino acid, here's an amino acid, right? So this is the beads of amino acids that make up the primary
structure of hemoglobin.
If I count, 1,2,3,4,5,6. The 6th amino acid on usually the most common chain it occurs on is the beta chain.
You know hemoglobin, adult hemogobin, it usually has two alpha and two beta.
Well on the beta chain is the 6th amino acid is normally, normally is glutamic acid.
Or they denote it with the three letter abbreviation GLU. What happens is, is there's a missense mutation
where GLU gets actually converted into valine.
And these amino acids that are different in there physical properties and in their PKa's. Okay, so then whats
going to happen then?
GLU right here, 1, 2, 3, 4, 5, 6, gets converted into valine. And valine is a hydrophobic amino acid.
Glutamic acid is a hydrophilic or polar amino acid. So it changes the overall three dimensional structure.
And what happens is, imagine this being a hemoglobin molecule right here. This black blob right here, what
happens is in the normal red blood cells, the hemoglobin
is polymerizing and start connecting to one another. And whenever they start connecting to one another and
polymerizing.
So again what are these molecules here called, they are called hemoglobin. The hemoglobin molecules
undergo polymerization and whenever they polymerize, they take on
this weird structure. And it takes on this sickle shape. And what is that sickle shape do to?
It is do to the polymerization of the hemoglobin molecules because of the missense mutation
from glutamic acid into valine. But let me be even more specific. You know sickle cell anemia it's not always
sickle cells, its not always in a sickle shape.
What actually causes it to go into the sickle shape and to polymerize like that? It's whenever they are not
bound to oxygen.
So whenever it's in this shape is when its not bound to oxygen. So normally, oxygen is bound here.
Whenever oxygen leaves, which is the internal respiration. When oxygen leaves, it changes the overall three
dimensional shape of the hemoglobin
molecule. And that's when it takes on that sickle shape because they start polymerizing to one another. And
whenever they get the oxygen back, it will actually de-polymerize and take it back
on. So this is that cycle, where you are going from a sickle shape to a normal red blood cell, what's that
process called?
It's called sickling. And this can consistently keep occurring and what's the problem with sickling?
These, look at these red blood cells. They're easier to get stuck in capillaries. And if they get stuck in
capillaries, they undergo hemolysis, they can occlude the blood
vessel, that's one of the big thing with sickle cell anemia is that it can cause a very, very
dangerous thing which is called vaso-occlusive crisis. So in other words, this can get stuck in other parts of the
body.
A very embarrassing area is one of them is the penile arterioles.
So usually these people, its very sad, they come to the ER and they actually have what is called priapism.
And its very sad and its just a very painful a prolonged erection due to the actual vessels
74
being clogged with the sickle cells. It can get stuck in the spleen, and that can cause splenomegaly. So they
might even have to remove the spleen, which is not good, depending on the age of
the individual because the spleen is important for being able to destroy encapsulated bacteria like
streptococcus pneumoniae, neisseria meningitidis and haemophilus influenzae.
This is really, really dangerous with sickle cell, they might have priapism, splenomegaly and other things where
it can get stuck.
So again, the reason why is because of a point mutation where glutamic acid is replaced with valine, changes
the overall structure.
And whenever it's not bound to oxygen, it sickles and polymerizes and makes this sickle shape. But then when
it binds to oxygen it goes back into the normal structure.
And this sickling again can lead to vaso-occlusive crisis, just a couple examples, priapism or
splenomegaly. Okay, there is a way that they try to treat this, they try to give tranfusions, they try to be able to
give them oxygen.
Actually, that is one of the biggest treatments, you give them a lot of oxygen. So one of the biggest treatments
is you give them oxygen.
So that's one way you can treat it, they also give pain relievers, so they sometimes will give them certain types
of opiods, maybe, depending upon the severity of the pain.
They probably give them fluids because of some of the blood loss that they might have. And another thing that
they can give that they are showing that they might have effect
is called hydroxy urea. And all hydroxy urea does is it increases the amount of fetal hemoglobin.
We are not going to get into that because that will take too long, but it just makes more fetal hemoglobin which
is helpful for them to get enough oxygen to the tissues.
One last cool thought, sickle cell anemia is been found with people who have it, it shows a resistance to
malaria.
Which is good, but at the same time, it's pick your poison right? So sickle cell anemia, again can have
resistance to the plasmodium plazforum which causes malaria,
alright. That's sickle cell. Let's going onto the next one, hemorrhagic anemia.
So if you look here, we got a guy, we're the ninja nerds right? So we have a little ninja nerd star, it hit this guy
and he is now bleeding.
He is losing blood. And this is the easiest one, if he is losing blood whats happening? You are losing red blood
cells.
If you're losing red blood cells, so again whats going to happen to this person. There is going to be a decrease
in red blood cells.
And if you decrease your red blood cells what do you do? You decrease the oxygen carrying capacity, right?
And if you decrease your oxygen carrying capacity, what do you have? You have a form of anemia.
But this is hemorrhagic anemia. Another thing that can happen, sometimes people that have what is called
Helicobacter Pylori
or they have been taking NSAIDs for a very long time, they can develop peptic ulcers.
And these peptic ulcers can actually eventually perforate and cause bleeding. And they are losing blood, and if
they lose that blood, what do they lose?
They lose red blood cells, they lose oxygen and it can keep going on and on. It could be gun shot wound, stab
wound, aortic aneurisms.
So if there's an aneurism of the aorta or an aneurism within the cerebral vessels, you're losing blood, you're
losing oxygen and it can cause anemia.
So this is a pretty easy one, it's just do to blood loss. Alright? And again for this one you're obviously going to
have to, maybe depending upon the severity,
75
give them more red blood cells, you might have to give them fluid, you might have to go into surgically fix
whatever vessel if its severely damaged.
Okay? Aplastic Anemia, Aplastic anemia is actually kind of a misnomer.
And the reason why is, I'll explain it here in a second, is that it's not just red blood cells that actually being
effected in this.
It's usually also platelets and white blood cells. So it's actually a misnomer to call it anemia. Alright, but
anyway, if you remember from the luekopoiesis and the erythropoiesis videos,
we have that hemocytoblast right? So I'm just going to be hemo-cyto-blast. That gets converted into a myloid
stem cell and it gets converted into a lymphoid stem
cell. What can happen is sometimes people for what, 65% of aplastic anemia is idiopathic.
In other words it can be caused by drugs, chloramphenicol, it could be caused by benzenes,
it could be caused by streptomycin, a lot of different drugs are usually the cause of aplastic anemias.
But it could be do to the viruses like cytomegaly virus, Epstein Barr virus, could be do to radiation, so many
causes.
There is another one called Fanconi syndrome. But were not going to talk about that, just know its usually
some type of destruction
of the bone marrow. And usually where it's effecting it is right here. Look what can myloid stem cells go and
form again?
They can form the three different types of lineages right? They can form, red blood cells.
They can form white blood cells. They can platelets.
And usually what happens is, this step right here is effected. You are usually destroying the myloid stem cell.
And if you are destroying the myloid stem cells you're not just destroying the red blood cell production and
white blood cell production, but also the platelet production.
So what does that mean then? That means that these people will have low red blood cells.
They'll have low white blood cells. And they'll have low platelets.
Now, we know red blood cells causes anemia. Low white blood cells leukopenia and low platelets is
thrombocytopenia.
But all together is actually called pancytopenia.
So thats one thing that you want to know about aplastic anemia.
It's not just usually red blood cells effected, but its also white blood cells and platelets are effected. And thats
called pancytopenia.
Now aplastic anemia, we already said a couple things about what it can be do to. Obviously these people,
depending upon the severity you might have to do a bone marrow
transplant. You might to be able to constantly undergo certain types of transfusions depending upon
the severity. With the destruction of the bone marrow there's not much you can do besides just trying to
treat the symptoms. And again if there is a possibility maybe a bone marrow transplant. Alright, thats pretty
much aplastic anemia in a nut shell.
And again so what would you notice about these people, they would have again pancytopenia as one of there
clinical signs.
And again some of their symptoms are going to be pretty much the same because they are not going to have
as much red blood cells. Oh!
What else would they have? Besides that, if you are losing white blood cells what would happen there? You
might have an increased incidence of infections, because your white blood cells are lower,
so thats one clinical sign. And if you're losing platelets, what would that cause? You would actually not be able
to clot as much.
And if you don't clot as much, what would these people have if they have thrombocytopenia? Im not sure how
you say it petechiae, but its basically small bruises, you would have
76
these little bruises that are kind of wide spread. So they can actually produced what is called increased
bruising or bleeding.
Okay? So that's one thing. And again bone marrow transplant is probably the best option for these individuals
but
trying to also treat them with antibiotics and giving them platelet transfusions and red blood cell transfusions.
That's going to be very important for these individuals too, okay. Last one here, Thalassemia.
Thalassemia's more common within the Mediterranean ancestry. So it's more common within the
Mediterraneans. Mediterranean ancestry.
Ok, this is more common within the Mediterranean ancestry and what it is, it's actually a genetic
condition. And genetic meaning that, remember hemoglobin?
One more time here, we had the hemoglobin A1 right? And that's made up of two alpha and two beta.
Whats the problem with these individuals? There's two types of thalassemia.
There is alpha thalassemia.
And then there's beta thalassemia.
Now by telling you that, I basically kind of gave you what's happening with these individuals.
It's usually whenever they are having a faulty or missing globin chain. If they are missing an alpha.
So let's say this person is missing an alpha. So they have only an alpha plus two beta.
What would this person have? If they only have one alpha and two beta? This would be what is called alpha
thalassemia.
And what if this person has two alpha but maybe they have, they lose one beta? So if they lose a beta, then
what does this one going to be?
This is going to be beta thalassemia. Okay?
And again with these individuals because its a genetic mutation, what they are actually
trying to.. Oh! One more thing actually before I mention that. Because you are missing hemoglobin, what
happens to the cell volume?
It would drop right? So again, what would they have? There Mean Corpuscular Volume would it be less than or
greater than 90 femtoliters,
because they are getting smaller, it would be less than. So they would have a mean corpuscular volume that
will be less than 90 femtoliters.
So what is that called? Microcytic anemia right?
So this is another type of microcytic anemia. The other one that we mentioned was iron deficiency. but
thalassemia is another type of microcytic anemia, because the mean corpuscular volume
is less than 90 femtoliters. With these individuals again they have, because of their condition usually the best
way to
treat this is constantly giving them perfusion, not perfusions, transfusions. They might even be taking iron
supplements, they might be getting oxygen.
But, hopefully if lord willing for them, if they can get what is called a bone stem cell
transplant, that would be ideal because they it would help them to be able to make more
functional hemoglobin. So again with these individuals it would be desireable for them to get a bone stem cell
transplant, but if not then they are going to be consistently getting transfusions and again its just trying to
manage the symptoms of these individuals.
Alright so, in a nut shell we basically described all the different types of a anemias.
Okay so what were those anemais one more time? In just a general look. Iron deficiency was one, right?
Which is a microcytic anemia. B-12 and Folic acid deficiency which is a macrocytic anemia.
Hereditary spherocytosis which is usually some type of genetic mutation, where they aren't making the specific
types of red blood cell membrane proteins and this is a hemolytic
anemia. G6PDH deficiency where they are actually again a mutated form or deficiency of this enzyme
77
that's needed for antioxidant help, because if not reactive oxygen species accumulate and cause damage and
heinz bodies and hemolytic anemia.
Sickle cell, which is again a genetic condition where there is actually a point mutation or missense mutation
where it changes the actual overall shape of the red blood cell into a
sickle shape and can lead to vaso-occlusive crisis. Hemorrhagic anemia just due to some type of blood loss
whether it be acute or chronic,
alright? Usually it's a little bit more acute but it can be chronic.
Aplastic anemia which is usually do to a misnomer because it should really be called aplastic pancytopenia,
where there is some type of bone marrow damage to the myloid stem cell
which is not only decreasing red blood cells but also platelets and white blood cells which can lead to anemia,
increase infections and bruising and bleeding right?
And again, the best way to treat these people is maybe a bone marrow transplant, but if not, you're going to
give them transfusions.
And then the last one, Thalassemia which is more common within the Mediterranean ancestry
and its a genetic condition in which they produce a faulty globin chain. If its missing an alpha, its an alpha
thalassemia.
If they're missing a beta globin, its beta thalassemia. And again with these individuals, the mean corpuscular
volume is low, so they have a
microcyctic anemia. And the best way to treat these people is constant transfusions, but if possible you
could possibly do a bone stem cell transplant. And one last thing, before I mention anything again, usually with
sickle cell anemia and
hereditary spherocytosis is sometimes depending on the severity of it. If it's very consistent and chronic
blocking vaso-occlusive crisis.
You might have to do a splenectomy, by removing the spleen, it is a danger because again,
depending on the age of the individual or just in general, they won't have the ability to fight off specific types of
encapsulated bacteria such as streptococcus pneumoniae,
neisseria meningitidis, and haemophilus influenzae, there is a danger of that.
In this video we covered all the anemias. I hope this made sense, see ya ninja nerds.
(end of transcript)
Anti-Anemia Drugs
(Flip) http://tmedweb.tulane.edu/pharmwiki/doku.php/antianemia_drugs idl niyo nalang siguro? Goess or

lagay natin here? Pwede rin lagay here para isahang print okay g wait ay i think nalagay na ni maam?? Include
nalang natin yung kulang niya
Antianemia Drugs
1. Erythropoietin (Epoetin alpha)

▪ Trade Names: erythropoietin, Epo, Epogen, Procrit ®
▪ Drug Class: Drug Used in Anemia (normocytic)

▪ Mechanism of Action:
▪ a glycoprotein that stimulates red blood cell production. Epoetin alfa is a 165 amino acid
glycoprotein manufactured by recombinant DNA technology, and has the same biological
effects as endogenous erythropoietin
78
▪ Hypoxia is the primary physiological stimulus for erythropoietin production in the body
▪ Indications: treatment of anemia in:

1. chronic renal failure patients
2. zidovudine-treated HIV-infected patients
3. cancer patients on chemotherapy
4. reduction of allogeneic blood transfusion in surgery patients. Erythropoietin
deficiency can result from compromised renal function (it's primary site of
production). Erythropoietin deficiency results in a normocytic anemia.
▪ Contraindications:
▪ Uncontrolled hypertension or known hypersensitivity to either mammalian cell-derived
products or to human albumin.
▪ Pharmacokinetics:
▪ given i.v. or s.c. Half life of 4-13 hrs in patients with chronic renal failure. It is measured in
international units (IU).
▪ Side Effects:
▪ a rapid increase in hematocrit & hemoglobin may cause hypertension & thrombotic
complications. These can be minimized by raising the hematocrit slowly and treating the
hypertension.
2. Ferrous Sulfate
▪ Trade Name: generic
▪ Drug Class: Drug Used in Anemia (microcytic)

▪ Iron combines with porphyrin and globin chains to form hemoglobin, which is critical for
oxygen delivery from the lungs to other tissues.
▪ Iron deficiency causes a microcytic anemia due to the formation of small erythrocytes with
insufficient hemoglobin.
▪ Indications:
▪ Iron deficiency anemia, blood loss related to pregnancy or GI bleeding (NSAIDs), hookworm
infestation, or excess coffee
▪ Patients with hemochromatosis, hemosiderosis or hemolytic anemia
▪ An oral (absorbable) iron formulation.
▪ Side Effects:
▪ Therapeutic doses - nausea, upper abdominal pain, constipation or diarrhea
▪ Iron overdose (1-2 g) can lead to circulatory collapse and death. Non-intentional iron
overdose has been a leading cause of fatal poisoning in children <6 years old. Keep
out of reach of children.
▪ Iron overdose can be treated by gastric lavage with a phosphate solution and deferoxamine
(iron chelator).
▪ Drug interactions:
▪ it may decrease the absorption of other medications
3. Iron Dextran
79
▪ Trade Name: INFeD ®
▪ Drug Class: Parental Iron Preparation

▪ Same as ferrous sulfate (but has a different route of administration)
▪ Indications:
▪ Patients with documented iron deficiency in whom oral administration is unsatisfactory
or impossible (e.g. malabsorption syndrome, prolonged salicylate therapy, dialysis
patients).
▪ Seldom used now (newer orally effective agents including iron sucrose & ferric gluconate
complex are most commonly used).
▪ Ferric gluconate & iron sucrose are two alternative parenteral forms of iron that can be
given i.v., but should NOT be given intramuscularly.
▪ Given by deep i.m. injection or i.v.
▪ Most adults with iron deficiency require 1-2 g of replacement iron, or 20-40 ml.
▪ The favored route of administration is i.v. infusion in several hundred mls of normal saline
over 1-2 hrs.
▪ Side Effects:
▪ More side effects compared to administering oral iron supplements
▪ Local pain & tissue staining (brown discoloration), headache, light-headedness, fever,
nausea, flushing, urticaria, bronchospasm, and rarely anaphylaxis & death.
4. Deferoxamine
▪ Trade Name: Desferal ®
▪ Drug Class: Iron Chelator
o Binds iron avidly, but poorly binds other essential trace metals. It competes in binding
loosely bound iron, but fails to bind iron that is biologically chelated, such as in microsomal
and mitrochondrial cytochromes and hemoproteins.
Indications:
▪ Iron poisoning. Used for treating both acute iron intoxication and in patients with secondary
iron overload from multiple transfusions.
▪ Deferoxamine plus hemodialysis may also be useful in treatment of aluminum toxicity in
renal failure. (It is not indicated for the treatment of primary hemochromatosis, since
phlebotomy is the method of choice for removing excess iron in this disorder.)
Contraindications:
▪ Patients with severe renal disease or anuria, since the drug and the iron chelate are
excreted primarily by the kidney
Pharmacokinetics:
▪ Given parentally (i.m., s.c. or i.v.). It is poorly absorbed if taken orally, and may actually
increase iron absorption if given orally
▪ Iron-chelator complexes are excreted in the urine, often turning the urine an orange-red
color
Side Effects:
▪ Rapid i.v. administration may cause hypotension
▪ Idiosyncratic responses such as flushing, rash, abdominal discomfort may occur
5. Folic acid
80
▪ Trade Name: Folvite ®
▪ Drug Class: Drug used in anemia (megaloblastic)

▪ Essential cofactor for synthesis of amino acids, purines and DNA
▪ Indications:
▪ Treatment of megaloblastic anemias due to a deficiency of folic acid as may be seen in
tropical or non-tropical sprue, in anemias of nutritional origin, pregnancy, infancy, or
childhood
▪ A reduced form of folic acid known as citrovorum factor (or leucovorin) is given to
replenish endogenous folic acid in patients on methotrexate (which inhibits dihydrofolate
reductase). Citrovorin (leucovorin) is better absorbed compared to folic acid.
▪ Folic acid should not be given alone in patients with pernicioius anemia without
knowing whether they also have a Vit B12 deficiency. The danger is that folic acid
supplements can mask the signs of Vit B 12 deficiency, yet not prevent the development of
irreversible neurological disease due to Vit B12 deficiency.
▪ The Shilling test can be used to test for abnormalities in Vit B12 absorption.
▪ 1 mg of folic acid orally daily is typically sufficient to reverse megaloblastic anemia & restore
normal folate levels.
▪ Side Effects:
▪ Allergic sensitization
6. Vitamin B12
▪ Generic Names: generic, cyanocobalamin, hydroxocobalamin
▪ Drug Class: Vitamin
▪ A cofactor for several essential biochemical reactions.
▪ Indications:
▪ Used to treat or prevent deficiency of Vit B12.
▪ The most common causes of Vit B12 deficiency are:
▪ Pernicious anemia (results from defective secretion of intrinsic factor by the gastric
mucosal cells)
▪ Fish tapeworm infection
▪ Partial or total gastrectomy
▪ Various intestinal disorders that impair absorption of Vit B12.
▪ Different formulations can be administered orally, or by parenteral injection.
Notes:
▪ Vit B12 deficiency leads to megaloblastic anemia, GI symptoms & neurological

abnormalities including degeneration of myelin sheaths in axons of the spinal cord & peripheral
nerves.
▪ Vit B12 deficiency symptoms: paresthesias & weakness in peripheral nerves, progressing to spasticity,
ataxia & other CNS dysfunctions.
81
▪ Vit B12 deficiency in elderly patients due to abnormal absorption of dietary Vit B12 is relatively common
and easily treated.
---END OF MODULE 1
82

Module 1 - Cardiovascular Agents

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Module 1 - Cardiovascular Agents

Uploaded by

Copyright:

Available Formats

PHARMACOLOGY 2 NOTES BY ALBANIA, NGILAY, OCTAVIO, RASGO

NOTRE DAME OF DADIANGAS UNIVERSITY (NDDU)

MODULE 1: CARDIOVASCULAR AGENTS

Introduction to the Cardiovascular System

Although the rhythmic beating of the heart is

Summary: The Conducting System of the Heart

We should also know that the wall of the left

The third definition is cardiac output. It is the

The cardiovascular system (CVS) is sometimes called the blood-vascular, or simply the

Structure of the Heart

Layers of the Heart Wall

Epi (Outer) Myo (Middle or the muscle part) Endo (Inner)

Epicardium → myocardium → endocardium (from outer to inner)

Chambers of the Heart

Classification & Structure of Blood Vessels

Arteries carry blood away from the heart. Pulmonary

Capillaries, the smallest and most numerous of the blood vessels,

Veins carry blood toward the heart. After blood passes

I. DRUGS USED IN THE TREATMENT OF CONGESTIVE HEART FAILURE

The effects of CHF

Transcript: Mechanism of Action of Digoxin

a) The dose of the agent

b. Effects of digitalis glycosides on the heart

2) Myocardial oxygen consumption (MVO2)

4. Therapeutic uses and contraindications

5. Digitalization and maintenance dosage

Difference between Digitoxin and Digoxin:

Diuretics lead to decreased potassium and so it precipitates the intoxication of digitalis.

7. Treatment of digitalis toxicity

Drugs used during toxic effects of digitalis:

D. Other drugs used in CHF

Q: Can we use calcium channel blockers for patients with CHF?

II. DRUGS USED IN THE TREATMENT OF ARRHYTHMIA

(Flip) Vid watch: EKG https://www.youtube.com/watch?v=791ZsLSmCjo

Transcript for EKG

negative deflection and this represents ventricular

T-wave inversions are usually indicative of

Now the only way we'll be able to determine why

Atrial flutter is this condition again is not

and again you'll notice the nature of fibrillation you

So we look here you're gonna see this one and

syndrome again thyrotoxicosis and obesity it can go

a. Action potential phases

(Flip) Heart conduction Vid Watch: https://www.youtube.com/watch?v=RYZ4daFwMa8

The cardiac conduction system consists of the following components:

5) Disturbances in cardiac conductance may underlie supraventricular or ventricular

6) In areas of injured myocardium, conduction may be slow, or refractoriness shortened,

3. Classes of antiarrhythmic drugs

There are 5 classes of antiarrhythmic drugs:

be used in case of systolic heart failures.

● Class V includes all drugs that act by other or unknown mechanisms.

POTASSIUM - excites heart (heart excitability)

CALCIUM - contracts heart (heart contractility)

Based on vaughan williams classification

B. Class IA antiarrhythmic agents

f. A/E. cardiotoxicity includes A-V block, ventricular tachyarrhythmias, and depression of

C. Class IB antiarrhythmic agent

D. Class IC antiarrhythmic agents

E. Class II antiarrhythmic agents: Beta-adrenergic antagonists (β-blockers)

a. Pharmacologic effects. The antiarrhythmic effect is due primarily to β receptor blockade

2. Beta 1-selective (cardioselective ) adrenergic antagonists

F. Class III antiarrhythmic agents

2. Amiodarone is an iodinated benzofuran derivative. It is highly lipid-soluble; its half-life is 20-100