2 Pharmacology 2 Cardiovascularand Diabetic Pharmacology 2015

IPBP IA Exam Study Guide:
Pharmacology 2: Cardiovascular and Diabetic Pharmacology
International Post-Baccalaureate
PharmD (IPBP) Program
Internal Assessment (IA) Exam
STUDY GUIDE
PHARMACOLOGY 2:
CARDIOVASCULAR AND DIABETIC
PHARMACOLOGY
2015
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Section I: Lipid Processing, Atherosclerosis, and Antihyperlipidemic

drugs
Physiological Processing of Lipids
You should be able to describe the origin of, and role of, each lipoprotein.
Chylomicrons (CM)
Very Low Density Lipoproteins
(VLDL)
Intermediate Density Lipoproteins
(IDL)
Low Density Lipoproteins (LDL)
High Density Lipoproteins (HDL)
Additionally, it is also important to know a few

of the key players that are involved in lipid
processing and metabolism. Below is a list of
these key players that you should be able to
define and understand how they function.
What is SR-B1?
What is CERP?
ApoB-100 & -48
ApoE
ApoC-II
Lipoprotein lipase (LPL)
Niemann-Pick C1-like protein (NPC1L1)
LDL receptors
LDL receptors are very important to understand as all drugs that lower circulating LDL levels lead to an
increase in LDL receptors. Thus you need to know how the level of LDL receptors are controlled,
specifically:
What do LDL receptors bind to?
What controls LDL receptors expression?
o Describe the function of PCSK9?
o Describe the function of SREBP?
Additionally it is important to know what the liver does with cholesterol

What are bile acids?
o Where and how are bile acids made?
o Are bile acids are recycled, but how?
o What does recycling of bile acids have to do with cholesterol levels in the blood?
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Arthrosclerosis
Arthrosclerosis is predominately an immune-mediated vascular derived disease thus much of the
information will be in the immunology packet. However there are a few key issues to think about
regarding the role of lipids in initiating this problem.
First the main problem is that oxidation of LDL damages the ApoB-100. This damaged ApoB-100
cannot be taken up by the LDL receptors. Thus oxidized LDL has a long half-life. Thus it is more
likely to have two things happen to it.
1) The greater LDL levels one has, or the longer the half-life of the LDL, the greater the chances
that it will deposit in the blood vessels. This is purely a probability effect.
a. Once LDL is deposited in the vessel it is more likely going to be oxidized due to the
environment.
2) Macrophages will engulf the oxidized LDL through scavenger receptors. The problem with this
is that Cholesterol is toxic and the scavenger receptors are not regulated by cholesterol levels like
LDL receptors. Thus if a macrophage encounters a large amount of oxidized LDL it will gorge
itself and turn into a Foam Cell.
a. The foam cell releases cytokines and attracts more macrophages that then engulf the rest
of the oxidized LDL leading to a cyclic immunological event.
Key mechanisms for preventing arthrosclerosis is the lowering of LDL levels, which reduces the
probability that LDL will deposit in the vessel and become oxidized.
You should also know the non-pharmacological approaches to treating atherosclerosis, and realize that
these treatments alone have been shown to be no different than drug treatment alone.
Also understand what CRP is and why it is used as a biomarker for arthrosclerosis, and understand its
limitations.
Antihyperlipidemic Treatments
Non-Pharmacological
Decreased lipid intake
Exercise, specifically aerobic exercise
Pharmacological
Stains
o What is the proper name for a statin?
o What do statins target?
o What are pleotropic effects, and what are some likely reasons for these effects?
You need to know the generic and trade name of the top 200 drugs; those with a trade name in the table
below are in the top 200. You also should know the metabolism of these drugs (also in table)
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Generic Trade Metabolism t hr. Notes

*Due to metabolites has a 20-30 hr t for
Atorvastatin Lipitor Cyp3A4 14* inhibition of HMG-CoA, can increase ALT & AST
but not due to injury
Simvastatin Zocor Cyp3A4 3 Prodrug activated in GI
Lovastatin Mevacor Cyp3A4 5.3 Prodrug activated in GI
Fluvastatin Cyp2C9 1-3 Only 75% metabolism by 2C9
Pitavastatin Cyp2C9 3
Not
*Some 2C9 metabolism, but most of the excreted
Rosuvastatin Crestor extensively 19
compound is rosuvastatin
metabolized*
Chemical
Doesn't have an extended distribution: stays in the
Pravastatin Pravacahol degradation 72
liver, excreted by both liver and kidney
in GI
Bile Acid Sequestrants

o Why would you use a bile acid sequestrant?
o When is the best time to take the drug?
o What happens to the drug after you take it, where does it go?
o What are some negative effects of bile acid sequestrants (both side effects and on-
target effects)?
o How does bile acid sequestrants increase LDL receptors on the liver?
Cholesterol absorption inhibitors

o What is the target of the cholesterol absorption inhibitor?
o How does inhibiting cholesterol absorption increase LDL receptors on the liver?
o What side effects are common, you may want to think of what happens if you have
increased cholesterol in your feces?
o What is Vytorin?
Fibrates
o What is the target of fibrates?
o Tricor is in the top 200 drugs, what is its generic name?
o When would you recommend using a fibrate?
Niacin
o What is the target of niacin and the trade name of niacin?
o Which patients is Niacin recommended for?
o What is the most common side effect?
Use the chart below to answer the following questions:

If you were to target a persons LDL what is the rank order of drugs you would use?
How would that change for HDL?
And what about TGs?
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Natural Products
Aside from the fish oils, there is little evidence that natural products (as westerners take them) have truly
significant effects. When dealing with patients always remember that the patient may not perceive
supplements/natural products as drugs and may not tell you they are taking them. Thus, you may have to
directly ask about natural products or supplements.
Omega-3 Fatty acids aka Fish oils

o What omega-3 fatty acids drugs are FDA approved?
o What are the two critical fatty acids in fish oil?
o These drugs work like a statin (SREBP) and Fibrate, therefore it is recommended for
patients with triglycerides over 500mg/dL.
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Section II: Blood Pressure and Renal Physiology & Pharmacology

Regulation of Blood Pressure
Be able to answer the following questions:
What is systolic blood pressure?
What is diastolic blood pressure?
What is mean blood pressure?
What is afterload?
What is preload?
What is the Frank-Starling Law?
o What happens as stroke volume increases?
How is the vasculature organized?
What type of arterial sensors is there and what do they do?
How do the arteries play a role in blood pressure?
What is the role of capillaries?
o Do capillaries contribute to blood pressure regulation?
o What are the three different types of endothelial cells and where do you find them?
How do the lungs and kidneys play a role in blood pressure regulation?
You also should know about the various vascular sensors and the formulas that underline blood pressure.
Note that the formulas will allow for you to determine if specific agents have an effect on blood
pressure.
Sensors:
Low pressure sensors located in right atria, large veins, and pulmonary arteries
High pressure sensors located in heart and proximal arteries
Heart makes natriuretic peptides
Baroreceptors (in arteries) signal to the brain and back to the heart through the ANS
Formulas:
Cardiac output (CO) = stroke volume (SV) x heart rate (HR)
Blood Pressure (BP) = CO x total peripheral resistance (TPR)
TPR is set by the radius of all the resistant vessels
Renal Physiology and Pharmacology

Here are some great resources that will help you with this topic:
http://www.youtube.com/watch?v=BBV-DaLf_n0
http://www.youtube.com/watch?v=VMvD29-Agtg
Renal physiology is primarily dealing with volume regulation, but since the body is a closed system,
when you reduce volume you also reduce pressure.
You should understand the fluid filtration formula (see below) as that will dictate why there are changes
in various compartments water levels under various disease states.
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Fluid Filtration =
is the permeability coefficient
is the hydrostatic pressure (traditional pressure)
is for capillary and is for interstitial fluid
is oncotic pressure (proteins)
is a correction factor that will vary based on the capillary
What does this formula mean?
o What happens if you have less albumin in the plasma, such as in liver diseases?
If we are talking about volume regulation there must be volume sensors in our body.
What are the volume sensors?
How do they work?
Do they always work?
If there are sensors then there must be something those sensors control (we dont have a check engine
light). We can call these things regulators. (see the figures below for a schematic diagram of the
regulators)
What are they?
How do they function?
The third regulator is the natriuretic peptides that bind to receptor guanylyl cyclase that makes cGMP in
the cells. cGMP functions very similarly to cAMP.
It is important to understand the general anatomy of the kidney and what each portion does. It would be
wise to know it well enough to diagram the kidney, and know which parts the drugs target. See the
figure at the bottom of this packet for the drug targets.
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Why is podocyte health important when thinking about pharmacology? (note this is a more of a thought
provoking question not one you will be tested on the IPBP exam.
Renal Terms
What is GFR?
o Is it measurable?
o Does it matter in
drug treatment?
What is the macula densa?

o What is auto
regulation?
o What is the primary
controller of
autoregulation?
Solute reabsorption
Where is Na+ reabsorbed?
K+ is essential to life, what
are the normal ranges of K+?
o How is K+ secreted?
What happens when K+
levels change?
How is glucose reabsorbed?
o Is all the filtered
glucose reabsorbed?
o What is the driving
force for glucose
reabsorption?
o What is the
difference between
SGLT2 and SGLT1,
and what does this
mean physiologically?
Plasma pH is also very tightly regulated, and this is a delicate balance between the lungs and the kidney.
As this is the renal set, you will need to know how the kidney replenishes bicarb.
(see the figures on the next page)
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Potassium secretion is controlled via aldosterone, and the

general mechanism of K+ secretion is shown to the left.
Below are the mechanisms, and pathways, regulating bicarbonate reabsorption and thus the renal
mechanism of acid/base regulation.
We started with volume so how is volume regulated by the kidney?

o What do those regulators that are referred to previously actually do?
Renal Pharmacology
First we will talk about targeting the regulators.
Very popular drug classes are those that inhibit the actions of angiotensin (Ang) II; therefore, you must
know what the actions of Ang II are and how Ang II is formed. (see the beginning of this set).
What are the three classes of drugs that block Ang II function?
Can you tell by the names of the drugs that target the Ang II system and what the drug targets?
What are the proposed benefits of each drug type?
What are the expected side effects of these drugs?
What are aquaretics?

What is nesiritide?
o What disease is it used for, and is it effective?
o What is the function of neprilysin (NEP)? Is there a drug that targets NEP?
There are a number of diuretics (see below)

Diuretics available in the US Not a Sulfonamide
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Drug type Target Drug names
Carbonic anhydrase inhibitors Methazolamide, Ethoxzolamide, Acetazolamide
Furosemide, Bumetanide, Ethacrynic acid, Etozolin,

Loop diuretics (Na+:K+:2Cl-)
Muzolimine, Piretanide, Torsemide
Sulfonamides Hydrochlorothiazide, Bendroflumethiazide,

Thiazides (SLC12A3 aka Hydroflumethiazide, Chlorothiazide, Polythiazide,
NCC) Trichlormethiazide, Cyclopenthiazide,
Methyclothiazide, Cyclothiazide
Thiazide-like drugs (act like

Quinethazone, Clopamide, Chlorthalidone, Metolazone,
thiazides but with a different
Xipamide, Indapamide
structure)
ENaC inhibitors Amiloride, Triamterene, Benzamil
K+-sparing
drugs Mineralocorticoid receptor
Spironolactone, Eplerenone
antagonists
Osmotic diuretics Mannitol
Carbonic anhydrase inhibitors:

All of these drugs end in zolamide
How is the action of carbonic anhydrases a diuretic?
What is an obvious side effect?
Loop diuretics:
What is the target of loop diuretics, and where is this channel expressed?
Why are these drugs such effective diuretics?
What diseases are treated with loop diuretics?
What are the negatives (potential adverse effects) of this class of drugs?
Similarly, what are the on target adverse effects?
Thiazides:
Thiazides are called this due to their chemical structure and thus they all end in thiazide.
Hydrochlorothiazide is the most prescribed, and it is one of the least expensive anti-hypertensive
medications.
What, and where, is the target of thiazides?
What is the advantage of the thiazide over the loop diuretic?
What is the precaution/side effect of these drugs?
Are thiazide and thiazide-like drugs equivalent?
Potassium Sparing Diuretics:
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By the name you can see what their benefit is, and expectedly two are considered critical drugs
by the WHO.
What two classes of drugs are K+ sparing?
What is the name of these drugs?
What is their molecular mechanisms?
What are their side effects?
What needs to be monitored when taking these drugs?
Mannitol:
How does a drug with no target cause diuresis?
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Section III: Antihypertensive drugs

Studying the pharmacology of anti-hypertensive drugs will enable us to effectively treat hypertension, a
silent killer and the most common cardiovascular disease. It is called silent killer because, in some cases,
it causes damages to vital organs, such the heart, blood vessels, kidney, brain, and other tissues, prior to
even being diagnosed during a routine checkup.
By reading these lecture materials, you should be able to:

(1) recognize determinants of blood pressure (BP),
(2) define BP as well as hypertension,
(3) assess its risk factors and how changes in BP determinants lead to hypertension,
(4) identify the site(s) where various factors act to affect BP,
(5) rationalize the use of various drugs as effective pharmacotherapeutic agents to treat hypertension,
(6) understand the exact mechanism of action of each drug or class of drugs, and
(7) justify the side effects and possible drug-drug or drug-food interactions.
Definition of blood pressure (BP) and its determinants:

Blood pressure is defined as the pressure that blood exerts on the wall of arterioles. The determinants of
BP are cardiac output (CO) and peripheral vascular resistance (PVR), each of which can be affected by
other measures/factors. For example, CO is a measure of the heart rate (HR), contractility state of the
heart and the filling pressure of the heart, the latter can be altered by the blood volume and venous
return. The PVR is determined by the arterioles volume. Accordingly, arteriolar constriction will lead to
increased peripheral resistance and thus increased BP as long as there is no change in CO. On the other
hand, arteriolar dilation will lead to decrease in PVR and thus reduction in BP, albeit if there is no
increase in CO. Similarly, the higher the blood volume and/or venous return, the greater the filling
pressure and thus the higher the CO given that the HR and force of contractility of the heart are not
changed. Furthermore, increases in HR and force of contractility of the heart can increase CO, thereby
leading to increases in BP if other factors remain unchanged.
Anatomical sites that play a functional role in regulating BP:

Different anatomical sites are involved in regulation of blood pressure, i.e., the heart, blood vessels
(arterioles and venules) and the kidney. (1) Arterioles are blood vessels that are responsible for the PVR
and thus the increase or decrease in their diameters can respectively increase or decrease PVR and thus
our BP. For example, vasodilators, such as alpha-1 antagonists, calcium channel blockers or ACE
inhibitors, by inducing vasodilatation reduce PVR and therefore decrease BP. On the other hand, agents
that cause vasoconstriction, such as NE or angiotensin II, increase BP. (2) The venules are capacitance
blood vessels, i.e., they have capacity to hold the blood and this capacity increases if there is
venodilation and decreases if there is venoconstriction. Therefore, drugs that cause venodilation, like
alpha-1 antagonist or nitroglycerin, can increase the capacity of these blood vessels to hold more blood
and therefore reduce venous return and thus preload. On the other hand, drugs that cause
venoconstriction, e.g. NE, decrease the capacity of venules, thereby increasing venous return and thus
preload. (3) The heart regulates BP via alterations in its force of contractility and rate, increases in each
of these will lead to increases in CO and therefore increases in BP. Drugs that decrease the force of
contractility of the heart and/ or the heart rate may be proven useful to treat BP (e.g., beta blockers,
calcium channel blockers). (4) The kidney is another anatomical site that plays a critical role in BP
control by regulating intravascular volume. Renin is a chemical released from the kidney and is
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important in the production of angiontensin I which will be converted to angiotensin II under the
influence of ACE and cause secretion of aldosterone, the function of which is to retain sodium. Sodium
retention will be followed by water retention, thereby leading to increased blood volume. Angiotensin II
is also a powerful vasoconstrictor and causes increases in PVR. Therefore, drugs that inhibit the release
of renin, or synthesis of angiotensin II or block its receptors can be useful for the treatment of BP. Also,
aldosterone antagonists or drugs that cause increase urine production by eliminating salt and/or water
can reduce blood volume and can provide a mechanism to reduce BP.
Baroreceptors and its importance in regulation of BP:

Baroreceptors are pressure sensing receptors located on the aorta, carotid arteries, renal blood vessels,
and at the level of vasomotor center. Activation/inhibition of these receptors is responsible for moment-
to-moment regulation of BP. This figures shows that changes in BP stimulate or inhibit baroceptors and
thereby sending signals to the vasomotor and/or kidney to tell them that something is wrong. For
example, if there is a decrease in BP, a signal is sent to the vasomotor center via the baroreceptors
causing activation of the sympathetic system which by increasing CO and PVR restore the BP. This for
example could happen if someone is getting up in the morning (which will be described in details later).
Reflex tachycardia or reflex bradycardia induced by various drugs can also be mediated via mediation of
these baroreceptors and activation. Changes in BP as well as changes in renal blood flow/pressure can
cause the release of rennin and activation of RAAS via mediation of baroreceptors located in the kidney
(described in details later).
Control of BP by the sympathetic nervous system:

The contribution of the sympathetic nervous system in controlling our BP from reclining to an upright
position, e.g., when someone is getting up (may be in the morning after a good night sleep), the change
in posture leads to redistribution of the blood to the periphery, thereby reducing venous return (the
amount of blood going to the heart). This will lead to a decrease in end-diastolic volume, thereby
leading to a decrease in stroke volume and thus reduction in CO, and eventually a decrease in BP. The
drop in BP is sensed by the baroreceptors, leading to activation of the sympathetic and deactivation of
the parasympathetic system. Activation of sympathetic system causes vasoconstriction and increases in
hear rate. These two effects will increase PVR and CO, respectively, and therefore BP will increase.
Regulation of BP by the RAAS:

A drop in BP or decreased blood flow to the kidney will cause secretion of renin which is responsible
for conversion of angiotensinogen to angiotensin I. Angiotensin I will then be converted to angiotensin
II, via the action of angiotensin converting enzyme (ACE). Angiotensin II, the active form of
angiotensin, has a direct vasoconstrictor effect, thereby leading to increases in PVR and thus rise in BP.
Angiotensin II also causes secretion of aldosterone from the adrenal cortex. Aldosterone in turn causes
sodium and water retention and therefore increases in blood volume which can affect the stoke volume
and thus CO.
The role of the anti-diuretic hormone (ADH; also known as vasopressin) in blood volume
regulation:
ADH can be released in response to increased blood osmolality (e.g., due to increased salt intake or
decreased water intake or dehydration). The osmoreceptors in the hypothalamus will be activated in
response to increased osmolality, thereby leading to thirst. This also causes the release of ADH from the
posterior pituitary. Feeling of thirst will make us to drink water or other fluids whereas the release of
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ADH will cause water retention by the kidney, thereby leading to increased blood volume and decreased
blood osmolality.
Regulation of BP by substances released from the endothelium of blood vessels:

Endothelin mediates both contraction and relaxation of vascular smooth muscle cells. Endothelin
precursors in endothelial cells are processed to endothelin-1. Endothelin-1 is secreted on the basal side
of the endothelial cell, where it interacts with ETA and ETB receptors present on vascular smooth muscle
cells. Activation of these receptors stimulates contraction by incompletely understood mechanisms. ETB
receptors are also expressed on endothelial cells. Endothelial cell ETB activation stimulates
cyclooxygenase (COX), which catalyzes the formation of prostacyclin from arachidonic acid.
Prostacyclin diffuses from the endothelial cell to the vascular smooth muscle cell membrane, where it
binds to and activates the isoprostanoid (IP) receptor. ETB activation also stimulates endothelial nitric
oxide synthase (eNOS), which catalyzes the formation of NO from Larginine (L-Arg is an amino acid).
Both prostacyclin and NO mediate vascular smooth muscle cell relaxation and thus vasodilation.
Production of NO is also stimulated by other agonists such as acetylcholine, bradykinin or other

endogenous or exogenous ligands (e.g., histamine). Stimulation of receptors by these agonists activates
Ca2+ second messenger systems and promotes direct entry of Ca2+ into the cytosol. The increased
cytosolic Ca2+ activates a Ca2+-calmodulin complex that stimulates endothelial nitric oxide synthase
(eNOS), an enzyme that catalyzes the formation of NO from L-arginine (L-Arg). NO diffuses from the
endothelial cell into subjacent vascular smooth muscle cells, where it activates guanylyl cyclase,
promoting smooth muscle cell relaxation. NO can also directly activate Ca2+-dependent K+ channels.
This parallel signaling pathway contributes to the relaxation of blood vessels by hyperpolarizing their
smooth muscle cells.
Definition of hypertension and different stages of HTN:

HTN is defined as a sustained increase in diastolic BP of above 90mm with concomitant increase in
systolic BP of 140 mm Hg. The normal BP is 120/80 mm Hg; a BP of 120-139/80-89 is considered a
pre-hypertensive state; a BP of 140-159/90-99 is considered as stage I of HTN and a BP of 159/99 and
above is considered stage II of HTN.
Risk factors of BP:

Sodium intake, food containing high fat as well as high cholesterol, stress, smoking, obesity, alcohol
consumption, family history of BP, Gender, ethnicity, etc., are some of the risk factors for the
development of HTN.
Etiology of HTN:
In most (85-90%) cases, the cause of HTN is not known. This form of HTN is called primary or
essential HTN. In only 10-15% cases, the cause of HTN is known. This form of HTN is called
secondary HTN and may be due to renal stenosis, tumor of the adrenal gland (pheochromocytoma)
which lead to excess catecholamines release, excess release of aldosterone (Cohns disease) can also be
the cause of HTN. Damage to the vasomotor center as well as an increase in intracranial pressure will
cause increase in sympathetic tone and thus increase in BP. Some heart problems can also increase BP
(e.g., complete heart block, narrowing of the aorta).
Management of HTN:
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Clinically available anti-hypertensive drugs include diuretics, sympatholytics, calcium channel blockers,
direct vasodilators, etc. Management of HTN is initiated with diet and exercise antihypertensive drugs.
The pharmacotherapy of HTN is usually initiated with a diuretic and/or beta blockers. However, an
effective pharmacotherapy of HTN requires a good understanding of patients condition and the
mechanisms of action of anti-hypertensive medications. In most cases, more than one pharmacotherapy
is used to effectively treat HTN. Sites of action of anti-hypertensive drugs: Different drugs exert their
anti-hypertensive effects via an action on the heart, kidney and/ or blood vessels. For example,
vasodilators can directly act on blood vessels and cause vasodilation. Sympatholytics can decrease heart
rate, and may cause vasodilation and a decrease in RAAS. Diuretics cause excretion of sodium and/or
water and act at different levels of a nephron. ACE inhibitors and ARBs work to reduce the action of
angiotensin II on blood vessels and its action on aldosterone secretion.
Examples of the anti-hypertensive drugs and their classes:
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Section IV: Blood Coagulation & Platelet Activation plus Antiplatelet,

anticoagulant, and fibrinolytic drugs
Blood Coagulation & Platelet Activation
Learning Outcomes
At the end, you should be able to:
Explain hemostasis, the physiology of blood coagulation (and coagulation factors), thrombolysis
and physiological prevention of coagulation
Understand and explain the various platelet signaling/activation pathways (e.g., GPCRs-
mediated), their role in clot formation and how they are initiated.
Explain the pathophysiological relevance of coagulation abnormalities, and thrombosis
development.
List the bodys endogenous inhibitors of coagulation.
Describe how coagulation is measured both in vitro and in vivo
Identify the theoretical strategies for producing anticoagulant, thrombolytic and procoagulant
effects
Blood
Blood volume ~ 5-6 L
Plasma/ Serum volume ~ 3-4 L
Blood cells
RBC
Platelets
WBC
Proteins
Albumin
Globulin
Clotting factor proteins
Lipids
Functions
Transport of O2, nutrients, waste
Defense
Blood, Plasma, and Serum

Blood
Plasma + blood cells
Plasma
Serum + fibrinogen + clotting factors
Serum
Water + serum proteins + antibodies etc.
How to prepare plasma/serum from blood?

Plasma
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Add an anticoagulant like sodium citrate or heparin and centrifuge the blood
supernatant will be plasma
Serum
Keep the whole blood after collection without adding any anticoagulant until the blood
clots, and centrifuge supernatant will be serum
Blood Cells
- Erythrocytes (RBC): 4.2-6.1 million/l

- Leucocytes (WBC): 5-10 k/l
- Platelets (thrombocytes): 250-500 k/l

Hemostasis: Spontaneous arrest of blood loss from injured blood vessels and is essential to life. Keep
the blood fluid and clot free.
Thrombosis: a pathological process in which thrombi occlude blood flow to vital organs.
Coagulation:
- Conversion of fluid blood into a gel clot
- Activation clot
- Inappropriate activation thrombus formation
- Decreased activation (Deactivation) bleeding
Anticoagulants: Substances which prevent coagulation
Anticoagulants in the Nature
Animals depending on a diet of fresh blood have evolved mechanisms that

interfere with the coagulation process of the blood donor.
Anticoagulants in the Nature (2)
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Leech: Hirudo medicinalis. These animals make:

1. Hirudin: thrombin inhibitor = Lepirudin: recombinant hirudin
2. Antistasin: Factor Xa inhibitor
Physiology of Coagulation
Initiated by injury or stasis
Platelets & Coagulation factors play major role
Coagulation factors (I-XIII)
Activated platelet, Fibrin, RBC thrombus/clot formation
Coagulation Factors and Pathways

Coagulation factors are plasma glycoproteins produced by hepatocytes.
Most are serine proteases in an inactive zymogen form that is converted to the active form by
proteolytic cleavage of a specific peptide bond.
In the coagulation cascade, an active coagulation factor cleaves and activates its substrate.
The goal of the coagulation cascades is to convert soluble fibrinogen to insoluble fibrin.
Extrinsic pathway - activated by tissue factor expression.
Intrinsic pathway - activated by contact of Factor XII with an anionic surface (collagen).
Platelet procoagulant activity is required for efficient blood clotting. Platelets provide a
phospholipid surface for the assembly of Ca2+- dependent coagulation complexes.
Thrombin in turn activates platelets to aggregate.
Platelet activation and blood coagulation are inter-dependent events for clot formation.
Coagulation Pathways
Contact Activation pathway or Intrinsic pathway (stimulus from factors in the blood)
Tissue Factor pathway or Extrinsic pathway (stimulus from factors outside the blood)
Contribute to the formation of a clot
Clot Formation
Link for a video that describes the process of hemostasis and clot formation
http://www.mhhe.com/biosci/esp/2002_general/Esp/folder_structure/tr/m1/s7/trm1s7_3.htm
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Platelets
- Platelets are cell fragments with a life span of around 10 days, that arise by budding from
megakaryocytes in the bone marrow. Platelets are small, membrane-bound discs contain cytoplasm but
lack nuclei (anucleated). Platelets play important role in hemostasis and thrombosis.
- The platelet surface contains many glycoproteins (GP) that serve as adhesive receptors for adhesive
proteins (e.g., fibrinogen, fibronectin, von Willebrand Factor (vWF)) present in blood and in the
subendothelial matrices of the blood vessel wall.
- In addition, platelets also contain agonist receptors for interaction with physiological stimuli such as ADP,
thrombin, thromboxane A2 (TXA2), collagen and epinephrine. Activated platelets undergo a series of
reactions that lead to the formation of hemostatic plugs and thrombi.
Platelet Adhesion, Activation & Aggregation
Platelet Secretion (Release Reaction)
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Platelet Adhesion, Activation & Aggregation (2)
Platelet Activation by Thromboxane A2
Platelet Activation by ADP (Adenosine DiPhosphate) and Thrombin
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The Role of the Coagulation Factors in Fibrin Formation
Coagulation Cascade
- Also known as secondary hemostasis
- Contact with surfaces (e.g. subendothelial cells) activates Contact Activation pathway (Intrinsic). This
pathway does not require external coagulation factors.
- Tissue Factor (TF) produced by vascular injury activates the Tissue Factor pathway (Extrinsic). This
pathway requires extrinsic factors.
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Coagulation Factor Activation on Phospholipid Surfaces
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How Coagulation is Prevented in the Body?

Protein C and the cofactor protein S
Activated to APC (or PCa) by thrombin
APC cleaves and thereby inhibits Va and VIIIa
Heparans (made by endothelial cells) prevents coagulation
Physiology of Thrombolysis
Endothelial cells secrete tissue plasminogen activator (t-PA). t-PA binds to fibrin and cleaves
plasminogen to plasmin, which digests fibrin thrombolysis. This is how the body gets rid of minor
clots, and restricts the formation of a plug to the site of injury.
Measures of Coagulation
PT (Prothrombin Time):
In vitro test
Indicator of extrinsic and common pathways
In this test, the patient's citrated plasma is added to a crude preparation of tissue factor
and phospholipids (called thromboplastin), and the time for formation of a fibrin clot is
measured
Expressed as Prothrombin Ratio (PR): ratio of patient PT to normal control PT (pooled
plasma from normal human).
12 15 seconds
Mainly monitor effects of warfarin, liver abnormalities (prolong)
INR (International Normalized Ratio)
Worldwide Standardized measure of PT
PT in patients sample compared to normal sample, normalized for the International
Sensitivity Index (ISI) of the laboratory's thromboplastin preparation compared to the
World Health Organization's reference thromboplastin preparation.
0.8 1.2
aPTT (activated Partial Thromboplastin Time)
Indicator of intrinsic and common pathways
Time taken for clotting of citrated plasma after addition of Ca++, phospholipid and kaolin
or silica.
Mainly monitor effects of heparin, hemophilia (prolonged)
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24 38 seconds
Bleeding Time
In vivo
Indicator of blood vessels and platelet function
Small incision made on forearm and blood wiped every 30 seconds with a blotting paper.
Should clot within 8-10 minutes
Deep Vein Thrombosis (DVT)

Occurs in deep vein
Due to stasis of blood
Long-term immobility
Surgery
Leads to embolism
Emboli: a fragment of the thrombi that can travel in blood vessel known as thromboembolism
Pulmonary Embolism
Caused mainly by blockade of an artery or one of its branches in the lung by a blood clot (due to DVT),
clumped tumor cells, or air bubbles.
How embolus from periphery gets into the lung?
Hemophilia
Hemophilia A
Most common hemophilia
Deficiency or reduced activity of clotting factor VIII hypocoagulability
Defective gene located on X chromosome
Currently treated with infusions of factor VIII
Hemophilia B (Christmas disease)
Deficiency or reduced clotting factor IX
Defective gene located on X chromosome
Von Willebrand's Disease
Very common
Deficiency of von Willebrand Factor (vWF)
vWF normally involved in platelet adhesion

Anti-Coagulants, Antiplatelets & Fibrinolytic Drugs

Learning Outcomes
At the end, you should be able to:
List the major drugs used as anticoagulants, antiplatelet agents, thrombolytics, and
procoagulants.
Explain the mechanisms of action of coagulants, anticoagulants, antitplatelet agents, and
thrombolytics, their major side effects, their clinical indications, how their activity is monitored,
and their antidotes, if any.
Recall drug interactions where these drugs are involved, and explain the mechanisms of
interactions.
Thrombosis
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Anti-Thrombotic Therapy
- Anti-coagulant and anti-platelet therapy:
Prevent thrombus propagation
Prevent thrombus formation
- Thrombolytic therapy:
Lysis of existing thrombi (fibrinolysis)
- Antiplatelet Drugs
prevent platelet activation
- Anticoagulants
prevent fibrin formation
- Procoagulants
enhance coagulation
Antiplatelet Drugs
Platelet activation can be inhibited via:
Prevent TXA2 synthesis
Antagonize ADP receptors
Antagonize the platelet glycoprotein GPIIb/IIIa
Inhibit Phosphodiesterase (PDE)
Platelet Activation
q When platelets adhere to the subendothelial tissues, they undergo degranulation (secretion; or
release reaction) and release cytoplasmic granules, which contain:
serotonin, a vasoconstrictor
ADP platelet activation and aggregation enhance clot formation
q Platelets will also synthesize:
Thromboxane A2 platelet activation and aggregation enhance clot formation
How to prevent platelet activation?
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Major Drug Targets for Inhibiting Platelet Function

I. ADP receptors (P2Y1/ P2Y12)
Activates GPIIb/IIIa receptors
Activates COX-1 enzyme
II. COX-1 enzyme
Produces TxA2
III. Fibrinogen receptors (GPIIb/IIIa)
When activated by other factors, fibrinogen binds to these receptors platelet aggregation
IV. Phosphodiesterases
Cyclic nucleotide PDEs degrades cAMP that inhibits platelet activation.
Major Antiplatelet Drug Classes

I. ADP Receptor Antagonists
Clopidogrel (Plavix )
Ticlopidine (Ticlid)
Prasugrel (Effient)
Ticagrelor (Brilinta)
II. Anti-thromboxane Drugs

Aspirin
III. GPIIb/IIIa Antagonists

Abciximab (ReoPro; antibody)
Eptifibatide (Integrilin) Peptide-based
Tirofiban (Aggrastat) non-peptide
IV. Phosphodiesterase Inhibitors
Dipyridamole (Persantine)
ADP Antagonists
v ADP receptor activation causes platelet activation clot formation
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v ADP antagonists can therefore reduce clot formation. Useful in aspirin intolerant patients.
v ADP activates purinergic receptors
v Major subtypes: P2Y1, P2Y12
v Clinically used ADP antagonists:
Mechanism of Action:
q Noncompetitive (irreversible) ADP (P2Y12) receptor antagonist, and is a prodrug that requires
activation via metabolism in the liver by CYP 3A4
q Thienopyridine derivative
q Reduces platelet activation. May be combined with aspirin
q Clopidogrel requires a loading dose to achieve a maximal antiplatelet effect rapidly.
q Available as clopidogrel bisulfate
q Side effects
Neutropenia (reduced white blood cell count; serious ADR)
q Slightly more favorable toxicity profile than ticlopidine (especially bone marrow toxicity)
q Drug-drug interactions: With drugs that are metabolized by CYP 3A4 (e.g., statins atorvastatin)
--- PPIs may decrease activity via CYP 2C19 interaction.
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Noncompetitive (irreversible) ADP (P2Y12) receptor antagonist, and is also a prodrug that
requires activation via metabolism in the liver
Thienopyridine derivative
Side effects
Neutropenia (reduced white blood cell count)
thrombocytopenia (reduced platelet count)
thrombotic thrombocytopenic purpura (reduced platelet count with blood clots)
Blood counts must be monitored frequently when using ticlopidine
Less potent and less safe than clopidogrel

Prasugrel (Effient )
Approved by FDA on July 2009

Noncompetitive (irreversible) ADP
(P2Y12) receptor antagonist, and is
also a prodrug that first undergoes
hydrolysis in the intestine and then
activation via metabolism in the liver
(CYP3A4 and CYP2B6 (thus, no
interaction with PPIs that inhibit
CYP2C19)
Requires a loading dose
Higher risk of bleeding compared to
clopidogrel
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Ticagrelor (Brilinta )
In December 2010, the FDA declined to approve this agent, but approved it on July 20, 2011
A competitive (reversible) ADP (P2Y12) receptor antagonist.

Thus, no persistent platelet inhibition after drug stoppage.
Ticagrelor is metabolized to an active equipotent metabolite mainly
by CYP3A4
Consider for patients with reduced CYP2C19 activity
Requires a loading dose
Antithromboxane Drugs
Aspirin
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o Acetyl salicylic acid (ASA)

o Derived from salicylic acid (Willow tree)
o Inhibits both COX-1 and COX-2 (non-selective COX inhibitor)
o Irreversibly/covalently acetylates serine residue of COX enzymes
o Because platelets cannot synthesize new cyclooxygenase, the inhibitory effect of aspirin lasts the
life span of the platelets.
o Inhibits the production of TXA2 in platelets
o Reduces platelet activation, aggregation inhibit clot formation
o Low doses (baby aspirin; 81 mg once/day) are used clinically for prevention of MI
Major Drawback of Aspirin Therapy

v Aspirin is a non-selective inhibitor of COX, inhibiting both COX-1 and COX-2
v COX-1 also produces prostaglandins which are gastro-protective (e.g. PGE2)
v By inhibiting the gastro-protective PGs, aspirin (and all other non-specific COX inhibitors) can
cause gastric mucosal damage bleeding
v However at low-doses used for antiplatelet effect, these side effects are minimal
v ADRs: GI bleeding, nephropathy, hepatic injury, aspirin-induced airway hyperreactivity in
asthmatics; Reye's syndrome (with viral disease)
Aspirin Resistance: Up to 20% of the population may not respond (are resistant) to aspirin
therapy
Why not Celecoxib or Ibuprofen?

1. Why not ibuprofen?
- Inhibition of the cyclooxygenase is not permanent.
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GPIIb/IIIa Antagonists:
v GPIIb/IIIa receptors activated by other factors such as GP receptors, ADP/PAR/TXA2 receptors
bind to fibrinogen mediate platelet aggregation (i.e., fibrinogen acts as a molecular bridge
between activated platelets). Thus, blocking fibrinogen interaction with GPIIb-IIIa will prevent
this final common pathway of platelet aggregation.
v GPIIb/IIIa antagonists reduce platelet activation
v Common antagonists
Abciximab (Reopro; monoclonal antibody)
Eptifibatide (Integrelin; synthetic cyclic peptide)
Tirofiban (Aggrastat; non-peptide)
Disadvantage: All good for parenteral (i.v.) administration only
Mechanism of Action:
Abciximab prevents the binding of fibrinogen to activated GPIIb/IIIa

receptors inhibit platelet aggregation reduce clot formation
Abciximab (ReoPro)
Monoclonal antibody Fab (fragment) directed against GPIIb/IIIa (essentially irreversible
antagonist)
Administered intravenously as an adjunct to aspirin and heparin in patients undergoing coronary
interventions
Reduces risk of restenosis, but at the risk of causing bleeding as an adverse drug reaction
Drawbacks: Immunogenicity limits the use to single administration; has to be administered
parenterally
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Phosphodiesterase Inhibitors (PDEI)
- cAMP inhibits platelet activity. Phosphodiesterases degrade cAMP increase platelet activation.
- Phosphodiesterase inhibitors prevent the degradation and, thus, lead to an increase in cAMP levels,
thereby inhibiting platelet activity reduced platelet aggregation and hence clot formation
MOA: Ca2+ is an important mediator of intracellular signal events that lead to platelet activation. Cyclic AMP
(cAMP) has an opposing effect of Ca2+ by sequestering cytosolic Ca2+ to its storage site.
Dipyridamole (Persantine)
ADRs: Coronary vasodilation
Anticoagulant Drugs
q Prevent formation of fibrin
q Major drugs
I. Heparin (parenteral)
II. Warfarin (oral)
Heparin
First extracted from liver by a 2nd year medical student (John Hopkins) in 1916
Commercially extracted from bovine lung, and porcine intestinal mucosa (found in mast cells)
Not a single compound - family of sulfated glucosaminoglycans (mucoploysaccharides)
Content and dose expressed in units not mass
Categorized into 1. unfractionated (standard) and 2. low molecular weight (obtained by gel
filtration of standard heparin)
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Administered IV/SC not PO (highly negatively charged not absorbed; degraded) or IM (cause
hematomas) Immediate effect
Mechanism of Action
Antithrombin inhibits several activated coagulation factors (proteases)
Heparin binds with antithrombin and accelerates its protease inhibition
Binding of heparin also induces a conformational change in antithrombin that makes the
reactive site more accessible to the protease
Prevents formation of fibrin prevent coagulation
Monitor by measuring aPTT
Mechanism of Action (2)
Heparin binds with antithrombin III and inactivates proteases:

IIa,VIIa, IXa, Xa, XIa, XIIa
Major Clinical Uses
Prophylaxis and treatment of thromboembolic diseases
Advantage: Unlike warfarin, heparin does not cross the placenta, therefore not associated with
fetal malformations drug of choice for anticoagulation during pregnancy.
Side Effects
- Minor side effects: alopecia, osteoporosis
- Major side effects: hemorrhage, thrombocytopenia, allergy rxn
- Thrombocytopenia = HIT type 1 (rare; reversible upon withdrawal)
2-14 days after initiation of therapy
Thrombosis !!! (rare; type 2 HIT: caused by antibodies against heparin-platelet factor 4
platelet activation clot formation death
- Anaphylactic type (life-threatening) hypersensitivity (rare; currently watched by the FDA)
LMWH is less liable to produce thrombocytopenia
Heparin Reversal
q Antidote for heparin hemorrhage: Protamine
Protein from salmon sperm with basic nature; given slow IV infusion
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Complex with heparin to form inactive complex

Most active against unfractionated heparin, and partially reverses the anticoagulant effects
of LMWH
Comparison of Heparins
LMWH
Hirudin & Lepirudin

Naturally occurring anticoagulant obtained from leech: Hirudin
Clinically used form: lepirudin prepared by recombinant DNA technique
Direct inhibitors of factor IIa (i.e., thrombin)
Action independent of antithrombin (ATIII)
Do not cause thrombocytopenia unlike heparin
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Fondaparinux
Warfarin (Coumadin)
Wisconsin Alumni Research Foundation

Used initially as rat poison
Mechanism of Action
Mechanism of action of warfarin. Vitamin K is a necessary cofactor in the post-translational carboxylation of

glutamate residues on factors II, VII, IX, and X. During the carboxylation reaction, vitamin K is oxidized to the
inactive 2,3-epoxide. The enzyme epoxide reductase converts the inactive vitamin K 2,3-epoxide into the active,
Page 37 of 71
reduced form of vitamin K. The regeneration of reduced vitamin K is essential for the sustained synthesis of
biologically functional coagulation factors II, VII, IX, and X. Warfarin acts on the carboxylation pathway by
inhibiting the epoxide reductase that is required for the regeneration of reduced (active) vitamin K. Dicumarol is
the natural anticoagulant formed in spoiled clover. Both warfarin and dicumarol are orally bioavailable, and are
often termed oral anticoagulants.
Pharmacokinetics
Delayed effect; 18-24 hrs (Why?)
Warfarin is almost completely (99%) bound to plasma proteins, principally albumin.
Vd: small
Half life: 36 h (metabolized by the liver)
Monitor INR (2-4)
- Has a narrow therapeutic index
Warfarin is usually started at a dose of 510 mg. The dose is then titrated to achieve the desired target INR
Warfarin Reversal
v Monitor INR (every 2-4 weeks)
v In emergency, reverse with Vitamin K (PO or IV). Plasma infusion is also used.
v Menadiol sod phosphate (synthetic analogue of Vit K)
How high doses of Vit K reverses warfarin effect?

Vitamin K, if present in high concentrations, also can be converted to the corresponding hydroquinone by a
second reductase, DT-diaphorase. This enzyme is less sensitive to coumarin drugs
Clinical Uses
Warfarin is often administered to complete a course of anticoagulation that has been initiated with heparin
Side Effects
- Bleeding - Birth defects (crosses placenta, NOT given during pregnancy)
- Skin rashes - Infrequent ADRs
alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal
cramps, and anorexia.
Drug Interactions: Due to potential interactions, care should be exercised while dispensing warfarin
New Label for Warfarin
Page 38 of 71
Novel Oral Anticoagulant

- Dabigatran Etexilate (Pradaxa ), which is
a direct competitive thrombin inhibitor. Its the
first oral anticoagulant approved in the U.S. in
over 50 years (approved in October 20 2010).
- Is a prodrug of dabigatran (a polar compound).
- When switching from warfarin to dabigatran,
warfarin should be stopped first and then
dabigatran can be started when the patients INR
is less than 2.1.
- ADRs: Bleeding; GI side effects including dyspepsia (most common ADR, and may
mandate discontinuation of therapy); and gastritis-like symptoms (e.g., GERD)
-DDI: A substrate for p-glycoprotein (a transporter found in the intestine), thus rifampin, St. Johns wort, are likely to reduce blood levels of dabigatran.
However, no dose adjustment is required with the P-glycoprotein inhibitors such as verapamil, amiodarone.

Rivaroxaban (Xarelto )
- An oral factor Xa inhibitor

- Approved in September of 2011
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Thrombolytic Drugs (Clot Busters)
Mechanism of Action
The Fibrinolytic System. Plasmin is formed by the proteolytic cleavage of plasminogen by tissue-type or
urokinase-type plasminogen activator. Plasmin formation can be inhibited by plasminogen activator
inhibitor 1 or 2, which binds to and inactivates plasminogen activators. In the fibrinolytic reaction,
plasmin cleaves crosslinked fibrin polymers into fibrin degradation products. 2-Antiplasmin, which
circulates in the bloodstream, neutralizes free plasmin in the circulation.
Streptokinase
- Plasminogen activator
- Protein extracted from cultures of the streptococci bacteria
- Administered IV for the treatment of patients with ST elevation myocardial infarction
Fibrinolytic therapy for the treatment of ST-segment elevation myocardial infarction
reduces mortality when administered within 12 hours of symptom onset.
- Plasminogen activator
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- Protein extracted from cultures of the streptococci bacteria

- Administered IV for the treatment of patients with ST elevation myocardial infarction
- Antibodies produced can reduce effect of further administration (~1 year).
Thus, previous administration is a contarindication to its use, because of the risk of anaphylaxis
ADR: thrombolytic actions of streptokinase are relatively nonspecific and can result in
systemic fibrinolysis.
Urokinase
- Trypsin-like plasminogen activator chemical produced by the kidney, and excreted in the urine
Recombinant tPAs
Tissue plasminogen activator (t-PA) is a serine protease produced by human endothelial cells; therefore,
t-PA is not antigenic. t-PA binds to newly formed (fresh) thrombi with high affinity, causing fibrinolysis
at the site of a thrombus. It is inactivated by plasminogen activator inhibitor
Recombinant (DNA) tPAs:
o Alteplase (Activase)
clot selective selective to fibrin-bound plasminogen
o Reteplase (Retavase)
Longer half-life
o Recombinant tPAs are less antigenic
Side Effects & CIs of Fibrinolytics

Bleeding, GI and cerebral hemorrhage
Contraindicated in invasive procedures, hemorrhagic cerebrovascular disease, serious GI
bleeding, hemorrhagic disorders, and severe uncontrolled hypertension.
Reversal of Fibrinolytic Effects
n 2-antiplasmin: present in plasma and rapidly inactivates plasmin.
n Aprotinin: naturally occurring polypeptide (inhibits plasmin, tPA and thrombin; increase risk of
postoperative acute renal failure)
n Aminocaproic acid and Tranexamic acid (inhibit plasminogen and plasmin; may not increase the
risk of postoperative acute renal failure)
n Fresh plasma (provides coagulation factors)
n Coagulation factors
Use of Fibrinolytics in Pregnancy
Fibrinolytics usually belong to pregnancy category C. Hence selection of fibrinolytics in pregnant

patients is difficult. Factors affecting the crossing of drugs to the placenta are molecular weight, lipid
solubility, drug pH, and binding to plasma proteins. Drugs with MW higher than 1,000 Da often poorly
Page 41 of 71
cross the placental barrier.

General Drug Interactions
P450 enzyme inhibitors & inducers
Inhibitors prolong effect (e.g. cimetidine)
Activators shorten the effect (e.g. barbiturates)
Bone marrow suppressants
Anticoagulants - antiplatelet agents - fibrinolytics
Botanicals
Ginko biloba (anti-platelet)
St. Johns wort (increased the activity of CYP3A4 in the liver, and this the activation of
clopidogrel)
Garlic (inhibition of platelet aggregation, and enhancement of fibrinolytic activity)
Procoagulant Drugs
Used in Acquired Clotting Defects
Liver diseases
Vitamin K deficiency (esp. in neonates)
Excessive anticoagulant therapy
Vitamin K (phytomenadione)
Replacement Therapy
Hemophilia
Provide factors VIII or IX
Why Replacement in Hemophilia?
Genes to generate Factors VIII (A) or IX (B) proteins are absent in Hemophilia patients. Hence Vit K
cannot enhance clotting in Hemophilia.
In-vitro Coagulation & Anticoagulants
Ultimate Goal of Anticoagulant Therapy:
Prevention of THROMBOSIS without causing BLEEDING!
Page 42 of 71
Section V: Regulation of a Heart Beat, Arrhythmias, and Antiarrhythmic

drugs
Regulation of a Heart Beat - EKGs
You should know the following terms:
Chronotrope/Chronotropic
Inotrope/Inotropic
Note there is also a term dromotrope/dromotropic that means to slow the conduction velocity. My
understanding is that this term is not used often in the clinic and that most drugs that change conduction
velocity also slow the heart rate, which makes sense so they are lumped with one of the groups above,
but which one.
Here are some great resources that will help you with the heart rhythm topics:
http://www.skillstat.com/tools/ecg-simulator#/-prep
You will not be expected to identify all of the arrhythmias listed, only the ones in this handout.
However, this is a great illustrator of EKGs
http://www.youtube.com/watch?v=T0enhzODPOM
http://www.accessmedicine.com.proxy.westernu.edu/resourceTOC.aspx?resourceID=651
There are excellent videos in Goodman and Gilmans The
Pharmacological Basis of Therapeutics. The links have
changed repeatedly so if this link does not work, please
find Goodman and Gilmans book through the library
webpage.
www.cvphysiology.com and www.cvpharmacology.com
These are also great resources, that I highly recommend.
Be able to answer the following questions:

What cell types conduct electricity in the heart?
Are all cells of this type the same, if not what are the differences?
What is the pacemaker?
o Why is it the pacemaker?
o What would happen if it failed?
Do the cells that conduct electricity in the heart have a true

resting potential?
Be able to draw the SA node and ventricular myocyte action

potential.
OK back to the heart beat now a pause?

What do I mean by that?
o Why does conductivity matter?
o What controls conductivity?
Page 43 of 71
The INa channels have 3 gates.

m gate is the main gate.
h and j are like railroad gates that also close as soon as m opens.
What does this relationship between these gates mean for how the channel acts?
These gates become refractory when what gates are closed?
What pumps are important to keep the heart beating (see

the picture to the right)?
Why are they so important (Hint: did your mother ever tell
you to clean your room)?
After completing all the questions above and watching

some of the videos recommended on the web, you should
know how the heart beats, but beating is only part of the
story we really care about contraction and pumping of the
blood, which is more than simple beating.
There are a few players and terms in this part of the story that you need to know. They are listed below;
make sure you know what each term represents and its molecular function.
Ca2+ induced Ca2+ release (CICR)
RyR
Troponin C
Myosin
SERCA
Calsequestrin
Phospholamban (PLB)
o How is PLB regulated, does this make sense in regards to how the heart contracts?
o What does the 1-AR do?
OK, now lets integrate this on a larger

scale, the EKG.
Make sure you can label the EKG,

meaning define what is happening at each
point (letter) and each interval (i.e. PQ
interval) see the questions below.
To fully understand the EKG you need to

be able to answer the following questions.
Ca2+ induced Ca2+ release (CICR)
What is the P wave?
What is the PQ interval?
Page 44 of 71
What is the QRS segment?

o Does the QRS segment always look like the one pictured above, and if not what does that
mean?
Note: the videos posted in the beginning of this handout should help with this answer.
What is the ST interval?
What is the T wave?
Mechanisms of Arrhythmias
I am using the following site for many of the images and it also gives great explanation of the
arrhythmia: http://www.skillstat.com/tools/ecg-simulator#/-prep
You will not be expected to identify all of the arrhythmias listed, only the listed here.
First, what is an arrhythmia?

What are two primary ways in which an arrhythmia can be formed?
Arrhythmias can be caused by numerous events, including:

Ischemia
Hypoxia
Acidosis
Alkalosis
Electrolyte abnormalities
Excessive ANS activity
Drug toxicity and normal drug function
Exaggerated stretch of the cardiac muscle
Scarred or otherwise diseased cardiac tissue
Do you understand what each of the above items refers to, and what diseases may cause some of these
events? You should understand the above items; the diseases will be covered elsewhere.
What are the two anatomical types of arrhythmias, and what does that mean?
Can you identify them on an EKG?
What are the different mechanistic properties behind arrhythmias?
ALTERED AUTOMATICITY
What are two normal physiological events that can be termed as an arrhythmia?
What controls those two events?
What anatomical arrhythmia is this?
What mechanistic arrhythmia is this?
What is the EKG below showing?
Escape Beats
Page 45 of 71
What is an escape beat?

What could give rise to these beats?
Ectopic Beats
What is an ectopic beat?
Where do they come from?
What causes these to occur (molecular level and the triggering event)?
TRIGGERED ACTIVITY
What are two classes of triggered activity?
Where in the action potential do they occur?
Can you draw these?
Early After Depolarizations (EADs)

What is an EAD?
Where in the AP does it occur?
Which ion is responsible for the EAD?
Why does hypokalemia lead to EADs (this will require some thought)?
Torsades de pointes is related to what type of arrhythmia?
Can you draw an EAD?
Why do EADs generally occur in the ventricle?
What is the EKG above showing?
Delayed After Depolarizations (DADs)

What is a DAD?
Where in the AP does it occur?
What is the predominate theory on how a DAD is formed?
Can you draw a DAD?
DADs cause two types of arrhythmias. What are the two types and why are there two
distinct types? (see next page for the EKG)
Page 46 of 71
RE-ENTRY CIRCUITS
What are the two types of re-entry circuits?
Please define a re-entry loop?
Anatomical
These are present at birth, and there are a multiple different types; we will cover two
general types.
Atrial to ventricle tract

Why do these alternative tracks cause a problem?
What regulates the top speed of the ventricles?
Ventricle to atria tract

Would such a tract always cause an arrhythmia? You will need to know how to
defend your answer hint this comes from the how a hear beats section.
What is the EKG below

showing?
How do we treat anatomical re-entry circuits today hint it is not through pharmacology?
Pathological
Pathological re-entry loops are created by disease of, or damage to, the myocyte tissue.
One key thing to picture when thinking about these loops is that the electrical charge
flows predominately through myocytes, but the heart is made up approximately only 40%
cardiac myocytes. Thus one can see that there are many areas that do not conduct the
electrical impulse very well. One can simplify these areas to non-conductive islands.
There are three things that are

needed for a loop to exist:
1) An obstacle that the
impulse needs to flow around
2) A unidirectional block
3) A slow conduction through
the unidirectional block so that
Page 47 of 71
the tissue on the other side is not refractory,
What is
a bi-
directional block?
Re-entry loops can occur anywhere in the heart, thus you can have atrial as well as
ventricular arrhythmias. What do the two EKGs below represent?
How do you suppose this patient is doing?
TRIGGERED ACTIVITY OR A RE-ENTRY CIRCUIT

Premature ventricular contractions (PVC) are the most common arrhythmia. However, it is
much harder to pin exactly how these form. It is known that they form from either triggered
activity (a DAD) or a re-entry loop.
Page 48 of 71
Below is a typical PVC EKG (yes you need to be able to recognize this)
What this shows is that there is a tall and wide spike after a T wave. This is the ventricle firing
on its own, and this generally shows an inverted second T wave.
Most importantly, this demonstrates that the DAD or re-entry loop can be transient!
CONDUCTION BLOCK
Conduction block is simply a failure of the impulse to propagate.
Is this the same as a bi-directional block?
Conduction blocks can be tricky. Depending on

where the conduction block is will dictate what
happens.
The skip a beat block would be near the AV

node and prevent the ventricle to beat.
Conduction block at the bundle of His could stop
the heart, stop one chamber, or slow one
chamber. When it comes to conduction blocks,
think of how the impulse flows through the heart
and what that impulse does, now put a block in
its path. What happens, can you visualize this?
Antiarrhythmic Drugs
Your greatest aid for this portion of the study guide is CV Pharmacology.
Since arrhythmias are always due to an alteration in the handling of ions, all antiarrhythmic drugs either
directly or indirectly affect ion movement in the heart. If you think about this for a bit, you will also see
that altering ion movement is also the cause of arrhythmias; therefore, a side effect of nearly all
antiarrhythmic drugs is the development of an arrhythmia!
Given that you are altering ion flow there are three general types of alterations that can be made:
Decrease or increase the conduction velocity
Alter the effective refractory period
Suppress abnormal automaticity
More specifically, we can alter:
Maximum diastolic potential in pacemakers
Resting membrane potential in pacemakers
Page 49 of 71
Rate of phase 4 depolarization

Threshold potential
Action potential duration (ERP)
Can you see how this will alter how a heart functions and how it could treat an arrhythmia?
Do you understand state-dependent block?

Look this up if you do not know the term.
There are 4 classes of antiarrhythmic agents, for the exam you will only need to identify the actions of
the classes except for a few exceptions as well as the miscellaneous drugs discussed at the end of this
section. You will also be expected to draw how these drugs alter the cardiac action potential as a class;
the classes are listed below as well as how they alter the action potentials
Class Basic Mechanism Notes
I Na+-channel blockade Reduce phase 0 slope and peak of action potential
IA - moderate Moderate reduction in phase 0 slope; increase APD and ERP
IB - weak Small reduction in phase 0 slope, reduce APD, & decrease ERP
IC - strong Large reduction in phase 0 slope with no effect on ADP and ERP
II 1-AR blockade Block sympathetic activity = reduce HR and conduction
III K+-channel blockade Delay phase 3; increase APD and ERP
Block L-type channels; most effective at SA & AV nodes; reduce HR,
IV Ca2+-channel blockade conduction, and force (lower CO)
APD = action potential duration, ERP = effective refractory period
All class I drugs have an effect on the SA node.
What is that effect and what does the graph look like?
Since Class I drugs alter the voltage required to defibrillate the heart these drugs should not be used with
implanted defibrillators!
Class IA
What do these drugs do to the myocyte AP (be able to draw it!)?
These drugs can be used to treat
Atrial Fibrillation
Atrial Flutter
Super Ventricular Tachycardia (SVT)
Ventricular Tachycardia
Drug Properties Side/Other Effects

quinidine Moderate Cinchonism, cramping, nausea, enhances digoxin toxicity
anticholinergic
procainamide Weak anticholinergic, Lupus-like syndrome in 25-30% of patients, metabolite is
short t pure class III drug
disopyramide Strong anticholinergic Negative inotropic effect, anticholinergic effects (mixed
data on digoxin)
Why is it dangerous to use Quinidine and Disopyramide to treat fast atrial rates?
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Class IB
What is use-dependent block?
Is this state-dependent block?
Premature Ventricular Contraction (PVC)
Ventricular Tachycardia
Ventricular Fibulation
Digitalis-induced arrhythmias
These drugs are very safe and are combined with other drugs. These are great for treatment of
disorders that have increased Na+ channel activity and long QT or other issues due to their safety.
Class IC
These drugs are only used in life threating conditions due to the side effects?
Drug Treatment of Side/Other Effects
flecainide SVT Can induce life-threatening VT
propafenone SVT and V-Tach b-blocking & Ca2+-channel blocking activity can worsen heart
failure
moricizine V-Tach Some class IB activity
Class II
What do these do to the AP, and which AP is this (be able to draw it!)?
The decrease in conduction rate slows the AV node, which would be good for which of the
arrhythmias?
Class III
What does this shape tell you that it will help with?
What does reverse use-dependency mean?
Amiodarone is one of the drugs you need to know, it is also one of the most popular antiarrhythmia
drugs on the market. This is due to its ability to act as each class of antiarrhythmic drug!
It can be used on nearly every arrhythmia
Dronedarone is a second generation version of amiodarone; it has fewer side effects, but it has some
rather potent and different side effects that include:
Liver toxicity in some patients
Counter indicated in patients with heart failure
The rest of the class III agents are used primarily to treat atrial flutter and fib; however there are a few
exceptions and additions that will be covered in the clinical portion of your studies.
What are the general side affects you would expect from class III drugs?
Are there exceptions and specific side effects to certain drugs in this class?
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Class IV
What are the primary effects of these changes to the AP?
Atrial tachycardia
Super ventricular tachycardias (SVTs)
Why are these not used to treat ventricular arrhythmias?
Drugs outside of the Vaughan-Williams scheme

Digitalis (Digoxin and Digitoxin)
These drugs are primarily used for heart failure. Their target is the Na+/K+ ATPase, and
indirectly this leads to greater intracellular Ca2+ levels. However, digitalis also increases vagal
tone through an unknown mechanism; and thus can be used to slow the AV node.
What would this do to the heart rate?
What arrhythmias would you treat with digitalis?
Digitalis has a very narrow therapeutic index (this will be discussed later in the heart failure
section), what does this mean?
Is there a specific benefit of digitalis over other drugs to treat the arrhythmias listed above?
Adenosine
In the heart there are A1 receptors that are coupled to Gi thus one mechanism is to act like the
M2 receptor. Can you draw this effect?
A second effect of the A1 receptor is to inhibit L-type Ca2+ channels.
What does this do?
A third effect of the A1 receptor is to decrease NE release from the sympathetic nerves in the
heart.
Adenosine is a first line treatment for returning a narrow-complex paroxysmal supraventricular

tachycardia (PSVT) to a normal rhythm; however, ~65% of patients present with a transient new
arrhythmia after administration of adenosine.
Ivabradine
This drug is not available in the US yet.
It targets If channels inhibiting automaticity.
How could it be used to treat arrhythmias?
Atropine
What does atropine do?
When would you use atropine?
Electrolyte Supplements
If a patients electrolytes are not in the proper range, then there is a greater likelihood of an
arrhythmia. Thus it is important to monitor patients and provide the correct amount of K+ and/or
Mg2+ to them.
Drug-Arrhythmia pairing worksheet

(fill this to use as a study guide) Page 52 of 71
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Section VI: Coronary Artery Circulation, Angina, and Drugs used to

treat Angina
Learning Objectives: By reading the following materials, you are expected to define angina pectoris,
describe various forms of angina, understand the coronary circulation, the system that supplies oxygen
to the heart muscle, justify how various factors affect myocardial oxygen supply & demand and
rationalize how angina can be induced, understand the mechanisms of actions (desirable and side
effects) of drugs used to treat angina, and rationalize the use of different classes of drugs for the
management of various forms of angina.
Ischemic heart disease is the most common cause of death in the developed world. In the USA alone
over 6 million peoples suffer from angina resulting from coronary artery diseases which cause
approximately one death per minute. Thus, it is essential to understand the pathophysiology of angina to
be able to effectively diagnose it, i.e., which form of angina the patient may be suffering from, and what
appropriate pharmacotherapy to use to treat the patient.
Coronary Circulation
Coronary circulation occurs during diastole and is essential for supplying oxygen and nutrients to the
heart muscle before the next systole is initiated. A normal circulation through the coronary arteries (left
and right coronary arteries and their branches) assures that the oxygen demand of the heart muscle is
met. In a healthy individual, an increase in oxygen demand of the heart muscle is met by increased
supply (due to healthy and functional coronary arteries). However, this normal balance between oxygen
demand and supply can be disturbed if endothelial cells are damaged (or blood vessels are narrowed due
to the presence of an atherosclerotic plaque or local vasospasm). Thus, angina can occur as a result of
reduced coronary blood flow or endothelial dysfunction and/or increased heart rate or its force of
contraction, e.g., during a physical or emotional stressful event. These problems lead to an increase in
oxygen demand of the heart, leading to chest pain without any tissue damage (angina pectoris) or with
myocardial cell death (myocardial infarction, also known as a heart attack).
Determinant of oxygen supply and demand of the heart
Oxygen supply is affected by perfusion pressure (aortic diastolic pressure), which is the tone of aortic
valve during diastole. The higher the tone of the aortic valve, the greater the perfusion through the
coronary arteries. The other factor determines circulation through the coronary artery is duration of
diastole. The longer the duration of diastole, the greater the circulation through the coronary arteries
because coronary circulation takes place during diastole. The other factor affecting the coronary
circulation is constriction of the coronary arteries. The greater the resistance of the coronary arteries, the
lesser the circulation (because the diameter of the blood vessels supplying oxygen and nutrients to the
heart muscle will be smaller when they constrict), thereby leading to decreased blood flow through the
coronary arteries. Another factor that alters oxygen supply to the heart is the amount of oxygen in the
blood. So, a normal amount of hemoglobin of blood is important to ensure sufficient oxygen delivery.
Oxygen demand of the heart is affected by alterations in heart rate, force of contractility of the heart
muscle and wall stress (i.e., pre-load and afterload). Any agent or condition that can increase one or
more of these factors can increase oxygen demand. For example, sympathetic activity can increase
oxygen demand because increases in sympathetic activity lead to positive chronotropic (increased heart
rate) and positive inotropic (increased force of contractility of the heart muscle) effects. Increased in LV
wall stress also leads to increased oxygen demand of the heart muscle which is explained in details in
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the next slide. Other factors involves are increased arteriolar tone leading to increased peripheral
resistance (e.g., induced by sympathetic activation or in hypertensive patients) can increase afterload
(end-systolic LV wall stress) leading to increased oxygen demand. Likewise, vasoconstriction of
capacitance blood vessels will increase venous return, leading to increased preload (end-diastolic wall
stress) and thus increased oxygen demand of the heart. So, the greater the tone of resistance arterioles or
capacitance venules, the greater the wall stress and thus the higher the oxygen demand of the heart
muscle.
Why angina occurs?
Angina can occur due to impairment of a normal balance between oxygen demand and oxygen supply.
For example, this could occur by the presence of an atherosclerotic plaque which narrows the lumen of
the coronary arteries, thereby leading to reduced blood flow through the affected blood vessel and thus
decreased oxygen supply to the heart muscle. An atherosclerotic plaque can alter the balance between
oxygen demand and supply in favor of decreased supply and increased demand during a stressful event
and can cause angina. The patient will have chest pain which is induced on a regular base by
precipitating factors, such as physical and emotional exertion, etc.
Different forms of angina
This slide discusses the forms of angina. The most common form of angina is stable angina. This form
of angina occurs due to the presence of a plaque, which causes the blood vessel lumen to become
narrower, leading to decreased blood flow and thus reduction in oxygen supply to a particular region of
the heart muscle. The reason this form of angina is called stable angina is because the patient has
symptoms on a regular basis and therefore this form of angina does not occur randomly. It is triggered
by a precipitating factor, such as exercise or emotional stress, etc. Unstable angina is another form of
angina. This form of angina is induced by rupture of the surface of an atherosclerotic plaque which
attracts platelets and thus a platelet plug is formed rapidly, thereby further narrowing the blood vessels
and reducing blood flow to the heart muscle. The platelet plug may dissipate, or a more stable thrombus
may form. This form of angina requires immediate intervention because the discomfort caused by
complete occlusion of the blood vessel is long lasting and more intense and importantly it is possible
that the blood clot may dislodge and block the blood vessel upstream of the plaque which could progress
to myocardial infarction. Another form of angina is also called the variant angina, or Prinzmetal's
angina. It is caused by intense coronary vasospasms. Unlike classic angina, chest pain may develop at
rest. Also, this form of angina may occur in association with or independent of atherosclerotic disease.
Anti-anginal drugs
Drugs used to manage angina fall into drugs that cause vasodilation, decrease heart rate and its force of
contractility, and alter the metabolic pathway of the heart. The overall effect of these drugs is to
decrease oxygen demand and/or increase oxygen supply to the heart muscle.
Nitrites and Nitrates
Some drugs in this class will get metabolized in the liver including nitroglycerine if taken orally but if it
is administered sublingually it will bypass that process, which is shown on this slide and this is the route
of administration for nitroglycerine. For example, isosorbide dinitrate, must be converted to mononitrite
in the liver and then nitrosothiols, the intermediate molecule for the synthesis of NO, in the endothelial
cells. The nitrosothiol is then converted to NO (nitric oxide) in the endothelial cells, which then diffuses
to the smooth muscle cells and activates the enzyme guanylyl cyclase that is present in the cytoplasm
since it is water soluble (that is the reason this enzyme is called soluble guanylyl cyclase) and increases
the level of cGMP, leading to activation of protein kinase G and eventually muscle relaxation which is
shown in the next two slides. If too much NO is synthesized, NO can be metabolized to peroxynitrite
which has an inhibitory effect of the enzyme guanyly cyclase and cancel the beneficial effect of NO to
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some extent. This is one of the mechanisms through which tolerance could develop to the action of these
drugs, i.e., if too much (excess) of nitroglycerine or related drugs are administered.
Tolerance can also develop if thiols are depleted because the presence of thiol is necessary for
conversion of these drugs to NO. If the tissue is depleted of thiol groups, these drugs will not work as
potently as they do in the presence of thiols, thereby tolerance develops. Thus, it is not a good idea to
pile up doses after doses of these drugs! There are other mechanisms for the development of tolerance to
the action of these drugs that we will discuss later.
Calcium channel blockers
Recall that muscle contraction occurs in the smooth muscle cells of blood vessels when calcium is
entering the muscle cell through the voltage-gated calcium channels leading to calcium-calmodulin
complex formation. This complex formation is essential for the activation of myosin light chain kinase
(shown as MLK+), leading to phosphorylation of myosin light chain (MLK-PO4) and thus enabling the
interaction between actin and myosin and leading to muscle contraction. When the smooth muscle of
blood vessel is constricted, this will lead to vasoconstriction. Nitrates and nitrites prevent muscle
contraction in smooth muscle of blood vessels and leading to vasodilation. These drugs release nitric
oxide (NO), thereby activating guanylyl cyclase and causing the accumulation of cGMP, necessary for
activation of myosin light chain phosphatase and thus dephosphorylation of myosin light chain. The
latter will prevent muscle contraction and thus leading to relaxation of smooth muscle of blood vessels.
Relaxation of smooth muscle of blood vessels will lead to vasodilation. Vendilation reduces preload and
therefore myocardial end-diastolic wall stress/tension, decreasing workload of the heart and thus its
oxygen demand. Recall the more volume in the heart the more forceful contraction of the heart (Frank-
Starling Law) and thus more oxygen and nutrients needed for the heart muscle to do so. By causing
arteriolar dilation (dilation of resistance blood vessels), nitrates reduce afterload which decreases
systolic wall stress, therefore decreasing workload of the heart and thus its myocardial oxygen demand.
Nitrates and nitrites dilate large epicardial coronary arteries, increasing blood supply to the heart. The
latter effect will increase oxygen supply to the heart muscle. Tolerance develops to the action of these
drugs, as described above. Other mechanisms that may lead to tolerance to the actions of these drugs are
that vasodilation in the arteries will lead to drop in blood pressure and activation of the RAAS.
Angiotensin II production will lead to vasoconstriction and the release of aldosterone and ADH,
increasing sodium and water retention. Vasoconstriction will increase afterload, thereby leading to
reduction in the ability of nitrates to cause arteriolar dilation. The increase sodium and water retention
leads to increase blood volume which decreases the ability of nitrates to reduce preload.
Nitrites and Nitrates act on the venous side more than the arterioles sides.
Organic nitrates exert the majority of their vasodilator action on the capacitance blood vessels (venous
side). This selective action on the venous side primarily results in decreased preload, with resultant
reduced myocardial O2 demand due to decreased end-diastolic wall stress because of decrease venous
return (the lesser the blood volume in the heart muscle, the lower the force of contraction according to
the Frank-Starling' Law). Organic nitrates also mildly dilate arteriolar resistance vessels, resulting in
decreased afterload (end-systolic wall stress) and thus reduced myocardial O2 demand. Myocardial O2
supply is mildly increased by dilation of large epicardial arteries.
Side effects
Side effects of these drugs are basically an extension of their pharmacological actions, dilation of blood
vessels could lead to drop in blood pressure, headaches due to dilation of blood vessels in the brain, etc.
One of the major drug-drug interactions occurs when nitrites and nitrates are administered in patients
who are taking Viagra or related drugs. The latter drugs prevent metabolism of cGMP, therefore
allowing cGMP to stay around for a longer time compared patients not receiving Viagra and related
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drugs. This will lead a significant fall in blood pressure and may lead to syncope and even death.
Calcium channel blockers

Calcium channel blockers (CCBs) is another class of drugs used for the management of angina. There
are three different classes of CCBs which are listed on this slide with prototypic drug in each class. As
stated earlier, calcium channels are present on the cardiac muscle (left panel) and smooth muscle of
blood vessels (right panel). Entry of calcium through the channels located on smooth muscle cells of
blood vessels (right panel) leads to calcium-calmodulin complex formation followed by activation of
myosin light chain kinase, thereby phosphorylation of myosin light chain which allows the interaction
between myosin and actin and thus muscle contraction. In the heart muscle (left panel), entry of calcium
through the calcium channels increase the release of more calcium from the intracellular pool (from the
sarcoplasmic reticulum = SR; this is what is called calcium-induced calcium release). The increase in
calcium inside the cell and its binding to troponin C causes a conformational shift in troponin molecules,
allowing the interaction between acting and myosin, thus muscle contraction. Blockade of calcium
channels in the cardiac muscle (left panel) will reduce the entry of calcium through the L-type calcium
channels, thereby reducing force of contractility of the cardiac muscle and thus leading to a decrease in
oxygen demand of the heart muscle. CCBs that are selective for the channels located on smooth muscle
cells of blood vessels (right panel) reduce calcium-calmodulin complex formation and thus leading to
vasodilation. The ultimate effect will be a decrease in afterload due to arteriolar dilation. The decrease in
afterload leads to a decrease in wall stress and thus a reduction in oxygen demand. Some
dihydropyridine (DHPs) CCBs, e.g., nifedipine, cause rapid vasodilation leading to drop in BP (bottom
panel). The latter response can lead to sympathetic activation because of the drop in BP and less signal
going to the vasomotor center via the baroreceptors mechanism to turn off the sympathetic nervous
system. Thus, there will be an increase in heart rate and force of contractility of the heart muscle by the
sympathetic activation. This in turn can result in increased oxygen demand. So, you need to be aware
that not all DHPs can reduce oxygen demand of the heart muscle to the same extent. So, for some (but
not all DHPs) this side effect could increase the oxygen demand (due to reflex tachycardia) and thus
may not be as useful as other CCBs that do not cause this side effect. In particular, those that act very
fast and the drop in blood pressure is rapid and drastic.
The overall effects of CCBs is to dilate coronary arteries and peripheral arterioles, but these drugs have
minimal effects on capacitance blood vessels (i.e., the venous side). Dilation of the coronary arteries
increases myocardial O2 supply. Dilation of systemic (peripheral) arterioles decreases afterload and
thereby decreasing systolic wall stress and thus myocardial O2 demand. However, recall that some Ca2+
channel blockers (especially some of the dihydropyridines CCBs) cause reflex tachycardia, which can
paradoxically increase myocardial O2 demand (not shown). Some CCBs also decrease cardiac
contractility, SA nodal automaticity, and AV nodal conduction. Decreased cardiac contractility leads to
a decrease in myocardial O2 demand because a forceful contraction requires more oxygen. The
decreased SA-nodal automaticity will lead to a decrease in heart rate, which will also reduce the oxygen
requirements of the heart. The inhibition of AV-nodal conduction by some Ca2+ blockers makes them
useful as antiarrhythmic agents.
Side effects
CCBs produce hypotension, decreased heart rate, constipation, angioedema, etc. It is advised that
verapamil and diltiazem should not be given to patients with sick sinus, AV nodal block, receiving
digitalis or beta blockers. In patients with sick sinus or AV nodal block or in patients receiving digitalis
(probably high dose leading to toxicity) the automaticity of the SA node and conduction through the AV
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node will be reduced. These CCBs will exacerbate these problems leading to deleterious side effects and
probably mortality. Also, if a patient has systolic heart failure, i.e., the muscle does not contract during
systole, these CCBs should not be used since these drugs further reduce force of contractility of the heart
muscle, leading to exacerbation of heart failure.
Basically, you need to know that you cannot administer verapamil and diltiazem in patients with
decreased SA nodal automaticity and AV nodal conduction. These drugs should not be used in patients
receiving beta blockers or digitalis. On the other hand, you can use DHP CCBs in patients with
decreased SA nodal automaticity or AV nodal conduction. Also, you can combine the DHPs with beta
blockers.
Beta- Blocker
These drugs reduce oxygen demand via a decrease in heart rate and reducing the force of contractility of
the heart muscle. However, these drugs increase the duration of diastole which allows for more time for
heart to be filled and thus the volume may increase inside the heart chamber. Nevertheless, these drugs
are beneficial; this effect is cancelled by the beneficial effects of these drugs. For the details of
mechanisms of action and side effects of these drugs, please review these drugs under the anti-
hypertensive section.
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Section VII: Cardiac Contraction, Heart Failure, and Drugs used to treat
Heart Failure
Physiology of Cardiac Contraction
The object of this study guide is to detail the physiology underlying how the heart beats. We have gone
into detail regarding the electrical side of the heart, now it is the mechanical. As with most electrical
machines the mechanical and electrical are linked; specifically, Ca2+ is required for contraction. We will
also discuss the PV loop, which is the most detailed graphical analysis of cardiac contractility that is
frequently measured by echocardiology. Below are a few links that detail what the PV loop is and how
to draw it. Please look over at least one of these videos to help you study.
http://www.youtube.com/watch?v=owZqtkAxtiE run time = 8:45
https://www.khanacademy.org/science/healthcare-and-medicine/pressure-volume-
loops/v/understanding-the-pressure-volume-loop run time = 9:18
http://www.youtube.com/watch?v=11wGp-5jXz0 run time = 5:20
The third video is from handwritten tutorials, which I highly recommend (and it is shorter). However, if
you are struggling with this information the series in the Khan academy is very helpful; however, before
viewing the videos first try to draw a PV loop
with the instructions near the end of this
handout. Doing this will make everything even
clearer!
You should know the definition of the following

terms:
Preload
Afterload
End Diastolic Volume (EDV)
End Systolic Volume (ESV)
Stroke Volume (SV)
Ejection Fraction (EF)
This portion of the guide is divided into three

sections: Heart anatomy (tissue and molecular),
Cardiology terms and their application to heart
function, and how to measure cardiac function.
HEART ANATOMY
The heart is a functional syncytium.
What does this mean?
Know the location and function of the following
items:
Tricuspid
Bicuspid
Chordae tendinea
Principles of Pharmacology by Golan: Figure 24-2
Aortic valves (semilunar)
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What are the three tissues that make up the heart?
How does myosin function?

Why is Ca2+ king?
What happens when you do not have ATP (hint it occurs in death)?
Can you trace the route that Ca2+ takes in the heart? Do you recall from previous lectures how all of this
is controlled?
CARDIOLOGY TERMS & FUNCTION

As discussed earlier, the Frank-Starling law dictates how the heart works under normal conditions.
There are a series of terms that are important to understand when dealing with the heart, and it is
important to understand what is the underlying factors controlling these events as that is what can be
manipulated pharmacologically.
Be able to define and explain the following terms:
Preload
End Diastolic Volume (EDV)
Afterload
End Systolic Volume (ESV)
Stroke volume is defined as the amount of blood pumped with each beat. Recall that SV x HR = CO.
We can now redefine SV and understand its relationship to ejection fraction. Can you figure out that
formula from the terms above?
MEASUREMENT OF CARDIAC FUNCTION

There are two methods to describe cardiac function. The first (1915) is the Frank-Starling law named
for two of the physiologists that developed the equations explaining how the heart beats. The second
more modern method was developed with more
sensitive probes and can be estimated with
echocardiograms and blood pressure measurements.
First lets discuss the Frank-Starling law.
The greater amount of volume in the heart will lead to a

greater stroke volume, but can that continue
indefinitely?
What then regulates stroke volume?
What does all of this tell you about the myosin-actin

arrangement?
Inotropes will shift the curve vertically. What

are positive inotropic agents, and why are these things inotropic?
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Can you explain negative inotropes?

Also can you draw these effects?
What happens when you alter blood volume/venous return?
Now lets focus on PV loops

The PV loop measures pressure on the Y-axis and volume on the X-axis. Time is hidden in the graph;
time is depicted by how long it takes to circle the loop. It is important to understand how to draw the
loop, as tracing it is mirroring how the heart is behaving and it will allow you to determine what
medications to use to treat a patient. PV loops can be created for any chamber, but it is the left and right
ventricles (in that order) that are examined most frequently.
Use the instructions and space below (next page) to draw a PV loop.
1) To draw PV loops first make the axis of a graph.
2) Start with an empty ventricle and move your pen to the right and slowly up.
This trace is the atria pumping blood into the ventricle. At first there is no resistance, but
as the ventricle fills the pressure grows and the heart stretches (Starlings law)
3) Now you want to move your pen straight up.
This is called isovolumic contraction (what does that mean)
4) Next move your pen to the left and upward a bit then back down to a bit less and complete this
arc over where you started drawing this PV loop.
The beginning of the curve is when the aortic valve opens and the arc you just drew is
pulse you feel on your neck. (What does this tell you about the carotid artery?)
5) You should now just have to draw a straight line down to the point where you started to complete
the loop.
When the line descends vertically is when the aortic valve closes, and it is the beginning
of the relaxation stage. A completed loop is one heartbeat, and the time it takes to
complete the loop is the heart rate (as stated time is hidden in this graph).
Points of interest are the corners of the PV loop. Can you label your PV loop?
Diastole begins at ESV and ends at EDV; Systole begins at EDV and ends at ESV.
What happens when you increase preload; can you describe this and draw this?
What happens when you increase afterload; can you describe this and draw this?
What is ESPVR?
When does the PV loop become skinner?
What happens when you add a positive inotrope to a skinny PV loop?
Heart Failure
This section is focused on the symptoms and classification of heart failure.
A great guide for this and the drugs section can be found at the Cleveland Clinics website:
http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/heart-failure/
A few terms you should know are listed below, and the heart failure terms are defined as per AHA
guidelines; however, before jumping to the terms lets ask one question.
What is heart failure?
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Terms
Dyspnea
Orthopnea
Cardiomyopathy
Systolic failure (HFrEF):
o The left ventricle loses its ability to contract normally. The heart can't pump with enough
force to push enough blood into circulation; this causes a backup into the lungs and the
right ventricle.
Diastolic failure (also called diastolic dysfunction) (HFpEV):
o The left ventricle loses its ability to relax normally (because the muscle has become stiff).
The heart can't properly fill with blood during the resting period between each beat; this
causes a backup into the lungs and the right ventricle.
Right ventricular (RV) heart failure:
o The right ventricle loses its ability to contract normally. The heart cannot deliver blood
to the lungs and heart; this causes a backup in the venous side.
Congestive heart failure:
o CHF is a symptom of systolic failure and in severe cases left plus right heart failure.
Congestion is the symptoms of heart failure, specifically the edema in the tissue and
lungs. Edema in the lungs makes a slurp sound when breathing.
What does a failing heart look like on a Frank-Starling curve?

How about on a PV loop?
Physiological Responses to heart failure
What would be the physiological responses to a failing heart (reduced SV)?

Why are most of these responses not helpful for heart failure?
We have not mentioned Pharmacology yet, but can you predict some drugs that would be used to treat
heart failure based on what you have learned in these guides? Try it out and see if you are correct in the
next series.
Drugs used to treat Heart Failure
Most of the drugs that are used to treat heart failure you have gone over previously in this guide;
therefore, only new drugs will be discussed and how and why we use the other drugs for heart failure.
You can think of this as a capstone to the cardiology block as heart failure is usually the final
cardiovascular disease a patient develops.
Before delving into the drugs, what are the physiological problems in heart failure? If you can list the
issues, and be specific, then you can easily see what type of drugs you would want to use to treat the
disease. You will also then know the side-effects expected and what drugs to either change or add to the
regimen to treat the patient.
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Now into the drugs

What are the pharmacological treatment options for heart failure?
Increase the strength of the heart muscle

List all the positive inotropic agents you have come across, and some of them will be used for heart
failure in certain instances.
The new group in this list is the cardiac glycosides (although you have seen one in the arrhythmias
section)
Cardiac glycosides (Digoxin and Digitoxin)

target the Na+/K+ ATPase.
How does targeting the Na+/K+ ATPase produce
a positive inotrope?
You will be expected to draw this mechanism.
What is the pharmacophore of the two drugs?

What is the chemical difference between the
two drugs?
What is the therapeutic range of these drugs,

and why is this a concern?
What does hypokalemia due to their efficacy, and can you explain this (see below for help)?
Why do antibacterials increase the plasma concentration of digoxin?
How is digoxin eliminated (also called cleared) from the body?
What drugs alter the clearance of digoxin, and what does that mean for the plasma concentration?
What alters digoxins affinity for the Na+/K+ ATPase?
Digitoxin has a small chemical difference, but what are the two other more important differences?
Elimination, but what is the difference?
Half-life, but which is longer?
Toxicity & Antidote

Rarely are you going to be taught an antidote to a drug back-to-back because most drugs are not as toxic
as digoxin-this answers your therapeutic range question above.
First, you need to know the signs of digoxin toxicity!

Second, what is the antidote and how does it work?
Digibind
DigiFab
o Both of these are antibodies that bind to the pharmacophore and induce a rapid
elimination through the kidney.
o Each vial (40 mg) can bind 0.5 mg of Digoxin
If there is a massive overdose how would you treat a patient, and you should know the dose?
The following link has much more info on this general topic.
Page 63 of 71
http://www.medscape.com/viewarticle/471331
Now we are to drugs that you have knowledge about from this guide, the rest should be easier
PDE inhibitors can be used to treat heart failure.

Why?
There are a few drugs you may not have seen before, but they all end in rinone
They are administered IV
What are the side effects and why do you suppose these side effects occur?
Would you use these drugs for long-term therapy?
-AR agonists are also used.

Why and when would you use these agents?
What side effects would you see?
Can you see that this is similar to the PDE inhibitor?
Can you draw these two on a PV loop?
Relieve some of the load on the heart

Recall heart failure is just a weak heart, so a common strategy is to reduce the force that the heat must
pump against.
What can you do to reduce the stress on the heart?
Preload
Preload is a volume problem so you want to first use diuretics.
What diuretic leads to the greatest volume loss?
Is there any concern in using this drug?
Other diuretics can be used, and keep in mind the side effects of these drugs.
Special consideration should be given to the MR antagonists spironolactone and eplerenone. Please note
that clinically there is more data for spironolactone, but that does not mean that eplerenone is not as
good, it means that spironolactone is older and has been used more often.
Understand why you would want to use these drugs (listed below).
K+ sparing
Improve diastolic dysfunction (not known why it does)
What is a venodilator and why would you use this drug in HF?
Can you draw the effect of reducing preload on a Frank-Starling curve? How about a PV loop?
Afterload
Afterload is a large problem for the failing heart.
For left heart failure afterload is what, and what would you use to reduce the afterload?
Note Aliskiren has been shown to be ineffective.
Page 64 of 71
The big surprise is that some -blockers are effective in treating heart failure.
Why is this a surprise?
The following -blockers are appropriate for treating heart failure?
Metoprolol XL
Carvedilol
Bisoprolol
Can you draw the effect of reducing preload on a Frank-Starling curve? How about a PV loop?
Reduced Pump activity

Reduction in pumping activity (heart rate) is also important as it helps the heart conserve energy and if
you recall the formula for blood pressure it becomes even more apparent why this is can be good.
Many of the drugs discussed would reduce that pumping activity, but there is one more choice
Ivabridine.
Therapeutic options
Can digitalis be used with -blockers since they seem to counter act each other?
Are there any side effects that you would expect?
Page 65 of 71
Section VIII: Diabetes and Antidiabetic drugs
Diabetes mellitus (DM)

Approximately 14,000,000 people have diabetes in the USA. DM results from a defect in insulin
secretion or insulin responsiveness or both. There are two types of DM: Type 1 (insulin-dependent;
IDDM) and Type 2 (non-insulin-dependent; NIDDM). Insulin is secreted from the beta cells of the
pancreas. There are other hormones that are released from the pancreas such as glucagon by the alpha
cells, amylin by the beta-cells, as shown below.
Pancreatic hormones
Type 1 (IDDM)
About 5% of diabetic patients have type 1 DM and is very common in juveniles (<35); very common
(b/w 10-16) more than in adults. Type I DM is the severe form of diabetes because it remains untreated
states associated with ketosis, which is deadly. This form of diabetes results from destruction of
pancreatic beta cell by a virus or infection; in most cases it is immune-mediated. It is a catabolic
disorder (no insulin, high glucagon, no beta cell response to insulin releasing stimuli) and therefore
insulin is needed from outside (exogenous sources, such as insulin injection, pump, etc.).
Insulin is a small protein made up of 51 AA (MW = 5808). It is arranged into two chains (A and B)
linked by disulfide bridges. It is stored in beta-cells in crystal forms consisting of 2 Zn + 6 insulin
molecules.
Page 66 of 71
Insulin secretion
Insulin is released from pancreatic beta-cells; its basal level is 5-15 micro units/mL (30-90 pmol/L) and
rise to 60-90 micro units/mL (360-540 pmol/L) during meals and following insulinogogues, i.e., stimuli
that cause the secretion of insulin, which include glucose, mannose, AAs (Leu, Arg), vagal activity, etc.
Figure 41-2 shows glucose uptake by beta-cells glucose transporter (GluT), provides energy (ATP).
When the level of ATP is increased, it causes closure of ATP-dependent potassium channels which
will depolarize the beta cells and leads to opening of calcium channels and finally release of insulin.
Insulin degradation
Insulin has a short half-life = 3-5 min and metabolized by the liver (60%) and kidney (35-40%).In
diabetics, when exogenous insulin is administered, this ratio is reversed. Metabolism of insulin starts
with hydrolysis of S-S bonds b/w chains A and B by insulinase (glutathione insulin transhydrogenase)
followed by proteases.
Page 67 of 71
Insulin receptor
Insulin receptor is made up of two alpha and two beta subunits; kinase activity is located in the
intracellular site. Various hormonal agents affect the affinity of insulin receptor for insulin (e.g.,
hydrocortisone, GH, etc.)
Glucose transporters (GluTs)

GluTs may play a functional role in the etiology and manifestations of diabetes. GluT4, lowering blood
glucose, is inserted by insulin into the muscle membrane and fat cells from intracellular vesicles.Defects
in GluT2-mediated transport of glucose into beta cells may contribute to the reduced insulin secretion
(type 2)
Insulins Actions
Promotes storage of fat as well as glucose in specialized cells
Influences cell growth and the metabolic function of various tissues
Increases storage of glucose as glycogen
Resets the liver in a fed state by reversing glycogenolysis, ketogenesis, and gluconeogenesis
P
Insulins actions on muscle
Insulin promotes protein synthesis by increasing AA transport and increasing ribosomal activity. In
addition, insulin promotes glycogen synthesis to replace expended stores due to muscle activity. These
effects accomplished by increasing storage of glucose into muscle cells, inducing glycogen synthase and
inhibiting phosphorylase.
Insulins actions on adipocytes

Insulin stores energy in the form of triglycerides; reduces FFA and increase TG storage by induction of
lipoprotein lipase, hydrolyzes TG from circulating lipoprotein, glucose transport into cells to generate
glycerophosphate, which permits esterification of FFA supplied by hydrolysis of lipoproteins. It also
reduces intracellular lipolysis of stored triglyceride by direct inhibition of intracellular lipase,
suppression of cAMP and dephosphorylation of the lipase in the fat cell
Insulin Preparations
There are 4 different types of insulin: (1) ultra-short acting, (2) short-acting, (3) intermediated-acting
and long-acting.
Examples of ultra-short acting include insulin lispro and insulin aspart. They work within 5-10 min and
last for a few hours. Short acting is referred to regular insulin and works within 30 min and last for 5-7
h. This is the only form of insulin to be administered I.V.
Intermediated acting
NPH (neutral protamine Hagedorn, or isophane is an intermediate acting insulin and its onset is delayed
by combining appropriate amounts (1:10) of protamine and insulin.
Long-acting
These are peakless insulin and last for up to 24 h. Examples are galagine and detemir.
Mixtures of insulins
Insulins mixtures are used to take over the drawback of the other form of insulin. For example, some
acts fast but not for a long time and therefore it is possible to observe a delayed hyperglycemia. If the
insulin does not work fast, then it is possible to observe postprandial hyperglycemia. To overcome these
problems, one can mix different forms of insulin. NPH is mixed with lispro (NPL) or aspart (NPA).
Page 68 of 71
Concentration of Insulin
Insulin is prepared as 100 U/mL (100U) in 10 mL vials but limited supply of 500U regular human
insulin is also available which can be used in rare cases of severe insulin resistance.
Insulin delivery systems

-Subcutaneous injection is the standard method
-Portable Pen Injectors (to facilitate multiple s.c. injections); portable pen-sized injectors, better
compliance
-Infusion (CSII, insulin pump), programmable to deliver individualized basal and bolus insulin
replacement
-Inhaled insulin
Treatment with Insulin

It is primarily used to treat type 1 DM. In most cases, type 2 diabetic patients do not need exogenous
insulin for survival, but many need exogenous supplementation to achieve optimum health.
Complication of Therapy
One of the most deadly side effects of insulin is to cause hypoglycemia, which can result from delayed
in taking a meal, greater physical exertion, large dose of insulin, and tight control without frequent
monitoring. Patients should carry an identification card, bracelet, or necklace. Signs of both sympathetic
(tachycardia, palpitation, sweating, tremulousness) and parasympathetic (nausea, hunger) hyperactivity
that may eventually progress to convulsion and coma, if left untreated.
Treatment of hypoglycemia
Mild hypoglycemia (patients are conscious and able to swallow), orange juice or any sugar-containing
beverages. More severe forms (unconscious), require IV glucose (20-50 ml of 50% glucose solution) or
glucagon (1 mg; s.c. or i.m.) will restore consciousness within 15 min to allow ingestion of sugar. If
glucagon is not available; small amount of honey or syrup can be inserted in the buccal pouch; oral
feeding contraindicated in unconsciousness.
The other side effect of insulin is to cause insulin resistance or insulin allergy. Lipodystrophy at
injection sites is also another side effect of insulin. The use of highly concentrated and purified insulin
preparations has reduced this problem significantly.
Type II diabetes
It may affect about 2% of adults but more than 90% of diabetic patients have this form of DM. It has a
gradual onset mainly in people >40; occasionally in adolescents and is a milder form; in most cases,
diagnosed during a routine medical examination. In this type of DM, insulin is produced but not enough
to meet the bodys need, especially overweight people; often the body is resistant to the effect of insulin.
Thus, type 2 diabetes is ranging from (1) predominantly insulin resistance with relative insulin
deficiency and/ or (2) predominantly secretary defects with insulin resistance. The tissue resistance to
insulin and the impaired beta-cell response to glucose appear to be further aggravated by increased
hyperglycemia. Thus, reducing hyperglycemia by various therapeutic strategies could ameliorate these
two defects.
Treatment of type 2 DM
Dietary attempts to reduce weight are usually helpful to correct hyperglycemia. If dietary treatments fail,
oral hypoglycemic agents should be used. There are different classes of oral hypoglycemic/euglycemic
Page 69 of 71
agents:
Sulfonylureas
Sulfonlureas are insulinogogues (cause secretion of insulin). These drugs block potassium channel on
the beta cells, causing depolarization of the cell and opening of calcium channels followed by exocytosis
of insulin. Other proposed mechanisms of this class of antidiabetic drugs are reduction of serum
glucagon, and extra-pancreatic effect to increase the effect of insulin on its target tissues (via
upregulation of insulin receptors). Due to blockade of potassium channels, they may cause
cardiovascular problems. Secondary failure & Tachyphylaxis to these drugs are due to inability to
dietary compliance, refractoriness in responding beta cells and progressive decrease in beta cell mass.
This class of antidiabetic drugs is classified, based on their potency, as first generation SURs, such as
tolbutamide, chlorpropamide and tolazamide. Second generation have higher potency with fewer side
effects. However, they should still be used with caution in cardiovascular and elderly patients. Second
generation SURs include glyburide, glipizide (glucotrol XL is a long acting - 24 h) and glimepride (once
daily alone/w insulin)
Meglitinides
These are fast acting insulin secretagogues by blocking the K channels on the beta cells, similar to
SURs. However, this class of drugs has its own binding site as well as an overlapping binding site with
SURs. Repaglinide (FDA approval in 1998) is a very fast onset & short duration of action (peak in 1 h;
liver t1/2 = 1 h); thus, used for postprandial control and can used alone or/w biguanides (contain no
sulfur).
Biguanides
Mechanism of action is unclear; they may increase direct stimulation of glycolysis in tissue, with
increased removal of glucose from blood. In addition, they reduce hepatic gluconeogenesis, slow down
glucose absorption from GI, with increased glucose to lactate conversion by enterocytes, reduce of
plasma glucagon levels. Unlike SURs and meglitinides, the presence of beta cells is not necessary for
biguanides to exert its beneficial effects in diabetic patients. These drugs do not affect fasting but
decrease postprandial glucose levels (euglycemic versus hypoglycemic). Phenformin was the first drug
in this class but was withdrawn because it was causing lactic acidosis. Buformin is another biguanide
but is not used in the USA. Metformin (USA, clinical trials 1995); not metabolized, excreted in urine; if
renal failure exists, lactic acidosis will occur since it blocks hepatic gluconeogenesis. Metformin is
prescribed in patients with refractory obesity insulin-resistant. It is advantageous over insulin and
sulfonylureas in these patients since it is an insulin-sparing agent, does not increase weight and does not
induce hypoglycemia.
Side effects of biguanides are anorexia, nausea, vomiting, abdominal discomfort, diarrhea (3-5%
discontinuation) and decrease absorption of B12 (chronic use). All of the above drugs are
contraindicated in patients with renal or hepatic disease; alcoholism; hypoxia.
Thiazolidinediones
These drugs bind to the PPARgamma which is involved in fat and sugar metabolism. Very effective
drugs that enhance target tissue sensitivity to insulin so that they reduce insulin resistance by increasing
glucose uptake; euglycemic drugs. Drugs in this class include troglitazone (due to hepatotoxicity it is no
longer used in the USA). Rosiglitazone and pioglitazone are other examples of this class of anti-diabetic
drugs.
Alpha-glucosidase inhibitors
These drugs inhibit the intestinal alpha-glucosidases; modulate postprandial digestion and absorption of
starch and disaccharides and thus slow down absorption of glucose in the blood stream. Only
monosaccharides can be transported of the intestine to blood. Disaccharides and polysaccarides (X);
Page 70 of 71
need to be digested by pancreatic alpha-amylase, alpha-glucosidase and also inhibit (sucrase; maltase;
beta-glucosidases, etc). This class of drugs has weak anti-diabetics effects. Acarbose and miglitol (6X >
Acarbose) are examples of this class of drugs. Side effects are annoying (GI), such as flatulence,
diarrhea, and abdominal pain. These drugs are used as adjunct therapy in patient who cannot achieve
glycemic goal by taking other medications. These drugs are contraindicated in patients chronic or
inflammatory bowel disease.
Glucagon
It is synthesized in the alpha cells and is released in response to low blood glucose. It is degraded in the
liver & kidney as well as in plasma and its receptor sites.
Pharmacological effects
Metabolic effects (increases cAMP; facilitates catabolism of stored glycogen and increases
gluconeogeneis and ketogenesis); its immediate action will be an increase in glucose at the expense of
glycogen. It also has cardiac effect (inotropic and chronotropic effect; cAMP-mediated). Also, it causes
relaxation of smooth muscle (profound relaxation of intestine; not mediated by AC).
Indications
Severe hypoglycemia as well as for endocrine diagnosis (insulin antibody is formed in insulin-treated
type 1; thus, measure C-peptide by RIA after glucagon), to treat beta-blocker poisoning (X in CHF) as
well as radiology of bowel (relax the intestine)
Islet Amyloid Polypeptide (Amylin, IAPP)

It is a peptide; produced by beta cells. About 1 molecule of IAPP is secreted along with 10 molecules of insulin. It
is believed to reduce glucagon, facilitate satiety, and slow down gastric emptying.
Page 71 of 71

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IPBP IA Exam Study Guide:

Pharmacology 2: Cardiovascular and Diabetic Pharmacology

Internal Assessment (IA) Exam

Section I: Lipid Processing, Atherosclerosis, and Antihyperlipidemic

Additionally, it is also important to know a few

Additionally it is important to know what the liver does with cholesterol

Generic Trade Metabolism t hr. Notes

Bile Acid Sequestrants

Cholesterol absorption inhibitors

Use the chart below to answer the following questions:

Omega-3 Fatty acids aka Fish oils

Section II: Blood Pressure and Renal Physiology & Pharmacology

Renal Physiology and Pharmacology

What is the macula densa?

(see the figures on the next page)

Potassium secretion is controlled via aldosterone, and the

We started with volume so how is volume regulated by the kidney?

What are aquaretics?

There are a number of diuretics (see below)

Drug type Target Drug names

Carbonic anhydrase inhibitors Methazolamide, Ethoxzolamide, Acetazolamide

Furosemide, Bumetanide, Ethacrynic acid, Etozolin,

Sulfonamides Hydrochlorothiazide, Bendroflumethiazide,

Thiazide-like drugs (act like

Carbonic anhydrase inhibitors:

Potassium Sparing Diuretics:

Section III: Antihypertensive drugs

By reading these lecture materials, you should be able to:

Definition of blood pressure (BP) and its determinants:

Anatomical sites that play a functional role in regulating BP:

Baroreceptors and its importance in regulation of BP:

Control of BP by the sympathetic nervous system:

Regulation of BP by the RAAS:

Regulation of BP by substances released from the endothelium of blood vessels:

Production of NO is also stimulated by other agonists such as acetylcholine, bradykinin or other

Definition of hypertension and different stages of HTN:

Risk factors of BP:

Examples of the anti-hypertensive drugs and their classes:

Section IV: Blood Coagulation & Platelet Activation plus Antiplatelet,

Blood, Plasma, and Serum

How to prepare plasma/serum from blood?

- Erythrocytes (RBC): 4.2-6.1 million/l

Anticoagulants: Substances which prevent coagulation

Anticoagulants in the Nature

Animals depending on a diet of fresh blood have evolved mechanisms that

Anticoagulants in the Nature (2)

Leech: Hirudo medicinalis. These animals make:

Coagulation Factors and Pathways

Platelet Adhesion, Activation & Aggregation

Platelet Secretion (Release Reaction)

Platelet Adhesion, Activation & Aggregation (2)

Platelet Activation by Thromboxane A2

Platelet Activation by ADP (Adenosine DiPhosphate) and Thrombin

The Role of the Coagulation Factors in Fibrin Formation

Coagulation Factor Activation on Phospholipid Surfaces

How Coagulation is Prevented in the Body?

Deep Vein Thrombosis (DVT)

Anti-Coagulants, Antiplatelets & Fibrinolytic Drugs

How to prevent platelet activation?

Major Drug Targets for Inhibiting Platelet Function

Major Antiplatelet Drug Classes

II. Anti-thromboxane Drugs

III. GPIIb/IIIa Antagonists