Pharmacology and

Medicinal Chemistry of
Cardiovascular and
Diuretic Drugs
By Dima Alnahas

Summary of chapter 10 from comprehensive pharmacy review eighth

edition

12/4/2014
Contents:

1- Antihypertensive Agents
2- Agents used to manage angina
3- Agents for the treatment of congestive heart failure
4- Antiarrhythmic agents
5- Antihyperlipidemic agents
6- Anticoagulants agents
7- Antiplatelet agents
8- Thrombolytic agents

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 Antiarrhythmic Agents : is often the result of underlying organic disease secondary to
myocardial infarction or genetic mutations in the specific ion channels responsible for
cardiac electrical activity
the orderly movement of electrical activity from the SA node, through the atrial body
to AV node, and through the His-purkinje system to the myocardium, is responsible
for the organized contraction of the heart.
Arrhythmias result in uncoordinated atrial and ventricular contractions that reduce
cardiac output and systemic blood pressure
SA nodal pacemaker cell are able to depolarize due to the leakiness of Na and Ca
producing action potential
AV nodal are also leaky Na/ Ca ions to depolarize, but more often, they conduct atrial
impulses through the His- Purkinje system
Atrial, His-Purkinje, ventricular myocardial cell are much less permeable to cations
Anti- and are triggered to depolarize by electrical impulses from SA nodes and AV nodes
Arrhythmic phase 0: ↑ Na
phase 1: ↓Na, ↑ K
Agents phase 2: ↑ Ca, ↓ K
phase 3: ↓ Ca, ↑ K
phase 4: rest

phase 4: slow depolarization

phase 0: rapid depolarization
phase 1: rapid repolarization
phase 2: plateau
phase 3: rapid repolarization

K channel blocker: will decrease the rate of repolarization

P wave: atrial depolarization
QRS wave: ventricular depolarization
T wave: ventricular repolarization

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 Type Drugs Activity Side effects
it has significant K channel
hypotension,
Quinidine blocking activity as well as alpha
syncope
adrenergic blocking
Quinidine, disopyramide,
lupus- like reaction
procainamide. They have disssimilar
specially with
structure but similar Na channel is metabolized to N-acetyl
patients who are
blocker activity to reduce excitability procainamide procainamide that has more
unable to actylate
in atrial fibrillation and flutter, and prominent K channel blocking
the drug
also decrease the recurrence of
effectively
ventricular arrhythmias
it has the ability to block K
disopyramide channel and depress cardiac HF
contractility
much more selective Na channel
blocking. IV lidocaine can be used
for th treatment of ventricular
fibrillation. Due to it's high
affi nity for Na channel in the
inactive state, it binds
Lidocine
preferentially to the channels on
1- Na+ channel seizures, tremor,
arrhythmic tissue but disociate
blockers Lidocaine, Mexiletine nystagmus, heart
readily as the channels transition
block
to the closed state. thus it has
less effect on normal myocardia
cells
is an oral derivative of lidocaine
that can be used to prevent the
Anti- Mexiletine
occurrence of ventricular
Arrhyt arrhythmias

hmic they are less selective Na channel

worsening of heart
Agents blockers than lidocaine, that are
failure symptoms,
used to manage supraventricular
and flecainide may
tachycardias such as atrial
initiate lethal
Flecainide, Propafenone fibrillation and have some
ventricular
activity against ventricular
arrhythmias in
arrhythmias. Both agents may
patient with
have activity on K channel and
ischemic disease
propafenone has some B
adrenoreceptor antagonist
may cause heart
has also prominent B
Sotalol block,bradycardia,
adenoreceptor antagonist
exacerbate HF
lethal pulmonary
fibrosis,
microcrystalline
it acts on Na+/ Ca+ channels and
coneal deposits,
may interfere with thyroid all of them
Amiodarone photosensitivity,
hormone function in the may
2- K+ channel Sotalol, Amiodarone, and may
myocardium causeTorsad
blockers Dronedarone, Ibutilide, Dofetilide causeheart
es de point
block,bradycardia,
arrhythmias
exacerbate HF
Ibutilide may activate Na+ channels

hepatotoxicity, and
may cause heart
Drondarone
block,bradycardia,
exacerbate HF

Continue..
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 Type Drugs Activity Side effects
they exert inhibitory actions on
tissue dependent on Ca+ channel
3- CCBs Verapamil, Diltiazem (SA, AV nodal), thus they used t0
treat supraventricular
tachycardias
reduction of sudden cardiac
death (due to ventricular
4- B blockers Propanolol, Metoprolo, Carvedilol
arrhythmias) after a myocardial
infarction

infusion is used to restore sinus

rhythm in patients with reentrant
supraventricular arrhythmias. The
Adenosine activation of adenosin receptor in
AV nodal tissue reduces the
resting membrane potential and
Anti- conduction velocity through this
Arrhyt tissue

hmic at low doses activates the

Agents parasympatheic nerves supplying
the heart and thus stimulation
5- Miscellaneous muscarinic receptors on AV node
agents to hyperpolarze the tissue and
Digoxin, Atropin, Adenosine Digoxin reduce elctrical conduction. It
used to decrease AV conduction
to prevent atrial fibrillation from
causing ventricular arrhythmias. it
is also used to manage reentrant
supraventricular arrhythmias by
the same mechanism

can block muscarinic M2 receptor

in the AV node to enhance AV
Atropine
conductions to treat condition
such as bradycardia due to
parasympathetic (vagal) input

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 most fatty acids and cholesterol absorbed from GI tract are associated with chylomicrons that
carry it via the lymphatic and circulatory system to the liver

the liver uses acetyl coenzyme A, via the rate limiting step of HMG-CoA reductase, to synthase
mevalonate and cholesterol
Anti
hyper-
lipidemic some of that cholesterol used to produce bile acid for the emulsification and digestion of fat in
the GI tract, while the rest with triglycerides is packaged into VLDL and secreted into blood
Total cholesterol: less than 200mg/dL
LDL: not more that 130 mg/dL
HDL: at least 40 mg/dL
triglycerides: not more than 200 mg/ dL

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 Types Drugs Adverse effects
They are hydrophilic, insoluble anion-
exchanger resins that are ingested in the
form of slurry or as gel formulation.
These resins are positively charged
(cholestyramine, colesevelam) or Cholestyramine: is aresin consisting gastric distress,
become positively charged (colestipol) of trimethylbenzylammonium groups bloating and
in the small intestine to bind negatively in a large copolymer of styrene and flatulence. These
charged bile acids. this signals the liver divinylbenzen agents have the
to increase the expression of the LDL ability to reduce
receptor to capture more LDL from the the absorption of
Cholestyramine,
1- Bile acid blood to recover cholesterol for the drugs such as
Colestipol,
sequesterants synthesis of fresh bile acids. diuretics, thyroxin,
Colesevelam
Colestipol: is a copolymer of warfarin, and
diethylenetriamine and 1-chloro-2,3- statins and have to
epoxypropane in a hygroscopic be administered 1
bile acid resins are able to lower
powder. hr before or 2 hr
circulating LDL levels by 10% to 25%,
after other drug
however this effect is not usually
Colsevelam: is a poly allylamine cross- ingestion
sustained because of the ability of the
linked with epichlorohydrin and
liver for de novo cholesterol synthesis
alkylated with 1-bromodecane and (6-
bromohexyl)-trimethylammonium
bromide in a hydrophilic gel
The fungal derivative lovastatin and
Anti simvastatin are composed of a closed
hyper- The liver is able to synthesize six- membered lactone ring attached
cholesterol from acetyl coenzyme A; the to a naphthalene ring via an ethyl
lipidemic conversion of hydroxymethylglutaryl- bridge. Estrases in the liver convert
CoA to mevalonate being the rate the lactone conformation to the
limiting step in this process active, open hydroxy carboxylic acid
form that mimics the mevalonate
intermediate.
statins are
The statins compete with HMG-CoA for associated with
binding to the reductase to prevent the very rare but
synthesis of mevalonate and cholesterol. the lactone in pravastatin, serious adverse
2- HMGCo-A
The inhibition of hepatic cholesterol fluvastatin, atorvastatin and effects;
reductase
synthesis by the statins results in rosuvastatin is in the open hydroxy hepatotoxicity,
inhibitor
increased expression of hepatic LDL acid form and the napthyl rings in the rhabdomyolosis,
receptor that scavenges LDL from the later three are replaced by other and potential birth
blood. it can lower the LDL up to 60%. aromatic derivatives defects if taken by
pregnant women
some of the statins (simvastatin,
rosuvastatin) are also able to increase
plasma HDL levels to produce additional
antatherogenic effect. Combination of
statins with other lipid lowering agents
(gemfirozil, bile acid resins, niacin,
ezitimibe) can produce even grater
lowering in LDL- cholesterol in patients
with more severe lipid abnormalities.

continue..

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 Types Drugs Adverse effects

skin rash, GI
disturbances,
these agents are thought to induce myopathies
Clofibrate, lipoprotein lipase to reduce VLDL (especially when
3- Fibric acid
Gemfibrozil, levels and also induce the production combined with
derivatives The esterified drugs (clofibrate,
Fenofibrate of apolipoprotein A1 and A2 to statins),
fenfibrate) have to be hydrolyzed to the
enhance HDL levels hepatotoxicity,
carboxylic acid form (gemfibrozil) in
arrhythmias, and
order to have therapeutic benefit
hypokalemia

these agents are more often used to

treat triglyceridemis and also to elevate
HDL
Anti this drug has the ability to reduce
hyper- dietary cholesterol absorption from
the gut to lower the cholesterol
lipidemic component of chylomicrons. The
reduce delivery of cholesterol to the
liver enhances LDL receptor
belong to new class of inhibitors of GI expression and decrease of up to upper respiratory
sterol transporter 20% in plasma LDL may be observed infections,
4- Ezetimibe diarrhea, pain in
the joints and
in response, the liver increase de extremities
novo cholesterol synthesis and
ezetimibe and ezetimibe- statin
combinations may be particularly
effective in lowering LDL levels, and
reduction in cardiovascular end
points are less obvious
has VLDL and LDL lowering capacity as circulating VLDL levels are lowered flushing, pruritus,
Niacin, Nicotinic
5- Niacin well as the ability to elevate HDL levels due to reduced hepatic triglyceride dyspepsia,
acid
Niacin is used to treat patients with synthesis and increased VLDL uptake vomiting, gastric

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 Types Drugs Adverse effects

Vitamin K is a cofactor in the Y-carboxylation of

nascent clotting factor such as factor 7,10,2 and Warfarin is coumarin
potent C and S and is converted to the epoxide form. derivatives. Minimal uncontrolled bleeding,
The epoxide has to be reduced to vitamin K by a structural requirements skin necrosis, purple
1- Vitamin K toe syndrome, and
Warfarin, hepatic reductase for the posttranslational activity are substitutions at
reductase alopecia are observed,
Anisindione modification of coagulant proteins to continue, and position 3 and 4 with the
inhibitors this step is selectively inhibited by warfarin and potential to form a cyclic birth defects are likely
anisindione hemiketal. if taken during
Warfarin is used to treat deep vein thrombosis, pregnancy
pulmonary embolism, and clots due to atrial
arrhythmias and prosthetic cardiac valves.
UFHs heparin are mucopolysaccharide polymers (60- UHF have the affi nity for
100 Kda) extracted from mast cells of bovine lung antithrombin 3 and catalyze
tissue or porcine intestinal mucosa. (LMWHs 2-10 KD activation of factor Xa and
a) are produced by careful fragmentation of UFH and 2a by AT-3, ultimately bleeding, heparin-
purification by gel filtration to produce agents such reducing the amount of induced
as enoxaparin, tinzaparin, dalteparin fibrin thrombocytopenia
2- LMWHs also bind to AT-3 (HIT), alopecia,
Unfractionated both UHFs and LMWHs have to be administered by but preferentially inhibit osteoporosis. Overdose
Enoxaparin,
and low- subcutaneous or intravenous injection but LMWHs factor Xa rather than 2a, but with HMWH or UFH can
Anti- Tinzaparin,
molecular- has longer half-life. These agents are used for the ultimate effect on treated with parenteral
coagulant Dalteparin
weight pulmonary emboli prophylaxis and to treat venous fibrin levels is much the administration of
agents heparins thromboemboli until transitioned to warfarin same protamine sulfate that
Fondaparinux is a synthetic pentasaccharide that neutralizes the
inhibits factor Xa through the actionof AT-3 polysaccharides via
Danaparoid is a mixture of heparin sulfate, dermatan ionic interaction
sulfate, and chondroitin sulfate extracted form
porcine mucosa and having a similar mechanism of
action as LMWHs

these agents are able to inhibit thrombin activity by

interacting with the catalytic or substrate recognition
site of the protease without the need for AT- 3
Lepirudin is a 65 amino acid recombinant derivatives bleeding, but
of hirudin, the anticoagulant found in the saliva of these agents administrated Dabigatran is also
Lepirudin, the medicinal leech parentally to inhibit
3- direct associated with GI
Bivalirudin, Bivalirudin is a synthetic 20 amino acid derivative of thrombin activity and
thrombin disturbances such as
Argatroban, hirudin, also used to prevent thrombosis after reduce the formation of
inhibitors esophageal reflux,
Dabigatran coronary angioplasty procedure thrombin gastric bleeding, and
Argatroban is also parentally administered, direct abdominal pain
thrombin inhibitor
all these three agents are used to treat HIT
Dabigatran is the first orally active direct thrombin
inhibitor and is used to prevent stroke in patients
with atrial fibrillation

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 Drugs Descriptions Adverse Effects

aspirin is used for the

the inhibition of cyclooxygenase by aspirin prophylaxis of myocardial
reduces the amount of thromboxane A2 infarction and, in conjucation
1- Aspirin
produced by platelets during the activation with other agents, it
process and leads to decreased shape change, decrease thrombosis after
aggregation, and release of granules coronary stenting

are antiplatelet agents used in stroke

prophylaxis in cerebrovascular ischemia or headache, dizziness, edema,
2- Dipyridamole after prosthetic valve replacement. Cilostazol and GI distress are the most
and Cilostazol is also used for intermittent claudication. often reported with this
These agents elevate cGMP in platelets by agents
inhibition of phosphodiesteras activity to
decrease therir activation and aggregation

they have to be bioactivated by hepatic CYP

enzymes before they are active.
Anti- 3- Thienopyridines metabolites covalently bind rare but serious:
Platele Thienopyridines ( to the P2Y12 receptor on platelets to prevent thrmbcytopenia purpura,
t Ticlopidine, ADP- mediated aggregation and adhesion to aplastic anemia, neutropenia,
Agents fibrin. cholestatic jaundice, fever,
clopidogrel,
prasugrel ) these drugs areused to decrease clot rash, and GI distress
formation after angioplasty and stenting
procedures and are often combined with
aspirin or GB2b/3a inhibitors

these are all parenteral agents that reduce the

interaction of platelets via the GP2b/3a
receptors to fibrinogen. The result of this bleeding, but abciximab also
4- Glycoprotein action is decreased platelet aggregation during cause hypotention, nausea,
2b/3a inhibitors formation and reduced thrombus size vomiting, and atrial
(Abciximab, fibrillation. Triofibrin has
Eptifibatide, Aciximab is the Fab fragment of a monoclonal caused thrombocytopenia,
Triofibrin antibody directed against GP2/3a, whereas especially when combined
Eptifibatide is a cyclized heptapeptide with with heparin
high affinity for the fibrinogen receptor. These
agents are used after a myocardial infarction
or during angioplasty and stent placement

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 Types Uses Adverse Effects

are normally released by

endothelial celss to activate
fibrin- bound plasminogen to these agents are used to bleeding, and this
1- Tissue plasmin. Plasmin then cleaves resolve clots during can be managed by
plasminogen fibrin strands to cause the myocardial infarction, the administration
disintegration of the clot
activators plumonary emboli, or of aminocaproic
Human tPA, Alteplase is
cerebral stroke acid
produced by recombinant
technology, Reteplase,
Thrombolytic Tenecteplase
Agents is produced by B- hemolytic
streptococcus that combines
with plasminogen to produce
it is used to treat deep vein bleeding, fever,
plasmin
2- Streptokinase thrombosis and myocardial rash, and
these agents is less clot- infarction anaphylxis
specific because it dose not
require the presence of fibrin
to activate plasminogen
is a serine protease that it is used to clear massive
cleaves plasminogen to pulmonary emboli a well as
3- Urokinase
plasmin that can then degrade treat patients with acute
formed clots myocardial infarction

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