CARDIOVASCULAR DRUGS

Arterial pressure is the product of cardiac output (CO) and peripheral vascular resistance.
Hypertension is the most common cardiovascular disease. The pressure elevated from the
normal arterial pressure induced pathological changes in the vasculature that produces
hypertrophy of left ventricle, which principally causes stroke, myocardial infarction, cardiac
arrest, renal insufficiency, and dissecting aneurysm of the aorta. It is important to note that the
risk of both fatal and nonfatal cardiovascular disease in adults is lowest with systolic B.P. less
than 120 mm Hg and diastolic less than 80 mm Hg. In severe levels of hypertension (systolic =
210 and/or diastolic = 120), Some patients develop arteriolopathy characterized by endothelial
injury and marked proliferation of cells in intima, leading to intimal thickening and causes
occlusion. This May also lead to severe microangiopathic haemolytic anaemia. Effective
Antihypertensive therapy will almost completely prevent haemorrhagic stroke, cardiac failure,
and renal insufficiency.
According to hydraulic equation, arterial blood pressure is directly proportional to CO and PVR.
BP = CO × PVR
BP is maintained by moment-to-moment regulation of CO and PVR, exerted at three anatomical
sites, that is, arterioles, postcapillary venules, and heart. The fourth anatomical control site, the
kidney contributes to the maintenance of blood pressure regulating fluid in the body.

Drugs Used for the Treatment of Hypertension

Antihypertensive drugs are defined as the drugs that are used to decrease the elevated blood
pressure (hypertension). It is one of the common cardiovascular disorders and it is a state of the
body in which the systolic blood pressure (BP) is 150 mm Hg or more and diastolic BP is 95 mm
Hg or more. Hypertension may be classified as primary and secondary hypertension.

Diuretics
Diuretics are substances that speed up the production of urine. Utilizing a diuretic increases the
flow rate of the urine, which increases the excretion of water and electrolytes (particularly
sodium and chloride ions) from the body without affecting other blood constituents. The kidney,
or more specifically, the nephron, is the main target organ for diuretics. Each nephron
component contributes to the functions of the kidney, making them potential targets for different
classes of diuretic drugs.

Sites of action of the diuretics in the nephron.

Bowman’ s capsule BC.
glomerulus, G.
proximal convoluted tubule, PCT with its various segments, S1, S2, S3.
proximal straight tubule, PST.
descending limb of the loop of Henle, DLH.
thick ascending limb of the loop of Henle, TALH.
Distal convoluted tubule, DCT; and the collecting duct, CD.
Osmotics diuretics

The Bowman's capsule allows mannitol to freely pass through and enter the renal tubules. It is a
non-absorbable substance that raises intraluminal osmotic pressure, causing water from the body
to pass into the tubule and thereby increasing the volume of urine and the excretion of water.
There were previously a few additional osmotic diuretics, but the majority have been removed
from the market. These substances include urea, isosorbide, and glycerin. Mannitol also has a
very restricted use, which is why these products are primarily used for the treatment of acute
kidney failure.

Physicochemical and Pharmacokinetic Properties

Water-soluble mannitol is given intravenously in solutions ranging from 5% to 50%.
Effectiveness requires high doses, ranging from 50 to 200 g. The drug is eliminated in its original
form.

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors prevent the formation of carbonic acid in the PCT and distal
tubular cells to limit the hydrogen ions that are capable of being exchanged with sodium. This
encourages the excretion of water and sodium. When more than 99 percent of the carbonic
anhydrase is inhibited, a diuretic response is seen. The unsubstituted acidic sulfonamides have an
extremely strong binding affinity for carbonic anhydrase. Sulfonamide that hasn't been
substituted acts as carbonic acid's isostere. An increase in urine pH happens because of Na+/H+
exchange being inhibited.
SAR
Two groups of Carbonic Anhydrase inhibitors are:
1. Heterocylic sulphonamides
2. Meta-disulphamoyl benzene derivatives

1. Heterocylic sulphonamides
•The C-2 sulphamoyl group is important for activity.
•The free sulphamolyl moiety is necessary to bind with Zn in the enzyme; hence, substitution of
sulphamoyl group gives inactive compound.
•The moiety to which the sulphamoyl group is attached must be aromatic in character.
•The heterocyclic sulphonamides with higher partition coefficient and lowest Pka value have
greatest inhibitory and diuretic activities. Example—acetazolamide, methazolamide.
•N-alkylation with methyl group on ring N- of acetazolamide yields active compound
(methazolamide).

2. m-Disulphamoyl benzene derivatives

•m-Disulphamoyl benzene do not have diuretic activity.
•Substituted m-sulphamoyl benzene exhibits diuretic activity.
•The unsubstituted sulphamoyl moiety is essential for the activity; any substitution leads to
affect the
potency of the compound.
•The sulphamoyl moiety can be replaced with similar electrophilic groups (e.g., carboxyl,
carbamoyl)
that may increase the potency of the compound.
•Maximum diuretic activity is obtained when 4th is substituted by Cl, Br, CF, or NO group.
•Substitution of amino group at 6th position increases aleuronic activity but decreases inhibitor
activity.

Synthesis of Acetazolamide

Assay of Acetazolamide: Dissolve the sample in dimethylformamide and titrate against 0.1 M
ethanolic sodium hydroxide.
Determine the end point potentiometrically.

Clinical Applications
There is limited use for carbonic anhydrase inhibitors as diuretics (prolonged use impairs the
effectiveness of these medications and causes blood acidosis). These medications are frequently
employed in the treatment (inhibition of) glaucoma. Ocular carbonic anhydrase lessens the
production of aqueous humour and intraocular (The pressure is decreased.)

Thiazide and Thiazide-Like Diuretics

Similar mechanisms of action govern the actions of thiazide and thiazide-like diuretics. These
diuretics are actively secreted into the PCT filtrate and transported to the DCT. Normally,
Na+/Cl- is reabsorbed into the DCT cell and then pumped out of the DCT cell and into the
bloodstream by the Na+ /K+ATPase (Na+/K+ pump), with Cl leaving through chloride channels.
Thiazides and thiazide-like substances compete with one another for the Cl-binding site of the
Na symporter, a member of the SLC12 cotransporter family, in DCT cells, preventing Na+ and
Cl from being absorbed and increasing their excretion. Additionally, thiazides and thiazide-like
substances weakly inhibit the enzyme carbonic anhydrase while also increasing the excretion of
HCO3 and raising the pH of urine. - + /Cl-. The thiazides also increase K+ and Mg excretion and
decrease Ca excretion by inhibiting their reabsorption.
SAR
● It should be noted that there is an initial distinction between thiazide and diuretics that act
similarly to thiazide which is the substitution of an "amide" for a "sulfonamide.".
Thiazides.
● The C6 position requires the presence of an electron-withdrawing group (e.g., Cl, CF3) for
its diuretic properties.
● The duration and lipid solubility of the trifluoromethyl-substituted diuretics are both
longer compared to their chloro-substituted analogues in terms of action.
 ● The sulphonamide group at position C7 plays a crucial role.
● An increase in activity of 10 times occurs at C3-C4 saturation.
● The potency and duration of a diuretic are significantly increased by substituting a
lipophilic group at the C3 position.
● Decreased polarity lengthens the half-life of the diuretic and is caused by alkyl
substitution at the N2 position.
● Hydrogen atom at the 2nd position is more acidic due to the presence of neighbouring
electron withdrawing sulphone group.
● Direct substitution of the 4th, 5th or 8th position with an ethyl group usually results in
diminished diuretic activity.

Thiazide-Like Agents
Similar functionality is displayed by the thiazide-like compounds, which are crucial for activity.
It should be noted that the thiazide-like compounds all contain an electron-withdrawing chlorine
group and an unsubstituted sulfonamide.

Physicochemical and Pharmacokinetic properties

• All thiazide-type diuretics and those that are like them have a sulfonamide group that is only
mildly acidic.
• sodium salts are prepared that are water-soluble and are administered via the intravenous route.
• All the thiazides, except for hydroflumethiazide, are excreted in the urine in their unchanged
form.
2,4-Disulfamyl-5-Trifluoromethylaniline is a metabolite.
In addition, thiazide-like diuretics do not significantly undergo metabolism with the exception of
indapamide which undergoes extensive metabolism.

Clinical Applications
The use of thiazide- and thiazide-like-diuretics is recommended for the management of
associated edema with ailments of the heart, liver, and kidneys.
These medications can be used alone (as an initial treatment) or in conjunction with additional
antihypertensive medications.
• These medications are typically given when the glomerular filtration rate is greater than or
equal to 30 to 40.
mL/min (GFR), even though metolazone and indapamide work well for patients whose GFR is
below 40 mL/min.
Synthesis of hydrochlorthiazide
Potassium-Sparing Diuretics

Potassium-sparing diuretics block the Na+ channel in both DCT and CD to have a diuretic effect.
The two medications, which are weak organic bases, inhibit the Na+ channel in the late channel
by interacting with the negatively charged areas that are charged inside the channel.
• The binding is pH-dependent, and amiloride, a stronger base with a pKa of 8 points, is
approximately 100 times more active than triamterene, with a pKa of 6 points.
• Na+ channel inhibitors, which increase Na+ and Cl- excretion inhibit K secretion.
Physicochemical and Pharmacokinetic Properties
Amiloride has a powerful base in the guanidino group.
• While triamterene is readily absorbed with a moderate (52% bioavailability) bioavailability,
amiloride has a variable bioavailability (between 30 and 90 percent). The action lasts for 24
hours.
• Triamterene is a substrate, and amiloride is excreted in roughly equal amounts in faeces and
urine, unchanged. Triamterene is a substrate for CYP1A2 that has a significant metabolic rate
that causes the aromatic ring to undergo 4'-hydroxylation by sulfate conjugation.

Clinical Applications
• Both drugs are used in combination with a thiazide or a loop diuretic in
the treatment oedema or hypertension.

Assay of Amiloride: Dissolve the sample in a mixture of 0.01 M hydrochloric acid and ethanol
and titrate against 0.1 M sodium hydroxide. Determine the end point potentiometrically.
Mineralocorticoid Receptor Antagonists
The Mineralocorticoid Receptor is in the late DCT and CD of the nephron. Aldosterone inhibitors
inhibit the aldosterone action on mineralocorticoid receptor, where aldosterone generates
aldosterone-induced proteins along with Na+ K+ ATPase and amiloride sensitive Na channels
that leads to the reabsorption of Na. Aldosterone inhibitors limit the reabsorption by binding
with mineralocorticoid receptor. Spironolactone is the only available aldosterone antagonist. A
-lactone ring at C17 and a substituent on C7 (the) are necessary for MR antagonists.
Aldosterone must bind to MR in an unobstructed C7 position.

Physicochemical and Pharmacokinetic Properties

Both spironolactone and eplerenone have good bioavailability (around 70%) and are quickly
absorbed. Both spironolactone and eplerenone have good bioavailability (around 70%) and are
quickly absorbed. Spironolactone and eplerenone are primarily (>90%) and sporadically (50%)
bound to plasma protein, respectively.
Biliary recycling might take place in some cases. Spironolactone has a brief half-life and may
function as a prodrug.

Metabolism
Both drugs are extensively metabolized and excreted in the urine and faeces.
Eplerenone was developed with the hope of reducing the formation of spironolactone
metabolites.
Synthesis of Spironolactone

Assay of Spironolactone: Dissolve the sample in methanol and measure the absorbance of the
solution after suitable dilution at the maxima of 238 nm using ultraviolet spectrophotometer.

High-Ceiling or Loop Diuretics

The thick ascending limb of the loop of Henle (TALH) is thought to be the site of action of loop
diuretics, which is why they are called loop diuretics.
These medications work by inhibiting the luminal Na+/K+/2Cl symporter, a protein found in the
cell's apical membrane, a member of the SLC12 cotransporter family.
The result of inhibition is significant Na+ and Cl- loss, along with Ca loss.

SAR
They are either 5-sulphamoyl-2-amino benzoic acid or 5-sulphamoyl-3-amino benzoic acid
derivatives.
1. The carbonyl group at C-1 provides optimal diuretic activity.
2. The substitution of activating group (X) in the position 4 by Cl, alkoxy, aniline, benzyl, or
benzoyl
group at 4th position increases the diuretic activity.
3. The presence of sulphamoyl group in the 5th position is essential for activity.
4. The two series of 5-sulphamoyl benzoic acid differ in the nature of the functional group that
substituted in 2nd and 3rd position.
5. The presence of furfuryl, phenyl, and thienyl methyl group at 2nd amino group of 5-
sulphomoyl-2-amino benzoic acid gives maximum diuretic activity.
6. The wide range of alkyl group can be substituted at 3rd amino group of 5-sulfamoyl-3-amino
benzoic acid without modifying the optimal diuretic activity.
7. A molecule with a weakly acidic group to direct the drug to the kidney and an alkylating
moiety to react with sulphydryl groups and lipophilic groups seemed to provide the best
combination of a diuretic in the class.

Physicochemical and Pharmacokinetic Properties

Loop diuretics are characterized by a fast onset and short duration of action.
These drugs are excreted primarily via the urine.

Metabolism
•The loop diuretics undergo various metabolic reactions including γ-hydroxylation of the butyl
chain of bumetanide (primarily unchanged drug), glutathione conjugate at the a
position of the α, ß double bond of ethacrynic acid and the glucuronidation of furosemide.
• Torsemide is prone to CYP2C9 oxidation of the methyl tolyl group to a carboxylic acid.

Synthesis of furosemide

Clinical Applications
• The primary use of the loop diuretics is for treatment of acute pulmonary edema.
• Unlike thiazide diuretics the loop diuretics, also referred to as high-ceiling diuretics, do
not exhibit a ceiling effect and therefore are quite valuable in treatment of edema.
•These drugs are prescribed for treatment of hypertension, but their short duration of
action limits their use to some extent.

Assay of furosemide: Dissolve the sample in dimethylformamide and titrate against 0.1 M
sodium hydroxide using bromothymol blue solution as indicator.

PERIPHERAL ACTING SYMPATHOLYTICS

The discussion of peripheral acting sympatholytic will focus on ß-blockers (ß-antagonists) and
α1-blockers (α1-antagonists), which are beneficial for the treatment of hypertension.

ß-Adrenergic Receptor Blockers

ß-Adrenergic receptor blockers bind to ß-adrenoceptors blocking the binding of epinephrine
to these receptors. Some of these drugs when bound to the ß-adrenoceptors partially activate
the receptor as ß-agonists with intrinsic sympathomimetic activity (ISA).
First-generation ß-blockers are nonselective, blocking both ß1- and ß2-adrenoceptors.
Second-generation ß-blockers are more cardio selective with selectivity for ß1-adrenoceptors.
Third generation ß-blockers (mixed α1/ß1-adrenergic blockers) possess vasodilator actions
through blockade of vascular α-adrenoceptors.

SAR
The SAR of aryloxypropranolamine ß-antagonists is summarized in the figure below and the
compounds in clinical use areshown below.
The S configuration of the carbinol carbon is essential, binding moieties in the same 3D
orientation as the R configuration of the agonists.
If indole replaces phenyl, some ß-agonist activity is observed. This is known as intrinsic
sympathomimetic activity. Polar aromatic rings (thiadiazole) or substituents (hydroxyl,
acetamido, morpholino) decrease log P, minimizing central adverse effects. Hydrophilic ß-
antagonists are primarily cleared through the renal system, while the more lipophilic
blockers undergo hepatic clearance.

Physicochemical and Pharmacokinetic Properties

Lipophilic drugs such as propranolol create the potential for CNS adverse effects while
hydrophilic drugs such as atenolol and nadolol have reduced CNS effects.
The ß-adrenergic receptor blockers are all readily absorbed following oral administration
and have good bioavailability.

Metabolism
Several of the ß-adrenergic receptor blockers are substrates for CYP2D6 (e.g.,
metoprolol, nebivolol, carvedilol), which raises the potential for significant difference in
Metabolic rates between poor and extensive metabolizers, which can affect the drug’s half-life.
Metoprolol’s major metabolite undergo O-demethylation by CYP2D6 along with N-dealkylation
and a-hydroxylation.
Nebivolol’s major metabolite results from O-glucuronidation but CYP-catalyzed aromatic
hydroxylation is also reported. CYP2D6 oxidations of propranolol occur via 4-hydroxylation and
N-dealkylation while aromatic hydroxylation at multiple sites followed by glucuronidation is
significant in carvedilol.
Hydrolysis and acetylation of acebutolol results in the formation of diacetolol a product
with activity equivalent to the administered drug. Pindolol is extensively metabolized to a
hydroxyl derivative, but the catalyst is not reported and esmolol undergoes hydrolysis.

Clinical Applications
ß-Adrenergic receptor blockers are recommended for treatment of heart failure and CAD in
combination with an ACE inhibitor or angiotensin receptor blocker (ARB).
ß-Blockers may also be used as monotherapy in the treatment of angina, arrhythmias, mitral
valve prolapse, myocardial infarction, migraine headaches, performance anxiety, excessive
sympathetic tone or “thyroid storm” in hyperthyroidism.

α1-Adrenergic Blockers
α1-Adrenoceptor antagonists are selective competitive blocker of α1adrenoceptors inhibiting
the binding of NE causing vasodilation of both arteries and veins. (Note: α1-adrenoceptors
are the predominant α-receptor located on vascular smooth muscle
[VSM]). α1-Adrenoceptors are linked to Gq-proteins that activate smooth muscle contraction
through the IP3 signal transduction pathway. These drugs block the effect of sympathetic
nerves on blood vessels. The vasodilator effect is more pronounced in the arterial
resistance vessels especially during elevated sympathetic activity (e.g., during stress).

Metabolism
Doxazosin and prazosin are extensively metabolized and primarily excreted in the faeces.
Terazosin is eliminated in both the urine and faeces and with minimal first-pass metabolism.
Doxazosin and prazosin undergo O-demethylation (6 and 7 demethylation) followed by
conjugation. Doxazosin also undergoes 6’ and 7’-hydroxylation on the benzodioxan ring.
Terazosin is hydrolyzed by an amidase enzyme resulting in an active metabolite.

Mixed α/ß-Adrenergic Receptor Blockers

Carvedilol and labetalol are third-generation nonselective blockers. The mechanism of action
involves blocking both adrenergic receptors. Vasodilation occurs via α1-blockade while the ß-
blocker helps avoid reflex tachycardia. Both drugs are administered as racemates: S-carvedilol
has α- and ß-blocking activity while the R-isomer exhibits α1-blocking activity; labetalol has four
stereoisomers with the R isomer being the active isomer.

Clinical Applications
α1-Blockers and mixed-acting blockers are effective agents for management of hypertension
although not as first-line drugs. They are recommended for management of more severe
hypertension (e.g., stage 2) and may be effective for both essential and renal
hypertension. α1-Adrenoceptor antagonists are also indicated for the treatment of benign
prostatic hyperplasia (BPH).
Central Acting Sympatholytics
Centrally acting sympatholytics block sympathetic activity by binding to and activating centrally
inhibiting α2-adrenoceptors (in the brainstem). More specifically the
guanidine-containing sympatholytics act at α2A-adrenoceptors. Binding reduces
sympathetic output to the vasculature decreasing sympathetic vascular tone leading to
vasodilation and reduced systemic vascular resistance thus decreasing arterial pressure.

Physicochemical and Pharmacokinetic Properties

• Methyldopa is a prodrug, which is converted into α-methylnorepinephrine following
transport into the CNS via aromatic amino acid transporter
• The drug is unstable to air, alkaline, pH and light.
• Methyldopa is available for parenteral use as a hydrochloride salt of the ethyl ester.
Metabolism.
• Metabolism of methyldopa is extensive and occurs in the GI tract and centrally with the
Majority of metabolites appear in the urine.
• The metabolites are inactive and primarily appear in the urine. Approximately 24% of 37% of
guanfacine is excreted unchanged.
Clinical Applications
• Methyldopa may be used in the management of hypertension during pregnancy
• Clonidine, guanabenz, and guanfacine are generally reserved for patients who fail to
Respond to therapy with a stage 1 drug (e.g., diuretics, calcium channel blockers, ACE
inhibitors, or angiotensin II blockers).

Calcium channel blockers

Calcium channel blockers act on the Ca channel receptors, block the release of calcium, and,
therefore, the calcium interaction with a protein calmodulin to form calcium calmodulin
complex is decreased. This leads to the decreased activation of myosin light chain
phosphorylation, which promotes muscle contraction by interacting between actin and myosin.
Examples include Amlodipine, Nifedipine, Nisoldipine, Felodipine etc.

SAR
The following structural features are important for activity of the 1,4-DHPs:
Physicochemical and Pharmacokinetic Properties
The N1 nitrogen of the 1,4-DHPs is part of a conjugated carbamate and as a result is not
basic. The 1,4-DHPs are all marketed as their racemic mixtures. The 1,4-DHPs possess good lipid
solubility and excellent oral absorption, however rapid first-pass metabolism results in variable
oral bioavailability depending on the extent of metabolism. Nicardipine and clevidipine are
available as parenteral preparations. Parenteral nicardipine is incompatible with IV
sodiumbicarbonate resulting in the precipitation of the calcium channel blocker.

Metabolism
Prehepatic first-pass metabolism by CYP3A4 enzyme occurs with some orally administered.
Calcium channel blockers, especially verapamil, with its low bioavailability of 20%–35%. The
Bioavailability of dilitiazem is 40%–67%, Nicardipine is 35%, Nifedipine is 45%–70%; And
amlodipine is 64%–90%. Verapamil Is metabolized by CYP3A4 N-demethylation to its principal
metabolite, norverapamil, which retains approximately 20% of the activity of verapamil, and by
O-demethylation (CYP2D6) Into inactive metabolities. Dilitazem Is metabolized by enzyme
hydrolysis of its primary metabolite, diacetyl derivative, which retains approximately 25%–50%
of the activity of Diltiazem.
Diltiazem undergoes N-demethylation by CYP3A4 and O-demethylation by CYP2D6. The N-
demethylated Metabolic pathways results in a mechanism-based inhibition of CYP3A4. The
Major metabolites are detected after oral and continuous intravenous administration, but not
following rapid intravenous administration.
Clinical Applications
With the exceptions of nimodipine (treatment of subarachnoid hemorrhage), they are
approved for the treatment of hypertension.
Both verapamil and diltiazem are used clinically in the management of angina, hypertension
(as sustained release formulations), and cardiac arrhythmia, whereas the nifedipine is used
more frequently as anantianginal and antihypertensive agents.

Drugs Used for the Treatment of Cardiac Arrhythmia

Antiarrhythmic agents are medications used to correct heart arrhythmias. Cardiac arrhythmias
are common in clinical practice, occurring in various patient populations such as those treated
with digitalis, undergoing anesthesia, or experiencing acute myocardial infarction. Several
factors can trigger or worsen arrhythmias, including ischemia, hypoxia, acidosis, alkalosis,
electrolyte imbalances, excessive catecholamine exposure, autonomic influences, drug toxicity,
stretching of cardiac fibers, and the presence of diseased tissue. All arrhythmias result from
disturbances in impulse formation, impulse conduction, or both.

Different types of cardiac arrhythmias include:

1. Extra systole: Premature beats originating from the atrioventricular (AV) node, atrium, or
ventricle, due to abnormal automaticity or after depolarization.
2. Paroxysmal supraventricular tachycardia: Sudden onset of atrial tachycardia, often caused by
circus re-entry within or around the AV node.
3. Atrial flutter: A rapid, regular atrial beat with a rate of 200-350 beats per minute.
4. Atrial fibrillation: Asynchronous activation of atrial fibres at a rate of 300-550 beats per
minute.
5. Ventricular tachycardia: A run of four consecutive ventricular premature beats, originating
from an ectopic focus, which can be sustained or unsustained.
6. Torsades de pointes: Twisting of the ventricles, leading to polymorphic ventricular
arrhythmia with asynchronous complexes.
7. Ventricular fibrillation: disorganized activation of ventricles, resulting in ineffective pumping
function.
8. Atrioventricular block: Impaired impulse conduction through the AV node and bundle of His,
often due to vagal influence and ischemia.
Action potential for a single cardiac cell over time and represents the changes in voltage.
Phase 0: Depolarization with Na+ channels stimulated to open with Na+ entering the cell.
Phase 1: Initial stage of repolarization.
Phase 2: Plateau stage with repolarization and a slow influx of Ca 2+ with extension of
refractory period.
Phase 3: Late stage of repolarization. When repolarization is complete a new stimulus can
occur.
Phase 4: Repolarization is complete (quiescent phase).

Class IA antiarrhythmic drugs

They act on nerve and myocardial membranes by blocking fast sodium (Na) channels, which
moderately slows conduction and inhibits phase 0 of the action potential. They primarily affect
myocardial membranes, leading to a decrease in the maximum rate of depolarization while not
altering the resting potential. These drugs increase the threshold of excitability, prolong the
effective refractory period, decrease conduction velocity, and reduce spontaneous diastolic
depolarization in pacemaker cells.

Physicochemical and Pharmacokinetic Properties

• R-quinidine is the active isomer with cardiovascular effects.
• The Class IA antiarrhythmic drugs are administered as water-soluble salts: disopyramide
phosphate, procainamide hydrochloride, and quinidine sulfate or gluconate.
• All three drugs in Class IA are well-absorbed (approximately 80% to 95%) when taken orally.
• A significant portion of Class IA drugs is eliminated from the body without undergoing any
changes.
• Quinidine binds highly to plasma proteins (85%), as does disopyramide (82%), while its N-
dealkyl metabolite binds moderately to plasma proteins (22% to 35%).
• Quinidine is a substrate for P-glycoprotein (P-gp) and inhibits the secretion of digoxin by
blocking its removal from the body.

Metabolism
• Disopyramide is broken down by the enzyme CYP3A4 through N-dealkylation, producing an
active metabolite.
• Quinidine is metabolized by CYP3A4 through O-demethylation and vinyl hydroxylation
(hydroxyethyl), resulting in two metabolites with weak activity.
• Procainamide undergoes N4 acetylation, which is an active process, and amide hydrolysis,
which renders the metabolite inactive.

Synthesis of procainamide

Assay
Analysis of Quinidine is done by dissolving the Quinidine in acetic anhydride and titrate with 0.1
M perchloric acid, using naphtholbenzein as an indicator.
Analysis of Procainamide is carried out by dissolve the sample in dilute hydrochloric acid and
perform the determination of primary aromatic amino nitrogen (Diazotization method).

Class IB antiarrhythmics drug

They act by blocking open cardiac sodium (Na+) channel proteins, although their blocking effect
on Phase 0 is relatively weak. They may induce conformational changes in the Na+ channel
protein, leading to a nonconducting state.These drugs shorten the repolarization phase,
resulting in a decrease in the duration of the action potential. They demonstrate selectivity for
ventricular tissue. It should be noted that mexiletine is structurally like lidocaine.

Physicochemical and Pharmacokinetic Properties:

• Lidocaine demonstrates effectiveness as an antiarrhythmic agent only when administered
intravenously.
• Lidocaine is ineffective when taken orally due to rapid metabolism during the first pass
through the liver. In contrast, mexiletine is orally active and undergoes metabolism at a slower
rate.
• The elimination half-life of lidocaine ranges from 1.5 to 2 hours, while that of mexiletine is
longer at 10 to 12 hours.
• Both drugs bind to plasma proteins, with a binding rate of 50% to 70%.

Metabolism:
• Both drugs are metabolized in the liver: lidocaine is a substrate for the enzyme CYP3A4,
whereas mexiletine is metabolized by CYP2D6.
• Lidocaine undergoes rapid metabolism, as evidenced by its short elimination half-life of 1.5 to
2 hours.
• Mexiletine was developed with the intention of reducing the rapid hydrolysis observed with
lidocaine.

Class IC Antiarrhythmic Drugs:

They block the sodium (Na+) channel proteins during Phase 0 of the cardiac electrical impulse,
which slows conduction and stabilizes myocardial cells. These drugs exhibit selectivity for cells
with a high conduction rate. They prolong the effective refractory period and have beta-
adrenergic blocking activity. They primarily affect the ventricular myocardium.

Physicochemical and Pharmacokinetic Properties:

• They are well absorbed when taken orally, but propafenone has low bioavailability due to
significant first-pass metabolism.
• Flecainide is approximately 40% bound to plasma proteins, while propafenone exhibits high
protein binding of around 97%.
• Flecainide has a long plasma half-life of 14 to 20 hours, while propafenone has a shorter half-
life ranging from 2 to 10 hours.
• Blood levels of both drugs may vary in individuals with different metabolization rates, as they
are substrates for the enzyme CYP2D6.
• Propafenone is administered as a mixture of both S and R enantiomers, with both
enantiomers displaying similar antiarrhythmic activity.

Metabolism
Extensive metabolism of both drugs results in decreased activity
Class II Antiarrhythmic Drugs:
They are ß-adrenergic blockers. Propranolol and sotalol are nonspecific blockers, while esmolol
is a selective ß1-adrenergic blocker. By blocking sympathetic stimulation of cardiac tissue, these
drugs reduce cyclic adenosine monophosphate (cAMP) levels, resulting in decreased calcium
influx and a decrease in the force and rate of cardiac contraction. Sotalol is classified as both a
class II agent due to its ß-adrenergic effects and a class III agent because it also blocks K+
channels.

Physicochemical and Pharmacokinetic Properties:

• They are water-soluble as hydrochloride salts and are administered as enantiomeric mixtures.
• Esmolol and propranolol are typically administered via intravenous infusion, while sotalol is
taken orally as a tablet or syrup.
• Esmolol has a half-life of approximately 9 minutes, Sotalol is nearly completely absorbed
following oral administration (with oral bioavailability of 90% to 100%), is not protein-bound
and propranolol has low bioavailability (30% to 40%) and is highly bound to plasma proteins.

Metabolism
Propranolol undergoes rapid first-pass metabolism, including processes like 4-hydroxylation, N-
dealkylation, and direct O-glucuronidation.
Esmolol undergoes rapid hydrolysis to an inactive carboxylate. Esmolol is excreted unchanged.

Synthesis of Sotalol
Assay: Dissolve the Sotalol in anhydrous formic acid and add acetic anhydride. Titrate with 0.1
M perchloric acid, determine the end point potentiometrically.

Class III Antiarrhythmic Drugs:

They block K+ channels, resulting in the inhibition of outward K+ current and a prolonged action
potential. Most class III drugs primarily act during phase 3 of the action potential. However,
some of these drugs also affect other parts of the action potential: Amiodarone blocks Na+
channels, inhibits ß-receptors, and has weak Ca2+ channel blocking activity; Dronedarone is like
amiodarone and also inhibits α-adrenergic receptors; Ibutilide produces an influx of Na+
through slow Na+ channels (this may be its major action); Sotalol is a nonselective ß-blocker.
Physicochemical and Pharmacokinetic Properties:
• Amiodarone is lipophilic and insoluble in water. It shares structural similarity with thyroid
hormones, which accounts for some of its adverse effects.
• Taking amiodarone and dornedarone with food can improve their variable oral bioavailability.

Metabolism:
• Amiodarone, dornedarone, and dofetilide are substrates for CYP3A4, with N-dealkylation
being a major metabolite.
• Inhibitors of CYP3A4 can significantly increase blood levels of dornedarone.
• Ibutilide undergoes extensive metabolic oxidation, but it does not involve CYP3A4 or CYP2D6.
• Sotalol is excreted without significant metabolism.

Assay: Dissolve the Amiodarone in a mixture of 0.01 M hydrochloric acid and ethanol. Perform
potentiometric titration using 0.1 M sodium hydroxide.

Class IV Antiarrhythmic Drugs:

These drugs selectively block the slow inward current carried by calcium. The slow inward
current in cardiac cells is important for the normal action potential and has been implicated in
the development of certain cardiac arrhythmias. When administered, class IV drugs prolong the
refractory period in the atrioventricular (AV) node and the atria, decrease AV conduction, and
inhibit spontaneous diastolic depolarization. These effects effectively block the conduction of
premature impulses at the AV node, making class IV drugs very effective in treating
supraventricular arrhythmias.

Vasodilators
Hydralazine, minoxidil, and diazoxide are vasodilators that act on the vascular smooth muscle
(VSM) and have similar mechanisms of action. Hydralazine and minoxidil open ATP-sensitive
potassium (K+) channels, leading to increased efflux of K+ from cells, hyperpolarization of VSM,
and closure of voltage-gated calcium (Ca2+) channels. This results in reduced intracellular Ca2+
levels, leading to vasodilation. Hydralazine also inhibits the release of Ca2+ from smooth muscle
storage sites induced by the second messenger IP3, further reducing smooth muscle cell
contraction.

Physicochemical and pharmacokinetic properties

Both hydralazine and minoxidil are well absorbed after oral administration. Hydralazine has low
bioavailability due to metabolism in the gastrointestinal lining. Minoxidil is a prodrug that
requires oxidative metabolism to its active form, N-O-sulfate. Hydralazine is highly bound to
plasma proteins (85%), while minoxidil is not bound to plasma proteins.

Metabolism
The vasodilators produce various metabolites, with only minoxidil N-O-sulfate being active. The
acetylation of hydralazine is influenced by genetics, with slow acetylators having higher plasma
levels compared to fast acetylators.
Clinical Applications
• Hydralazine and minoxidil are not typically the first-choice drugs for treating hypertension.
• They are reserved for cases of severe hypertension or when other medications have not been
effective. This is because they can cause significant adverse effects.
• Minoxidil is applied topically to stimulate hair regrowth in men with male-pattern alopecia
(hereditary hair loss) and in women to treat hair loss.

Nitrodilator
Sodium nitroprusside is a drug that releases nitric oxide (NO) and falls under the category of
NO-releasing drugs. It works by releasing NO through the action of glutathione in red blood
cells and tissues, forming a compound called S-nitrosothiol. This process involves the
spontaneous release of NO.

Clinical Applications
• Sodium nitroprusside is administered intravenously to treat hypertensive crises in emergency
situations.
• It can also be used to manage acute congestive heart failure (CHF).

Drugs used to treat heart failure.

They are also known as Congestive Heart Failure, are aimed at addressing the heart's inability to
effectively pump blood at a rate that satisfies the metabolic needs of tissues. This condition is
caused by reduced contractility of the cardiac muscles, particularly in the ventricles, leading to a
decrease in cardiac output and an accumulation of blood volume in the heart (referred to as
"congestion"). A group of drugs called cardiac glycosides were discovered to alleviate most of
these symptoms and complications. Presently, only one cardiac glycoside, digoxin, is available
for therapeutic use.

Digoxin, a cardiac glycoside, functions as an inhibitor of the Na+/K+ ATPase enzyme located in
the outer layer of the cardiac muscle cell membrane (sarcolemma). It works by blocking the
Na+/K+ ATPase, which results in an increase in intracellular sodium (Na+) concentration. This, in
turn, leads to elevated levels of intracellular calcium (Ca2+) through the Na+/Ca2+ exchanger
protein, which becomes less effective at exporting calcium.

The binding of calcium to troponin C activates myosin, exposing binding sites for actin and
promoting muscle contraction. Digoxin's activity relies on certain structural features: the rings
A-B and C-D must be fused in a cis configuration to bind to the Na+/K+ ATPase, and digoxin has
a U-shaped molecular structure. Additionally, an unsubstituted hydroxyl group at position C14
and an a,β-unsaturated 17-lactone are necessary for its cardiotonic effects.

In terms of physicochemical and pharmacokinetic properties, digoxin has reduced lipophilicity

compared to other cardiac glycosides due to the presence of a C12 hydroxyl group on the
aglycone and a triglucose glycoside at position C3. This results in a shorter half-life of
approximately 1 to 2 days. Digoxin is well absorbed after oral administration (70% to 85%) and
exhibits moderate protein binding (25% to 30%). It is a substrate for P-glycoprotein (P-gp) efflux
in the intestinal lining and kidneys, which may lead to potential drug interactions. Digoxin is
primarily excreted unchanged (50% to 70%) via the kidneys, with less than 13% undergoing
metabolism.

Phosphodiesterase Inhibitors
An increase in the levels of cyclic adenosine monophosphate (cAMP) can initiate a positive
inotropic action on the heart. This can be achieved by stimulating cAMP synthesis through the
actions of a β-adrenergic agonist or by inhibiting the breakdown of cAMP with
phosphodiesterase 3 (PDE3) inhibitors.
Cardiac contraction involves a G-protein signal transduction pathway, in which increased
intracellular cAMP leads to an increase in intracellular calcium (Ca2+), thereby stimulating
cardiac muscle contraction. PDE3 inhibitors also promote vasodilation by relaxing vascular
smooth muscle (VSM).

Pharmacochemical and Pharmacokinetic properties

Milrinone and inamrinone are both administered intravenously as water-soluble lactate salts.
Milrinone exhibits greater selectivity for PDE3 than inamrinone. It has a short plasma half-life
(30 to 60 minutes), an elimination half-life of 2.3 hours, is 70% bound to plasma protein, and is
primarily eliminated unchanged (83%) in the urine. Milrinone is chemically incompatible with
furosemide, which can cause precipitation.

ß-Adrenergic Receptor Agonists

Dobutamine, a β-adrenergic agonist, primarily stimulates the myocardium through β1-
adrenergic receptors. Activation of these receptors leads to increased intracellular cAMP
through a G-protein signal transduction pathway. Like PDE3 inhibitors, increased cAMP results
in an increase in intracellular calcium (Ca2+) and myocardial contraction.

Pharmacochemical and pharmacokinetic properties

Dobutamine hydrochloride, a water-soluble formulation, is administered intravenously (IV). The
catecholamine structure of dobutamine makes it susceptible to air oxidation, so sodium
bisulfite is added to the IV preparation for stabilization. Dobutamine is eliminated through
COMT (catechol-O-methyltransferase) and O-sulfate conjugation, with excretion occurring in
the urine.
Hyperpolarization-Activated Cyclic Nucleotide-Gate (HCN) Inhibitor

Ivabradine is a medication that selectively blocks the "funny" (If) current/channel in the
sinoatrial node. This current is responsible for carrying Na+/K+ ions across the sarcolemma.
Activation of the If current is dependent on intracellular cAMP and hyperpolarization-activated
channels. By blocking the open If current/channels, unbound cAMP/If is reduced, resulting in a
lower heart rate, and decreased myocardial oxygen demand.

Pharmacochemical and pharmacokinetic properties

Ivabradine is nearly completely absorbed when taken orally, with a bioavailability of
approximately 40%. The absorption may be slowed, and plasma exposure increased when
taken with food. Its elimination half-life is around 2 hours, and it exhibits moderate plasma
protein binding (50% to 70%). The active N-desmethyl metabolite is bound to plasma proteins
at a rate of 60% to 80%. The primary route of excretion is through the kidneys.

Metabolism
Metabolism of ivabradine involves the major metabolite, the CYP3A4 oxidative N-desmethyl
metabolite. Additional metabolites include the O-desmethyl metabolite and aromatic oxidation.
Clinical uses
Digoxin is primarily used for the treatment of congestive heart failure (CHF). It is also employed
in cases of atrial flutter or fibrillation and paroxysmal atrial tachycardia. Milrinone and
inamrinone, both PDE3 inhibitors, are used for short-term treatment of CHF. These medications
increase myocardial contractility (inotropy) while reducing ventricular wall stress and oxygen
demands through their vasodilatory actions. Milrinone is preferred over inamrinone due to its
shorter half-life and lower toxicity.
Dobutamine is utilized for short-term treatment of advanced CHF in patients with systolic
dysfunction, aiming to promptly improve myocardial contraction and increase cardiac output.
Ivabradine, on the other hand, is indicated to reduce hospitalization due to worsening heart
failure in patients with stable, symptomatic chronic heart failure, specifically those with a left
ventricular ejection fraction of 35% or lower and a resting heart rate of 70 beats per minute or
higher. Ivabradine's selectivity minimizes the common adverse effects associated with β-
blockers.

ANTIANGINAL AGENTS
Angina is a condition characterized by severe chest pain resulting from inadequate blood flow
and oxygen supply to the heart due to the accumulation of metabolites in the muscles. It is a
common problem, often caused by atherosclerotic obstruction in the large coronary vessels.
However, transient spasms in localized areas of these vessels can also lead to myocardial
ischemia and pain. The imbalance between oxygen delivery and myocardial oxygen demand can
be corrected by reducing oxygen demand or increasing coronary blood flow. Vasodilators are
commonly used to achieve these goals. In the case of variant angina, caused by coronary vessel
spasms, nitrates or calcium channel blockers can reverse the spasm. It is important to note that
while all vasodilators are effective in treating angina, not all agents used for angina are
vasodilators (e.g., propranolol). Unstable angina, which is characterized by changes in chest
pain at rest, is often caused by nonocclusive thrombi at the site of a fissured or ulcerated
plaque. Pharmacological therapy for angina includes the use of antiplatelet agents, lipid-
lowering agents, and angiotensin-converting enzyme (ACE) inhibitors to prevent myocardial
infarction and reduce the risk of coronary artery disease. In cases of unstable angina, non-ST-
segment elevation myocardial infarction, and coronary stenting, a combination of anti-lipid
drugs, heparin, and antiplatelet agents is recommended.
Angina can be categorized into different types, and the choice of therapy depends on the
specific type of angina. For chronic stable angina, long-acting nitrates, calcium channel blockers,
or β blockers are commonly prescribed. Combination therapy using these drugs has been found
to be more effective than using them individually.
In the case of vasospastic angina, which is caused by coronary artery spasms, nitrites and
calcium channel blockers are effective in reducing and preventing ischemic episodes. These
medications can eliminate angina attacks in around 70% of patients.
Unstable and acute coronary syndromes, characterized by recurrent ischemic episodes at rest,
are often caused by thrombotic occlusions resulting from fissuring of atherosclerotic plaques
and platelet aggregation. Anticoagulant and antiplatelet drugs play a crucial role in managing
these cases to prevent further complications.
Overall, the choice of therapy for angina depends on the type and severity of the condition, and
a combination of medications may be necessary to effectively manage the symptoms and
reduce the risk of complications.

Organic Nitrates

Organic nitrates are compounds that are esters of an organic alcohol and nitric acid. Although
these compounds are not very stable, they mimic the actions of naturally produced nitric oxide
(NO) in the body. Nitric oxide, which is released by vascular endothelial cells, causes relaxation
of vascular smooth muscle (VSM).
Organic nitrates release nitric oxide by a process involving a thionitrite complex. This complex,
such as the sulfhydryl group of cysteine within the aldehyde reductase, decomposes
nonenzymatically to release nitric oxide. Nitric oxide, in turn, stimulates the production of cyclic
guanosine monophosphate (cGMP) by activating guanylyl cyclase, leading to increased levels of
cGMP.
The elevation of cGMP has several effects. It blocks the influx of calcium ions into the cell,
thereby preventing vascular contractions. Organic nitrates can also increase the concentrations
of cGMP within platelets, inhibiting platelet aggregation.
In summary, organic nitrates act by releasing nitric oxide, which increases cGMP levels. This
leads to vasodilation and inhibition of platelet aggregation, contributing to the therapeutic
effects of organic nitrates in conditions such as angina.

Physicochemical and Pharmacokinetic Properties

- Organic nitrates are sensitive to moisture and can undergo ester hydrolysis.
- They are lipophilic (soluble in lipids) and have low boiling points, which allows for inhalation
administration.
- Organic nitrates can be administered through various routes such as infusion, sublingual
(under the tongue), sustained-release formulations, oral spray, transdermal patches, and
ointments.
- Sublingual administration results in rapid absorption within 1 to 5 minutes for nitroglycerin,
providing a quick onset of action but short duration (around 30 minutes). Isosorbide dinitrate
has a longer duration of action lasting 4 to 6 hours.

Metabolism
It occurs through mitochondrial aldehyde dehydrogenase, which removes the nitrate group.
Isosorbide dinitrate is converted to isosorbide mononitrates, while nitroglycerin is converted to
1,2- or 1,3-dinitrate, although with reduced activity.

Clinical Applications
- Organic nitrates are indicated for the relief of angina attacks or acute prophylaxis (prevention)
of angina pectoris.
- They are used in both stable and unstable angina.
- Organic nitrates also have some applications in myocardial infarction (heart attack).

Late Sodium Current Inhibitor – Ranolazine

• Ranolazine is believed to modify the levels of intracellular sodium ions (Na+) in a way that
affects the Na+-dependent calcium channels during myocardial ischemia.
• This medication specifically inhibits the late sodium current (INa), reducing the accumulation
of intracellular sodium.
• By doing so, ranolazine helps alleviate the abnormalities in ventricular repolarization and
contractility, thus contributing to its cardioprotective effects.

Physicochemical and Pharmacokinetic Properties

- Ranolazine has good oral bioavailability of 76% when administered in extended-release tablet
form.
- Most of the drug is excreted through the urine, accounting for approximately 75% of
elimination.
- Ranolazine is a substrate and inhibitor of P-glycoprotein (P-gp) and undergoes extensive
metabolism primarily by the enzyme CYP3A4, resulting in the formation of numerous inactive
metabolites.

Clinical Applications
- Ranolazine is approved for the treatment of angina.
- When combined with a calcium channel blocker, β-adrenoceptor antagonist, or a nitrate,
ranolazine can be effective in patients who are unresponsive to other antianginal medications,
without increasing the workload on the heart.

Endothelin Receptor Antagonists

Pulmonary arterial hypertension (PAH) is a progressive condition characterized by increased
resistance in the pulmonary blood vessels, leading to right ventricular failure and death.
Vasoconstriction, remodelling of the vessel wall, and thrombosis are associated with this
disease. Impaired production of vasoactive mediators like nitric oxide (NO) and prostacyclin, as
well as an overexpression of vasoconstrictors such as endothelin-1 (ET-1), contribute to these
effects. Therefore, ET-1 receptor antagonists have been developed as a targeted
pharmacological approach.
- ET-1 is a 21-amino acid peptide produced by the endothelium, which binds to endothelin
receptors ETA and ETB on vascular smooth muscle cells.
- Activation of ETA receptors cause strong vasoconstriction through the Gq protein pathway,
leading to an increase in cytosolic calcium levels and sustained vasoconstriction, as well as
proliferation of smooth muscle cells.
- ETB receptors, found on both endothelial and smooth muscle cells, can also stimulate the
production of vasodilators such as prostacyclin and NO through endothelial nitric oxide
synthase, resulting in transient vasodilation.
Bosentan acts as an antagonist for both ETA and ETB receptors, while ambrisentan selectively
targets ETA receptors with a significantly higher selectivity for ETA over ETB. Studies indicate
that in the state of pulmonary hypertension, it may be necessary to block both ETA and ETB
receptors for optimal therapeutic effect.

Physicochemical and Pharmacokinetic Properties

• Both inhibitors of ET-1 exhibit high plasma protein binding (~98%) and have bioavailabilities of
50% for bosentan and 80% for ambrisentan.
• The half-life of bosentan is 5.4 hours, while ambrisentan has a longer half-life of 15 hours.

Metabolism
• Bosentan is metabolized by CYP450 enzymes.
• Inhibitors of CYP3A4 can increase bosentan plasma levels, and bosentan itself acts as an
inducer of CYP2C9, which can affect clotting time when combined with warfarin.
• Ambrisentan undergoes primary metabolism involving UGT enzymes (1A9, 2B7, 1A3), leading
to the formation of acyl glucuronide. The drug is also a substrate for P-glycoprotein.

Prostanoids
Prostacyclin (PGI2) is a potent vasodilator, antithrombotic, and antiproliferative substance
produced in the vascular endothelium from arachidonic acid. It and its analogs, known as
prostanoids, are effectively used in treating pulmonary hypertension.
Adverse effects associated with Bosentan and Ambrisentan include hypotension, headache,
flushing, increased liver enzymes (which may indicate potential liver injury), leg edema, and
anemia. Patients with hypersensitivity to sulfonamides should be excluded from using these
medications. Both Bosentan and Ambrisentan are teratogenic in animal models, leading to
potential birth defects, and are contraindicated during pregnancy. Ambrisentan carries
additional severe warnings such as hepatotoxicity, pulmonary and peripheral edema, a marked
decrease in hemoglobin levels, and reduced sperm count.
Prostanoid analogs mimic the effects of PGI2 by activating platelet and endothelial cell
receptors, resulting in the production of cAMP by adenylyl cyclase. This leads to reduced
platelet aggregation and smooth muscle relaxation/vasodilation through the activation of
protein kinase A (PKA). It is worth noting that all three prostanoids are structurally similar.
Physicochemical and pharmacokinetic properties
Epoprostenol sodium salt (pH 10) is unstable and undergoes acid-catalyzed hydrolysis. The drug
needs to be reconstituted shortly before use and administered via continuous IV infusion.
Treprostinil, a synthetic derivative of PGI2, is available as a stable sodium salt for injection (IV or
subcutaneous) or in solution for inhalation, packaged in foil pouches to protect it from light.
Iloprost can be used through inhalation or IV therapy. The half-lives are approximately 10
minutes for epoprostenol, 85 and 34 minutes for treprostinil (SC or IV, respectively), and 20 to
30 minutes for iloprost.

Metabolism
It involves extensive conversion to inactive metabolites, although the specific structures of
these metabolites are not available. Several metabolites of epoprostenol retain the 6-oxo
structure.
The adverse effects of prostanoids include nausea, vomiting, headache, hypotension, and
flushing. Epoprostenol may also cause chest pain, anxiety, bradycardia, and tachycardia.
Treprostinil has been associated with jaw pain and localized pain at the delivery site. Iloprost
use is frequently linked to a high incidence of cough.
In terms of clinical applications, both ET-1 inhibitors and prostanoids are indicated for the
treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and prevent
the worsening of the condition. Treatment with ET-1 inhibitors or prostanoids can lead to an
increase in walking distance. Other medications prescribed for PAH include anticoagulants,
calcium channel blockers, and diuretics.
Regarding the chemical significance, medications for cardiovascular diseases encompass various
chemical entities, ranging from inorganic nitric oxide to analogs like β-blockers and calcium
channel blockers. Understanding the chemical structure of new compounds allows pharmacists
to categorize them into specific classes with their corresponding mechanisms of action,
physicochemical and pharmacokinetic properties, metabolic traits, and therapeutic potential.
This knowledge helps evaluate the advantages of these compounds over traditional agents in
terms of onset, duration, and potential adverse effects. A strong background in functional
group-related metabolism aids in recognizing and predicting metabolic reactions associated
with individual drugs.
In summary, prostanoids have common adverse effects such as nausea, vomiting, headache,
hypotension, flushing, and specific effects for each subtype. They are used for the treatment of
pulmonary arterial hypertension, along with ET-1 inhibitors, and have shown positive outcomes
in increasing walking distance. Understanding the chemical structure and metabolism of these
compounds is crucial for assessing their therapeutic benefits and potential adverse effects.

AGENTS AFFECTING THE RENIN–ANGIOTENSIN PATHWAY

The renin-angiotensin pathway plays a crucial role in maintaining cardiovascular homeostasis
by regulating blood volume, arterial blood pressure, and electrolyte balance. Excessive
production of renin and angiotensin II can lead to hypertension and heart failure. Angiotensin II
contributes to high blood pressure and heart failure through various mechanisms, including
vasoconstriction, increased sodium reabsorption in the kidneys, aldosterone release, and
hypertrophy and remodelling of blood vessels and cardiac cells.
The renin-angiotensin pathway involves two main enzymes: renin and angiotensin-converting
enzyme (ACE). Renin cleaves angiotensinogen to form angiotensin I, which is then converted to
angiotensin II by ACE. Angiotensinogen is continually synthesized and secreted by the liver. ACE
is relatively nonspecific and can also degrade other substances like bradykinin, which has
vasodilatory effects. The nonspecific nature of ACE gives it additional proteolytic activity.
Given the significant effects of the renin-angiotensin pathway on the cardiovascular system,
inhibiting the actions of renin or ACE, as well as blocking the binding of angiotensin II to its
receptors, is important for the treatment of hypertension and other cardiovascular diseases.
These compounds can help regulate blood pressure and prevent the detrimental effects
associated with excessive angiotensin II activity.

ACE inhibitors
They hinder the conversion of angiotensin I to angiotensin II. They achieve this by interacting
with three main sites in the catalytic pocket. Firstly, there is a cationic site that binds to the
anionic carboxylate end of the peptide substrate. Secondly, there is a zinc atom near the labile
peptide bond, which helps stabilize the negatively charged tetrahedral intermediate. Lastly,
there is a hydrophobic pocket that provides some specificity for the C-terminal aromatic or
nonpolar residue.
Additionally, ACEIs imitate the tetrahedral transition state of peptide hydrolysis and are
resistant to hydrolysis themselves. Since ACE (angiotensin-converting enzyme) is a relatively
non-specific dipeptidyl carboxypeptidase, ACEIs also inhibit the breakdown of bradykinin. This
inhibition leads to several physiological effects, including potentiation of the hypotensive action
of the ACEIs through vasodilation. However, it can also result in bronchoconstriction, which
manifests as a dry cough. ACEIs also contribute to increased synthesis of prostaglandins, which
further promotes vasodilation, vascular permeability, and the production of certain types of
pain and inflammation.
i. Sulphahydryl containing ACE inhibitors.
Captopril

ii. Dicarboxylate containing ACE inhibitors.

SAR

• The N-ring section must have a carboxylic acid component to bind to the cationic site in ACE.
• Larger heterocyclic rings in the N-ring section enhance effectiveness and modify how the drug
is processed in the body.
• The zinc binding group can be either (A) sulfhydryl, (B) carboxylate, or (C) phosphinate.
• The -SH group demonstrates superior binding to zinc.
• Compounds containing -SH groups can cause a high occurrence of skin rashes and a loss of
taste. They can also form disulfides and dimers, which may shorten the duration of the drug's
effects.

Physicochemical and Pharmacokinetic Properties:

- All ACEIs (except captopril and fosinopril) are amphoteric, while captopril and fosinopril are
acidic.
- The carboxylic acid attached to the N-ring has a pKa range of 2.5 to 3.5 and becomes ionized
at physiological pH.
- The second carboxylic acid in the dicarboxylate series is ionized in the active form but remains
unionized when in the prodrug (ester) form.
- The ACEIs have good lipid solubility, except for captopril, enalaprilat, and lisinopril.
- Lisinopril, despite being highly hydrophilic, exhibits good oral bioavailability because it likely
exists as a di-zwitterion in the duodenum, where the ionized groups are internally bound to
each other.

Metabolism:
- Lisinopril and enalaprilat are excreted unchanged, while all other ACEIs undergo some form of
metabolism.
- Dicarboxylate and phosphinate prodrugs undergo hydrolysis to convert into active forms,
mainly facilitated by hepatic esterases.
- Captopril can form dimers or conjugate with cysteine.

Synthesis of Enalapril
Synthesis of Lisinopril

Assay
Enalapril:
Dissolve the sample in water and titrate with 0.1 M sodium hydroxide. Determine the end point
potentiometrically.
Lisinopril:
Dissolve the sample in water and titrate with 0.1 M sodium hydroxide. Determine the end point
potentiometrically.

Clinical Applications:
- ACEIs are primarily approved for the treatment of hypertension (high blood pressure) and
heart failure.
- Some ACEIs, such as captopril, enalapril, and trandolapril, are also indicated for the
management of left ventricular dysfunction following a myocardial infarction (heart attack).
- ACEIs have been found to slow the progression of diabetic nephropathy (kidney damage) and
are therefore recommended for use in hypertensive patients with diabetes.
- ACEIs have additional uses that are not officially approved, including the management of
hypertensive crisis, prevention of strokes, prophylaxis for migraines, treatment of nondiabetic
nephropathy (kidney disease), and chronic kidney disease.

Angiotensin II Receptor Blockers

Angiotensin II exerts its effects by interacting with two receptor subtypes, namely AT1 and AT2.
AT1 receptors are present in various tissues such as the brain, neurons, blood vessels, kidneys,
liver, adrenal glands, and heart muscle. AT2 receptors are found in the brain, central nervous
system (CNS), as well as in the heart and kidneys.

Mechanism of Action (MOA):

- AT1 receptor activation leads to vasoconstriction, increased secretion of aldosterone and
vasopressin, enhanced sodium reabsorption, release of catecholamines, and remodeling of the
left ventricle.
- Interaction with AT2 receptors produces cardioprotective effects, such as vasodilation, release
of nitric oxide (NO), regression of hypertrophy, and induction of apoptosis.
Regarding ARBs (angiotensin receptor blockers):
- Currently available ARBs are highly selective for the AT1 subtype and act as competitive
antagonists.
- It is preferable to have a selective AT1 blocker since blocking AT2 receptors would diminish or
eliminate its apparent cardioprotective effects.
SAR (Structure-Activity Relationship):
- Initial research focused on developing peptide analogs of Angiotensin II.
- Saralasin, an octapeptide, was developed as a prototype compound where the Asp1 and Phe8
residues of Angiotensin II were replaced with Sar (sarcosine, N-methylglycine) and Ala,
respectively.
- However, saralasin had limitations such as poor oral bioavailability and partial agonist activity,
leading to the development of peptide mimetics to overcome these drawbacks.
- 1-benzyl-5-acetyl-imidazoles were identified as mimetics that mimic the key amino acid
residues crucial for blocking the action of Angiotensin II, forming the pharmacophore of ARBs
(angiotensin receptor blockers).
- The R group in ARBs can be H, Cl, or vary.
- The -CH2-COOH group can be replaced with a hydrogen bonding moiety such as
hydroxymethyl or a ketone, which is part of a benzimidazole.
- R2 can be -COOH or an o-substituted phenyl group.
- O-substituents can be either -COOH or a tetrazole ring.
- The n-butyl chain can be an ethyl ether or an n-propyl group.

Peptidomimetic Design:
- Peptidomimetics are designed using a three-step rational approach: identification of crucial
amino acid residues, determination of their spatial arrangement, and utilization of a template
to position the key functional groups correctly. 1-benzyl-5-acetyl-imidazoles fulfill these
requirements as a peptidomimetic of Angiotensin II.

Physicochemical and Pharmacokinetic Properties:

- ARBs are acidic due to the presence of the tetrazole ring (pKa = 6) and carboxylate groups (pKa
= 3-4).
- The tetrazole and carboxylic acid groups are ionized at physiological pH.
- ARBs containing the tetrazole ring have higher binding and are more lipophilic than those
without it.
- All ARBs have low but sufficient oral bioavailability (15% to 33%), except for irbesartan (60% to
80%) and telmisartan (42% to 58%).
- ARBs can be taken with meals.
- All ARBs are highly protein-bound.
- They have elimination half-lives that allow once or twice daily dosing.
- Most ARBs are primarily eliminated via the fecal route, except for olmesartan.
- None of the ARBs require dosing adjustment in renal impairment.
- Losartan and telmisartan are the only two that require dose reductions in patients with
impaired hepatic function.

Metabolism:
- Losartan is metabolized by CYP2C9 and 3A4 enzymes to an active metabolite, and both
contribute to its hypertensive effects. Losartan is not a prodrug.
- Candesartan and olmesartan are hydrolyzed to their active metabolites in the intestinal cell
wall.
- Most other ARBs are eliminated primarily unchanged (80%). However, irbesartan, telmisartan,
and eprosartan are metabolized to inactive carboxylic glucuronides.

Clinical Applications:
- ARBs are approved for the treatment of hypertension, either alone or in combination with ACE
inhibitors, diuretics, β-blockers, and calcium channel blockers.
- Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation and
bronchoconstriction.
- Other indications for ARBs include:
- Irbesartan and losartan are approved for the treatment of nephropathy in type 2 diabetics.
- Losartan is approved for stroke prevention in patients with left ventricular hypertrophy.
- Candesartan and valsartan are approved for the treatment of heart failure.
- Telmisartan is approved to reduce the risk of myocardial infarction (MI) and stroke.

Renin Inhibitors:
Renin inhibitors were developed as peptide mimetics to mimic the octapeptide sequence (Pro7-
Phe8-HisHis13-Asn) of angiotensinogen that is recognized by renin. Currently, aliskiren is the
only renin inhibitor available in the market. Aliskiren is based on an amino amide nonpeptide
template.
Aliskiren directly inhibits the formation of both angiotensin I and angiotensin II. Renin
hydrolysis of angiotensinogen, regulated by hemodynamic, neurogenic, and humoral signals, is
the rate-limiting step in this pathway. Unlike ACE inhibitors (ACEIs) and angiotensin receptor
blockers (ARBs), aliskiren does not cause a compensatory increase of renin in the plasma.

SAR:
- As there are currently no other marketed renin inhibitors, there is no SAR information
available.
- Aliskiren contains four chiral centers and is marketed as the pure 2S, 4S, 5S, 7S enantiomer.

Physicochemical and Pharmacokinetic Properties:

- Aliskiren is a basic compound and is marketed as the hemifumarate salt.
- It has a log P value of 4.32 for the unionized form and is highly water-soluble in its salt form.
- The oral bioavailability of aliskiren is approximately 2.5%, with peak plasma levels reached
within 1 to 3 hours.
- High-fat meals can decrease its absorption.
- Elimination is primarily via the hepatobiliary tract.
- No dose adjustment is necessary for renal or hepatic impairment, but aliskiren should be
avoided in patients with severe renal impairment.

Metabolism:
- Approximately 90% of aliskiren is excreted unchanged.
- Ten percent undergoes metabolism to the O-demethylated alcohol derivative and a carboxylic
acid derivative via the enzyme CYP3A4.

Clinical Application:
- Aliskiren is approved for the treatment of hypertension as either monotherapy or in
combination with hydrochlorothiazide, amlodipine, or valsartan.
Clinical Significance
The development of drugs targeting the renin-angiotensin pathway has greatly improved the
treatment of hypertension and heart failure. By identifying key binding residues in proteolytic
enzymes (renin and ACE) and angiotensin II receptors (AT1 and AT2), medicinal chemists have
been able to design renin inhibitors, ACE inhibitors, and ARBs for cardiovascular diseases. Renin
inhibitors and ARBs are peptide mimics that resemble natural peptide substrates but are more
bioavailable and stable. For example, ARBs are modeled after 1-benzyl-5-acetyl-imidazoles,
mimicking key amino acid residues in angiotensin II for binding to the AT1 receptor. ACE
inhibitors end in "...prilat" (e.g., enalaprilat), indicating the active free carboxylate form
necessary for binding to the enzyme's active site zinc atom.
Pharmacists, possessing knowledge of these chemical facts, play a crucial role in discussing
appropriate drug choices for specific therapeutic scenarios. Understanding the chemical
structure's role not only in the mechanism of action but also in absorption, distribution,
metabolism, and elimination equips pharmacists with valuable knowledge to benefit patients
and enhance their quality of life.

Antihyperlipidemics
They are drugs used to treat dyslipidemia, which refers to abnormalities in serum lipid and/or
lipoprotein levels. Dyslipidemia can lead to negative cardiovascular events, such as
atherosclerosis and coronary heart disease (CHD). It can be primary, resulting from genetic
predisposition, or secondary, resulting from pathological conditions or lifestyle choices.
Hyperlipidemia is characterized by elevated levels of serum cholesterol, cholesterol esters,
triglycerides, and/or phospholipids, increasing the risk of CHD. Hypertriglyceridemia, a form of
hyperlipidemia, specifically increases the risk of pancreatitis. Hyperlipoproteinemia involves
elevated levels of lipoproteins that transport lipids through the bloodstream, including low-
density lipoproteins (LDLs) or very low-density lipoproteins (VLDLs), and/or decreased levels of
high-density lipoproteins (HDLs).
Therapeutic approaches to treating hyperlipidemia and hyperlipoproteinemia include inhibiting
intestinal reabsorption of bile acids, inhibiting triglyceride biosynthesis and VLDL formation,
inhibiting intestinal absorption of dietary cholesterol, stimulating serum triglyceride cleavage
and clearance, and inhibiting de novo cholesterol biosynthesis through HMG-CoA reductase
inhibitors.
Cholesterol biosynthesis starts with the conversion of 3-hydroxy-3-methylglutaryl-CoA to
mevalonic acid, catalyzed by the enzyme HMG-CoA reductase. Cholesterol is a precursor for
corticosteroids, sex steroids, and bile acids. Bile acids, in their anionic conjugate base form
called bile salts, promote the intestinal absorption of lipids and fat-soluble vitamins.
Triglycerides are long-chain fatty acid esters of glycerol. Enzymes involved in triglyceride
biosynthesis include phosphatidic acid phosphatase (PAP), monoacylglycerol acyl transferase
(MAGAT), and diacylglycerol acyltransferase (DAGAT). Triglycerides are stored in adipose tissue
and are hydrolyzed by lipases to release free fatty acids (FFAs) when metabolic energy is
needed. Triglycerides are transported in the bloodstream solubilized by VLDL.
Bile Acid Sequestrants (BAS)
Cholestyramine, colestipol, and colesevelam are used to treat hypercholesterolemia.
Bile acid sequestrants (BAS) are nonabsorbable anionic exchange resins that work by trading
chloride anions bound to strongly cationic centers for intestinal bile salts, such as glycocholate
and taurocholate. The resin's cationic amines have a higher affinity for bile salts than chloride
anions, causing bile salts to be held or sequestered by the resin through strong ion-ion bonds.
As a result, bound bile acids are excreted in the feces instead of being returned to the liver.

The loss of hepatic return of bile acids stimulates the oxidation of hepatic cholesterol through
7a-hydroxylase-mediated pathways and increases the clearance of low-density lipoprotein
(LDL). Although de novo cholesterol biosynthesis is stimulated, it cannot compensate for the
loss of cholesterol from oxidation. The overall effect is a decrease in total serum cholesterol and
LDL levels. However, triglyceride and very low-density lipoprotein (VLDL) levels may transiently
rise or persistently increase in patients with hypertriglyceridemia.

SAR
BAS contain permanently or potentially cationic amines that strongly bind to intestinal
glycocholic and taurocholic acids. Cholestyramine and colesevelam, for example, are examples
of BAS with quaternary amines and exhibit pH-independent action.

Colestipol, an example of a bile acid sequestrant, requires protonation of its secondary and
tertiary amines in the intestine to effectively sequester bile salts. This pH-dependent action
limits its anion exchange capacity. On the other hand, colesevelam, another bile acid
sequestrant, has a unique polymer structure that allows for greater selectivity towards bile
salts, resulting in fewer drug interactions.

Physicochemical and pharmacokinetic properties

They are water-insoluble resins that are not absorbed across gastrointestinal membranes. They
are metabolically inert and, along with the irreversibly bound bile salts, are excreted in the
faeces. The normal transit time of bile acid sequestrants within the gastrointestinal tract is
typically 4 to 6 hours.

Clinical Applications
bile acid sequestrants are usually administered once or twice daily. When co-administered with
niacin or statins, careful attention is required for timing of administration. The statin in bile acid
sequestrant-statin co-therapy blocks the surge in cholesterol biosynthesis induced by the faecal
loss of bile acids. It's important to note that bile acid sequestrant tablets are large and should
be avoided in patients with swallowing disorders. The therapeutic benefit of bile acid
sequestrants, such as decreased LDL cholesterol, can be realized within one week to one month
of treatment.

Niacin (Nicotinic Acid)

Niacin stimulates the GPR109A receptor found in adipocytes, spleen, and macrophages. Its
activity relies on an ion-ion bond with a cationic receptor Arg. Niacin inhibits the lipolysis of
stored triglycerides, leading to decreased production of triglycerides, Free Fatty Acids (FFA),
Very Low-Density Lipoprotein (VLDL), and Low-Density Lipoprotein (LDL), although the decrease
in FFA is temporary. It also lowers serum triglycerides by inhibiting DAGAT2, blocking the
acylation of diglycerides to triglycerides. Niacin inhibits receptor-mediated uptake of High-
Density Lipoprotein (HDL), resulting in increased serum HDL levels.

SAR
Niacin must be anionic to be effective as an antihyperlipidemic agent. The carboxylic acid
moiety is essential, and nonionizable amides (such as nicotinamide) are inactive. Any
modification to the niacin structure generally leads to inactivation of its antihyperlipidemic
properties.

Effect of Niacin (>1.5 g/day) on Plasma Concentrations of Lipids/Lipoproteins

Physicochemical and pharmacokinetic properties.

It is amphoteric due to its carboxylic acid and pyridine nitrogen, with the active anion form
prevailing at pH 7.4. Niacin is rapidly absorbed from the gastrointestinal tract, but its short half-
life of 1 hour requires frequent dosing of immediate-release formulations. Extended-release
formulations extend the duration of action to 8 to 10 hours and delay the time to reach peak
plasma concentration to 4 to 5 hours. It's important to note that niacin dosage forms are not
interchangeable.

Niacin is metabolized by being excreted in the urine either unchanged or conjugated with
glycine as nicotinuric acid.
Clinical Applications
Niacin is dosed up to 6 g/day as an antihyperlipidemic, whereas as a vitamin (B3), it is dosed at
13 to 20 mg/day. High doses of niacin can cause cutaneous vasodilation due to GPR109A
stimulation and activation of phospholipase A2. This can lead to adverse effects mediated by
prostaglandin D2 (PGD2). To counteract vasodilation, pretreatment with over-the-counter
nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin or indomethacin is employed, as
NSAIDs inhibit cyclooxygenase and block the conversion of released arachidonic acid to PGD2.
Other strategies to minimize vasodilation-related adverse effects include administering niacin at
bedtime, gradually increasing the dose over 1 to 4 months, and allowing normal tolerance to
develop over 3 to 6 weeks.

Ezetimibe

Ezetimibe is a medication that selectively inhibits a cholesterol-active transporting protein in

the intestinal brush border. By blocking the absorption of dietary cholesterol, it increases the
clearance of LDL (low-density lipoprotein) from the bloodstream and reduces total serum
cholesterol levels. Although there is a surge in cholesterol biosynthesis as a compensatory
mechanism, the overall effect is a decrease in serum LDL.
SAR
The presence of the 1,4-diaryl-β-lactam structure is crucial for ezetimibe's activity. The phenolic
and alcoholic hydroxyl groups help keep the medication localized in the small intestine.
Additionally, the incorporation of p-fluoro groups prevents intestinal CYP-mediated aromatic
hydroxylation, which extends the duration of action.

Physicochemical and pharmacokinetic properties.

Its phenolic hydroxyl group, with a pKa value of 9.72, remains predominantly unionized in the
intestinal pH range. The medication is rapidly absorbed after oral administration and is not
influenced by food intake.
Approximately 60% of an administered dose of ezetimibe is absorbed into the body. Both
ezetimibe and its active metabolite have high protein binding and exhibit half-lives of around 22
hours.

Metabolism
The active metabolite is formed from the p-phenol in both the gut and the liver. The fraction
produced in hepatocytes is actively transported back to the intestine through the bile. About
9% of the dose is excreted in urine as the glucuronide conjugate.

Clinical Applications
It is available as a stand-alone medication and in combination with the statin prodrug
simvastatin. Generally, the pure compound is well tolerated, but caution is advised in patients
with moderate to severe hepatic dysfunction.

Phenoxyisobutyric Acids (Fibrates)

Fibrates derive their common name from the chemical name of their active anionic form,
phenoxyisobutyrate (phibrate = fibrate).
The mechanism of action of fibrates involves the activation of peroxisome proliferator-activated
receptor alpha (PPARα), a nuclear protein primarily found in the liver. PPARα plays a role in
regulating genes that control fatty acid metabolism.
Fibrates work by activating a liver-specific nuclear protein called peroxisome proliferator-
activated receptor alpha (PPARα), which plays a crucial role in regulating genes involved in
controlling the metabolism of fatty acids.
Stimulation of PPARα by fibrates leads to several beneficial effects. It enhances the expression
of lipoprotein lipase, which promotes the breakdown of triglycerides in very low-density
lipoproteins (VLDL) and facilitates their clearance through receptor-mediated processes. Fatty
acid oxidation is also increased, while the synthesis of triglycerides is inhibited. As a result,
fibrates reduce levels of serum triglycerides and VLDL, while increasing levels of high-density
lipoprotein (HDL), often referred to as "good cholesterol." Fibrates also aid in the removal of
cholesterol from the liver. However, it's important to note that excessive accumulation of
biliary cholesterol beyond its solubility limits can occur with fibrates.

Metabolism:
- Gemfibrozil is rapidly metabolized by the enzyme CYP3A4, which oxidizes its aromatic methyl
groups through a process called benzylic hydroxylation. The resulting primary alcohol
metabolite is inactive.
- Gemfibrozil has a short elimination half-life of 1.5 hours, requiring twice-daily dosing.
- The metabolized gemfibrozil undergoes cytosolic oxidation to form the carboxylic acid, which
is then conjugated with glucuronide to form a glucuronide ester.
- Gemfibrozil can interact with other drugs that are substrates, inducers, or inhibitors of
CYP3A4, although the resulting toxicity is usually insignificant.
- Fenofibrate, on the other hand, needs to be hydrolyzed to release its active form, fenofibric
acid.
- Steric hindrance caused by the branched alkyl moieties in fenofibrate slows down the
activation of the prodrug.
- Both fenofibrate and fenofibric acid are resistant to oxidation. Fenofibrate has a longer
elimination half-life of 22 hours, allowing for once-daily dosing.
- Both fibrates can be excreted as glucuronide esters of the isobutyric acid moiety.
- Gemfibrozil competes with all statins except fluvastatin for a specific glucuronidating isoform,
increasing the risk of serious toxicity when used together.
SAR:
- The key structural feature required for fibrate antihyperlipidemics is phenoxyisobutyric acid.
- Fibrates bind to PPARα by forming an ion-dipole bond with a specific tyrosine residue
(Tyr.464).
- The pKa of fibric acid is approximately 3.5, with the fibrate anion being the predominant form
at pH 7.4.
- Fibrate esters need to undergo hydrolysis to release the active anion.
- PPARα is flexible, allowing for a spacer of up to three carbon atoms between the isobutyrate
and aryloxy groups.
- Spacer groups increase the lipophilicity of the molecule and promote its penetration through
gastrointestinal and hepatic membranes.
Physicochemical and Pharmacokinetic Properties:
- Fibrates are highly lipophilic, allowing them to passively distribute from the gut into the liver.
- Gemfibrozil, despite being strongly anionic at pH 7.4, is lipophilic due to the presence of an n-
propyl spacer and two aromatic methyl groups.
- Fenofibrate, despite lacking a hydrocarbon spacer, has a higher log P (lipophilicity) compared
to gemfibrozil. This is attributed to the carbon-rich nonionizable isopropylcarboxylate ester and
the second phenyl ring with its p-chloro substituent.
- Gemfibrozil should be taken with meals, and administration 30 minutes prior to meals leads to
increased maximum concentration (Cmax) and area under the curve (AUC).
- The food dependency of fenofibrate varies depending on the formulation. Taking it with meals
enhances absorption efficiency.
- Fenofibrate requires bioactivation, resulting in a delayed peak serum concentration of the
active drug compared to gemfibrozil (4 to 8 hours versus 1 to 2 hours).
- Fibrates are predominantly excreted by the kidneys (60% to 90%), with 5% to 25% excreted in
feces. Fenofibrate is more likely to undergo fecal excretion.

Clinical Applications:
- Fibrates are well tolerated and effective in reducing serum triglyceride and VLDL levels.
- Fibrates are not effective in treating elevated chylomicron levels (Fredrickson's type I
hypertriglyceridemia).
- Fibrates can be used in combination with other antihyperlipidemics in complex dyslipidemias
with appropriate precautions.
- Gemfibrozil is contraindicated, while fenofibrate should be used with caution in severe renal
dysfunction. Fenofibrate is generally well tolerated in patients with mild to moderate
impairment.
- If cotherapy with gemfibrozil and a statin is required, fluvastatin should be considered as it
does not compete for the glucuronidating isoform used by gemfibrozil.
 HMG-CoA Reductase (HMGR) Inhibitors

HMGR inhibitors are commonly known as statins.

Mechanism of Action of Statins:

- Statins act as competitive inhibitors of HMGR (3-hydroxy-3-methylglutaryl-CoA reductase), the

enzyme responsible for the rate-limiting step in cholesterol biosynthesis.

- By competing with the endogenous substrate HMG-CoA, statins effectively block access to the
active site of HMGR.

- The dihydroxyheptan(en)oic acid segment of statins mimics the chemical structure of HMG
and binds to HMGR in a similar manner.

- An ion-ion bond forms between the anionic statins and the cationic amino acid Lys735,
providing an anchoring interaction.

- The remaining ring component of the statin structure binds to hydrophobic and polar residues
within a flexible receptor pocket.
- Statins exhibit an affinity that is 1000- to 10,000-fold higher than HMG-CoA, ensuring potent
inhibition of the enzyme.

- The expression of LDL (low-density lipoprotein) reuptake receptors is increased, leading to

enhanced clearance of LDL from the bloodstream.

- The two most powerful statins, rosuvastatin and atorvastatin, also have the ability to lower
serum triglyceride levels.

SAR (Structure-Activity Relationship) of Statins:

- Statins need to be anionic to anchor to the amino acid Lys735 in HMGR (3-hydroxy-3-
methylglutaryl-CoA reductase). The dihydroxyheptan(en)oic acid segment is crucial for this
interaction.

- Hydroxyl groups at chiral carbon positions 3 and 5 play a significant role in the binding to
HMGR and must have the correct absolute configuration.

- The R configuration is required at carbon 3.

- The optimal configuration at carbon 5 depends on the saturation status of carbon 6 and 7.
Dihydroxyheptanoic acid statins have a 5R stereochemistry, while dihydroxyheptenoic acids
have a 5S configuration.

- The ring component of statins falls into two general types:

- Naturally occurring statins have a 2',6'-dimethylhexahydronaphthylene ring system

substituted with a methylbutyrate ester at carbon 8'.

- Addition of an α-CH3 group to the methylbutyrate (lovastatin vs. simvastatin) increases

activity two-fold.

- Synthetic statins feature heteroaromatic ring systems. Isopropyl (or cyclopropyl) and p-
fluorophenyl substituents contribute to receptor affinity.
- Statins with polar functional groups positioned to bind to Arg568 and Ser565 (such as
rosuvastatin and atorvastatin) exhibit significant increases in affinity and potency. On the other
hand, statins with polar functional groups forced to interact with lipophilic HMGR residues
(such as pravastatin) demonstrate decreased affinity and potency.

Metabolism:

- Prodrug statins need to undergo hydrolysis to generate the essential carboxylate anion.

- Some statins are metabolized by the enzymes CYP3A4 and 2C9.

- Except for pravastatin, saturated dihydroxyheptanoic acid statins are metabolized by CYP3A4.

- Unsaturated dihydroxyheptenoic acids are metabolized by CYP2C9.

- Pravastatin is resistant to metabolism by these enzymes. Instead, it is oxidized or decomposed

in the gut and liver, resulting in a less active major metabolite.

CYP3A4 and CYP2C9 are enzymes involved in the metabolism of statins:

- CYP3A4 catalyzes the inactivation of lovastatin and simvastatin acids through alicyclic
hydroxylation and ω-1 hydroxylation. It also catalyzes the aromatic hydroxylation of
atorvastatin. The metabolites formed from these reactions are equally active compared to the
parent drugs.

- CYP2C9 catalyzes the N-demethylation of rosuvastatin, forming a metabolite that retains

activity but is produced in low amounts (5% to 10% of the dose). It also catalyzes the aromatic
hydroxylation and N-dealkylation of fluvastatin, as well as the inactivating aromatic
hydroxylation of pitavastatin. Co-administration of pitavastatin with CYP3A4 inhibitors can
increase its toxicity, possibly due to competition for organic anion transporting protein (OATP)
1B1.

- All statins can undergo glucuronidation, where they are conjugated with glucuronic acid,
before being excreted in bile or urine. Pitavastatin glucuronide can undergo reversible
lactonization, which can hydrolyze to regenerate active pitavastatin. Similar reversible
lactonization is presumed to occur to some extent with all statins, such as atorvastatin and
simvastatin.

Statins are classified as lipophilic or hydrophilic based on the characteristics of the ring
component of their structure.

- Lipophilic statins, including fluvastatin, pitavastatin, atorvastatin, lovastatin, and simvastatin,

have a log P (lipophilicity coefficient) greater than 3. They have carbon-rich ring systems that
dominate over the influence of any polar substituent.

- Hydrophilic statins, such as pravastatin and rosuvastatin, have a log P less than 1.5. They are
carbon-poor and contain a polar functional group.

- Lipophilic statins, but not hydrophilic statins, are absorbed across the membranes of the
gastrointestinal tract, liver, and muscle cells primarily through passive diffusion.

Pharmacokinetic Parameters of HMG–CoA Reductase Inhibitors

OATP Affinity:

- Prodrug statins, in their unionized form, do not have any affinity for OATP (organic anion
transporting protein).
- Statins that are anionic at the pH of the intestines can be actively transported across
gastrointestinal membranes by OATP2B1.

- Hydrophilic statins are actively transported across hepatic membranes mainly by OATP1B1.

- Lipophilic statins also utilize the carrier system to some extent.

- OATP2B1 on muscle cell membranes actively transports certain anionic statins into myocytes,
which can lead to muscle toxicity.

- Atorvastatin, fluvastatin, and rosuvastatin have the highest affinity for muscle cell OATP2B1.

- Pitavastatin and pravastatin bind to OATP2B1 in the intestine (pH 6.0), but not on muscle (pH
7.4).

Hepatoselectivity:

- Hydrophilic statins, such as pravastatin and rosuvastatin, are considered highly

hepatoselective.

- Hydrophilic statins enter hepatocytes predominantly through one-way carrier-mediated

transport by OATP1B1.

- Hydrophilic statins cannot exit hepatocytes through passive diffusion and remain trapped at
the site of action.

- Fluvastatin is also highly hepatoselective.

Individual Drugs
- Lomitapide inhibits microsomal triglyceride transfer protein (MTTP), which stops the transfer
of triglycerides to apolipoprotein B (apoB). This halts the production of hepatic VLDL, LDL, and
chylomicrons.

- Lomitapide is administered orally and can cause gastrointestinal distress and hepatic steatosis
(accumulation of fat in the liver).

- CYP3A4 enzyme inactivates lomitapide, and the drug and its metabolites are eliminated in
feces and urine.

- Lomitapide is contraindicated in patients with moderate to severe liver disease or those taking
potent CYP3A4 inhibitors.

Statins:

- Statins have pleiotropic effects, meaning they have multiple beneficial effects.

- They reduce levels of C-reactive protein (CRP), a marker of inflammation, and have shown
promise in treating inflammation-related conditions such as coronary artery disease (CAD) and
vascular dysfunction associated with insulin resistance in diabetes.

- Lipophilic statins may have a positive impact on bone density.

- Co-administration of statins with nonsteroidal anti-inflammatory drugs (NSAIDs) has shown a

chemoprotective effect for some types of cancer, although not all.

Mipomersen Sodium

Mipomersen:

- Mipomersen is an antisense inhibitor that targets the synthesis of apolipoprotein B (apoB).

- It binds to the coding region of apoB/mRNA and promotes its degradation, resulting in a
decrease in circulating apoB levels.

- This reduction in apoB leads to a significant decrease in VLDL and LDL concentrations.
 - Mipomersen is administered through subcutaneous or intravenous injection because it is an
oligonucleotide.

- The inclusion of 2’-O-2-methoxy ethyl moieties in mipomersen helps inhibit nuclease activity
and extends its duration of action.

- Due to the risk of serious hepatotoxicity (liver damage), it is important for both patients and
healthcare providers to follow safe drug usage practices when using mipomersen.

Chemical Significance

The treatment of coronary artery disease (CAD) with antihyperlipidemic medications,

particularly statins, has increased following therapeutic guidelines released by medical
associations. Pharmacists play a crucial role in advising patients and healthcare teams about the
benefits and risks of specific cholesterol-lowering drugs. Their knowledge of medicinal
chemistry allows them to identify unique therapeutic and adverse actions associated with
different drug structures. For example, they can determine if a statin can be safely taken with
grapefruit juice or certain drugs, or if a fibrate needs to be taken twice daily. Pharmacists can
also guide patients on interactions between medications, such as avoiding the combination of
certain fibrate and statin drugs to prevent muscle toxicity. They can provide insights on bile acid
sequestrants based on the presence of specific amine groups. Additionally, pharmacists can
explain strategies to manage side effects, such as using aspirin to alleviate itching or headaches
caused by niacin. Their expertise in interpreting antihyperlipidemic drug structures and
understanding relevant clinical information sets them apart as drug experts within the
healthcare team.

URICOSURIC AGENTS

Gout is a condition characterized by joint inflammation caused by the accumulation of crystals

of monosodium urate monohydrate in the joints and surrounding tissues. Uric acid, produced
from the oxidation of purine bases, is a key factor in the development of gout. The enzyme
xanthine oxidase plays a role in uric acid production and is targeted by certain antigout drugs.
Elevated levels of uric acid and monosodium urate can occur due to excessive production or
compromised urinary excretion through the urate anion transporting protein (URAT1). When
the synovial fluid becomes oversaturated, crystals precipitate in the joints, leading to gout
symptoms. Gout primarily affects men, with African American men being more susceptible than
Caucasian men. Incidence is also linked to factors such as weight, high blood pressure, a diet
rich in purines, and alcohol consumption. Acute gout can be triggered during periods of stress,
fatigue, or excessive eating. Certain drugs that increase uric acid levels can also precipitate gout
attacks. Chronic gout refers to advanced stages of the disease characterized by joint destruction
and deformity, known as tophaceous gout.

Colchicine

It is a natural product that reduces inflammation by increasing the pH of synovial tissue. This
action enhances the solubility of uric acid, aiding in the dissolution of crystals associated with
gout. Colchicine can be used to prevent or treat acute gout attacks. The enzyme CYP3A4 plays a
minor role in metabolizing colchicine, primarily producing 2- and 3-desmethylcolchicine.
However, if strong CYP3A4 inhibitors are taken concurrently, the parent drug may accumulate
in the body, leading to serious and potentially fatal toxicity risks. The primary metabolite of
colchicine is N-deacetylcolchicine, which is formed through hydrolysis in the liver.
Probenecid (p-(Dipropyl-sulfamoyl) benzoic acid)

Probenecid is a uricosuric agent that increases the excretion of uric acid by the kidneys. Its
carboxylic acid structure allows it to bind to the URAT1 transporter protein, which normally
returns excreted uric acid back into the bloodstream. By blocking URAT1, probenecid prevents
the reabsorption of uric acid, leading to more of it being retained in the urine. The n-propyl
sulfonamide substituents in probenecid contribute to its effective blocking activity of URAT1.
However, probenecid's nonselective blocking of organic acid transporters (OATs) can potentially
interact with other drugs that are eliminated through these transporters, such as loop diuretics,
penicillins, and NSAIDs. The metabolic reactions of probenecid are predictable and involve both
phase I and II reactions. The metabolites produced still retain some uricosuric activity due to
the presence of a carboxylic acid moiety.
Synthesis

SAR
The presence of its electron withdrawing carboxy and sulphonamido-moieties, has not been
reported to undergo any aromatic hydroxylation, which explains its fast absorption after an oral
administration.

Allopurinol (1H-Pyrazolo [3, 4-d] purimidin-4-ol; 1, 5-Dihydro-4H-pyrazolo [3, 4-

d] pyrimidin-4-one)
Allopurinol is a medication that inhibits the biosynthesis of uric acid. It is structurally like
hypoxanthine, one of the naturally occurring purine substrates for the enzyme xanthine
oxidase. By binding tightly to xanthine oxidase, allopurinol effectively blocks the enzyme's
activity and disrupts the normal production of urate, which is the end product of uric acid
biosynthesis.

Alloxanthine is the result of allopurinol being oxidized by xanthine oxidase. It is structurally like
xanthine and acts as a long-acting inhibitor of xanthine oxidase. With prolonged use of
allopurinol, the accumulation of alloxanthine explains the increased reduction in uric acid
biosynthesis observed over time.

Synthesis
The synthesis of allopurinol involves several chemical reactions starting from
ethoxymethylenemalonitrile and hydrazine. Through deethylation, addition, and cyclization, 3-
amino-4-cyanopyrazole is formed. This compound can be hydrolyzed with sulfuric acid to yield
3-amino-4-amino pyrazole. Further heating with formamide results in the insertion of the last
carbon atom, leading to the formation of allopurinol. Allopurinol is structurally like
hypoxanthine and acts as a xanthine oxidase inhibitor. It is used in the long-term treatment of
chronic gout. By blocking the conversion of hypoxanthine and xanthine to uric acid and
reducing purine synthesis, it helps lower the concentration of uric acid in the blood. This
gradual decrease in uric acid levels leads to the resolution of tophi (uric acid crystal deposits)
and reduces the risk of uric acid stone formation. Allopurinol is known to exhibit tautomerism,
which refers to the ability of the molecule to exist in two or more forms due to the
rearrangement of its atoms.

Febuxostat
It is a nonpurine xanthine oxidase inhibitor that works by noncompetitively blocking the
enzyme's catalytic site, preventing the endogenous substrates hypoxanthine and xanthine from
accessing it. This action halts the biosynthesis of uric acid. Febuxostat undergoes extensive
metabolism by various CYP (cytochrome P450) enzymes and glucuronidating isoforms. The
hydroxylated metabolites produced during metabolism may still possess some therapeutic
activity. However, caution should be exercised when coadministering drugs that rely on
xanthine oxidase metabolism, such as mercaptopurine, azathioprine, and theophylline, as it
may lead to unwanted toxicity. The concurrent use of the more toxic mercaptopurine and
azathioprine is contraindicated due to the increased risk of adverse effects.

Pegloticase

It is a recombinant enzyme that has been modified with polyethylene glycol (PEG) to increase
its stability and prolong its effects. It works by metabolizing uric acid, a substance associated
with gout, into a more water-soluble metabolite called allantoin. Allantoin is then further
broken down into glyoxylic acid and urea. By facilitating the conversion of uric acid into these
more soluble compounds, pegloticase helps to reduce the levels of uric acid in the body and
alleviate the symptoms of gout.

Uric acid metabolism.

Pegloticase, a protein-based drug used for the treatment of gout, is not effective when taken
orally and must be administered through intravenous (IV) infusion. To minimize the risk of
infusion-related anaphylaxis, patients are typically given antihistamines and corticosteroids as
premedication. It is important to note that individuals with glucose-6-phosphate
dehydrogenase deficiency are at a higher risk of experiencing infusion reactions and
anaphylaxis, and therefore should not receive pegloticase. In cases where pegloticase
treatment may trigger acute gout flares, proactive treatment with NSAIDs and/or colchicine is
recommended. This prophylactic treatment should start at least one week prior to pegloticase
administration.