Mechanism of drug action

of therapeutic drugs I
By Akshata Salvi
LIPID LOWERING DRUGS
Several drugs decrease plasma lipoprotein concentrations. Drug therapy is used
in addition to dietary measures and correction of other modifiable
cardiovascular risk factors. The main agents used clinically are:
1. statins: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors
2. PCSK9 inhibitors
3. fibrates
4. inhibitors of cholesterol absorption
5. nicotinic acid or its derivatives
2) Proprotein convertase subtilisin/kexin type-9
(PCSK9) inhibitors
• PCSK9 is synthesized in inactive form by many tissues, including brain and liver.
• It is activated autocatalytically by proteolytic cleavage, which removes a section of
its peptide chain that blocks its activity
• It is a protein that targets LDL receptors for degradation, therefore reducing
the liver's ability to remove LDL-cholesterol (LDL-C), or "bad" cholesterol,
from the blood.
• Family members who inherit a hyperactive form of the PCSK9 gene suffer from
severe hypercholesterolemia;
• individuals with inactivating mutations in this gene have low circulating LDL and a
low incidence of atheromatous disease. Individuals homozygous for inactivated
PCSK9 have very low plasma concentrations of LDL and are healthy.
• the development of monoclonal antibodies that block PCSK9, thereby
preventing it from combining with LDL receptors and marking them down for
lysosomal destruction.
• Evolocumab , alirocumab are used for treatment of primary
hypercholesterolemia in patients whose circulating LDL is not controlled by a
statin.
• Adverse effects: Nasopharyngitis and influenza-like symptoms
• Other agents that work by inhibiting this pathway, for example, a small
interfering RNA that causes long-lasting block of PCSK9 synthesis, are also
being developed
1. Evolocumab:
• Evolocumab is a monoclonal antibody designed for the treatment of
hyperlipidemia
❖ Mechanism of action:
• Evolocumab is a human IgG monoclonal antibody which targets PCSK9.
• PCSK9 is a serine protease produced by the liver which binds LDL receptors and
creates a complex to be targeted for lysosomal degradation. LDL receptors typically
bind LDL-cholesterol ("bad" cholesterol) for cellular reuptake, therefore the
formation of these complexes with PCSK9 inhibits LDL receptor recycling to the cell
surface, resulting in decreased cellular reuptake of LDL-C and increased levels of
free LDL-C in the plasma.
• Individuals with familial hypercholesterolemia often may have "gain of function"
mutations in the PCSK9 molecules in their body, resulting in increased LDL-C
plasma levels and a consequent cardiovascular risk. Evolocumab is able to bind
both the normal PCSK9 and the "gain of function" mutant, D374Y.
• The exact mechanism of the binding has not been published, however the
precursor molecule, mAb1, is indicative of the interaction. The mAb1 molecule
binds on the catalytic site of PCSK9 next to the binding site for the LDL receptor
and creates hydrogen bonds and hydrophobic interactions, resulting in the steric
inhibition of binding between PCSK9 and the LDL receptor.
• Because the formation of complexes between LDL receptor and PCSK9 are
prevented, the internalized LDL receptors are less likely to be degrated by
lysosomes and may recycle to the surface of the cell to serve their function of
3) Fibrates
• Also known as fibric acid derivatives includes bezafibrate, ciprofibrate,
gemfibrozil, fenofibrate & clofibrate.
• reduce circulating VLDL, and hence triglyceride, with a modest (approximately
10%) reduction in LDL and an approximately 10% increase in HDL.
1. Fenofibric:
• Fenofibric acid is a lipid-lowering agent that is used in severe
hypertriglyceridemia, primary hyperlipidemia, and mixed dyslipidemia.
• Due to its high hydrophilicity and poor absorption profile,1 prodrug ,
fenofibrate, and other conjugated compounds of fenofibric acid, such as
choline fenofibrate, have been developed for improved solubility,
gastrointestinal absorption, and bioavailability, and more convenient
administration.
 Mechanism of action:
• Fenofibric acid has ability to activate peroxisome proliferator receptor alpha (PPAR-
alpha)
• By activating PPAR-alpha, fenofibric acid increases lipolysis and the elimination
of triglyceride-rich particles from plasma by actuating lipoprotein lipase and
reducing production of apoprotein C-III, which acts as an inhibitor of lipoprotein
lipase activity.
• The resultant decrease in triglycerides causes an alteration in the size and
composition of low-density-lipoprotein from small, dense particles to large,
buoyant ones
• The size of these larger low-density-lipoprotein particles have a greater affinity
for cholesterol receptors and are therefore catabolized more rapidly
• Additionally, fenofibric acid's activation of PPAR-alpha also induces an increase
in the synthesis of apoproteins apo A-I, apo A-II, and high-density-lipoprotein
• the use of fenofibric acid can also act to reduce serum uric acid levels in
ordinary or hyperuricemic individuals by increasing the urinary excretion of uric
acid
 Metabolism:
• The CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A4 enzymes are not known to play a
role in the metabolism of fenofibric acid
• Rather, fenofibric acid is predominantly conjugated with glucuronic
acid and then excreted in urine
• A small amount of fenofibric acid is reduced at the carbonyl moiety
to benzhydrol metabolite which is, in turn, conjugated with
glucuronic acid and excreted in urine
 Adverse effects:
• Rhabdomyolysis is unusual but severe, giving rise to acute renal failure
associated with excretion of muscle proteins, especially myoglobin, by the
kidney.
• It occurs particularly in patients with renal impairment, because of reduced
protein binding and impaired drug elimination
• Fibrates should be avoided in such patients and also in alcoholics, who are
predisposed to hypertriglyceridemia but are at risk of severe muscle
inflammation and injury.
• Gastrointestinal symptoms, pruritus and rash are more common than with
statins. Clofibrate predisposes to gallstones, and its use is therefore limited
to patients who have had a cholecystectomy (i.e. removal of the gall
bladder).
4) Drugs that inhibit cholesterol absorption
❑ EZETIMIBE
• Ezetimibe is one of a group of azetidinone cholesterol absorption inhibitors, and is
used as an adjunct to diet and statins in hypercholesterolemia.
• It inhibits absorption of cholesterol (and of plant stanols) from the duodenum by
blocking a transport protein (NPC1L1) in the brush border of enterocytes, without
affecting the absorption of fat-soluble vitamins, triglycerides or bile acids.
• Ezetimibe is administered by mouth and is absorbed into intestinal epithelial cells,
where it localizes to the brush border, which is its presumed site of action
• It is also extensively (>80%) metabolized to an active metabolite
• lite. Enterohepatic recycling results in slow elimination.
• The terminal half-life is approximately 22 h. It enters milk (at least in animal studies)
and is contraindicated for women who are breastfeeding. I
• it is generally well tolerated but can cause diarrhea, abdominal pain or headache;
rash and angio-oedema have been reported.
ANTICOAGULANTS
• injectable anticoagulants (heparin and newer thrombin inhibitors);
• oral anticoagulants (warfarin and related compounds; orally active thrombin
inhibitors).
I) Heparin
• Heparin is an anticoagulant indicated for thromboprophylaxis and to
treat thrombosis associated with a variety of conditions such as
pulmonary embolism and atrial fibrillation.
• Unfractionated heparin is a highly acidic mucopolysaccharide formed of
equal parts of sulfated D-glucosamine and D-glucuronic acid with
sulfaminic bridges.
• Heparin inhibits reactions that lead to the clotting of blood and the
formation of fibrin clots both in vitro and in vivo.
• Mechanism of action
o Under normal circumstances, antithrombin III (ATIII) inactivates thrombin
(factor IIa) and factor Xa. This process occurs at a slow rate.
o Administered heparin binds reversibly to ATIII and leads to almost
instantaneous inactivation of factors IIa and Xa.
o The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin.
o The mechanism of action of heparin is ATIII-dependent.
o It acts mainly by accelerating the rate of the neutralization of certain activated
coagulation factors by antithrombin, but other mechanisms may also be
involved.
o The antithrombotic effect of heparin is well correlated to the inhibition of
factor Xa.
o Heparin is not a thrombolytic or fibrinolytic.
o It prevents progression of existing clots by inhibiting further clotting. The lysis
of existing clots relies on endogenous thrombolytics.
Administration and pharmacokinetics aspects
Heparin acts immediately following intravenous administration, but the onset is
delayed by up to 60 min when it is given subcutaneously. The elimination half-life
is approximately 40–90 min. In urgent situations, it is therefore usual to start
treatment with a bolus intravenous dose, followed by a constant-rate infusion
LMWHs are given subcutaneously. They have a longer elimination half-life than
unfractionated heparin, and this is independent of dose (first-order kinetics), so
the effects are more predictable and dosing less frequent (once or twice a day).
Absorption
Heparin is not absorbed through the gastrointestinal tract and is therefore
administered via a parenteral route. Peak plasma concentration and the
onset of action are achieved immediately after intravenous administration
Metabolism
Heparin does not undergo enzymatic degradation.
• Unwanted effects:
Haemorrhage
Thrombosis
Osteoporosis
Hypoaldosteronism
Hypersensitivity reaction
2) Warfarin
Warfarin is an anticoagulant drug normally used to prevent blood clot
formation as well as migration.
Warfarin does not actually affect blood viscosity, rather, it inhibits vitamin-k
dependent synthesis of biologically active forms of various clotting factors in
addition to several regulatory factors.
Mechanism of action:
Warfarin is a [vitamin K] antagonist which acts to inhibit the production of
vitamin K by vitamin K epoxide reductase.
The reduced form of vitamin K, vitamin KH2 is a cofactor used in the γ-
carboxylation of coagulation factors VII, IX, X, and thrombin.
Carboxylation induces a conformational change allowing the factors to bind
Ca2+ and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and
thrombin are biologically inactive and therefore serve to interrupt the
coagulation cascade.
The endogenous anticoagulation proteins C and S also require γ-
carboxylation to function. This is particularly true in the case of thrombin which
must be activated in order to form a thrombus.
vitamin KH2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction
catalyzed by γ-glutamyl carboxylase.
Vitamin K epoxide is then converted to vitamin K1 by vitamin K epoxide reductase
then back to vitamin KH2 by vitamin K reductase.
Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly
inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the
conversion of vitamin K epoxide to vitamin K1.
This process creates a hypercoagulable state for a short time as proteins C and S
degrade first with half lives of 8 and 24 hours, with the exception of factor VII which
has a half life of 6 hours.
Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours
resulting in a dominant anticoagulation effect.
In order to reverse this anticoagulation vitamin K must be supplied, either
exogenously or by removal of the vitamin K epoxide reductase inhibition, and time
allowed for new coagulation factors to be synthesized.
It takes approximately 2 days for new coagulation factors to be synthesized in the liver.
Vitamin K2, functionally identical to vitamin K1, is synthesized by gut bacteria leading
to interactions with antibiotics as elimination of these bacteria can reduce vitamin K2
• Administration and pharmacokinetic aspects
Warfarin is absorbed rapidly and completely from the gut after oral administration. It
has a small distribution volume, being strongly bound to plasma albumin
Warfarin is metabolized by CYP2C9, which is polymorphic (see Ch. 12). Partly in
consequence of this, its half-life is very variable, being of the order of 40 h in many
individuals
Warfarin crosses the placenta and is not given in the first months of pregnancy
because it is teratogenic, nor in the later stages because it can cause intracranial
hemorrhage in the baby during delivery. It appears in milk during lactation. This
could theoretically be important because newborn infants are naturally deficient in
vitamin K. However, infants are routinely prescribed vitamin K to prevent
hemorrhagic disease, so warfarin treatment of the mother does not generally pose a
risk to the breastfed infant.
• Unwanted effects of warfarin:
Hemorrhage
Teratogenic
Necrosis of soft tissues
ANTACIDS
1) Magnesium hydroxide
• Magnesium hydroxide is an inorganic compound
• Magnesium hydroxide can be used as an antacid or a laxative in
either an oral liquid suspension or chewable tablet form
• As a laxative, it is used for the relief of occasional constipation by
promoting bowel movements for 30 minutes and up to 6 hours.
 Mechanism of action
• The suspension of magnesium hydroxide is ingested and enters the
stomach. According to the amount ingested, the magnesium hydroxide will
either act as an antacid or a laxative.
• Through the ingestion of 0.5-1.5 grams (in adults) the magnesium
hydroxide will act by simple acid neutralization in the stomach.
• The hydroxide ions from the magnesium hydroxide suspension will combine
with the acidic H+ ions of the hydrochloric acid made by the stomachs
parietal cells.
• This neutralization reaction will result in the formation of magnesium
chloride and water.
Metabolism:
Unless a patient is deficient in magnesium, very little is absorbed by the
intestine. Overall, about 15%-50% of the magnesium hydroxide suspension
is absorbed systemically. However, it does not undergo any metabolism as it
is rapidly excreted in the urine.
 Toxicity
• Common side effects include drowsiness or flushing (warmth,
redness or tingly feeling).
• Daily use of magnesium hydroxide can result in fluid and electrolyte
disturbances.
• Excessive use of the laxative effects of magnesium hydroxide may
result in abdominal cramping, nausea and/or diarrhea.
• In overdose, symptoms of gastrointestinal irritation and/or watery
diarrhea may occur.
• Magnesium hydroxide poisoning can result in hypermagnesemia
which includes symptoms of: nausea, vomiting, flushing, thirst,
hypotension, drowsiness, confusion, loss of tendon reflexes, muscle
weakness, respiratory depression, cardiac arrhythmias, coma and
cardiac arrest.
 2) Mg trisilicate
. Magnesium trisilicate is an antacid used for the symptomatic treatment of
peptic ulcers.
Pharmacodynamics: Magnesium trisilicate works by increasing the pH of
gastric juice via a neutralisation reaction. It also precipitates colloidal silica,
which can coat gastrointestinal mucosa conferring further protection.
Mechanism of action: The gelatinous silicon dioxide, formed by the reaction
of magnesium trisilicate with gastric contents is said to protect ulcerated
mucosal surfaces and favor healing.
Absorption: The hydrated silicon dioxide formed in the stomach and passes
into the intestinal track where, silica can be partly absorbed.
Toxicity: Adequate doses of magnesium trisilicate may cause diarrhea due
to the action of soluble magnesium salts in the enteric tract. Approx 5% of
the magnesium is absorbed
 3) Aluminum hydroxide
• Aluminum hydroxide is an antacid used for the symptomatic relief of
heartburn, acid indigestion, and sour stomach.
• Aluminum hydroxide is an inorganic salt used as an antacid. It is a
basic compound that acts by neutralizing hydrochloric acid in gastric
secretions.
• Pharmacodynamics: Gastric-peptic disease occurs as a result of an
imbalance between protective factors, such as mucus, bicarbonate,
and prostaglandin secretion, and aggressive factors, such as
hydrochloric acid, pepsin, and Helicobacter pylori (H. pylori). Antacids
work by restoring acid-base balance, attenuating the pepsin activity
and increasing bicarbonate and prostaglandin secretion.
• Mechanism of action: Aluminum hydroxide is a basic inorganic salt
that acts by neutralizing hydrochloric acid in gastric secretions.
Aluminum hydroxide is slowly solubilized in the stomach and reacts
with hydrochloric acid to form aluminum chloride and water. It also
inhibits the action of pepsin by increasing the pH and via adsorption.
Cytoprotective effects may occur through increases in bicarbonate ion
Bismuth chelate
Bismuth chelate (tripotassium dicitratobismuthate) is sometimes used in
combination regimens to treat H. pylori.
It has toxic effects on the bacillus, and may also prevent its adherence to the
mucosa or inhibit its bacterial proteolytic enzymes.
It is also believed to have other mucosa-protecting actions, by mechanisms
that are unclear, and is widely used as an over-the-counter remedy for mild GI
symptoms.
Very little is absorbed, but if renal excretion is impaired, the raised plasma
concentrations of bismuth can result in encephalopathy.
Unwanted effects include nausea and vomiting, and blackening of the tongue
and faeces
omeprazole
• Omeprazole is a proton pump inhibitor used to treat GERD associated conditions such as heartburn and gastric acid
hypersecretion, and to promote healing of tissue damage and ulcers caused by gastric acid and H. pylori infection
• Pharmacodynamics
1) Effects on gastric acid secretion
This drug decreases gastric acid secretion. After oral administration, the onset of the antisecretory effect of omeprazole
is usually achieved within one hour, with the maximum effect occurring by 2 hours after administration. The inhibitory
effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days.
2) Effects on serum gastrin
In studies of 200 or more patients, serum gastrin levels increased during the first 1-2 weeks of daily administration of
therapeutic doses of omeprazole. This occurred in a parallel fashion with the inhibition of acid secretion. No further
increase in serum gastrin occurred with continued omeprazole administration. Increased gastrin causes
enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels
may lead to false positive results in diagnostic studies for neuroendocrine tumors
Mechanism of action:
• Hydrochloric acid (HCl) secretion into the gastric lumen is a process regulated mainly by the H(+)/K(+)-ATPase of the
proton pump 10, expressed in high quantities by the parietal cells of the stomach. ATPase is an enzyme on the parietal
cell membrane that facilitates hydrogen and potassium exchange 9
through the cell, which normally results in the
extrusion of potassium and formation of HCl (gastric acid) .
• Omeprazole is a member of a class of antisecretory compounds, the substituted benzimidazoles, that stop gastric
acid secretion by selective inhibition of the H+/K+ ATPase enzyme system. Proton-pump inhibitors such as
omeprazole bind covalently to cysteine residues via disulfide bridges on the alpha subunit of the H+/K+ ATPase pump,
inhibiting gastric acid secretion for up to 36 hours 11. This antisecretory effect is dose-related and leads to the
inhibition of both basal and stimulated acid secretion, regardless of the stimulus
 Mechanism of H. pylori eradication
• peptic ulcer disease (PUD) is frequently associated 12
with Helicobacter pylori bacterial infection (NSAIDs) . The
treatment of H. pylori infection may include the addition of
omeprazole or other proton pump inhibitors as part of the treatment
Label 13
regimen
14
, . H. pylori replicates most effectively at a neutral
pH . Acid inhibition in H. pylori eradication therapy, including proton-
pump inhibitors such as 13
omeprazole, raises gastric pH, discouraging
the growth of H.pylori . It is generally believed that proton pump
inhibitors inhibit the urease enzyme, which increases the
pathogenesis of H. pylori in gastric-acid related conditions.
• Absorption
• Omeprazole delayed-release capsules contain an enteric-coated
granule formulation of omeprazole (because omeprazole is acid-
labile), so that absorption of omeprazole begins only after the
Label
granules exit the stomach .
• Absorption of omeprazole occurs rapidly, with peak plasma Label
concentrations of omeprazole achieved within 0.5-3.5 hours .
• Absolute bioavailability (compared with intravenous administration)
is approximately 30-40% at doses of 20-40 mg, largely due to pre-
systemic metabolism. The bioavailability of omeprazole increases
slightly upon repeated administration of omeprazole delayed-release
• Protein binding
Approximately 95% bound to human plasma proteins
• Metabolism
Omeprazole is heavily metabolized in the liver by the cytochrome P450
(CYP) enzyme system. The main part of its metabolism depends on the
polymorphically expressed CYP2C19, which is responsible for the formation
of hydroxyomeprazole, the major metabolite found in plasma. The remaining
part depends on CYP3A4, responsible for the formation of omeprazole
sulphone.
Route of elimination
After a single dose oral dose of a buffered solution of omeprazole, negligible
(if any) amounts of unchanged drug were excreted in urine. Most of the dose
(about 77%) was eliminated in urine as at least six different metabolites.
Two metabolites were identified as hydroxyomeprazole and the
corresponding carboxylic acid. The remainder of the dose was found in the
feces. This suggests significant biliary excretion of omeprazole metabolites.
Three metabolites have been identified in the plasma,
the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole.
These metabolites possess minimal or no antisecretory activity
Overdose
• Symptoms of overdose include confusion, drowsiness, blurred vision,
tachycardia, nausea, diaphoresis, flushing, headache, and dry mouth.
Ranitidine
Ranitidine is a histamine H2 antagonist used to treat duodenal ulcers,
Zollinger-Ellison syndrome, gastric ulcers, GERD, and erosive
esophagitis.
This drug helps to prevent and treat gastric-acid associated conditions,
including ulcers,
2,11
because of its ability to decrease gastric acid
secretion. Ranitidine is often referred to as Zantac, and is available
in various forms, including tablet, injection, and effervescent tablet
preparations.
Mechanism of action
After a meal, the hormone gastrin, produced by cells in the lining of
the stomach, stimulates the release of histamine, which then binds to
histamine H2 receptors, leading to the secretion of gastric acid.
Ranitidine reduces the secretion of gastric acid by reversible binding
to histamine (H2) receptors, which are found on gastric parietal cells.
This process leads to the inhibition of histamine binding to this
receptor, causing the reduction of gastric acid secretion. The relief of
gastric-acid related symptoms can occur as soon as 60 minutes after
administration of a single dose, and the effects can last from 4-10
hours, providing fast and effective symptomatic relief.
• Absorption
Ranitidine is rapidly absorbed with peak concentrations reached within 1-3 hours after
administration, and varying greatly among patients. Bioavailability is about 50%-60% due to
hepatic metabolism. In a pharmacokinetic study of healthy
7,13
males, the AUC 0-infinity was about
2,488.6 ng x h/mL and the median Tmax was 2.83 hours. Food or antacids have limited effects on
8
absorption. One clinical study found that the administration of a potent antacid (150 mmol) in
subjects in the fasted state led to decreased absorption of ranitidine.
Protein binding
The plasma protein binding of ranitidine is approximately 15%.
Metabolism

The major metabolite in the urine is N-oxide, which represents less than 4% of the dose. Other
metabolites of ranitidine include S-oxide (1%) and desmethyl ranitidine (1%). 11,13
The feces contain
the remainder of the excreted ranitidine dose. Liver dysfunction has been shown to cause small,
but clinically insignificant, changes in various ranitidine pharmacokinetic parameters.
•
Oral doses of 1,000 mg/kg in mice and rats were not 12 found to be lethal. Intravenous LD50 values
in mice and rats were 77 and 83 mg/kg, respectively.
• Overdose information
• There has been limited experience with ranitidine overdose. Reported acute ingestions of up to
18 grams orally were followed by temporary adverse effects similar to the normal adverse effects
of this drug, including12tachycardia, bradycardia, dizziness, diarrhea, nausea, and vomiting,
among other effects. Gait abnormalities and hypotension have also been observed. When an
overdose with ranitidine is suspected, remove unabsorbed ranitidine from the gastrointestinal
tract if possible, and monitor the patient and provide supportive therapy as required.
Sucrafalfate:
sucralfate is a medication that is widely used to prevent and treat
Label
a number of
diseases in the gastrointestinal tract such as duodenal ulcers , gastro-
esophageal reflux disease (GERD), gastritis, peptic ulcer disease, stress
ulcer, in addition to dyspepsia
It is considered a cytoprotective agent, protecting cells in the gastrointestinal
tract from damage caused by agents such as gastric acid, bile salts, alcohol,
and acetylsalicylic acid (aspirin), among other substances
Mechanism of action:

This drug aids in the healing of duodenal ulcers, relieving painful

inflammation by creating a protective mechanical barrier between
2
the lining or
skin of the gastrointestinal tract and damaging substances . In addition,
sucralfate acts to increase levels of growth factors locally, and also causes an
increase in prostaglandins which are important in the healing of the mucosa
(lining) of the gastrointestinal tract
• in both humans and animals have indicated that sucralfate forms a
complex that binds to protein-rich exudate found on the surface of
ulcers. It binds to albumin and fibrinogen 7,8 preventing blood clot lysis
by stomach acid (hydrochloric acid). Sucralfate increases the tissue
levels of fibroblast growth factors and epidermal growth factors,
5,6
leading to an increase in prostaglandins at the gastrointestinal tract
lining, which promotes the healing of gastrointestinal ulcers.2
• Pepsin has been shown to be damaging to tissues, further aggravating
ulcer lesion inflammation 4. Bile salts have been implicated in mucosal
injury to the gastrointestinal tract 9,10. Sucralfate has also been shown
to adsorb bile salts in the laboratory, setting, which could further
contribute to its beneficial effects in ulcer healing.
• In the laboratory setting, a sucralfate-albumin film provides a barrier
against the entry of hydrogen ions, which are a component of gastric
acid.
• Volume of distribution
This drug is absorbed in a very small quantity, and normally localizes to
inflamed gastrointestinal lesions.
• protein binding
Sucralfate is bound to plasma proteins, especially albumin and
transferrin.
Metabolism
This drug is absorbed in very small quantities and is not significantly
metabolized
Route of elimination
The negligible amount of this drug that is absorbed is excreted mainly in
the urine within 48 hours
Toxicity : refer drug bank
CVS : Amlodipine
• Amlodipine is a calcium channel blocker used to treat hypertension and angina.
• is a popular antihypertensive drug belonging to the group of drugs
called dihydropyridine calcium channel blockers
Pharmacodynamics and mechanism of action:
• mlodipine has a strong affinity for cell membranes, modulating calcium influx by
inhibiting selected membrane calcium channels. This drug's unique binding
properties allow for its long-acting action and less frequent dosing regimen
• Mechanism of action on blood pressure
• Amlodipine is considered a peripheral arterial vasodilator that exerts its action
directly on vascular smooth muscle to lead to a reduction in peripheral vascular
resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine
calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the
influx of calcium ions into both vascular smooth muscle and cardiac muscle.
Experimental studies imply that amlodipine binds to
both dihydropyridine and nondihydropyridine binding sites, located on cell
membranes. The contraction of cardiac muscle and vascular smooth muscle are
dependent on the movement of extracellular calcium ions into these cells by
specific ion channels. Amlodipine blocks calcium ion influx across cell membranes
with selectivity. A stronger effect of amlodipine is exerted on vascular smooth
muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular
smooth muscle result in reduced blood pressure
• Mechanism of action in angina
• The exact mechanism by which amlodipine relieves the symptoms of
angina have not been fully elucidated to this date, however, the
mechanism of action is likely twofold:
• Amlodipine has a dilating effect on peripheral arterioles, reducing the
total peripheral resistance (afterload) against which the cardiac
muscle functions. Since the heart rate remains stable during
amlodipine administration, the reduced work of the heart reduces
both myocardial energy use and oxygen requirements 9.
• Dilatation of the main coronary arteries and coronary arterioles, both
in healthy and ischemic areas, is another possible mechanism of
amlodipine reduction of blood pressure. The dilatation causes an
increase in myocardial oxygen delivery in patients experiencing
coronary artery spasm (Prinzmetal's or variant angina) and reduces
coronary vasoconstriction caused by smoking
Propranolol
• Propranolol is a non-selective beta adrenergic antagonist used to treat
hypertension, angina, atrial fibrillation, myocardial infarction, migraine,
essential tremor, hypertrophic subaortic stenosis, and
pheochromocytoma.
• Mechanism of action:
Propranolol is a nonselective β-adrenergic receptor antagonist.
2
Blocking of these receptors leads to vasoconstriction, inhibition of
angiogenic factors like vascular endothelial growth factor (VEGF) and
basic growth factor of fibroblasts (bFGF), induction of apoptosis of
endothelial cells, as well as down regulation of the renin-angiotensin-
aldosterone system.
• Absorption
Propranolol has a Tmax of approximately 2 hours, though this can range
from 1 to 4 hours in fasting patients.5 Taking propranolol with food does
5
• Protein binding
Approximately 90% of propranolol is protein bound in plasma
Metabolism
Propranolol undergoes side chain oxidation to α-naphthoxylactic acid,
ring oxidation to 4’-hydroxypropranolol,
7
or glucuronidation to
propranolol glucuronide. It can also 1be N-desisopropylated to
become N-desisopropyl propranolol. 17% of a dose undergoes
glucuronidation and 42% undergoes ring oxidation.
Toxicity
Symptoms of overdose include hypotension,
8
hypoglycemic seizure,
restlessness, euphoria,
8
insomnia. Patients with asthma may develop
bronchospasm. In case of8 overdose, monitor vital signs, mental
status, and blood glucose. Treat hypotension with intravenous fluids,
bradycardia with8 atropine, and isoproterenol and aminophylline for
bronchospasm. If patients do not respond to intravenous fluids, follow
up with glucagon 50-150µg/kg intravenously, then 1-5mg/hour,
8,9,10
followed by catecholamines. Dialysis will not be useful as
propranolol is highly protein bound
Question bank

1. explain NSAIDs
2. Biosynthetic pathway of prostaglandins
3. Elaborate on cardiovascular drugs : amlodipine ; cardiac glycosides; propranolol
4. Elaborate on antacids
5. Write a note on lipid lowering drugs:
6. Elaborate on statins
7. Write a note on anticoagulants.