Pharmacology ii (mb) vol ii

PES College of Pharmacy, Dept of Pharmacology, Sub I/C K.P.S.Gowda
III PharmD, Pharmacology II (Theory) Date of commencement-2-11-2011 (Wednesday)
Class No-1 Date-2-11-2011
1. Pharmacology of Drugs acting on Blood and blood forming agents-
a) Anticoagulants- These are the drugs used to reduce the coagulability of blood.
Classification-
I. Used in vitro-
A. Heparin- 150U to prevent clotting of 100ml blood.
B.Calcium complexing agents-Sodium citrate, anticoagulant acid citrate dextrose solution,
sodium oxalate, sodium edetate.
II. Used in vivo
A.Heparin- Low molecular weight heparin. Heparinoids-Heparan sulfate. Hirudin.
B.Oral anticoagulants -i) Coumarin derivatives-Bishydroxycoumarin (dicumarol), warfarin sod,
acenocoumarol.
ii) Indandione derivatives- Phenindione.
Heparin-It is a mucopolysaccharide with MW 10,000 to 20,000. It carries strong electronegative
charges and it is the strongest organic acid present in the body. It is present in the mast cells,
liver and lungs.
Pharmacological actions- 1.Heparin activates anti-thrombin III (comes from liver). Anti-
thrombin is a small protein molecule (glycoprotein) produced by the liver and consists of 432
amino acids. It inactivates several enzymes of the coagulation system. Activated anti-thrombin
III catalyzes the inactivation of thrombin (factor II), factors IX, X, XI, XII, and XIII.
2. Heparin decreases the platelet aggregation, this prolongs the bleeding time.
3. Heparin stimulates the release of LPL (lipoprotein lipase), this reduces the TG level.

ADME-Heparin is not absorbed orally. It is given by sc, iv bolus, infusion. Onset of action –sc-
after 60 min, iv-immediate. It remains in the vascular compartment only. It is metabolized by
heparinase in liver and lung. Low molecular weight heparin is given s.c., has longer duration of
action. It is safe in pregnancy and does not cross placenta.
ADRs-1.Haemorrhagic complications- bleeding from peptic ulcer, piles, kidneys, development
of hematoma (blood in the outside the blood vessels), hemarthrosis (bleeding into joint spaces).
2.Thrombocytopenia due to platelet aggregation. 3. Allergic reaction- anaphylaxis – allergy test
is necessary. 4. Hepatotoxicity. 5. Transient alopecia. 6. Osteoporosis- If used for more than 6
months.
Dose- i.v.5,000 to 10,000 IU, SC 10,000 to 20,000 IU.
Low molecular weight heparin- (LMWH) is given SC. It has longer duration of action. It has
less effect on platelets. It is less antigenic. Enoxaparin is one of the low molecular weight
heparin.
Heparinoids- Eg.Heparan sulfate. Heparinoids are mucopolysaccarides obtained from different
animal organs like duodenum through soft extraction processes. They have low anticoagulant
property.
Therapeutic applications of heparinoids
1. Degrades the lipids by stimulating lipoprotein lipase.
2. Inhibition of cell proliferation in the vascular walls.
3. Prevents lipoprotein (LDL,chylomicrons,etc) deposition in the vascular walls.
3.Weak anticoagulation effect.
Hirudin- It is a naturally occurring peptide in the salivary glands of medicinal leeches. It is also
produced by DNA recombinant technology. Hirudin inactivates the thrombin. It prevents the
conversion of fibrinogen to fibrin. It also prevents the thrombin induced platelet aggregation. It is
given by i.v. infusion only. It has shorter duration of action.
b.Oral anticoagulants-i)Coumarins -Bishydroxycoumarin (dicumarol), warfarin sod,
acenocoumarol.
ii) Indandione derivatives- Phenindione-not used because of agranulocytosis.
Coumarins- Warfarin Na
Mechanism and actions- Warfarin- and related 4-hydroxycoumarin containing molecules
decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles
oxidized vitamin K to its reduced form after it has participated in the carboxylation of several
blood coagulation factors. Warfarin act by competitively blocking the Vit K actions and thereby
inhibit the synthesis of clotting factors-II, VII, IX and X in the liver. Effect is enhanced in
presence of liver diseases.

ADME- Rapid and complete absorption on oral administration. Warfarin is 99% PPB. It crosses
Placenta and secreted in milk. They have slow onset of action-16-48h and slow recovery.
Dose- Warfarin- 5mg OD / BID.
ADRs-
1. Haemorrhagic complications-hematuria, hemoptysis (coughing with blood), epitaxis
(nasal bleeding), ecchymoses, (The passage of blood from ruptured blood vessels into
subcutaneous tissue, marked by a purple discoloration of the skin), bleeding from peptic
ulcer, uterus and gums.
2. Teratogenic effects- Hemorrhagic complications in fetus.
3. Venous embolism- due to inhibition of protein kinase C.( family of enzyme that are
involved in controlling the functions of other enzymes).
Drug interactions-1.Activity of oral anticoagulants is enhanced by antiplatelet drugs,
broadspectrum antibiotics,sulfonamides, etc.
2. Activity of oral anticoagulants is decreased by phenobarbitone, oral contraceptive pills, etc.
Uses of anticoagulants-
1. Post operative prophylaxis.
2. Pulmonary embolism (sudden blockage of lung artery), deep vein thrombosis.
3. MI, unstable angina(heart attack).
4. CVA stroke. Cerebro vascular accident-it occurs when blood supply to part of the brain is
disrupted, causing brain cells to die.
CVA Pulmonary embolism

5. Prior to defibrillation.
7. Rheumatic heart disease (It is a disorder in which the heart valves are damaged due to
rheumatic fever caused by streptococcus bacteria).
8. Reccurent thromboembolism (formation of clot within blood vessel) .
9. Gangrene (death or decay of tissues due to lack of blood flow).
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Continued (class No 2,3, and 4 taken by R.Srinath)
Class No-5 Date- 10-11-2011, (9-10AM)
Folic acid- It is so called as it is present in green leaves (folia). Chemically it is pteroylglutamic
acid (PGA) consisting of pteridine,PABA and glutamic acid.Its structure is similar to
methotrexate. This is needed for the maturation of the RBCs.

Sources of folic acid-Green leafy vegetables, some fruits, eggs, meat, milk. Prolonged boiling
during cooking destroys most of the folic acid.
Metabolic functions of folic acid. It is involved in the following metabolic reactions. These
reactions are necessary for the synthesis of nucleic acid.
1. Conversion of homocysteine to methionine. This reaction requires methyl tetrahydrofolate as a
methyl donar and utilizes vitamin B12 as a cofactor.
2. Conversion of serine to glycine.
This reaction is essential for the
synthesis of thymidylate.
3. Metabolism of histidine to glutamic acid.
4. Synthesis of purine and pyrimidine nucleotides.
5. Incorporation of formate into the purine ring.

ADME-In the food folic acid is present in the inactive form-Polyglutamate. It is reduced by
folate reductase to dihydrofolate. Dihydrofolate is reduced by dihydrofolate reductase (DHFR) to
tetrahydrofolate. Tetrahydrofolate is utilized for the DNA synthesis (thymidylate synthesis).
Serine gets converted to glycine and tetrahydrofolate is converted into methyl tetrahydrofolate.
Folic acid mainly absorbed from small intestine as methyl tetrahydrofolate by active transport
process. When administered orally in large doses a fraction of it is absorbed by passive diffusion.
It is distributed in all tissues. It is stored mainly in the liver. Total body folic acid content is 5 to
10mg. Its exact metabolism and degradation in the body is not known. It is excreted in bile and
urine.
Daily requirement- Children-100µg, adults- 200 µg, pregnancy and lactation-400 µg.
Uses of folic acid-1.Megaloblastic/ macrolytic anaemia
2. Anemia in pregnancy.
3. Methotrexate toxicity.
Therapeutic dose- 5mg/day po. Prophylaxis-0.5mg/day.
Preparations- Folic acid 5mg tabs
Contraindications- 1.Leukemias, anemia with malignancy, chronic infections- where active cell
proliferation by folic acid can lead to aggravation of the conditions.
2. In pernicious anaemia without using vitamine B12. The folic acid may correct the
hematological abnormality but it precipitates or worsens the neurological complications due to
the deficiency of vit B12. Because vitB12 is essential for the integrity of CNS and peripheral
nerves.
Marketed preparations of folic acid-
Plasma expanders- These are high molecular weight substances which exert colloidal osmotic
(oncotic) pressure. When these are administered intravenously they help in retaining the fluid in
the vascular compartment.
Eg- Dextran, human albumin, hydroxyethyl starch (HES), Degraded gelatin polymer, Polyvinyl
pyrrolidone.
Desirable properties of plasma expanders-

1. Should exert osmotic pressure comparable to plasma. 2. Should remain in the blood
circulation. 3. Should be inert.4.Should not be pyrogenic or antigenic.
5. Should not interfere with grouping and cross matching of blood. 6.Should be cheap, stable and
easily sterilizable.
1.Dextran- It is a polysaccharide obtained from sugar beet. It is available in 150-70-40 thousand
molecular weight varieties. D-70 is the commonly used dextran. It is used as 6 to 10% solution.
Its dose is 10mg/kg. Oncotic effect is like plasma proteins. Duration of action is approximately
24h. It is slowly excreted by the kidneys. It prevents rouleaux formation, this improves
microcirculation. It interferes with grouping and cross matching of the blood. It produces allergic
reactions like uriticaria, bronchospam and anaphylaxis as it is antigenic. It also interferes with
blood coagulation and platelet function.Dextran-40 causes renal tubular damage, obstruction-
hence it is not preferred.
1.Dextran-70 6% sol in dextrose or saline
2Dextran-40 10% sol in dextrose or saline.
T.Uses- 1. Restoration of circulatory volume during surgery.
2.Prevention of postoperative deep-vein thrombosis.
2.Human albumin- It is obtained from pooled human plasma. 100ml 20% of human albumin =
400ml plasma or 800ml blood. Blood grouping/ cross matching is not required. It does not affect
blood coagulation, no hypersensitivity reactions, no transmission of disease. But it is costly.
Preparations- Human albumin-20% 50, 100ml inj
Indications-1.Emergency treatment of hypovolemic shock. (It is an emergency condition in
which severe blood and fluid loss makes the heart unable to pump enough blood to the body). 2.
In burn therapy- 3. In hypoproteinemia- During major surgery, patients can lose 50% of total
albumin; in these patients it is useful. 4.In adult respiratory distress syndrome (ARDS). (It is
characterized by deficient oxygenation due to pulmonary edema). It is useful if it is given along
with diuretics. 5.Acute liver failure, 6.In renal dialysis.
3.Polyvinyl pyrrolidine- It is a synthetic polymer (M.W.40,000) used as a 3.5% solution. It
interferes with grouping and cross matching of the blood. It causes histamine release. It binds
with insulin and penicillin. It is less commonly used as a plasma expander.
4.Gelatin polymer- It is a polypeptide. (M.W.30,000). It is used as 3.5% solution. It is non
antigenic, no affect on blood grouping and cross matching. Its duration of action is 12h. It is
more expensive than dextran.
Preparations-Polygeline-(Haemaccel)- each 100ml contains 3.5 g of degraded gelatin polymer.
T.Uses- Hypovolemic shock, burns and trauma. It is also used for priming the heart-lung
machine. It can also be used as a vehicle for some drugs.

5.Hydroxy ethyl starch (HES). It is composed of more than 90% amylopectin. Its M.W. is
about 4.5lacks. It is used as 6% solution.It has distinct plasma retention and volume effect. It
excert oncotic pressure similar to human albumin. Bronchospasm, anaphylactic shock may
occur. It does not interfere with grouping and cross matching of the blood.
Preparations- Expan-6% inj.
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Class No-6 Date-11-11-2011
2.Pharmacology of drugs acting on Renal System
a) Diuretics, b) Antidiuretics
a) Diuretics- Elimination of larger amounts of urine than normal is called ‘diuresis’ and
compounds which promote the flow of urine are termed as ‘diuretics’. The diuretics are
particularly useful in the treatment of ascites, CHF, edema of the lung, kidney and liver. In these
conditions fluid abnormally accumulates in the body. Since diuretics increase excretion of Na+
,
this is useful to produce antihypertensive effect. They are also used in salicylate, barbiturate
poisoning.
Ascitis kidney edema
Classification-
1. High efficacy diuretics (inhibitors of Na+
-K+
2 Cl-
co transport)
Furosemide, bumetanide. Torsemide, Ethacrynic acid, Mersalyl.
2. Medium efficacy diuretics (inhibitors of Na+
- Cl-
symporter)
a.Thiazides- i.Short acting (6-12h)-Chlorthiazide, hydrochlorthiazide, bezthiazide.
ii.Long acting (>12h) – Polythiazide.
b. Thiazide related drugs- Indapamide, metolazone, chlorthalidone, xipamide.
3. Weak or adjunctive diuretics
a.Carbonic anhydrases inhibitors- Acetazolamide.
b.Potassium sparing diuretics- Spironolactone,triamterine, amiloride.
c.Osmotic diuretics- Mannitol, isosorbide, glycerol.
d.Xanthines- Theophylline.

1.High efficacy (high ceiling or potent) diuretics (inhibitors of Na+
-K+
2Cl-
cotransport)
Furosemide bumetanide. Torsemide, Ethacrynic acid, Mersalyl.
Furosemide, bumetanide and torsemide are sulfonamide derivatives. As they act on ascending
loop of Henley, they are called loop diuretics. There is no ceiling on the response, response
increases as dose increases. Hence they are also called high ceiling diuretics.
MOA- In the loop of Henley about30-40ml/min reabsorption takes place. Glucose, amino acids
and other nutrients are not present, as these are already reabsorbed. On the apical surface of thick
ascending loop of Henley, there are Na+
K+
2Cl-
symporter (or cotransporter). The main effect of
these symporters is absorption of Na+
and Cl-
. The entered Na+
ions get transported by Na+
K+
ATPase by active transport into interstitial fluid. Then these Na+
ions diffuse into blood vessels.
The entered 2Cl-
ions flows out through free Cl-
channels, and then diffuse into blood vessels.
The K+
ions enter the tubular cells through Na+
K+
2Cl-
symporter and Na+
K+
ATPase. The
entered K+
ions secreted through free K+
channels. The movement of these positively charged K+
into tubular fluid through apical membrane K+ channels leaves the interstitial fluid and blood
with a –ve charge related to fluid of ascending loop of Henley. This relative negativity promotes
the reabsorption of Na+
, K+
, Ca2+
and Mg2+
via paracellular route. Loop diuretics act by blocking
the Na+
K+
2Cl-
symporter. This causes loss of Na+
and water and leads to diuresis.
ADME-Given orally or iv. Onset of action is quick. Excreted unchanged by filtration +
secretion. Short duration of action. Potency: bumetanide>torsemide>furosemide. Torasemide is
long acting drug and is given OD.
ADRs-1.Fluid and electrolyte imbalance-excessive loss of Na+
, K+
, Cl-
, H2O.
2. Acute fluid loss, hypotension can occur following vigorous loop diuretic therapy.

3.Hypokalemia- Following loop diuretic therapy, massive amount of Na+ is delivered into distal
tubule and CD. Because of this aldosterone is secreted, and due to this some Na+ gets reabsorbed
in exchange with K+ ions. Hence K+ excretion increases. This leads to hypokalemia.
4. Hypomagnesium- Loop diuretics cause deficiency of magnesium. This can be corrected by
magnesium rich diets.
5.Hyperuricemia- Both uric acid and furosemide enter the lumen of the PCT and for this entry
furosemide compete with uric acid. This reduces the secretion of uric acid into the lumen of the
tubule. This increases the uric acid levels and causes the development of gout.
6.Ototoxicity- This is due to chronic use of loop diuretics.
Therapeutic uses of loop diuretics-
1. Acute pulmonary edema- due to CHF.
2.Edema- In all varieties of edema. Cardiac, hepatic, renal.
3. Hypertension- In hypertensive emergency, higher dose of furosemide can be given for short
term.
4.In hyperkalemia- Furosemide excretes excess K+
ions.
5.Acute renal failure- Loop diuretics in such condition can promote urination and K+
excretion.
6.Hypercalcaemia
Preparations- 1. Furosemide/frusemide (LASIX) 20-80mg tabs.
2. Bumetamide (BUMET) 1mg tab.
Lasix tablets Lasix injection(10mg/ml)
2. Medium efficacy diuretics (inhibitors of Na+
- Cl-
symporter)
a.Thiazides i.Short acting (6-12h)-Chlorthiazide, hydrochlorthiazide, benzthiazide.
ii.Long acting (>12h) – Polythiazide.
b. Thiazide related drugs- Indapamide, metolazone, chlorthalidone, xipamide.

MOA- The apical membrane of the DCT expresses Na+
Cl-
co-transporter (symporter). The Na+
and Cl-
get reabsorbed by these symporters. The entered Na+
gets transported by Na+
K+
ATPase
into the interstitial fluid. From here they get diffused into blood vessels. The exchanged K+
ions
move out through K+
channels. The entered Cl-
ions move out the cells through Cl-
free channels.
From interstial spaces, then they get diffused into blood vessels. Thiazide diuretics inhibit
sodium chloride reabsorption in DCT. These agents act on the apical membrane of the early DCT
as competitive antagonists of NaCl for Na+
Cl-
cotransporter (symporter). They cause only
modest natriuresis (loss of Na+
). Because almost 90% of Na+
is already reabsorbed before the
fluid reaches the DCT, hence the diuretic effect is moderate.
Pharmacological actions-
1. Thiazide causes decreased excretion of Ca2+
and increased excretion of K+
and Mg2+
ions.
2. As thiazide decrease excretion of Ca2+
, they have been used to decrease urinary Ca2+
wasting
in osteoporosis and to diminish hypercalciurea in those at risk of kidney stones.
3.The thiazides increase the excretion of Na+
and decrease the peripheral resistance. Hence they
have antihypertensive effect.
4. Metabolic actions- Thiazides elevate the blood sugar levels, cholesterol and TG levels.
Thiazide decreases the uric acid excretion. This increases the serum uric acid level and
precipitates the gout.
ADME- Administered orally. Onset of action is within 1h. Some thiazides show high PPB and
lipid solubility. They have longer duration of action.
Dose-25-100mg/day in 2-3 dd. Diuretics are not generally given in the evening (to avoid sleep
disturbance)

ADRs-1.Hypokalemic, hypochloremic alkalosis. Hypokalemia is characterized by weakness,
muscle cramps, fatigue, and cardiac arrhythmias.
2. Allergic reactions- Thrombocytopenia, blood dyscrasia, and skin reactions.
3. Hyperglycemia, gout, lipid level abnormalities.
4. Aggravation of hepatic- renal insufficiency.
5. Cholestatic jaundice.
Therapeutic uses-
1. Generalized edema.
2. Edema due to CCF.
3. Edema due to kidney and liver disease.
4. Used in nephrogenic diabetes insipidus (depletion of ECF due to diuresis increases the tubular
reabsorption of Na+
and H2O, this decreases diuresis.
5. Used as antihypertensive agent.
6. Used in the treatment of kidney stones.
3. Weak or adjunctive diuretics
d.Xanthines- Theophylline.
MOA- Acetazolamide is a sulfonamide derivative which noncompetitively, but reversibly
inhibits the enzyme carbonic anhydrase in PCT cells. This decreases the availability of H+
ions
for H+
/Na+
exchange mechanism, leading to excretion of Na+
accompanied by H2O.Due to lack
of Na+
, bicarbonate (HCO3
-
) is excreted in urine in large amount. So plasma Cl-
is increased
leading to metabolic acidity. As the reabsorption of Na+
, K+
and HCO3
-
is reduced, they are
excreted in urine producing alkaline urine. They also increase phosphate excretion (mechanism
unknown), but have no effect on the excretion of Ca++
and Mg++
.

Pharmacological actions- (extra renal effects)
1. Decreases IOP, as there is decreases formation of aqueous humour.
2. Very larger doses of acetazolamide causes decrease HCl and pancreatic NaHCO3secretion.
3. Raised levels of CO2 in the brain-pH decreases –sedation.
4. Alterations of CO2 transport in the lung.
ADME-Absorbed orally and excreted unchanged in urine. Action of a single dose lasts for 8-12
h.
ADRs- 1.metabolic acidosis. 2. Hypokalemia. 3. Sulfonamide allergic reactions-rashes, blood
dyscrasias, crystalurea, renal damage. 4. Rarely parasthesia, drowsiness.5.Increases ammonia
reabsorption causing hepatic encephalopathy. 5. As it causes alkaline urine, precipitate renal
stone formation.
hepatoencephalopathy
DI- With salicylates, PPB of acetazolamide decreases, excretion also decreases causing toxicity.
Uses- Its use is restricted for diuretic purpose because of its adverse effects. The current uses of
this drug are glaucoma, prophylaxis in mountain sickness, to alkalinize the urine, periodic
paralysis, etc.
Preparation- Acetazolamide-250mg tabs OD-BD

Spironolactone- It is a steroid, chemically related to aldosterone. It is a competitive antagonist
of aldosterone. Aldosterone acts on the late DCT and CD by combining with an intracellular
mineralocorticoid receptor. The AL-MR complex enters the nucleus and stimulate gene of the
particular region of the DNA. This leads to DNA transcription and relevant mRNAs are formed.
These mRNAs come out from the nucleus and then directs the synthesis of aldosterone induced
proteins. These include Na+
channels and Na+
K+
ATPase. These The Na+
channel get translocated
to the luminal membrane and Na+
K+
ATPase translocated to basolateral membrane. All these
changes promote the reabsorption of Na+
and secretion of K+
ions. Spiranolactone act by
competitively blocking the mineralocorticoid receptor (MR). This decreases the reabsorption of
Na+
ions and decreases the secretion of K+
ions. This increases the excretion of Na+
and
decreases K+
excretion. As about 95% of Na+
already reabsorbed in the other parts of the tubules,
there is little scope for diuretic action. Hence they are considered as weak diuretics. Amiloride
and triampterine are not aldosterone antagonists, these act by decreasing the Na+
permeability in
the Na+
channel, thereby increases the Na+
excretion and decrease K+
secretion.
ADME- given orally, high PPB, FPM, enterohepatic circulation, produces active metabolites.
Preparation- Spiranolactone-25-50mg tab BD-QID.
ADRs- Hyperkalemia, depression of heart, gynacomastia, decreases libido, menstrual
abnormalities.
Uses-1.As it is a weak diuretic, it is given in combination.2. It is more useful in cirrhotic and
nephritic edema. 3. Used to counteract K+
loss due to thiazide and loop diuretic. 4. Used to treat
hypertention. 5. To treat CHF.
MOA- They act in the PCT and loop of Henle. By extracting water from the intracellular
compartments they expand extracellular fluid volume, decrease blood viscosity and inhibit
rennin release. These effects increase renal blood flow. The increased renal medullary blood
flow removes NaCl and urea from the renal medulla and reduces medullary toxicity. The osmotic

diuretics increase the urinary excretion of nearly all electrolytes including Na+
, K+
, Ca++
, Mg++
,
Cl-
, HCO3
-
and PO4
-
.
Mannitol is a sugar (polyhydroxy aliphatic alcohol with 4 hydroxy groups). It is
pharmacologically inert. They are filtered by the glomerulus without getting metabolized in the
body. Their presence in the lumen increases osmolality of proximal tubular fluid-> prevents the
reabsorption of water. This leads to the dilution of the Na+
in the luminal fluid-> decrease Na+
reabsorption. Mannitol is not absorbed orally, has to be given i.v. route as 10-20% solution.
Preparation- mannitol 10,20, 25% solution in 50ml amp- 100 to 500ml by I.V.infusion.
ADRs-Mannitol can escape from the hemorrhagic vessels and can cause dehydration of brain
cells by osmosis, acute congestive glaucoma, head injury, stroke,
Uses- Mannitol used in barbiturate poisoning, acute renal failure (due to rapid decrease in GFR),
cerebral edema,Glaucoma.
CI- Mannitol is contraindicated in dehydration, CCF and acute cerebral haemorrhage.
d.Xanthines- Theophylline. It is a methylxanthine . It produces mild transient diuresis. It acts
by increasing renal blood flow and glomerular filtration rate (GFR). It also acts by inhibiting the
tubular reabsorption by blocking adenosine A1 receptors. It is not used as a primary diuretic.
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Antidiuretics- These are the drugs used in the treatment of neurogenic diabetes insipidus. They
act by increasing the reabsorption of water in the PCT and CD of the nephron. The neurogenic
diabetes insipidus is due to deficiency of ADH (vasopressin). In neurogenic diabetes insipidus
the posterior pituitary gland fails to secrete ADH. This may due to defect or damage of posterior
pituitary gland in the brain. In nephrogenic diabetes insipidus, the secretion of ADH is normal,
but there is defect in the ADH receptors in the nephron. The destruction of the ADH receptor
may be due to gene defect or due to some drugs (e.g lithium).
ADH (vasopression)- It is the hormone secreted by the posterior pituitary gland. It is a 9
aminoacid peptide hormone. It acts on various types of vasopression receptors. Type 2
vasopressin receptors (V2) are expressed on the principal cells of the DCT and CD of the
nephron. These are G protein coupled receptors. When ADH bind with V2 receptors. This leads
to the activation of adenylyl cyclase (AC). The cAMP concentration increases within the cell.
This second messenger activates the PKC. The activated PKC causes the translocation of
aquaporin-2 channels to the luminal membrane. These channels get incorporated into the luminal
membrane of the cell. Through these channels water get reabsorbed.This restrict the urine out
flow. In neurogenic diabetes insipidus, there is lack of ADH. Hence there is excess urine out
flow. The synthetic vasopressin and desmopressin (vasopressin analogue) act on V2 receptors and
increases the tubular reabsorption and decreases urine out flow. Thus these are used in the
treatment of neurogenic diabetes insipidus.

Actions through V1 receptors. V1 receptors are expressed mainly on the smooth muscles of the
blood vessel. V1 is a G protein coupled receptor, when it is activated by vasopressin, the PLC get
stimulated. Through IP3 and DAG pathway, Ca2+
concentration increases, this combines with
calmodulin. The Ca2+-calmodulin complex activates myosin light chain kinase (MLCK). This
enzyme phosphorylate myosin light chain and causes vascular smooth muscle contraction.
Desmopressin not produces this effect as it is the selective V2 agonist. Hence vasopressin
produces vasoconstriction effect. This increases the B.P.
ADME- It is not administered orally as it is destroyed by the trypsin. It can be administered by
parenteral route or by intranasal route. It is metabolized in the liver and kidney. The metabolites
are eliminated through urine.
ADRs of vasopression-
1. Nasal irritation, congestion, ulceration.
1. Fluid retention and hyponatremia.
2. Precipitates the angina by coronary vasoconstriction.
3. Bronchospasm particularly in asthmatics.
The following are the antidiuretic drugs-
1. Vasopressin (Petressin).2. Lypressin (diapid), 3.Desmopressin. (desmopression acetate). 4.
Thiazide diuretic, 5.Amloride, 6.Chlopropamide.
Uses- 1. Used in the treatment of neurogenic diabetes insipidus.
2. Used to treat bed wetting in children and nocturia in adults.
3. Used to perform urine concentration test.
4. Used to treat hemophilia.

5. Used to treat bleeding esophageal varices- Used to stop the bleeding from the swallon veins of
the lower esophagus.
6. Used to remove the gases from the bowel, before abdominal radiography.
Preparations-1. Vasopressin (petressin) inj. It is a sterile aqueous solution of synthetic
vasopressin (8-L-Arginine vasopressin). It is administered by IM or SC route.
2. Lypressin (diapid)-It is a synthetic lysine vasopressin. It is administered by nasal spray.
3. Desmopression-It is a synthetic analogue of vasopressin. It is the selective V2 agonist. It is 12
times more potent than vasopressin. It may be administered orally, intravenously or nasal spray.
Thiazide- It is a diuretic; it produces diuretic effect by decreasing tubular reabsorption of Na+
. It
acts by inhibiting the Na+
Cl-
symporter in the DCT. The vasopressin or desmopressin is
ineffective in nephrogenic diabetes insipidus. There are no specific drugs for the treatment for
this disorder. However the thiazide administration along with salt restriction is indicated in NDI.
The thiazide act on the DCT, its therapy leads to decreased ECF; this increases the tubular
reabsorption of Na+
in the PCT, causing salt and water retention. Thiazide is also given along
with K+
sparing diuretic-amloride to prevent the K+
loss.
3.Chemotheraphy- a.Introduction-
Chemotheraphy- It is the technique in which specific chemical agents are used for the treatment
of parasitic diseases caused by microbes, protozoa and helminthes in order to inhibit their growth
and multiplication or to kill them with minimum injury to the host tissues. The term
chemotherapy was introduced by the famous German chemist Paul Ehrilh in 1891. He is known
as father of chemotheraphy.
Chemotherapeutic agent- These are the drugs used for the chemotheraphy. They are divided
into four groups.
1. Antimicrobial agents- e.g. antibacterial agents, antiviral agents, antifungal and antiviral agents.
2. Antiprotozoal agents.
3. Anthelmintic agents.
4. Anticancer agents.

Due to analogy between cancer cells and microbes, drugs used in the treatment of cancers are
called cancer chemotheraphy.
Antibiotics- Antibiotics are the drugs effective against microbes, which are obtained from the
microbes. E.g. Penicillin,ampicillin, tetracycline, chloramphenicol,streptomycin, etc.
The following are antimicrobial agents, but not antibiotics; Sulfonamides,
quinolones,chloroquine, co-trimaxazole, etc.
Chemotherapeutic Index (CTI)- It is the ratio of maximum tolerated dose to minimum curative
dose of a chemotherapeutic agent. The higher the index, the safer the chemotherapeutic agent,
e.g. Penicillins, cephalosporins, etc.
Chemoprophylaxis- It is the use of chemotherapeutic agents for the prevention of infectious
diseases during the incubation period i.e. before the development of clinical manifestations of
the disease, e.g. isoniazide for T.B.,dapsone in leprosy, penicillin in rheumatic fever, etc.
Classification of chemotherapeutic agents-
A.According to source- These are three groups.
1.Natural compounds- e.g. Quinine, emetine, vincristine etc.
2. Semisynthetic compounds- e.g.Ampicillin, cephalexin, doxycyclin, dehydroemetine, etc.
3.Synthetic compounds-Sulfonamides, quinolones, dapsone, chloroquine, metrinadazole.
B.According to the chemical structure-
1.Sulfonamides- e.g. Sulfadiazine, sulfadoxine etc.
2. Diaminopyrimidine- e.g. Trimethoprim and pyramethamine.
3.Quinolones-e.g.Nalidixic acid, norfloxacin.
4.Nitrofurans- e.g.Nitrofurantoin, nitrofurazone.
5. Nitroimidazoles- e.g. Metrinidazole and tinidazole.
6.Sulfones- e.g.Dapsone.
7. 4-aminoquinolines- e.g.Chloroquine
8. 8-aminoquinolones-e.g. Primaquine and pamaquine.
9. 8-hydroxyquine-e.g. Diiodohydroxyquine, and iodohydroxyquine.
10.Antibiotics- Pencillins, cephalosporins, tetracyclines.
C.According to type of action- These are two groups-
1.Bacteriostatic drugs,e.g. Sulfonamides, dapsone, tetracyclines, chloramphenicol, ethambutol,

2.Bactericidal drugs- e.g. Penicillins, cephalosporines, streptomycin, gentamicin, rifampicin,
isoniazide, cotrimoxazole.
D.According to mechanism of action-
1.Drugs inhibiting bacterial cell wall synthesis-Penicillins, cephalosporins.
2.Drugs causing damage of bacterial cell membrane- e.g.Polymyxin-B, amphotericin-B, nystatin.
3.Drugs inhibiting bacterial protein synthesis-e.g.Tetracyclines, chloramphenicol, erythromycin
etc.
4.Drugs causing misreading of mRNA- e.g.Streptomycin, gentamicin, neomycin.
5.Drugs inhibiting bacterial DNA synthesis/function, e.g. Rifampicin, quinolones and
metrinadazole.
6.Drugs inhibiting viral DNA synthesis-e.g.Acyclovir, zidovudine.
7.Drugs producing antimetabolite action- Sulfonamide, sulfones, trimethoprime.
8.Drugs damaging cellular microtubules- e.g. Griseofulvin, vinblastine.
Combination of antimicrobial agents- Sometimes two or more antimicrobial agents are used in
combination for the following advantages.
1.To prevent the resistant strains of organism as in tuberculosis and leprosy.
2. To enhance the antimicrobial activity.
a.Sulfamethoxazole and trimethoprime in bacillary dysentery.
b.Penicillin and gentamicin in enterococcal wndocarditis.
c.Gentamicin and carbenicillin pseudomonas infection.
d.Amoxacillin and clavalanic acid in UTI.
3.To broden the antibacterial spectrum in cases of mixed infections (peritonitis, brain abscess,
bronchiactesis and septicemia)- to cover both gram positive and gram negative microorganisms.
Disadvantages -1.Increased toxicity (local and systemic). 2.Posibility of super infection.
3.Development of resistance against both the drugs.
Superinfection (Opertunistic infection)- It is the appearance of a new infection during
chemotherapy of a primary infection. It is a potentially dangerous condition. Most antimicrobial
agents cause suppression of growth of normal microbial flora of the host present in the intestinal,
upper respiratory and genitourinary tracts. These microflora produces bacteriocin, which inhibits
the growth of pathogenic microbes.Micro-organisms that commonly produce superinfection are
Candida albicans, Staphylococci, Proteus, Pseudomonas and Clastridium difficile.

Drug resistance (Microbial resistance to drugs)- It is the unresponsiveness of microorganisms
to antimicrobial agents. It may be natural resistance or acquired resistance.
1. Natural resistance- It is the inherent resistance in some – microorganisms, from the
beginning. E.g M.tuberculosis to penicillins, gram positive bacteria to streptomycin.
2.Acquired resistance- It is the development of resistance in some micro-organisms after
prolonged use of antimicrobials. Some micro-organism,e.g. Staphylococci, E.coli, proteus,
M.tuberculosis, etc develop rapid resistance to antimicrobials. Gonococci develop rapid
resistance to sulfonamides but slow resistance to penicillins.Some bacteria produce enzymes that
reside at or within the cell surface and inactivated the drug, e.g.β lactimase (penicillinase)
produced by Staphylo cocci, gonococci etc. inactivating penicillin-G.
Aquired resistance is of different types.
a.Nongenetic resistance: Once the infection has been brought under control by antimicrobial
agents, a few bacteria may remain dormant (inactive) in the host and unable to multiply. These
non-multiplying bacteria are resistant to antimicrobial agents.
b.Genetic resistance: It is due to chromosomal genetic alterations occur in the micro-organisms.
It may be due to extrachromosomal genetic element called plasmids present in the micro-
organisms. Genetic mutation occurs by transfer of resistant gene from one bacterium to other
bacterium.
Cross resistance- It is the development of resistance of microorganism to one antimicrobial drug
having resistance to another antimicrobial drug due to similarity of chemical structures between
these drugs, e.g.resistance to one sulfonamide means resistance to another sulfonamide,
resistance to one tetracycline means resistance to another tetracycline etc.
b) Sulfonamides and co-trimoxazole
Sulfonamides: These are synthetic antimicrobial agents. Gerhard Domagk (1935) discovered
that azo dye ‘Prontosil’ when administered is broken down in the body to sulfanilamide, which is
the active compound for antimicrobial activity against many micro-organisms. He was awarded
the Nobel Prize in medicine in 1938 for this discovery. These were the first antimicrobial agents
effective against pyogenic bacterial infections. But now their uses have diminished due to
introduction of antibiotics, which are more effective and less toxic.
Chemistry: Sulfonamides are the derivatives of para-amino benzene sulfonamide
(sulfanilamide), which resembles para-amino benzoic acid (PABA) in chemical structure.
sulfanilamide
PABA

The individual sulfonamides differ in the nature of sulfonamide (SO2NH2) group. A free amino
group in the para position is required for the antibacterial activity.
Classification:
1. Sulfonamides used for the treatment of systemic infections. These are absorbable.
Depending on their duration of action, these are divided into 3 groups.
a. Short acting sulfonamides: (4 to 8h) –Sulfadiazine, sulfadimidine.
b.Intermediate acting; (8-16h)- Sulfamethoxazole and sulfamoxole.
c.Long acting sulfonamides: ( up to 7 days)-Sulfamethopyrazine, sulfadoxine.
2.Sulfonamides used for the treatment of bowel infections: These are poorly absorbable, e.g.
Sulfaguanidine, phthalyl sulfathiazole, succinyl sulfathiazole, sulfasalazine.
3.Sulfonamides used topically in eye and skin infections: Sulfacetamide (eye drops), silver
sulfadiazine (skin ointment).
MOA-Sulfonamides are bacteriostatic drugs and act by inhibiting the folic acid synthesis in the
susceptible bacteria. Sulfonamides are structural analogs and competitive antagonists of PABA.
They prevent the utilization of PABA in the synthesis of folic acid (pteroyl glutamic acid).
Sulfonamide act by inhibiting the enzyme dihydropteroate synthase. This prevents the formation
of dihydrofolic acid. The trimethoprime inhibits the dihydrofolate reductase. This prevents the
formation of tetrahydro folic acid. This prevents the formation of purine bases for the synthesis
of DNA. This retard the protein synthesis in bacteria. This leads to bacteriostatic effect.Human
cells also require folic acid (FA) but they utilize preformed FA supplied in the diet and are
unaffected by sulfonamides.Only those microbes which synthesize their own FA are susceptible
to sulfonamides. Sulfonamides are ineffective in presence of pus, as it contains more PABA.

Mode of action
Sulfonamide resistance: 1.An alteration of the enzyme dihydropteroate synthase, which
utilizes PABA in the bacteria.
2. An increased bacterial capacity to inactivate the drug.
3. Development of an alternate metabolic pathway in the bacteria to synthesize folic acid.
Pharmacokinetics: Sulfonamides for systemic uses are rapidly and completely absorbed from
the GIT. The small intestine is the major site of absorption but small amount is absorbed from
the stomach and large intestine. Peak plasma concentrations are achieved in 2 to 6h. In the blood
they are bound to plasma proteins (albumin and globulin). They are widely distributed in the
body tissues and fluids. They can cross BBB and the placental barrier. They are metabolizing
mainly in the liver by acetylation. The acetylated metabolites have no antibacterial activity, but
retain the toxicity as that of parent compound. The free sulfonamides and its metabolites are
excreted through urine. Small amount of sulfonamides are excreted in faeces, bile, milk and
other secretions. Sulfonamides for intestinal uses are poorly absorbed from the GIT and are
excreted mainly in faeces.
Clinical uses:
1. Absorbable systemic sulfonamides are used in UTI -pyelitis ( inflammation of the renal
pelvis), pyelonephritis (bacterial kidney infection) and cystitis(bladder inflammation) caused by
E.coli.

Pyelitis Cystitis
2. Acute bacillary dysentery: Sulfonamides are used in acute bacillary dysentery caused by
Shigella organisms, but due to development of bacterial resistance, these are less preferred now.
Shigella
3. Ulcerative colitis (an inflammatory bowel disease): Salfasalazine is used orally in ulcerative
colitis.
Ulcerative colitis Meningococcal meningitis Meningococci
4. Meningococcal meningitis: Systemic sulfonamides may be used in this infection caused by
meningococci, but due to the development of bacterial resistance sulfonamides are less preferred.
5. Nocardia infection ( Nocardia infection is a rare disorder affecting the lungs, brain, or skin.) It
occurs mainly in people with weakened immune systems.) Sulfadiazine or sulfafurazole is used
in nocardiosis.
Nocardia infection

6.Toxoplasmosis: (Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma
gondii . This infection passes from animals like cat to humans). Sulfadiazine with
pyramethamine is used in this treatment.
Taxoplasmosis Malaria causing mosquito
7. Sulfadoxine with pyramethamine is used in the treatment of malaria.
8. Trachoma and inclusion conjunctivitis: Trachoma is the eye infection due to Chlamydia
trachomatis. It causes roughening of the inner eyelids. sulfacetamide is used as eye drops to treat
these infections. Inclusion conjunctivitis is the inflammation of conjunctiva caused by
Chlamydia trachomatis.
Trachoma Inclusion conjunctivitis Sulfadiazine injection
Preparations-
Silver sulfadiazine sulfadoxine-pyramethamine tabs Sulfacetamide eye drops
ADRs: 1.GIT- Nausea, vomiting and abdominal pain.

2. Nephrotoxicity-(albumin urea, crystal urea and hematurea)In the presence of acid urine, the
acetylated sulfonamide is precipitated. The renal complications can be minimized by
administration of alkali mixture and plenty of water intakes.
3.Hypersensitivity (allergic) reactions-
Skin rash Drug fever Erythema nodosum
Stevenson Jonson syndrome Exfoliative dermatitis
4. Blood dyscrasias (haemopoietic toxicity); Haemolytic anemia due to deficiency of G-6-PD in
RBCs. Prolonged use can leads to bone marrow depression.
5. Neurological toxicity: Peripheral neuritis,
Confusion Depression Tinnitus

Fatigue Goiter
6. Endocrine disorders: Prolonged use leads to goiter and hypothyroidism by inhibiting the
synthesis of thyroid hormones.
7.Kernicterus in newborn- When administered in new born infants especially in premature
babies, they may produce kernicterus by displacing bilirubin from plasma proteins (albumin)
binding site, which is deposited in the basal ganglia and subthamic nuclei of the brain.
Contraindications: Sulfonamides are contraindicated in new born infants, lactating mothers,
pregnant women and history of hypersensitivity reactions.
Drug interactions: Displaces from PPB sites: Phenytoin, oral anticoagulants, oral antidiabetics
and methotrexate.
Cotrimoxazole:It is a combined preparation of trimethoprime (80mg) and sulfamethoxazole
(400mg) in ratio 1:5. Trimethoprime is a pyrimidine derivative and sulfamethoxazole is an
intermediate acting sulfonamide. When used individually they are bacteriostatic drugs but when
used in combination they become bactericidal drugs. This is because they block two successive
steps (sequential block) in the same metabolic pathway for the synthesis of folic acid of the
bacteria, which is required for the synthesis of nucleic acids (adenine, guanine, cytosine and
thymine) in the bacteria.
Advantages of combination:
1.Individually both are bacteriostatic-> combination is bactericidal.
2.Antibacterial spectrum is wider.
3.Delayed development of bacterial resistance.
ADRs: Similar to sulfonamides.

MOA:
Clinical uses:
1.UTI caused by E.coli/Proteus.
2.RTI: (Respiratory tract infections)
Tonillitis Sinusitis Pharyngitis
Chronic bronchitis Otitis media
3. Bacterial dysentery due to Schigella, E.coli.
4. Typhoid. 5. Wooping coughs (pertussis).

Typhoid Whooping cough
Preparations:
1.Cotrimazole tabs (80+160mg)
2.Cotrimazole DS (160mg+ 800mg)
3.Cotrimoxazole paediatric tablet: (20mg+ 100mg)
4.Cotrimoxazole suspension (40 mg + 200mg).
c) Penicillins and Cephalosporins (Betalactum antibiotics).
Betalactum antibiotics contain a betalactum ring in their chemical structure. These are
penicillins and cephalosporins.
Penicillins: These are a family of antibiotics that contain 6-aminopenicillanic acid in their
chemical structures.
History: It is the first antibiotic discovered by Sir Alexander Fleming in 1929 from fungus. Later
on two chemists Florey and Chain purified it in crystalline form and introduced its clinical
practice. They were awarded Nobel Prize in medicine in 1941 for their work on penicillin.
Source: Penicillin is obtained from Penicillium notatum and Penicillium chrysogenum.
Chemistry: The basic structure of all penicillins is 6-aminopenicillanic acid (6-APA), which
consists of a thiazolidine ring , fused with a beta-lactum ring , to which a side chain is attached.

Semisynthetic penicillins are produced by altering the composition of the side chain attached to
6-APA. Both side chain and 6-APA nucleus are essential for antibacterial activity. The side chain
also determines the stability of penicillin against inactivation by gastric acid and the enzyme
penicillinase (beta lactamase) produced by some bacteria.
Classification:
1.Natural penicillins: e.g. Penicillin-G (benzyl penicillin).
2.Semisynthetic penicillins: (newer penicillins).
a.Acid resistant penicillins:e.g.Phenoxymethyl penicillin (penicillin V).
b.Penicillinase (beta lactamase ) resistant penicillins,e.g Methicillin, oxacillin, cloxacillin,
dicloxacillin.
c.Extended spectrum penicillins. These are
Aminopenicillins-e.g. Ampicillin, amoxicillin, pivampicillin and bacampicillin.
Carboxy penicillins:e.g.Carbenicillin and ticarcillin.
Ureidopenicillins;e.g.Piperacillin,azolcillin.
Amidino penicillins: Mecillinam.
Penicillins with beta lactamase inhibitors: Amoxacillin with clavulanic.
MOA: Penicillins are bactericidal antibiotics. They are effective against rapidly multiplying
(growing) bacteria. The bacterial cell wall is made up of a chemical substance called
peptidoglycan, which gives rigid mechanical stability to the cell wall and protects the bacteria
from the external environment.
Two types of glycan chains are N-acetyl murA) and N-acetyl-glucosamine (NAG).Short peptide
chains (stem peptides) connects adjacent NAMAs. Each stem peptide is cross linked with
another peptide. This is produced by the process called transpeptidation, which is catalysed by
the enzyme transpeptidase. Penicillin binding proteins are bacterial enzymes located in the inner

cell membrane. These enzymes are responsible for the synthesis and cross linkage of the
peptidoglycans in the cell wall. Penicillins bind with these proteins and inactivate them, there by
inhibits the transpeptidation. This weakens the bacterial cell wall and so water medium (plasma)
enters the bacterial cells. This leads to lysis and death of bacteria.
Penicillin-G: (Benzyl penicillin): It is narrow spectrum penicillin. It is effective mainly against
G + and G – cocci and some G + bacilli. G- bacilli are resistant its action.
ADME: It is poorly absorbed from GIT as it is lipid insoluble. A small portion of oral dose is
found in faeces as it is mostly inactivated by the intestinal flora. In infants and elderly persons it
is absorbed from GIT to a great extent due to lower gastric acidity. Presence of food in stomach
and intestine interfere with its absorption, as it is adsorbed on the food particles. Hence it is
administered 1h before or 2 h after a meal. When administered parenterally it is rapidly and
completely absorbed. Its peak plasma concentration reached with in 30min and disappears from
the plasma within 6h. Hence it should be administered 6hly.After absorption it is widely
distributed in the body tissues and fluids mainly ECFs. It can cross placental barrier, but can’t
cross BBB in normal persons as it is lipid insoluble. In meningitis, the inflammed meninges
become permeable to it. About 60% of the drug bound to plasma proteins (albumin). It is (about
30%) metabolized in the body by unknown mechanism. It is excreted by glomerular filtration
and tubular secretion. It is also excreted through bile, milk and saliva in small amounts.
Probenecid blockes the tubular secretion of penicillins, thereby increasing the duration action of
penicillins.
Clinical uses:
1.In streptococcal infections: Pharyngitis, scarlet fever, pneumonia, otits media,mastoiditis,

Scarlet fever Pneumonia Lung abscess Mastoiditis acute nephritis
2.In staphylococcal infections: Boils, abscesses,enterocolitis,osteomyelitis, otitis media,
enterocolitis,, osteomyelitis and bacterial endocarditis.
Boils Abscesses Osteomyelitis
3. Pneumococcal infections: Pneumonia, empyema, pericarditis, meningitis, otitis media and
osteomyelitis.
Empyema Meningitis
4. Meningo coccal infections: Meningitis, septicaemia.
5. STDs: Gonorrhoea and syphilis.
Gonorrhoea Syphilis

6. Anthrax and actinomycosis:
Anthrax Actinomycosis
7. Diphtheria, tetanus and gasgangrene.
Diphtheria
Preparations of penicillins:
1. Short acting preparations:
a. Benzyl penicillin (sodium or potassium salt) 5 to 10 lack units /vial, i.v. or IM injection.
b. Benzyl penicillin potassium (pentids) tabs: (2to 8 lac units).
2. Long acting penicillins:
a. Procaine benzyl penicillin.(6lac, 12lac units)
b.Fortified benzylpenicillins: (3lac Procaine pen.+1 lac benzyl pen.)
c.Benzathene penicillin-G (penidure): (6,12,24 lac units/vial).
d.Penicillin G: with aluminium monostearate: It is now not used.
ADRs:
1. Hypersensitivity reactions: These occur in 1 to 2% patients. These include skin rashes,
pruritus,, serum sickness, fever, eosinophilia, arthralgia, asthma, hematurea, albuminurea, and
hemolytic anaemia.Anaphylaxis is the most serious reaction that occurs in 0.005% of
patients.Intradermal skin test with dilute solution of penicillin must be done to detect
anaphylaxis.
2. Jarisch-Herxheimer reaction- It is observed in patients with syphilis.
3. Super infection: It is rare with penicillin-G.
4. Hyperkalemia: It may occur if excessive amount of potassium penicillin G is administered to
patients with impaired renal function.

5. Miscellaneous reactions: It can rarely produce nephrotoxicity. When administered
intrathecally in meningitis, it can produce CNS toxicity like headache, dizziness, auditory and
visual disturbances. Oral penicillin G may produce nausea and vomiting.
Cephalosporins (beta lactum antibiotic). These are a family of antibiotics that contain 7-
aminocephalosporanic acid in their chemical structures to which two side chains at R1 and R2 are
attached to produce different cephalosporins.
Classification (based on generation)
1.First generation cephalosporins: a.Oral: Cephalexin, cefadroxil. b.Parenteral: Cephalothin,
cefazolin and cephaloridine.
2.Second generation cephalosporins: a.Oral: Cefuroxime axetil, cefactor.
.b.Parenteral:Cefuroxime, cefoxitin.
3.Third generation cephalosporins: a.Oral : Cefixime and cefpodoxime proxetil.
b.Parenteral:Cefotaxime, ceftriaxone.

4.Fourth generation cephalosporins: Parenteral –cefepime and cefpirome.
MOA:
The MOA of cephalosporin is similar to penicillin. Cephalosporins are resistant to betalactamase,
but sensitive to cephalosporinase produced by some strains of gram negative bacteria.
Cephalosporinase destroys the betalactum ring of cephalosporins and thus the bacteria become
resistant to them. The cephalosporins have wide range of activity against gram positive and gram
negative bacteria. The fourth generation cephalosporins are more resistant to some betalactamase
producing bacteria.
ADME: Cephalosporins are administered orally or intravenously; IM injection is painful. After
absorption majority of cephalosporins are not metabolized in the liver, except cephalothin,
cefazolin and cefotaxime, which are deacetylated in the liver. Their body distribution is similar
to penicillins. They can penetrate into CSF, synovial and pericardial fluids in sufficient
concentrations. They are excreted in urine and bile. Like penicillins, probenecid slows the renal
excretion of cephalosporins by blocking their renal tubular secretion. Their renal excretion is
reduced in renal insufficiency.
Clinical uses: They are widely used and therapeutically useful antibiotics. They are effective as
both therapeutic and prophylactic agents.
1. As alternative to penicillin G in patients developing allergic reactions.
2. Respiratory, urinary and soft tissue infections caused by gram negative organisms.
3. Penicillinase producing staphylococcal infections.
4. Septicaemias (a condition caused by pus forming microorganisms in the blood) caused by
gram negative bacteria.
5.Surgical prophylaxis. 6. Various types of meningitis. 7. Various forms of gonorrhea.
8. Typhoid 9.Mixed aerobic-anaerobic infections. 10. Prophylaxis and treatment of infections in
neutropenic patients.
ADRs: These are more toxic than penicillins.

1. Their common adverse effects are hypersensitivity reactions like penicillins. They can cause
blood dyscrasias like neutropenia and thrombocytopenia (by bone marrow depression).
2. Disulfiram like effects with some cephalosporins.
3. Diarrhoea due to superinfection.
4.CNS toxicity: Nystagmus (uncontrollable movements of the eye), cerebral irritation and
hallucinations (perception in the absence of stimulus).
Cerebral irritation Hallucinations
5.Nephrotoxicity: When larger doses are administered along with frusemide or gentamicin.
Some preparations: 1.Cephalexin caps, tabs and dry syps. 2.Cefadroxil caps, tabs and dry syps.
3.Cefuroxime axetil caps. 4.Cefotaxime injection. 5.Ceftriaxone inj.6.Cefuroxime inj.
7.Cefepime inj. 8.Cefpirom inj

d) Tetracyclins and Chloramphenicol (broad spectrum antibiotics)
These are broad spectrum antibiotics, as they active against a wide range of micro-organisms
including bacteria, rickettsiae and chlamydiae.
Tetracyclins: These are tetracycline compounds contain 4 cyclic rings in their structures.
Basic structure of tetracycline
Source: The first tetracycline ‘chlorotetracycline’ was isolated from Streptomyces aureofaciens. This was
followed by oxytetracycline, isolated from Streptomyces remosus. Tetracycline was prepared by
catalytic degradation of chlorotetracycline.
Classification:

1.Natural tetracyclines (older tetracyclines)- Chlorotetracyclines, oxytetracyclins and tetracyclines.
2.Semisynthetic tetracyclines: (newer tetracyclines):Dimethylchlorotetracyclines, methacycline,
doxycycline and minocycline.
Antibacterial activity: They possess a wide range of antimicrobial activity against aerobic and anaerobic
gram positive and gram negative bacteria, rickettsiae, spirochetes(gram negative bacteria),
Mycoplasma(bacteria without cell wall), clamydia (bacteria causes STD), Actinomyces(causes long term
bacterial infection that effects face and neck), Entamoeba histolytica , Plasmodia, except viruses and
fungi.
Mycoplasma actinomycosis
Entamoeba histolytica
RBCs gets infected by plasmodia

MOA: The bacterial ribosomes are made up of 30S and 50S subunits. The mRNA attaches to the
30S ribosome.The tetracyclines block the bacterial translation by binding reversibly to the 30S
ribosomal subunit. This prevents the binding of the aminoacyl tRNAs (charged tRNAs) to the A-
(acceptor) site of the ribosome. During protein biosynthesis, the new t-RNA with the amino acid
attempts to bind to A-site of the ribosome. However, since the A-site is blocked by the
tetracycline, the aminoacyl-tRNA cannot bind to it. Thus without the sequential attachment of
the tRNA at the A-site, protein biosynthesis cannot occur. By inhibiting protein biosynthesis
tetracyclines cause cell death of the bacterial cell.
MOA of bacterial resistance to tetracyclines:
1. Decreased accumulation of tetracyclines as a result of decreased antibiotic influx pathway.
2.Decreased access of tetracyclines to the ribosome because of the presence of ribosomal
protection protein.
3.Enzymatic inactivation of tetracyclines.
ADME: The older tetracyclines are incompletely absorbed from g.i.t., absorption is better if
taken in empty stomach. Doxycycline and minocycline are completely absorbed irrespective of
food. Tetracyclines have chelating property- form insoluble complexes with calcium and other
metals, milk, antacids, iron preparations. Most absorption takes place from the stomach and
upper part of small intestine in acidic medium. After absorption, they are distributed widely in
the body tissues and fluids. They accumulate in RE cells of liver, spleen and bone marrow and in
bone. In the CSF, they reach only 20% of that of plasma concentrations but minocycline and
doxycycline being lipophillic can attain high CSF concentrations (50% of that of plasma
concentrations). Tetracyclines cross placental barrier and enter the fetal circulation and amniotic
fluid. They are also secreted in milk. They are metabolized in the liver and excreted mainly in
the urine by glomerular filteration except doxycycline which is excreted through liver and bile.
Hence, only doxycycline can be used in renal insufficiency.
Clinical uses:
1. Rickettsial infections (murine, scrub typhus)

2.Clamydial infections (pneumonia, bronchitis)
3.Mycoplasma infections.(bronchitis, urethritis)
4.STDs: (gonorrhoea, syphilis.)
5.Bacillary infections (peptic ulcer, bacillary dysentery.)
6.Coccal infections: Pneumococcal infections, meningococcal infections.
7.UTI: Cystits, prostatis and urethritis.
8.RTI: Pharyngitis, sinusitis and chronic bronchitis.
9.Acne volgaris.
Acne volgaris Lyme disease
10. Other infections: Actinomycosis, nocardial infections (nocardiosis is an infectious
disease affecting either the lungs (pulmonary nocardiosis) or the whole body (systemic
nocardiosis),brucellosis (brucellosis is an infectious disease that occurs from contact with
animals carrying Brucella bacteria), Lyme disease,
Preparations.
1.Tetracycline caps 250, 500mg.1% ophthalmic ointment.

2.Doxycyline 100mg caps. 3.Minocycline 100mg caps
ADRs:
1.GIT side effects: Nausea, vomiting ,epigastric distress, diarrhea, stomatitis(inflammation of the
mucous lining of the mouth),, glossitis and proctitis.
Epigastric distress Stomatitis Glossitis
2.Hypersensitivity reactions: Skin rashes, uriticaria, fever, exfoliative dermatitis, anaphylaxis and blood
dyscrasias (leucopenia, thrombocytopenia, anemia).
Uriticaria Tetracyclin deposited teeth
3. Tooth and bone effects: Tetracyclins chelate calcium forming a calcium orthophosphate complex,
which is deposited in areas of calcification in the bones and teeth. Hence tetracyclines should be
avoided in infants and children up to 8years and also during pregnancy.

4.Azotemia (rise in blood urea nitrogen/BUN)-In patients with renal impairment tetracyclines may cause
azotemia by inhibition of protein synthesis leading to accumulation of aminoacids and excessive
formation of nitrogenous waste products.
5.Other adverse effects: Hepatotoxicity, superinfection, increased intracranial pressure, renal damage.
Drug interactions:
1. They interfere with the bactericidal action of betalactum antibiotics.
2. They potentiate the anticoagulant effects of coumarin drugs.
3. Drugs like gastric antacids, iron salts, bismuth salts, milk products decrease bioavailability of
tetracyclines.
4. Drugs like phenytoin, barbiturates decrease the plasma half lives of tetracyclines.
Chloramphenicol
Source: It was isolated from Streptomyces venezuelae by Burkholder in 1947. It is now prepared
synthetically. It is a broad spectrum antibiotic.
Chemistry: It is a derivative of dichloroacetic acid and contains a nitrobenzene moiety.
Antibacterial activity: It has antibacterial spectrum like tetracycline. It differs from tetracycline in the
following aspects.
1.It is highly active against Salmonella typhi, where tetracycline is ineffective.
2.It is more active than tetracycline against H.pertusis, K.pneumoniae and anerobes.
3. It is less active than tetracycline against cocci, Shigalla organism, Vibrio cholerae, P.pestis,
brucella,etc.
4.It is not active against mycobacteria, actinomyces, pseudomonas and protozoa like E.histolytica.

MOA:Chloramphenicol inhibits bacterial protein synthesis by interfering with ‘transfer’ of elongating
peptide chain to the newly attached aminoacyl-t RNA at the ribosome-mRNA complex. It specifically
attaches to 50S ribosome and prevent the binding of aminoacyl-tRNA to the acceptor site for aminoacid
incorporation.
ADME: It is completely absorbed from the GIT after oral administration. It has a high bioavailability. It is
widely distributed in the body including CSF and CNS. About 60% get bound to plasma protein. About 90
% of the drug get metabolized in the liver by conjugation with glucuronic acid and the water soluble
glucuronides are excreted mainly in urine. The remaining 10% free drug also eliminated through urine.
It undergo enterohepatic recycling.
Clinical uses:
1.Typhoid fever: Chloramphenicol is the drug of choice in typhoid fever.
2.Since choramphenicol crosses the BBB it is used to treat bacterial meningitis caused by H.influenzae.
3.Chloramphenicol is effective against most anaerobic bacteria including Bacteroids fragils.
4.Rickettsial infections.
5.Miscellaneous conditions: Brucellosis, plague, whooping cough, bacillary dysentery, ocular infections
(as it penetrates into the intraocular fluid). It is also used topically in chronic otorrhoea (discharge from
inflamed ear) and in skin infections.
Otorrhea Typhoid fever Ocular infections

Plague symptoms Bacillary dysentery
Preparations:
Chloramphenicol 250,500mg caps C.Palmitate dry syrup 125mg/5 C.Sodium Succinate inj
ADRs: Chloramphenicol has some major adverse reactions and so it should not be used where other
alternatives are available.

1.Bone marrow toxicity: The nitrobenzene radical of the chloramphenicol is responsible for bone
marrow toxicity.
2.Neonatal toxicity: (Gray baby syndrome):
Gray baby syndrome Angioneurotic edema Atropic glossitis
When chloramphenicol is used in neonates (premature babies) in high doses then gray baby syndrome is
produced. Low levels of glucuronyl transferase enzyme in the lever and immaturity of the renal
development leads to the accumulation of the choramphenicol in the neonates causing gray baby
syndrome.
3.Hypersensitivity reactions: Skin rashes, drug fever, angioneurotic edema, exfoliative dermatitis,
atropic glossitis (smooth tongue) and haemorrhages from GIT, urinary bladder and skin.
4.Chloramphenicol rarely causes superinfection as it is completely absorbed from GIT.
5.Miscellaneous reactions:Nausea, vomiting, unpleasant taste and diarrhea(GIT side effects). It can
produce peripheral neuritis, optic neuritis, mental confusion, depression and delirium (CNS side effects).
Drug interactions:
1.Chloramphenicol is a hepatic microsomal inhibitor. It decreases the metabolism of phenytoin,
tobutamide, warfarin leading to their toxic effects.
2.Microsomal enzyme inducers like phenobarbitone and rifampicin increase the metabolism of
chloramphenicol leading to decreased therapeutic effects of chloramphenicol.
e) Macrolides, Aminoglycosides, Polyene & Polypeptide antibiotics
Macrolide antibiotics: These are antibiotics having a macrocyclic lactone ring with attached
sugars. The first macrolide antibiotic- erythromycin was prepared from ‘Streptomyces erythreus’
in 1952. Roxithromycin, clarithromycin and azethromycin are semisynthetic derivatives of
erythromycin.

Chemistry: Erythromycin is a macrolide antibiotic. Roxithromycin, clarithromycin and
azethromycin differ from erythromycin by addition of methyl substituents at different positions
of lactone ring. These structural modifications improve gastric acid stability and tissue
penetration and broaden the antibacterial activity.
MOA: Erythromycin act by inhibiting bacterial protein synthesis. It binds reversibly with 50S
sub unit of the bacterial ribosome. They can inhibit the elongation of protein by the peptidyl
transferase, the enzyme that forms peptide bonds between the aminoacids. It acts by interfering
with the translocation. After peptide bond formation between the newly attached aminoacid and
the nacent peptide chain at the acceptor (A) site the elongated peptide is translocated back to the
peptidyl (P) site, making the A site available for next aminoacyl tRNA attachement. This is
prevented by the macrolide antibiotics.
Mechanism of bacterial resistance: It results from 3 types of plasmid mediated alteration.
1.A decrease in the penetration of the drug through the cell envelop as in Strepto.epidermitidis.
2.Decreased drug binding due to the production of methylase enzyme.

3.Hydrolysis of macrolide antibiotics by some bacteria like E.coli.
ADME: Erythromycin is acid labile. To protect it from gastric acid it is given as enteric coated tablets or
as capsules containing enteric coated pellets that dissolve in the duodenum. Food delays its absorption
by increasing gastric acidity. Roxithromycin, clarythromycin and azethromycin are more resistant to
gastric acid and are better absorbed from GIT after oral administration. They are widely distributed in
the body tissues and fluids except CSF as it not crosses the BBB. About 70-80% bound to plasma
proteins. It is partly metabolized and excreted through bile. Renal excretion is minor.
ADRs:
Nausea Allergic reactions-fever, dermatitis
Allergic reactions-uriticaria, lymphadenopathy Cholestatic hepatitis and Jaundice
Superinfection
Therapeutic uses: Erythromycin is an effective substitute for penicillin in the treatment of infections
caused by penicillin sensitive bacteria. It is particularly useful in patients, who are allergic to penicillins
and in those in whom bacteria have developed resistance to penicillins. It is effective as tetracycline in
the treatment of mycoplasma pneumonia and clamydial pneumonia. It is the drug of choice in whooping
cough and chancroid.

Mycoplasma pneumonia Bacteria causing Chlamydia pneumonia Whooping cough
Diphtheria Bacterial infection transmitted through sexual contact Tetanus
Preparations:
1.Erythromycin stearate tabs (100,250, 500mg), syrup.
2.Erythromycin estolate, 250,500mg tabs,

3.Roxithromycin 75mg, 150mg, 300mg tabs
4.Clarithromycin 250, 500mg tabs.
5.Azithromycin 250,500mg tabs, susp.
Drug interactions: 1. Erythromycin potentiate the effects of certain drugs like carbamazepine, digoxin,
cyclosporine, warferin, theophilline, etc. as it inhibit the cytochrome P450 enzymes.
2. It can interfere with the action of chloramphenicol and bactericidal antibiotics like penicillins.
Semisynthetic macrolides cause less drug interactions than erythromycin.

Aminoglycoside antibiotics: Aminoglycosides consists of two or more amino sugars joined in
glycosidic linkage to a hexose nucleus, which is usually in the central position. This hexose is
either streptidine (found in streptomycin) or 2-deoxystreptamine (found in other aminoglycoside
antibiotics).They are polycations (molecule having positive charges at several sites) and their
polarity is responsible for their pharmacological properties. They are mainly used to treat
infections caused by aerobic gram negative bacteria. Although most inhibitors of bacterial
protein synthesis are bacteriostatic but these antibiotics are bactericidal.
The first aminoglycoside antibiotic streptomycin was isolated from’ Streptomyces griseus’ in
1944. Then other aminoglycosides antibiotics were isolated and some were prepared
semisynthetically. All aminoglycoside antibiotics are produced by soil actinomycetes and have
many common properties.
1.All are used as sulfate salts, which are highly water soluble.
2.They ionize in solution, are not absorbed orally, distribute only extracellularly, donot penetrate
brain or CSF.
3.All are excreted unchanged in urine by glomerular filteration.
4.All are bactericidal and act by interfering with bacterial protein synthesis.
5.All are mainly effective against aerobic gram negative bacteria.
6.They have narrow margin of safety.

7.They show only partial cross resistance, an organism resistant to one amino glycoside may still
respond to another.
8.All exhibit ototoxicity and nephrotoxicity.
Classification:
a.Natural: Streptomycin (Streptomyces griseus), kanamycin (Streptomyces kanamyceticus),
Tobramycin (Streptomyces tenebrarius), paramomycin (Streptomyces rimosus), framycetin
(Streptomyces lavendulae).
Gentamicin and sisomicin are obtained from Micromonospora species.
b.Semisynthetic derivatives: Dihydrostreptomycin (of streptomycin), amikacin (of kanamycin),
netilmicin ( of sisomicin).
MOA:
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Pharmacology ii (mb) vol ii

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