Preface

Agam is a group of budding medicos, who are currently doing their under graduation in
various Medical Colleges across Tamil Nadu and Pondicherry. The group was initiated on 18th
November 2017, in the vision of uniting medicos for various social and professional causes.

We feel delighted to present you Agam pharmacology notes prepared by Agam Divide and
Rule 2019 Team to guide our fellow medicos to prepare for university examinations.

This is a reference work of 2017 batch medical students from various colleges. The team
took effort to refer many books and make them into simple notes. We are not the authors of the
following work. The images used in the documents are not copyrighted by us and is obtained from
various sources.

Dear readers, we request you to use this material as a reference note, or revision note, or
recall notes. Please do not learn the topics for the 1st time from this material, as this contain just the
required points, for revision.
Acknowledgement

On behalf of the team, Agam would like to thank all the doctors who taught us Pharmacology.
Agam would like to whole heartedly appreciate and thank everyone who contributed towards the
making of this material. A special thanks to Kareeshmaa H C, who took the responsibility of leading
the team. The following are the name list of the team who worked together, to bring out the
material in good form.

• Taher Hussain
• Puvasree N P
• Joanna P
 INDEX

Chapter 1: Diuretics

Essay
1. Diuretics…..…………………………..………………………. 1

Short Notes
2. Furosemide....………………………………………………… 4
3. Carbonic Anhydrase Inhibitors……………………….. 6
4. Spironolactone……………………………………………….. 8

Short Answers
5. Pottasion Sparing Drugs…………..…………………… 10
6. Osmotic Diuretics…………………………………………. 10
7. ADR of Triamterene………….………………………….. 10
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1. DIURETICS

THIAZIDE DIURETICS

PHARMACOLOGICAL ACTION
➢ Inhibitors of Na+- Cl- symport at the luminal membrane.
➢ They are medium efficacy diuretics.
➢ They act on distal tubular cell.
➢ They do not cause significant alteration in acid – base balance of the body.
➢ Decrease renal calcium excretion
➢ Increase magnesium excretion

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MECHANISM OF ACTION

USES
1. Edema: They act best in cardiac edema and they are less effective in hepatic and
renal edema.
2. Hypertension: chlorthalidone and indapamide are the first line of drugs.
3. Diabetes Insipidus: decreases positive free water clearance.
4. Hypercalciuria: reducing calcium excretion.

COMPLICATIONS
❖ Hypokalemia
❖ Acute saline depletion: overuse of diuretics may cause dehydration and marked
fall in BP, hemoconcentration and increased risk of PVT.
❖ Dilutional hyponatremia: patients feel very thirsty due to decreased salt in the
body
❖ GIT and CNS disturbances: Nausea, vomiting, diarrhea, headache, giddiness etc
may be seen
❖ Hearing loss

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❖ Allergic manifestations
❖ Hyperuricemia
❖ Hyperglycemia and dyslipidemia
❖ Hypocalcaemia
❖ Magnesium depletion
❖ Toxemia of pregnancy leading to increased risk of miscarriage, fetal death

INTERACTIONS
1. Thiazide and high ceiling diuretics potentiate all other hypertensives.
2. Hypokalemia induced by diuretics enhances digoxin toxicity, increases risk of
polymorphic ventricular tachycardia
3. High ceiling diuretics and aminoglycoside antibiotics are both ototoxic and
nephrotoxic
4. Indomethacin and other NSAIDS diminish the action of High ceiling diuretics.
5. Probenecid competitively inhibits tubular secretion of furosemide and thiazides.
6. Serum lithium level rises

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2. FUROSEMIDE

➢ Furosemide is classified under the high ceiling loop diuretics

➢ Inhibits the Na+-K+-Cl- co-transporter.
➢ First prototype of this class, rapidly acting, highly efficacious.
➢ It is secreted in the proximal tubule by the organic anion transport and
reaches thick ascending loop where it acts on the luminal surface of the
membrane.
➢ K+ secretion is increased mainly due to high Na+ load reaching distal tubule.

Other actions of furosemide:

• Intravenous furosemide causes prompt increase in systemic venous
capacitance and decreases left ventricular filling pressure, even before the
diuretic response is apparent. This action also appears to be PG mediated
and is responsible for the quick relief it affords in LVF and pulmonary
edema.

• Furosemide has weak CAse inhibitory action; increases HCO3 ¯ excretion as

well; urinary pH may rise but the predominant urinary anion is Cl¯.
Therefore, acidosis does not develop.

• Causes acute changes in renal and systemic hemodynamics. Renal- after

5mins of i.v injection, renal blood flow is increased and there is
redistribution of blood flow from outer to mid-cortical zone.

• G.F.T is not increased due to compensatory mechanism. Systemic-pressure

relationship between vascular, tubular and interstitial compartments is
altered the net result is decreased PT reabsorption.

• Increases Ca+ excretion as well Mg2+ excretion

• Increases blood uric acid level by competing with its proximal tubular
secretion and also PT reabsorption as a result of reduced g.f.r

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Mechanism of action:

Binds with the Cl binding site of the 12 membrane spanning domain of

Na -K+-2Cl¯ co-transporter.
+

Pharmacokinetics:
• Bioavailability: 60%
• Lipid solubility: low
• Binding to plasma membrane: high
• Plasma t1/2: 1-2 hrs, prolonged in pulmonary edema, renal and hepatic
insufficiency.
• Excretion: partly conjugated with glucoronic acid and mainly secreted
unchanged in the urine
• Similar drugs:
▪ BUMETANIDE ( 40 times more potent, Hyperuricemia, k+ loss,
glucose intolerance and ototoxicity less marked)
▪ TORSEMIDE (2-3 times more potent)

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Uses:
• Edema
• Acute pulmonary edema
• Cerebral edema
• Hypertension
• Hypocalcaemia of malignancy

3. CARBONIC ANHYDRASE INHIBITORS

𝑯𝟐 𝑶 + 𝑪𝑶𝟐 ↔ 𝑯𝟐 𝑪𝑶𝟑 ↔ 𝑯+ + 𝑯𝑪𝑶−
𝟑

Acetazolamide: Sulfonamide derivative that non-competitively and reversibly

inhibits CAse.

MECHANISM OF ACTION:

Inhibition of
INHIBITION ↓ hydration ↓ H+ FOR mild alkaline
HCO3-
OF CAse of CO2 EXCHANGE diuresis
reabsorption

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Other renal actions:

• Secretion of H+ by intercalated cells in PT and DCT
• Inhibition of distal Na+-K+ exchange resulting in marked kaliuresis.

Extra-renal causes:
• Lowering of intraocular tension due to decreased formation of aqueous
humor

• Decreased gastric HCl and pancreatic NaHCO3 secretion: This action

requires very high doses

• Raised level of CO2 in brain and lowering of pH: sedation and elevation
of seizure threshold

Uses:
• Glaucoma
• Epilepsy
• Mountain sickness
• Periodic paralysis

Adverse effects:
• Acidosis
• Hypokalemia
• Drowsiness
• paresthesias
• fatigue
• Abdominal discomfort.
• Hypersensitivity reactions—fever, rashes.

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4. SPIRONOLACTONE

▪ Steroid chemically related to aldosterone

▪ Classified under potassium sparing diuretics.

MECHANISM OF ACTION:

Aldosterone combines with intracellular mineral corticoid receptor (MR) and

induces the formation of aldosterone induced proteins (AIP’s). Spironolactone
acts from the interstitial side of the tubular cell, combines with MR and inhibits
the formation of AIPs in a competitive manner.

→ K+ sparing action starts develops over 3-4 weeks.

→ Has mild Diuretic action because majority of Na+ is reabsorbed proximal to its
site of action.

Pharmacokinetics
• Oral bioavailability: 75%
• Metabolism in liver: highly bound to plasma proteins and completely
metabolized to form active metabolites.
• Active metabolite: canrenone
• T1/2 of Spironolactone: 1-2 hrs
• T1/2 of canrenone : ~8 hrs

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Adverse effects:
• Drowsiness
• Ataxia
• mental confusion
• epigastric pain
• loose motions
• Most serious action is hyperkalaemia (especially in renal failure)
• Acidosis(especially if cirrhotic)
• Peptic ulcer is aggravated

• Spironolactone reacts with progestin and androgen receptors causing

estrogen clearance leading to
• Gynaectomasia
• Erectile dysfunction
• Loss of libido in men
• Breast tenderness or menstrual irregularities in women.

Interactions:
• Spironolactone and K+ supplements may produce dangerous
hyperkalaemia.
• More pronounced hyperkalaemia in patients receiving ACE/ARD inhibitors.
• Increases digoxin concentration.
• Aspirin blocks tubular excretion of canrenone.

Uses:
• To counteract k+ loss due to thiazide and loop diuretics
• Edema
• Hypertension
• Heart failure
• Primary hyperaldosteronism

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5. K+ sparing diuretics

• Aldosterone antagonists:
▪ Spironolactone
▪ Eplerenone
• Renal ENaC inhibitors:
▪ Amiloride
▪ Triamterene

6. Osmotic diuretics
▪ Mannitol
▪ Isosorbide
▪ Glycerol

7. ADR of Triamterene
▪ Nausea
▪ Dizziness
▪ Muscle cramps
▪ Rise in blood urea level
▪ Impaired glucose tolerance
▪ Photosensitivity

Kidney Agam Pharmacology

 INDEX

Chapter 2: Antidiuretics

Short Notes
1. Vasopressin....………………………………………………… 11

Short Answers
2. Vasopressin Analogues.…………..…………………… 14
3. Vasopressin Antagonists………………………………. 14
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1. VASOPRESSIN
• It is an antidiuretic hormone (ADH)
• Non-peptide secreted by posterior pituitary along with oxytocin.
• Given in pharmacological doses, it has a vasopressor action and hence is
called vasopressin. The two main stimuli for ADH release are rise in
plasma osmolarity and contraction of e.c.f volume.

Mechanism of action:
AVP acts on two G protein coupled cell membrane receptors, V1 (V1a and
V1b) and V2.

V1 receptors

● V1a receptors present on vascular smooth muscle, uterine and other visceral
smooth muscles, interstitial cells in renal medulla, cortical CD cells, adipose
tissue, brain, platelets, liver, etc. They are not stimulated by physiological
concentration of hormone
● V1b receptors are localized to the anterior pituitary, certain areas in brain and
in pancreas; involved in vasopressin- stimulated secretion of ACTH
● V1 receptors function mainly through the Phospolipase C - IP3/DAG pathway-
release of Ca2+ from intracellular stores causing vasoconstriction, visceral
smooth muscle contraction, Glycogenolysis, platelet aggregation, ACTH
release, etc.
● These actions are augmented by DAG mediated protein kinase C activation
which enhances Ca2+ influx, they additionally activate Phospolipase A2.
● Persistent V1 receptor stimulation activates proto-oncogene resulting in
hypertrophy of vascular smooth muscle and other responsive cells

V2 receptors

● These are located primarily on the principal cells of collecting ducts in kidney
where they regulate water permeability through cAMP production
● Some located on TAL cells, activate Na+K+2Cl- co transporter.

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● Vasodilatory V2 receptors are present on endothelium of blood vessels.

Physiological and pharmacological actions:

● Kidney-
➢ AVP acts on principal cells in the CD
↓
➢ increased water permeability
↓
➢ Water reabsorption and reduced urine volume (antidiuretic action).

→ V1a activation–> reduced renal medullary blood flow.

→ Production of PGE2 is stimulated
→ The antidiuretic response is enhanced by NSAIDs, chlorpropamide and
carbamazepine
→ inhibited by lithium and demeclocycline.

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• Blood vessels
→ V1 receptor–> constriction ; at lower doses this is counterbalanced
reflexly by lowering C.O.; but at higher doses rise in BP occurs as well as
when reflex is inoperative (hypotensive states).
→ V2 receptor–> vasodilatation; unmasked in presence of V1 antagonist

• Other visceral smooth muscles: contract; increased peristalsis in gut.

• CNS: as neurotransmitter
• Miscellaneous: Platelet aggregation and hepatic Glycogenolysis; V2–>
release coagulation factor VIII and von Willebrand's factor from vascular
endothelium.

Pharmacokinetics:
▪ inactive orally
▪ Administered parenterally or intranasal application.
▪ Metabolized in liver and kidney.
▪ Plasma t1/2 ~25min.

ADR:
Nausea, biliary colic, abdominal cramps, hypotension, shock.

Contraindications:
Ischemic heart disease, hypertension, chronic nephritis and psychogenic polydipsia.

Uses:

A. Based on V2 actions (desmopressin is drug of choice)

❖ Diabetes Insipidus It is effective in central (neurogenic) DI but ineffective in
nephrogenic DI. If desmopressin is not available, AVP may be used. Lifelong
therapy is required, except when DI occurs transiently (head injury/
neurosurgery)
❖ Bedwetting in children and nocturia in adults Desmopressin intranasally or
orally at bedtime is used for short term treatment. Fluid intake must be
restricted 1hr before and till 8hr after to avoid fluid retention. Monitor BP and

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body weight periodically to check fluid overload. Treatment is withheld 1 week

every 3 months for reassessment.
❖ Renal concentration test 5-10 U i.m. Of aqueous vasopressin or 2ug of
desmopressin causes maximum urinary concentration
❖ Haemophilia,von Willebrand's disease AVP may check bleeding

B. Based on V1 actions

❖ Bleeding esophageal varices Vasopressin/ Terlipressin stops bleeding by

constricting mesenteric blood vessels and reducing blood flow through the
liver to the varices, allowing clot formation. Terlipressin has fewer side effects.
❖ Before abdominal radiography occasionally used to drive out gases from
bowel.

1) Vasopressin analogues

● Lypressin
● Terlipressin
● Desmopressin (selective V2)

2) Vasopressin antagonists

• Tolvaptan (V2 selective antagonist)

• Mozavaptan (V2 selective antagonist)
• Conivaptan (V1a and V2 antagonist)

Kidney Agam Pharmacology