Pharmacology review for final exam

SEM 6

Pharmacology Review for Final exam (2013 batch)

CREDIT 6.5

PHARMACOLOGY FINAL EXAM review 2016

EDITED BY

BHAGATH M S

RAJEEV BISWAS

Pharmacology Review for Final exam (2013 batch)

Contents Title Introduction Pharmacokinetics Pharmacodynamics Factors Affecting Drug Effects Efferent Nervous System Pharmacology Cholinoceptor Agonist Anticholinesterase Druds and Cholinesterase Reactivators Cholinoceptor Antagonist (I) – M – receptor Antagonist Cholinoceptor Antagonist (II) – N – receptor Antagonist Adrenergic Receptor Agonist Adrenergic Receptor Antagonist

Page no

Mid term

Local Anesthetic Sedative Hypnotic Drugs Antipileptics and Anticovulsants Antiparkinsonian Drugs Psychotolytic Analgesics Antipyretic – Analgesic and Anti – Inflammatory Drugs Antiarrhythmic Drugs Renin and Angiotensin Diuretics Drugs Used For Therapy of Hypertension Pharmacotherapy of Congestive Heart Failure Treatment of Myocardial Ischemia Drugs for Therapy of Dyslipidemia and Anti - Atherogenic Anticoagulants, Coagulants and Antianemia Drugs Histamine and Anti - Histamines Drugs Affecting Respiratory System Drugs Affecting the Gastrointestinal System

Adrenocortical Hormones Agents Affecting the Thyroid Glands Insulin and Oral Hypoglycemic Drugs Antimicrobial Agents Beta – Lactam Antibiotics Aminoglycosides and Spectinomycin Macrolides, Clindamycin and Polypeptide Antibiotics Tetracyclines and Chloramphenicol Artificial Synthetic Antibacterial Drugs Antiviral Agents and Antifungal Agents Anti – mycobacterial Drugs Anti – Parasitic Drugs Antineoplastic Agents

Final term

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Pharmacology Review for Final exam (2013 batch)

Pharmacology Review 1. Describe the pharmacological effects and the clinical uses of HI histamine blockers.

Note :: H1 antagonists, also called H1 blockers, are a class of medications that block the action of histamine at the H1 receptor, helping relieve allergic reactions. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines; other agents may have antihistaminergic action but are not true antihistamines.

PHARMACOLOGICAL EFFECTS i. Effects related to reversible competitive antagonism of H1 receptors (present in both first and second generations) 1- On smooth Muscles: inhibit effects of histamine on smooth muscles, especially the constriction of the bronchi.

2- On blood vessels: inhibit the vasodilator effects that are mediated by activation of H1 receptors on endothelial cells (synthesis/release of NO and other mediators). Residual vasodilation is due to H2 receptors on smooth muscle and can be suppressed by administration of an H2 antagonist.

3- On capillary permeability: inhibit the increased capillary permeability and formation of edema brought about by histamine.

ii. Effects not related to blockade of H1 receptors (present in some of the first generation drugs) 1- Anticholinergic Effects:  Many of the first-generation H1 antagonists inhibit responses to acetylcholine that are mediated by muscarinic receptors (have atropine-like actions) e.g., promethazine. The second-generation H1 antagonists have no effect on muscarinic receptors.  Anticholinergic effects include dry mouth, blurred vision, constipation and urinary retention  Perhaps because of their anticholinergic effects, some of the H1 antagonists have suppressant effects on drug-induced parkinsonism symptoms.

2- On the central nervous system:  Therapeutic doses of most of the first generation histamine H1 receptor antagonists produce CNS depression manifest as sedation.  Excitation rather than sedation may occur in children and rarely in adults  Overdoses produce central excitation resulting in convulsions, particularly in children.  Some of the first generation drugs can prevent motion sickness  The second-generation ("nonsedating") H1 antagonists do not affect the CNS because they do not cross the blood-brain barrier when given in therapeutic doses.

Pharmacology Review for Final exam (2013 batch)

CLINICAL USES •

Allergic rhinitis (common cold)

•

Allergic conjunctivitis (pink eye)

•

Allergic dermatological conditions

•

Urticaria (hives)

•

Angioedema (swelling of the skin)

•

Puritus (atopic dermatitis, insect bites)

•

Anaphylactic reactions (severe allergies)

•

Nausea and vomiting (first generation H1-antihistamines)

•

Sedation (first generation H1-antihistamines)

•

Motion sickness: diphenhydramine, dimenhydrinate or cyclizine.

2. What are the clinical uses of Heparin and its adverse effects?

Note:: Heparin is a widely used injectable blood thinner. It is used to treat and prevent deep vein thrombosis and pulmonary embolism (collectively known as venous thromboembolism) and is also used as part of the treatment of myocardial infarction and unstable angina.

Heparin is used on the inside surfaces of various devices such as test tubes and kidney dialysis machines.

Heparin's normal role in the body is unclear. Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is defense at such sites against invading bacteria and other foreign materials.

CLINICAL USES • The major antithrombotic drug for the treatment of acute deep-vein thrombosis and pulmonary embolism.

• Prevent postoperative venous thrombosis in patients undergoing elective surgery (for example, hip replacement) and those in the acute phase of myocardial infarction.

• Extracorporeal devices (for example: dialysis machines) to prevent thrombosis.

ADVERSE EFFECTS • • • •

Bleeding complications Hypersensitivity reactions Heparin-induced thrombocytopaenia (HIT) Osteoporosis (long-term only)

3. What are the anti-coagulant mechanism of heparin and warfarin?

Note:: Warfarin, also known by the brand names Coumadin among others, is an anticoagulant normally used in the prevention of thrombosis and thromboembolism, the formation of blood clots in the blood vessels and their migration elsewhere in the body, respectively.

> Heparin Mechanism of Heparin action 1 -

All heparins inhibit the coagulation process by enhancing the activity of the endogenous inhibitor, antithrombin.

-

induces a conformational change in antithrombin, increasing the affinity for thrombin.

Pharmacology Review for Final exam (2013 batch) Mechanism of Heparin action 2 -

Unfractionated heparin binds to both antithrombin and thrombin to form a ternary complex…

-

then dissociates, leaving the enzyme irreversibly

-

Once dissociated, heparin is free …

-

to bind to another antithrombin molecule…

-

…inhibit more thrombin.

> Warfarin Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.

4. Describe the pharmacological effects and clinical uses of fibrinolytic drugs.

Note:: There are three major classes of fibrinolytic drugs: tissue plasminogen activator (tPA), streptokinase (SK), and urokinase (UK). While drugs in these three classes all have the ability to effectively dissolve blood clots, they differ in their detailed mechanisms in ways that alter their selectivity for fibrin clots.

PHARMACOLOGICAL EFFECT -

Acute thromboembolic disease in selected patients may be treated by the administration of agents that activate the conversion of plasminogen to plasmin, a serine protease that hydrolyzes fibrin and, thus, dissolves clots .

THERAPEUTIC USE -

Originally used for the treatment of deep-vein thrombosis and serious pulmonary embolism，

-

also used to dissolve clots that result in strokes.

5. How does aspirin act as antiplatelet drug?

Note:: Aspirin is a salicylate. It works by reducing substances in the body that cause pain, fever, and inflammation. It is used to treat pain, and reduce fever or inflammation. It is sometimes used to treat or prevent heart attacks, strokes, and chest pain (angina).

Aspirin inhibits thromboxane A2 synthesis from arachidonic acid in platelets by irreversible acetylation of a serine, resulting in a blockade of arachidonate to the active site and, thus, inhibition of COX-1 6. What are the pharmacological effects, the clinical use and the side effects of furosemide?

Note:: Furosemide, sold under the brand name Lasix among others, is a medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. Its a loop diuretic (water pill) that prevents your body from absorbing too much salt. This allows the salt to instead be passed in your urine. It is used to treat fluid retention (edema) in people with congestive heart failure, liver disease, or a kidney disorder such as nephrotic syndrome. Is also used to treat high blood pressure (hypertension).

Pharmacology Review for Final exam (2013 batch)

PHARMACOLOGICAL EFFECT • Diuretic activity is strong Loss of diluting ability: Increased Na, Cl and K excretion Loss of concentrating ability:

•

–

reduction in the medullary osmotic gradient

–

Loss of ADH-directed water reabsorption in collecting ducts

Decrease renal vascular resistance, increase renal blood flow -

promote the synthesis of PGE

THEURAPEUTIC USE •

Acute pulmonary edema

•

Chronic renal failure or nephrosis

•

Hypercalcemia

•

Chemical intoxication (to increase urine flow)

•

Hypertension crisis

SIDE EFFECT •

Ototoxicity Tinnitus and deafness (usually with large parenteral doses and rapid administration and in renal impairment)

•

Hyperuricemia occassionally leading to gout

•

Hypokalemia

•

Hypomagnesemia

7. What are the clinical uses of thiazide diuretics?

Note:: Thiazide diuretics are one type of diuretic. There are a number of thiazide diuretics - they include bendroflumethiazide, chlortalidone, cyclopenthiazide, indapamide, metolazone, and xipamide. Each comes in a different brand name.

Thiazide diuretics (water pills) are medications that are used to treat high blood pressure (hypertension) and reduce fluid accumulation in the body. They work by reducing the ability of the kidneys to reabsorb salt and water from the urine and into the body thereby increasing the production and output of urine (diuresis). So, they are sometimes called 'water tablets'. There are different types of diuretics which work in different ways.

1) Hypertension •

they should be considered first-line therapy in hypertension (effective, safe and cheap)

•

Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect

2) Edema (cardiac, liver ,renal) 3) Diabetes Insipidus

Pharmacology Review for Final exam (2013 batch) 4) Idiopathic Hypercalciuria •

condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion

•

thiazide diuretics used to prevent calcium loss and protect the kidneys

8. Describe the drugs used for peptic ulcer, their classification and mechanism.

DRUGS USED FOR PEPTIC ULCER :: • Antacids CHARACTERISITCS o Antacids are weak bases that are taken orally and that partially neutralize gastric acid and reduce pepsin activity.

o Antacids reduce the pain associated with ulcers and may promote healing.

CLASSIFICATION Feature

Sodium

Calcium

Magnesium hydroxide

Aluminium

bicarbonate Onset of action

Rapid

Intermediate

Rapid

Slow

Duration of

Short

Moderate

Moderate

Moderate

Yes

?

No

No

---

constipation

laxative

Constipating

action Systemic alkalosis Effect on stool

• Inhibitors of gastric acid production - Proton pump inhibitors - H2-receptor antagonists - Muscarinic antagonists - Gastrin receptor antagonist • Mucosal Protectants - These compounds, known as cytoprotective compounds, have several actions that enhance mucosal protection mechanisms, thereby preventing mucosal injury, reducing inflammation, and healing existing ulcers.

Sucralfate Bismuth （Pepto-Bismol®）

• Anti-Helicobacter pylori. drugs - Aimed at eliminating H. pylori - Bismuth ( Pepto-Bismol®) - Gentamicin[,dʒentə'maisin]

Pharmacology Review for Final exam (2013 batch) - Amotriptyline (Amoxil ® ) - Clarithromycin - Tetracycline (Achromycin V ®) - Metronidazole (Flagyl ® ) 9. List drugs used in the treatment of asthma and describe their mechanism.

Antiasthmatic Drugs such as :: I. Bronchodilators 1. β receptor agonists

2. Theophylline - Inhibit phosphdiesterase (PDE); - Block adenosine receptors; - Increase endogenous catecholamine (CA) releasing; - Interfere with receptor-operated Ca2+ channels → [Ca2+]i↓; - Anti-inflammatory action

3. Muscarinic antagonists - prevent bronchoconstriction II. Anti-inflammatory agents 1. Steroids 1. Broad anti-inflammatory efficacy - Block the synthesis of arachidonic acid by phospholipase A2.

- Reduce bronchial reactivity.

2. Increase the responsiveness of β-adrenoceptors in the airway.

2. Anti-leukotriene agents •

Leukotrienes are substances released when a trigger, such as cat hair or dust, starts a series of chemical reactions in the body

•

Leukotrienes cause inflammation, bronchoconstriction, and mucus production

Pharmacology Review for Final exam (2013 batch) •

Result: coughing, wheezing, shortness of breath

•

Antileukotriene agents prevent leukotrienes from attaching to receptors on cells in the lungs and in circulation

•

Inflammation in the lungs is blocked, and asthma symptoms are relieved

III.Anti-allergic agents 1. Stabilizer of inflammatory cell membrane - example:: Disodium Cromoglycate (SCG) - Stabilizer of mass cell membrane: decrease the release of mediators from mast cells.

- Inhibit the function of sensory nerve ending and neurogenic inflammation in airway.

- Decrease bronchial hyperreactivity.

2. H1 receptor blocker - example:: Ketotifen - Prevent and inverse down-regulation of β2-receptor.

10. What are the major effects and clinical uses of glucocorticoids?

Note :: Glucocorticoids are one of the corticosteroids (adrenal cortical steroids) released from the adrenal gland. The physiological stimulus for glucocorticoid release is corticortiotropin (adrenocorticotropic hormone) from the anterior pituitary.

Any of a group of corticosteroids (e.g. hydrocortisone) which are involved in the metabolism of carbohydrates, proteins, and fats and have anti-inflammatory activity. Glucocorticoids e.g. cortisol and cortisone, are essential for the utilization of carbohydrate, fat and protein by the body and for normal response to stress. Naturally occurring and synthetic glucocorticoids have very powerful anti-inflammatory effects and are used to treat conditions that involve inflammation. They also decrease the body’s immune response. Mineralocorticoids e.g. aldosterone are necessary for regulation of salt and water in the body.

I. Metabolic effect: 1. Carbohydrate metabolism 2. Protein metabolism 3. Fat metabolism 4. Electrolyte and water

II. Permissive effects Glucocorticoids enhances the effects of other hormones such as catecholamine, ACTH, and growth hormone

III. Anti-Inflammatory effects 1) Strong 2) Nonselective 3) Whole process of inflammation 4) No antibacterial effect

Pharmacology Review for Final exam (2013 batch) IV. Immunosuppressive effect & anti-anaphylaxis effects 1) Immunosuppressive effects Mechanisms ① Inhibits macrophages & other antigen-presenting cells function; ② Decreases circulating lymphocyte number; ③ Low dose mainly inhibits cellular immunity, and high dose inhibits humoral immunity 2) Anti-anaphylaxis effects Inhibits histamine release by basophils / mast cells V. Anti shock effect Mechanisms ① Decreases inflammatory factors release; ② Increases body resistance to the bacterial endotoxin; ③ Contracts blood vessel dilated & increases myocardial contractibility ④ Decreases vascular sensitivity to some vasoconstrictors ⑤ Decreases myocardial inhibitant factor MIF generation because of stabilizing lysosome membrane.

VI. Hematic effect 1) Stimulation of hematopoiesis in bone marrow red cells↑, hemoglobin ↑; platelets ↑, fibrinogen ↑(in high dose); neutrophils increases in number, but decreases in function 2) Lymphatolysis lymphocytes in blood ↓ VII. GI effects gastric acid ↑, pepsin ↑ →peptic ulcer VIII. CNS exciting effects Euphoria, excitation, insomnia; Anoia induced occasionally; High dose induces convulsion in children

CLINICAL USE 1. Adrenocortical insufficiency Addison’s disease, anteriorhypopituitarism , post-subtotal bilateral adrenalectomy .

2. Acute serious infections: adjuvant > Bacteria infection: fulminant dysentery, bacterial meningitis, toxic pneumonia, heavy typhoid, acute miliary tuberculosis, scarlatina, septicemia > Virus infection: heavy infectious hepatitis, epidemic parotitis, measles, Japanese encephalitis

Pharmacology Review for Final exam (2013 batch) 3. Sequelae of some inflammation: conglutination or scar pyogenic meningitis, encephalitis, pericarditis, rheumatic heart disease, traumatic arthritis, testitis, iritis, keratitis, burn.

4. Autoimmunity diseases & allergic diseases 1) Autoimmunity diseases rheumatic fever, rheumatic myocarditis, rheumatic arthritisďźŒ rheumatoid arthritis, systemic lupus erythematosus , polyarteritis nodosa, dermatomyositis, nephrotic syndrome, etc.

2) Organ transplantation rejection 3) Allergic diseases urticaria, pollenosis, serum sickness, angioneurotic edema, allergic rhinitis, asthma, etc.

5. Shocks 1) Septic shock: early, short, large dose.

2) Anaphylactic shock: the support drugs 3) Cardiogenic shock 4) Hypovolemic shock: transfusion first 6. Hematic diseases acute lymphoblastic leukemia, aplastic anemia, granulocytopenia, thrombocytopenia, allergic purpura syndrome 7. Local use on skin contact dermatitis, eczema, anus tickle, psoriasis, neurodermatitis Hydrocortisone, prednisolone & fluocilonone prefered 11. What are the side effects and clinical uses of glucocorticoids?

COMPLICATIONS DURING CHRONIC USES 1) Cushing’s syndromes body obesity, rounded face, increased fat around the neck, thinning arms & legs, acne, hirsutism (abnormal growth of hair on a person's face and body, especially on a woman), edema,

2) Inducement or aggravation of infections 3) Complications of digestive system - inducement or aggravation of peptic ulcer - pancreatitis, sebaceous hepatitis appeared occasionally 4) Complications of cardiovascular system - hypertension, atherosclerosis.

5) Osteoporosis, sweeny and wound healing delay 6) Other complications - anoia, teratogenesis

hypokalemia, hypertension, diabetes.

Pharmacology Review for Final exam (2013 batch) 12. Describe the mechanism and clinical uses of thioamides.

Note:: Thioamides (anti-thyroid drugs) are also a class of drugs that are used to control thyrotoxicosis (overactive thyroid : excessive production of thyroid hormone). Thioamide group include methimazole, carbimazole (converted in vivo to methimazole), and propylthiouracil.

MECHANISM - All thioamides inhibit peroxidase-catalyzing reactions - Iodine organification - Iodotyrosines condensation - Propylthiouracil also inhibit T4 converting to T3

CLINICAL USES treatment of hyperthyroid 1. Mild hyperthyroid and those surgery & 131I not permitted; 2. Operation preparation; 3. Thyroid crisis (comprehensive therapy).

13. List drugs used in the treatment of hyperthyroidism.

Class

Thioamides Iodides Radioactive Iodine β-adrenoceptor blockers

Representative Propylthiouracil Methylthiouracil Methimazole Carbimazole KI, NaI 131 I propranolol

14. Describe the major pharmacokinetics and the clinical uses of insulin.

Note:: The hormone insulin helps control the amount of sugar (glucose) in the blood. Insulin currently cannot be taken orally because, like nearly all other proteins introduced into the gastrointestinal tract.

MAJOR PHARMACOKINETICS 1) Regular Insulin -> Refer to as ‘clear or unmodified insulin’ -> ONSET OF ACTION :: 30-60 min, peak action :: 2 – 3 hours, duration :: 6 – 8 hours -> USES :: Premeal subcutaneous IV for hyperglycaemic crisis

2) Rapid acting insulin analogs -> Current agents include :: lispro, aspart and gluisine -> Remain monomeric after injection, resulting in rapid absorption and relatively rapid onset and onset.

-> ONSET OF ACTION :: 5 – 15 min, peak action :: 60 – 90 min, duration :: 3 – 6 hours

Pharmacology Review for Final exam (2013 batch) 3) Long acting insulin -> Detemir (12 – 24 hours), Glargine (20 – 24 hours) -> ONSET is 90 minutes and it is vertically peakless -> Duration :: 20 – 24 hours, provides flat basal insulinization -> Cannot be mixed with other insulins

4) Premixed insulin -> Premixed combinations of short and intermediate acting insulins (Biphasic) -> Cloudy -> ONSET (30 minute, peak 2 – 8 hours, duration :: 24 hours) -> USES in treatment of type 1 diabetes mellitus 15. List the major adverse effects of insulin.

1. Hypoglycemia -

may occur due to insulin overdose, insufficient caloric intake (missed meal, improper meal content, delayed meal, etc.).

-

Ethanol consumption promotes hypoglycemic response.

-

Symptoms: ↑ HR, diaphoresis, MS changes, anything (diabetics are usually really good at recognizing hypoglycemic symptoms).

2. Hypokalemia: -

insulin draws K+ into the cell with glucose (hyperglycemia with normal K+).

3. Anaphylaxis: -

when sensitized to non-human insulin gets non-human insulin (now rare).

4. Lipodystrophy (at injection site) 5. Weight gain 6. Injection complications

16. List oral hypoglycemic drugs and compare the properties of each group.

Note :: Oral hypoglycemic drugs are used only in the treatment of type 2 diabetes which is a disorder involving resistance to secreted insulin.

Type 1 diabetes involves a lack of insulin and requires insulin for treatment. There are now four classes of hypoglycemic drugs: Sulfonylureas(stimulating insulin secretion), Metformin(increase insulin action but not directly), Thiazolidinediones(reverse insulin resistance by acting on muscle, fat and to a lesser extent liver to increase glucose utilization and diminish glucose production), αglucosidase inhibitors (inhibit the upper gastrointestinal enzymes that converts dietary starch and other complex carbohydrates into simple sugars which can be absorbed)

 Insulin secretagogues : - Sulfonylureas - Meglitinides (Non-SU) - GLP-1 agonists and DPP-4 inhibitors

Pharmacology Review for Final exam (2013 batch)  Insulin sensitizers : - Thiazolidinediones (TDs) - Biguanides  α-glucosidase inhibitors  Amylin analogue

Mechanism of Action

Class of Agent

Indications for uses

Stimulators of insulin secretion

Sulfonylureas Glinides

Primary

Insulin sensitizers

Thiazolidinediones (PPAR agonists)

Primary or Secondary

Biguanides

Primary or Secondary

Alpha-glucosidase Inhibitors Glinides GLP1 analogs DPPIV inhibitors

Secondary

Suppressors of hepatic glucose production

Reduces postprandial glucose excursion Enhance incretin/GLP1 action

Secondary

Side Effect

Effect of plasma

Risk of hypoglycemia

Hypoglycemia, caution renal insufficiency, elderly Liver, LE edema, congestive heart failure, MI GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl Flatulence, diarrhea

Yes

Nausea, vomiting (given by injection)

No

No

No

No

17. What are the side effects of sulfonylureas and biguanides.(modified) Note:: Sulfonylureas are antidiabetic drugs widely used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.

Biguanide refers to a group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver, improving the body’s sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines.

ADVERSE EFFECTS OF SULFONYLUREAS  These agents tend to cause weight gain, hyperinsulinemia and hypopglycemia.  Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia. There are a number of drug-drug interactions.  Elderly patients appear particularly susceptible to the toxicities of these agents.

ADVERSE EFFECTS OF BIGUANIDES  GI intolerance (20-30%) → bloating, anorexia, diarrhea, and flatulence.  Lactic acidosis is rare, but may be severe.

Pharmacology Review for Final exam (2013 batch)

Previous year review questions (2012 batch) 1. Mechanism of furosemide 2. Describe the clinical use of H2 histamine blockers Note :: Histamine H2-receptor antagonists, also known as H2-blockers, are used to treat duodenal ulcers and prevent their return. They are also used to treat gastric ulcers and for some conditions, such as Zollinger-Ellison disease, in which the stomach produces too much acid.

3. Distinguish the mechanism and characteristics of gastric acid secretion inhibitors.

4. List the drug used in treatment of hypothyroidism.

5. What are hypoglycemic mechanism sulfonylureas and biguanides.

Questions from Lab 1. What are the pharmacological mechanisms of diuretics and dehydration?

2. What is the difference between furosemide and hypertonic glucose on the effect of urination?

Pharmacology Review for Final exam (2013 batch)

Review question (Drugs affecting the cardiovascular system) 1. How are antihypertensive agents classified? List the representative drugs in each group Note :: Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. The most important and most widely used drugs for lowering blood pressure are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

1. DIURETICS - which lower blood pressure by depleting the body of sodium and water, reducing blood volume.

–

- Thiazides 2. SYMPATHOPLEGIC AGENTS, - which lower blood pressure by reducing Sympathetic activity, - These agents are further subdivided according to their putative sites of action.

(1) Centrally acting sympathoplegic drugs（α2 Agonists） Clonidine (2) Ganglion-blocking agents : Mecamylamine (3) Adrenergic neuron-blocking agents （ Adrenergic Neural Terminal Inhibitors）, Reserpine (4) Adrenoceptor antagonists（ 1. α1 Blockers : Prazosin 2. β-Blockers: propranolol ) 3. AGENTS THAT BLOCK PRODUCTION OR ACTION OF ANGIOTENSIN and thereby reduce peripheral vascular resistance and blood volume.

(1) Angiotensin Converting Enzyme Inhibitors（ACEI） (2）angiotensin receptor blocker( ARB) 4. CALCIUM CHANNEL BLOCKER : Amlodipine 5. DIRECT VASODILATORS,（ Peripheral Vasodilators） - which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and increasing capacitance

2. Describe the features and mechanisms of agents used as "the preferred first-line medication" for treatment of hypertension Notes :: ACEIs :: Angiotensin II is a very potent chemical produced by the body that primarily circulates in the blood. It causes the muscles surrounding blood vessels to contract, thereby narrowing the vessels. The narrowing of the vessels increases the pressure within the vessels causing increases in blood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by the enzyme angiotensin converting enzyme (ACE). (Angiotensin I in the blood is itself formed from angiotensinogen, a protein produced by the liver and released into the blood..) angiotensin converting enzyme inhibitors (ACE inhibitors) are medications that slow (inhibit) the activity of the enzyme ACE, which decreases the production of angiotensin II. As a result, blood vessels enlarge or dilate, and blood pressure is reduced. This lower blood pressure makes it easier for the heart to pump blood and can improve the function of a failing heart. In addition, the progression of kidney disease due to high blood pressure or diabetes is slowed. Drugs :: benazepril, captopril, enalapril, fosinopril, Lisinopril, moexipril, perindopril, quinapril, Ramipril, trandolapril.

CCBs :: are several medications that disrupt the movement of calcium (Ca2+) through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel

Pharmacology Review for Final exam (2013 batch) blockers are also frequently used to alter heart rate, to prevent cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

Drugs :: Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil Β-blockers :: Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits normal sympathetic effects that act through these receptors. Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers, when they bind to the beta-adrenoceptor, partially activate the receptor while preventing norepinephrine from binding to the receptor.

1.Diuretics Features :: - The thiazide diuretics increase urine by inhibiting reabsorption of sodium, potassium, chloride ions and water from in the cortical thick ascending limb and the early distal tubule in the kidneys by blocking the Na+-Cl− symporter.

Mechanism ::  Reduce extracellular and circulating volume, Initial antihypertensive effects come from diuresis.  Chronic effect: Vasodilating effect (reduce the peripheral vascular resistance primarily by depleting body sodium stores)

2. ACEIs (ARBs) Features :: 1. Particular effective in Younger patients 2. Particular useful in Antihypertension with heart failure ( no negative inotropic effect) 3. Particular useful in patients with diabets ( Reduce Insulin Resistance ), and diabetic nephropathy 4. Particular useful in patients with Metabolic disorders (hyperlipidemia, gout) (have beneficial effect to or at least no detrimental effect on metabolism in lipids, sugar and urid acid Mechanism :: 1. reduce Ang II production in circulation and tissues .

2. Increased formation of bradykinin by inbibiton of its breakdown 3. Modulation of sympathetic nerve activity, inhibit NE release.

4. Vasodilating effects without increasing heart rate 5. reduce salt and water retention ( by reducing aldosterone secretion) 6. inhibit the remodeling of heart and vessels, inhibit hypertension develope into heart failure and lead a reduction in mortality (10%)

3. Calcium channel blocker Features:: Are a group of drugs that block the calcium channel and inhibit the entry of calcium into excitable cells of the body, like the muscle cells of the heart and the arteries,or the neuron cells.

Pharmacology Review for Final exam (2013 batch)

 Voltage-dependent calcium channels (VDCC)  Ligand operated channel Mechanism :: A) Action in cardiac cells (1). negative inotropic action 

By blocking the entry of calcium, CCBs decrease contraction of the heart--Cardiac muscle ( highly dependent upon calcium influx for its contraction ).



-----may induce or deteriorate the heart failure



Verapamil, diltiazem, have more inhibition on heart. They should not be used in heart failure



In vitro, Dihydropyridines have a little negative inotropic effect (direct) , but in vivo Dihydropyridines a little positive inotropic effect --- because of their stronger vasodilating effect that induce sympathetic nerve exciting ---Reflecting adrenergic activity caused by reduced blood pressure) .



(indirect effect counteract (surpass)its direct effects)

(2) Negative chronotropic/dromotropic 

The action potentials (Ica-L dependent) in SA node and AV node may be reduced or blocked by all of the calcium channel blockers. but only verapamil and diltiazem at clinical doses can slow the heart rate and atrioventricular conduction in vivo.



Verapamil and diltiazem be called bradycardic CCBs. May be used as antiarrhythmic agents in reducing heart rate



Dihydropyridines have minimal direct inhibitory effects on SA node and AV conduction in vitro.



but in vivo, dihydropyridines can increases pacemaker rate in sinus node and conduction velocity in atrioventricular node because of their stronger vasodilating effect that induce sympathetic nerve exciting



The hypotensive action of most Dihydropyridines may usually result in a reflex increase of sinoatrial nodal rate. May increase oxygen consumption, cause arrhythmia, cardiac ischemia( angina), heart failure.



most DHPs should not be used in heart failure and arrhythmias.



Some Dihydropyridines (e.g., amlodipine) have very little effect(slow or accelerate) on heart rate and contraction so they are safer to use in individuals with heart failure.

Pharmacology Review for Final exam (2013 batch)

B) Actions in Vascular smooth muscles 

Calcium channel blockers blocking entry of calcium into the muscle cells and reducing intracellular calcium concentration. the actin-myosin interaction is prevented and vasodilation occurs.



Vascular smooth muscle appears to be the most sensitive to CCBs. (bronchial, gastrointestinal smooth muscle and nervous cells )

4. β Adrenoceptor -Blockers Features :: 

β-adrenoceptor-blocking agents have a mild antihypertensive effect. very useful for lowering blood pressure in mild to moderate hypertension with over excitation of sympathetic nervous system



In severe hypertension, β-blockers are Combined with other drugs . They especially useful in preventing the reflex tachycardia that often results from vasodilators.

Mechanism :: 1. Cardiac β1-receptor blocking: Negative Chronotropic& Inotropic Effects - Reduction in cardiac output 2 . Renal β1-Blocking: inhibition of Renin Release β–blocker’s antihypertensive effect is in part due to depression of the renin-angiotensin-aldosterone system.

3. CNS effects: the brain appears likely to be the one site of the hypotensive action of β-blockers .

- inhibit Sympathetic Nervous center by blocking the β1 receptor on the excitatory neurons in the centre - the Lipophilic of β-blockers (penetrate brain and blood barrier) usually have a better effect than the hydrosoluble(water soluble --atenolol) - blocking the prejunctional β2 receptors: inhibit peripheral adrenergic neurons to excrete catecholamine by probably blocking presynaptic β2 receptor’s positive feedback effects on norepinephrine release.

- Resetting of baroreceptor levels

Pharmacology Review for Final exam (2013 batch)

3. List antiarrhythmic agents according to their classification, the main features of each group and the main therapeutic uses of the representative drugs in each group.

There are five main classes in the Vaughan Williams classification of antiarrhythmic agents: Class I: sodium channel blockers.. (inhibit the influx of sodium, slow the speed of fast depolarization called phase 0 (Vmax), which leads to a decrease of the rate of conduction.)  class IA : - moderately inhibit sodium current (intermediate association/dissociation with channel ) , - Moderately reduce Vmax of depolarization ( in phase 0 slope ) and conduction of action potential; increase APD and ERP..

- Quinidine, Procainamide  class IB: - slightly inhibit sodium current (fast association/dissociation) , - Slightly reduce Vmax and conduction of action potential, reduce APD and ERP. - lidocaine, phenytoin, and mexiletine .  class IC: - severely (markedly) inhibit sodium current (slow association/dissociation) , - Pronounced reduction in phase 0 slope (Vmax ) and conduction of action potential, minimal effect on APD or ERP. - Propafenone, Flecainide, Encainide Class II: β–adrenergic receptor blockers.  Block sympathetic activity; reduce heart rate and AV conduction.  Propranolol, Atenolol ,Metoprolol Class III. potassium-channel blockers  these drugs block potassium current (Ikr), Delay (prolonging) repolarization (phase 3 and 2) and thereby increase APD and ERP.  Amiodarone, Sotalol,Bretylium, Class IV. Bradycardiac Calcium channel blocker:  Block L-type calcium-channels , slows conduction in regions where the action potential upstroke is calcium dependent, eg, the sinoatrial and atrioventricular nodes; reduce rate and AV conduction.

Class V :  Miscellaneous agents work by other or unknown mechanisms.  Digoxin, Adenosine, Ivabradine，Zetabradine， It should be noted that Class V agents are not part of the original Vaughan-Williams classification system. They be Added later on

Pharmacology Review for Final exam (2013 batch)

4. Why do organic nitrates reduce myocardial oxygen consumption? And why do they usually combined withβ-adrenoceptor blockers in treating angina pectoris ？ Note:: Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption.

Decrease Myocardial oxygen consumption 1) Peripheral vasodilation - At General dose marked relaxation of veins  decrease blood returning to heart  decrease ventricular end diastolic volume and pressure [preload] …..

Ventricular wall stress in diastole  oxygen consumption significantly reduced 2) Large Dose Dilate arterioles  decrease peripheral resistance (decrease afterload of heart)  ventricular wall stress in systole  oxygen consumption reduced

CONCOMITANT USE for β-Blockers • Undesirable effects of b -blocking agents in angina include an increase in end-diastolic volume and an increase in ejection time (due to their negative inotropic effect).

• Increased diastolic volume partially offset the beneficial effects of β-blocking agents.

• These potentially deleterious effects of b -blocking agents can be balanced by the concomitant use of nitrates . Therefore b -blocking agents usually used with nitrates concomitantly .

• Combination of usage produce synergistic effect but dosage should be reduced

Effects of nitrate alone with β-blockers Nitrate

β-blockers

Combination of

results

Alone

alone

nitrate & β-blockers

Heart rate

Increase

Decrease

Decrease

Beneficial

Ejection time

Decrease

Increase

None

Beneficial

End-diastolic

Decrease

Increase

None or Decrease

Beneficial

Contractility

Increase

Decrease

None

Beneficial

Blood pressure

Decrease

Decrease

Decrease

Beneficial or

volume

Unbeneficial

Pharmacology Review for Final exam (2013 batch) 5. How many groups of drugs can be used to treat angina pectoris? List the representative drugs in each group.

Notes :: Angina pectoris is the sensation of chest pain, pressure, or squeezing, often due to ischemia of the heart muscle from obstruction or spasm of the coronary arteries. The most specific medicine to treat angina is nitroglycerin. It is a potent vasodilator that decreases myocardial oxygen demand by decreasing the heart's workload. Beta blockers (eg: carvedilol, propranolol, atenolol) and calcium channel blockers (such as nifedipine (Adalat) and amlodipine) act to decrease the heart's workload, and thus its requirement for oxygen.

Nitroglycerin should not be given if certain inhibitors such as Sildenafil (Viagra), Tadalafil (Cialis), or Vardenafil (Levitra) have been taken within the previous 12 hours as the combination of the two could cause a serious drop in blood pressure.

4 major classes of agents :: 1.Organic nitrates (Nitroglycerin ) 2. β-adrenergic blockers (propranolol) 3. Calcium channel blockers: amlodipine 4. Other agents: - Partial Fatty Acid Oxidation Inhibitors ( pFox inhibitors) - Ranolazine - Angiotensin Converting Enzyme Inhibitors (ACEI) - aspirin Are used individually or in combination to treat angina:

6. How many groups of drugs can be used in treating heart failure? Please discuss therapeutic uses and adverse reactions of cardiac glycosides ,aceis and β-adrenoceptor blockers according to its pharmacological effects.

I. Cardiac glycosides II. Inhibitors of renin-angiotensin-aldosterone system. This category of drugs includes: (a) angiotensin converting enzyme inhibitors (ACEI); (b) angiotensin II receptor blockers; (c)aldosterone antagonist III. Diuretics IV. β-Adrenoceptor blockers V. Others (a) vasodilators; (b) calcium channel blockers; (c) non-glycoside positive inotropic agents

CARDIAC GLYCOSIDES > THERAPEUTIC USES (1) CHF  Cardiac glycosides are the traditional positive inotropic agents for the treatment of various types of CHF.

Pharmacology Review for Final exam (2013 batch)  glycosides increase strength of the heart contractions and cardiac output ,Lowers heart rate, Prolongs relaxation period, save the energy consumption.  They can effectively relief symptoms of CHF.  The sole kind of drugs without hypotensive effects.

ANTI-ARRHYTHMIAS  atrial flutter and fibrillation  are useful in the treatment of atrial flutter and fibrillation for slowing the ventricular rate (not abolish or cancel atrial flutter and fibrillation)  By their parasympathomimetic action, cardiac glycosides effectively increase the refractory period of the atrioventricular node ( reducing the pulses pass through the AV node ) to reduce ventricular rate.  glycosides are banned in ventricular arrhythmias

ADVERSE REACTION 1. the most common is the gastrointestinal reaction including - nausea, vomiting, anorexia, and diarrhea.

- This toxicity may be partially caused by direct effects on the gastrointestinal tract but also the result of central nervous system actions, including chemoreceptor trigger zone stimulation.  require no more than reducing the dose or suspending the medication.

2. CENTRAL NERVOUS SYSTEM ::  common: nausea, vomiting --- vagal and chemoreceptor zone stimulation.  Much less often: disorientation and hallucinations especially in the elderly (Hallucinations are sensations that appear real but are created by one’s mind. For example, one might hear a voice that no one else in the room can hear or see )  visual disturbances: visual changes:Xanthopsia. Chloropsia (aberrations of color perception )  Agitation and even convulsions are occasional 3. Cardiac toxicity :: PROARRHYTHMIA  digitalis can cause virtually every variety of arrhythmia. The most common cardiac manifestations of glycoside toxicity include 1 .Sinus bradycardia-- HR<60 is an indication for glycosides withdrawal 2. decreased AV conduction second-degree atrioventricular blockade.

3. SV tachycardia - atrioventricular junctional rhythm 4. VT- delayed afterdepolarizations

Pharmacology Review for Final exam (2013 batch)  ventricular premature beat, ventricular tachycardia, ventricular fibrillation. . ventricular premature beat is an indication for glycosides withdrawal

ACE  THERAPEUTIC USES - Hypertension - Heart Failure and Left Ventricular Dysfunction - Myocardial ischemic (angina pectoris, Infarction） - Diabetic Nephropathy

 ADVERSE REACTION - A persistent dry cough - Angioedema (due to increased bradykinin levels) - Retention of potassium & hyperkalemia (angiotensin II & aldosterone is responsible for increasing the excretion of potassium) - Hypotension (because of vasodilating effect) - Renal insuffuciency (decrease glomerular filtration pressure) - Less common adverse effects include :: - Skin Rashes - Hepatotoxicity - Fetal injury: Fetal hypogenesis

Β- RECEPTOR BLOCKERS  THERAPEUTIC USES   -Receptor blockers are recommended for routine use in CHF patients of Class II or III symptoms unless contraindication or inability to tolerate  blockers are only indicated in cases of compensated, stable congestive heart failure;  They are normally used in combination with diuretics and ACEIs.  ADVERSE EFFECTS - In the short term  -Receptor blockers have the potential to worsen heart failure and hypotension.

- They are not of value in acute failure and may be harmful if systolic dysfunction is severe.

Previous year review questions Please discuss therapeutic uses and adverse reactions of calcium channel antagonists according to its pharmacological effects

Pharmacology Review for Final exam (2013 batch)

Review question (Chemotherapeutic drugs) ANTI-BIOTICS NOTES :: Agents that kill microbes are called microbicidal, while those that merely inhibit their growth are called biostatic. The use of antimicrobial medicines to treat infection is known as antimicrobial chemotherapy, while the use of antimicrobial medicines to prevent infection is known as antimicrobial prophylaxis.

1. What are the major mechanisms of action for antimicrobial?

-> Inhibition of cell wall synthesis： penicillin -> Inhibition of cytoplasmic membrane synthesis or damage: polymyxins -> Modification in synthesis or metabolism of nucleic acids  Quinolones: DNA gyrase  Rifampin: DNA-dependent RNA polymerase.

-> Inhibition of protein synthesis : Aminoglycosides -> Modification in energy metabolism : Sulfonamides 2. What are the major mechanisms of resistance for antimicrobial?

A. Bacterial resistance to an antimicrobial agent falls into three general categories: (1) The drug not reach its target.

(2) The drug is not active.

(3) The target is altered.

B. Altered expression of protein  Enzyme related inactivation eg. β-lactamses destroy penicillin  Modification of target sites eg. alteration of target site in which penicillin is binding to protein.

C. Decreased accumulation eg. alteration of porins; efflux pump D. Genetic alterations leading to drug resistance  gene mutation eg. DNA gyrase mutation; RNA polymerase mutation  transformation bacteria can take up exogenous DNA from their environment  Understanding Bacterial Transformation  transduction Virus transfer the genes between bacteria E. Conjugation passage of resistance conferring DNA between bacteria 3. What are synergic mechanisms of combined use of sulfonamides and TMP? Notes :: Sulfonamides - The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Sulfonamides displace bilirubin from albumin, kernicterus (brain damage due to excess bilirubin) is an important potential side effect of sulfonamide use.

TMP - is an antibiotic used mainly in the treatment of bladder infections, although it may be used against any susceptible aerobic bacterial species. Other uses include for middle ear infections and travelers' diarrhea.

Pharmacology Review for Final exam (2013 batch)

SULFONAMIDES  The structure of sulfonamides are similar to that of para-aminobenzoic acid (PABA)  Sulfonamides competitively inhibit dihydropteroate synthase and prevent normal bacterial utilization of PABA (therefore, sulfonamides is bacteriostatic rather than bactericidal)  Trimethoprim (TMP) inhibits bacteria dihydrofolic acid reductase

TMP

 TMP synergies sulfonamides on blocking folic acid synthesis resulting in enhancement of bacteriostatic activity - Double blocking  TMP is often used with sulfamethoxazole (SMZ); the compound of SMZ and TMP is called as cotrimoxazole (Co- SMZ) 4. What are the general differences between1st, 2nd, 3rd and 4th-generation cephalosporins, describe the properties of cephalosporins?

Notes :: Cephalosporins are indicated for the prophylaxis(preventive medicine) and treatment of infections caused by bacteria susceptible to this particular form of antibiotic.

FIRST GENERATION  active against a variety of gram-positive bacteria except enterococci, penicillin-resistant pneumococci and methicillin-resistant staphylococci -> Cefazolin is the only first-generation parenteral cephalosporin still in general use. It penetrates well into most tissues and is the drug of choice for surgical prophylaxis.

-> Cefazolin is an alternative to an antistaphylococcal penicillin for patients who are allergic to penicillin.

PROPERTIES 1. These have narrow spectrums for cephalosporins, but the spectrums are similar to ampicillin.

2. They have some resistance to β-lactamases.

3. They are the most active cephalosporins for Gram-positive bacterial infections.

SECOND GENERATION  active against organism affected by 1st generation drugs  Extended gram-negative coverage, less active against gram-positive bacteria.  Primarily used to treat sinusitis, otitis, or lower respiratory tract infection.

Pharmacology Review for Final exam (2013 batch)  No activity against enterococci or P. aeruginosa.  Cefuroxime is the only second-generation drug that crosses the blood-brain barrier, but it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used.

PROPERTIES 1. They have broader spectrums and are more resistant to β-lactamases 2. An important use of first- and second-generation cephalosporins is prophylaxis during surgery if an infection is likely to occur.

THIRD GENERATION  Extended gram-negative coverage  The ability to cross the Blood-Brain-Barrier (BBB) (to treat meningitis)  Used to treat a wide variety of serious infection caused by organisms that are resistant to most other drugs.  Ceftriaxone and cefixime are first-line drugs for treatment of gonorrhea now that many strains of N gonorrhoeae are resistant to penicillin.  They should be used in combination with an aminoglycoside for treatment of meningitis caused by P aeruginosa.

PROPERTIES 1. The broadest spectrums 2. The highest activities against Gram-negative bacteria 3. The lowest activities against Gram-positive bacteria 4. The highest resistance to β-lactamases 5. The highest lipid solubilities 6. The best penetration into the Cerebro-Spinal Fluid, CSF 7. The most clinical usefulness FOURTH GENERATION  cefepime  More resistant to hydrolysis by chromosomal β-lactamase  Some extended spectrum β-lactamase that destroy 3rd drugs  It penetrates well into cerebrospinal fluid  Cefepime has good activity against most penicillin-resistant strains of streptococci, and it may be useful in treatment of enterobacter infection.  Good activity against enterobacteriaceae or P. aeruginosa.

5. What are the shared properties of aminoglycosides (antibacterial spectrum, mechanism of action, resistant mechanism, and adverse reaction)?

Notes :: Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial therapeutic agents that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar); the term can also refer more generally to any organic molecule that contains aminosugar substructures.

ANTI-BACTERIAL SPECTRUM  Highly active against Gram negative aerobic rods E coli, Pseudomonas aeruginosa, Klebsiella, Enterobacter Spp. Serratia Spp., Alcaligenes, Burcella, Salmonella, Haemophilus, Pasteruella, Acinetobacter, Pneumoniae, Streptococcus pyogenes and rikettsia  Not active against

Pharmacology Review for Final exam (2013 batch) Streptococcus Pneumoniae, pyogenes and rickettsia  Often used in combination with β-lactams to extend coverage to Gram-positive bacteria MECHANISM OF ACTION o Diffuse through outer membrane of gram-negative bacteria to enter the periplasmic space, tightly bind to ribsome 30s subunit o Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen-dependent process. o Transport may be enhanced by cell wall-active drugs, such as penicillin or vancomycin; this enhancement may be the basis of the synergism.

(A) Interfere with “initiation complex” of peptide formation by stopping the beginning of peptide synthesis (B) Misreading of mRNA which leads to incorporation of an incorrect amino acid (C) Causing premature termination of translation and eliciting incompletely synthesized proteins RESISTANT MECHANISM o Ribosome alteration Single step mutations in chromosomal genes encoding 30S ribosomal subunit. o Decreased permeability Absence or alteration in the aminoglycosides transport system, inadequate membrane potential, and modification in the LPS (lipopolysacchaccarides) phenotype. o Inactivation of aminoglycosides AAC: acetytransferases; ANT: nucleotideyltransferases APH: phosphotransferases ADVERSE REACTION  Ototoxicity can cause vestibular and auditory dysfunction which are largely irreversible In animal models have indicated that aminoglycosides accumulation in the ear is dose-dependent & saturable.

 Nephrotoxicity several day’s administration impair renal function, which is almost reversible once medication is stopped.

Serum creatine levels are frequently used to monitor the possible renal toxicities, because nephrotoxicity has been defined by an elevation of serum creatine.  Neuromuscular blockade inhibit prejunctional release of acetycholine while reducing postsynaptic sensitivity (curare-like effect， muscle relaxation ) Calcium salt is the preferred treatment for this toxicity.

Ca2+ overcomes the effect of the aminoglycosides at the neuromuscular junction.

Pharmacology Review for Final exam (2013 batch)  Allergic reactions Little allergenic potential.

Include rash, itching, eosinophilia, fever, swelling, dizziness, and trouble breathing.

6. What are the adverse reactions of chloramphenicol and tetracyclines?

Notes:: Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections. This includes meningitis, plague, cholera, and typhoid fever. Its use is only recommended when safer antibiotics cannot be used.

Tetracycline is used to treat many different bacterial infections, such as urinary tract infections, acne, gonorrhea, chlamydia, and others.

ADVERSE REACTION OF CHLORAMPHENICOL  Toxicity for newborn infants (gray baby syndrome) - new born especially premature newborn, for lack of an effective glucuronic - acid conjugation mechanism to metabolize chloramphenicol  Gastrointestinal disorders - Nausea, vomiting, and diarrhea  Bone marrow disturbances - Suppression of red cell production at dosages exceeding 50 mg/kg/d after 1-2 weeks. Reversible anemia is apparently dose-related .

- Aplastic anemia probably develops in one of every 24,000-40,000 patients who have taken chloramphenicol (A rare consequence of chloramphenicol administration by any route ).

ADVERSE REACTION OF TETRACYCLINE  Gastrointestinal disorders (drink more water, either two hours after eating or two hours before eating) Nausea, vomiting, and diarrhea often develop in patients.  Bone and teeth  deposited in newly formed bone or teeth in children as the drugs binds to calcium Tetracyclines are contraindicated for use in children under 8 years of age  It can also be deposited in bone, where it may cause deformity or growth inhibition  Liver toxicity Impair hepatic function.  Pregnancy  In patients with preexisting hepatic insufficiency  When high doses are given intravenously.  Hepatic necrosis has been reported with daily doses of 4 g or more intravenously.  Kidney toxicity - Cause renal injury  Outdated tetracycline preparations cause renal tubular acidosis and other renal injury resulting in nitrogen retention (uric acid, creatinine).

Pharmacology Review for Final exam (2013 batch)  Tetracycline given along with diuretics may produce nitrogen retention.  Tetracycline other than doxycycline may accumulate to toxic levels in patients with impaired kidney function .  Photosensitization eg. Demeclocyclines and doxycycline can induce mild to severe sensitivity to sunlight.  Local Tissue Toxicity  Intravenous injection can lead to venous thrombosis  Intramuscular injection produces painful local irritation and should be avoided.

7. Describe the therapeutic application of amphotericin B, flucytosine, and griseofulvin.

AMPHOTERICIN B • Active against most of fungi and yeast • Gold standard for treating disseminated infections caused by Aspergillus and Candida FLUCYTOSINE  Effective against a limited range systemic fungal infections Oral flucytosine is indicated for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans.  Drug resistance commonly arise if given alone usually combined with amphotericin B for severe systemic infections such as candidiasis and cryptococcal meningitis GRISEOFULVIN - Used to treat dermatophyte infections of skin or nails

8. How are antineoplastic agents classified according to action mechanism?

1. Inhibition of the synthesis of nucleic acids: Antimetabolites---S phase-specific Methotrexate (MTX) flurouracil (5-FU) inhibit enzymes in the purine or pyrimidine biosynthetic pathways or DNA polymerases.

2. Interference of DNA structure Alkylating antineoplastic agents cause alkylation of nucleophilic sites within the DNA double helix, leading to inhibition of DNA replication and cell death.

Bleomycin  Binds to DNA  Causes strand breaks  inhibition of DNA synthesis 3. Inhibition of RNA synthesis -

Dactinomycin

-

Doxorubicin

-

Dauorubicin

Pharmacology Review for Final exam (2013 batch) -

binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase.

4. Inhibition of protein synthesis -

Vinca alkaloids

-

vincristine

-

vinblastine -

binds to tubulin dimers, inhibiting assembly of microtubule structures and arresting mitosis in metaphase.

5. Hormone related mechanism - Antiandrogens: primarily used to treat prostate cancer.

Flutamide Bicalutamide -

Antiestrogens： treat for breast cancers that contain the estrogen receptor.

-

Tamoxifen： useful for treatment of both early-stage and metastatic breast cancer.

9. Please tell the major mechanisms of resistance for penicillins.

Notes :: Penicillin antibiotics were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci.

   

Inactivation of antibiotics by β-lactamase Modification of target PBPs Impaired penetration of drug to PBPs The presence of an efflux pump

10. Describe the mechanisms, adverse reactions, and therapeutic uses of vancomycin.

Notes :: Vancomycin is used to treat an infection of the intestines caused by Clostridium difficile, which can cause watery or bloody diarrhea. It is also used to treat staph infections that can cause inflammation of the colon and small intestines.

MECHANISM  Rapid bactericidal agent for dividing microorganisms  It inhibits the synthesis of the cell wall in sensitive bacteria by binding with high affinity to the D-alanyl-Dalanine terminus of cell wall precursor units.

ADVERSE REACTIONS o Common adverse reactions include - Auditory impairment, nephrotoxicity and hypersensitivity - reactionsa (side effect of the early impure versions of vancomycin). Later trials using purer forms of vancomycin found nephrotoxicity is an infrequent adverse effect - Should not be used in combination with ototoxic or - nephrotoxic drugs - e.g. aminoglycosides, polymyxin B and some diuretics o Red man syndrome - This syndrome, usually appearing within 4–10 min after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso - less likely to occur with slow infusion

Pharmacology Review for Final exam (2013 batch) THERAPEUTIC USES  Treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillinresistant S. aureus]] MRSA) and multiresistant Staphylococcus epidermidis (MRSE)) or in individuals with serious allergy to penicillins.  For treatment of infections caused by gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials.  Antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk.

11. Please tell the adverse reactions induced by amphotericin B (newly added)+ new slide Notes :: Amphotericin b should be used to treat only serious fungal infections. Due to its extensive side effects, it is often reserved for severe infections in critically ill, or immunocompromised patients. It is considered first line therapy for invasive mucormycosis infections, cryptococcal meningitis, and certain aspergillus and candidal infections

ADVERSE REACTION a. Fever and chills:These occur most commonly 1 to 3 hours after starting the IV administration. b. Renal impairment: patients may exhibit a decrease in glomerular filtration rate and renal tubular function.

Creatinine clearance can drop, and potassium and magnesium are lost. c. Hypotension: A shock-like fall in bood pressure accompanied d. by hypokalemia may occur, requiring potassium supplementation. e. Anemia f. Neurologic effects g. Thrombophlebitis: add heparin to the infusion can alleciate this problem.

Previous year question paper Essay question (totally 50 marks) 1. Please describe the major pharmacological effects and therapeutic application of adrenaline? (8 points) 2. How are antiarrhythmic agents classified? List the representative drugs in each group. (9 points) 3. Why do organic nitrates reduce myocardial oxygen consumption? Why do they usually combined with β – adrenoceptor blockers in treating angina pectoris? (8 points) 4. Describe the pharmacological effects and the clinical uses of H1 histamine blockers. (7 points) 5. What are the major mechanisms of action for anti-microbial? (9 points) 6. How are anti-neoplastic drugs classified according to action mechanism? (8 points)