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LECTURE 1: NSAIDS AND STEROIDS

INTRODUCTION

I. INFLAMMATION

A. Characteristics in Macroscopic Level

• Erythemea (redness)

• Edema (swelling)

• Tenderness (Hyperalgesia)

• Pain

B. Process of Inflammation

1. Acute Phase

-initial response mediated by Autacoids, characterized by local vasodilation and increased

capillary permeability

-there is vasodilation of vessels, gap formation in vessels, transmigration of cells

2. Immune Response

-immunologically competent cells activated: response to foreign organisms ot antigens

-Beneficial: immune system asks cells to phagocytose invading organism

-Deleterious: process of inglamtaion may proced chronic inflammation w/o resolution

3. Chronic Phase

-proliferative; release of mediators not prominent in Acute Response

-there is tissue degeneration and fibrosis occurs

II. SOME COMPONENTS

A. Components Released at site of Injury

• Kinins, Neuropeptides, Histamine

• Complement Components

• Cytokines

• Other Products of Leukocytes and Platelets

B. Events Occuring:

• Stimulation of Neutrophhil Membranes = Oxygen-derived free radicals

• Formation of Superoxide Anions = Stimulates production of other reactive molecules

• Interaction with Arachidonic Acid = Generates Chemotactic SubstancesMore Inflammation!!!

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III. RESULTS OF INFLAMMATION

A. Accompanying Pain

-we give mild to moderate Analgesics

-Pain of Inflammation and Tissue Injury: from local stimulation of pain fibers & enhanced pain

sensitivity due to increased excitability of the Central Neurons in Spinal Cord

**NSAIDs (non-steroidal anti-inflammatory drugs)

-effective in settings where inflammation has caused sensitization of pain receptors to normally

painless mechanical or chemical stimuli

B. Fever

-may be the result of: Infection, Inflammation, Graft Rejection, Malignancy, other disease stated

-enhanced by formation of Cytokines (an Autacoid) = increase synthesis of Prostaglandins which trigger

for fever by increased Heat Generation and Decrease in heat loss-Cytokines Synthesis of Prostaglandins Fever

**NSAIDS

-supresses fever by inhibiting the synthesis of Prostaglandins

-effective in lowering temperature elevation set by the Hypothalamus to normal

-ineffective in temperature elevations caused by exercise or increase in ambient temperature

C. Cell Damage

-release of Lysozomal Enzymes from Leukocytes liberation of Arachidonic Acid = Eicosanoids

-Cyclooxygenase Pathway is important

1. Cyclooxygenase Pathway = Prostaglandins

**COX-1 Isoform -constitutive (whether it happens or not, COX-1 is always present)

-it is Homeostatic in function

-found in many blood vessels, stomach and kidneys

**COX-2 Isoform -induced during inflammation by cytokines and inflammatory mediators

-facilitates the inflammatory response

-inhibited by some NSAIDs

*COX-2 Inhibitors -highly selective; without loss of effectivity

2. Lipooxygenase Pathway = Leukotrienes-has chemotatic effect on Eosinophils, Neutrophils, and Macrophages

-promotes Bronchoconstriction; alters vascular permeability

-NOT Inhibited by the NSAIDs

IV. GOALS OF TREATING INFLAMMATION

• Relief of Pain

• Slow Down or Arrest the tissue damaging process

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V. DRUGS USED (ANTIINFLAMMATORY)

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Glucocorticoids

• Slow Acting Anti-Rheumatic Drugs (SAARDs) or Disease Modifying Anti-Rheumatic Drugs (DMARGSs)

OVERVIEW OF NSAIDS-suppress signs of symptoms of inflammation

-can be Antipyretic or Analgesic Effects

-all are probably effective for the following: Rheumatoid Arthritis. Osteroarthritis, Seronegative

Spondyloarthropathies, Localized Musculoskeletal Syndromes and Gout (except Tolmetin)

I. COMMON PHARMACOKINETIC PROPERTIES

• As given, all are weak organic acids (except for Nabumetone: ketone pro-drug metabolized into an acidic

active drug)

•

Most are well absorbed: food does not change bioavailability substantially• Most are highly metabolized: some by Phase I and II Mechanisms; other phase II (glucuronidation) alone

(mostly occurs in the liver)

• Most NSAIDs: metabolisms proceeds by way of CYP3a or CYP2c enzymes in the Hepatic P450 System

• Most are excreted through the Kidneys (Renal Excretion: for most, but varying degrees of biliary and

enterohepatic circulation)

• Most NSAIDs are highly Protein-Bound (usually bound with Albumin)

• Ass NSAIDs can be found in Synovial Fluid after repeated dosing

• In their Chemistry:

o Racemic: Ibuprofen

o Single Enantiomer: Naproxen

o No Chiral Center: Diclofenac

II. COMMON PHARMACODYNAMIC PROPERTIES

• Anti-Inflammatory Activity = Inhibition of Biosynthesis of Prostaglandins

• Inhibition of Chemotaxis

• Down-Regulation of Interleukin-1 production

• Decreased production of Free Radicals and Superoxides

• Interference with Calcium-mediated Intracellular Events

III. DURING NSAIDS THERAPY• Inflammation is reduced by: decreasing release of mediators from Granulocytes, Basophils, Mast Cells

• Decrease in the sensitivity of blood vessels to Bradykinin and Histamine

• Affect production of T-Lymphocyes (effect on Immune Response)

• Reverse Vasodilation

• In Varying Degrees, ALL newer NSAIDs are Analgesic, Anti-Pyretic, Anti-inflammatory

• ALL (Except COX-2 Selective Inhibitiors) inhibit platelet aggregation (therefore: increased bleeding time,

more prone to bleeding because coagulation is inhibited)

• ALL are Gastric Irritants

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**Aspirin -irreversibly acetylates and blocks cyclooxygenase (Irreversible Effect)

-all other NSAIDs are reversible inhibitors

B. Highly Selective COX-2 Inhibitors

o Celecoxib

o Rofecoxib

o Valdecoxib

NSAID DRUGS

Acetaminophen

Aspirin Indomethacin

Diclogenac

Mefenamic Acid

Ibuprofen

Pyroxicam

Celecoxib

Rofecoxib

I. ACETAMINOPHEN (PARACETAMOL)

A. Pharmacokinetics

-active metabolite of Phenacitin

-Oral Administration

-Absorption: related to gastric emptying time

-Binding: slightly bound to plasma protein

-Metabolism: partially by hepatic enzymes = <5% Excreted Unchanged

-Half-Life = 2-3 hours

B. Indications:

o Effective as Analgesis and Antipyretic (good drug with pain, but no inflammation)

o Lacks anti-inflammatory effect, platelet inhibiting properties

o Mild-Moderate Pain

o Alternative for Aspirin Allergic Patients

o Does not antagonize effects of Uricosuric Agents

o History of Hemophilia, Peptic Ulcer, Aspirin-Induced Bronchospasm, Children with Viral Infections

C. Adverse Effects:

o Mild Hepatic Enzyme Induction

o Large Doses: dizziness, excitement, disorientation

o >15g = fatal: hepatonecrosis, acute renal tubular necrosis

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o Renal Damage w/o hepatic damage – with usual doses

II. ASPIRIN (Irreversible Effects)

A. Pharmacokinetics of Aspirin

-Salicylic Acid: pKa of 3.0

-Acetylsalicylic Acid (Aspirin): pKa of 3.5 – more effective analgesic

-Salicylates: rapidly absorbed; bound to Albumin; binding is saturable (total body load > 600mg) once

it reaches 600mg, we may experience signs of toxicity

-NOTE: To reverse toxicity of aspirin: Alkalinization of Urine = increases rate of excretion of free

salicylated and water soluble conjugates

B. Pharmacodynamics

**Anti-inflammatory Effects:

-ASA: non selective COX-1 and II Inhibitor; Irreversibly inhibits COX (interferes with mediators

of Kallikrein System

-Salicylate: less effective Inhibitor of Isoforms

**Analgesic Effects

-Effective for Mild-to-Moderate Pain

**Antipyretic Effects

-ASA: reduces elevated temperature

-normal temperature – slightly affected

**Platelet Effects

-a low dose (80mg daily) doses = prolonged bleeding time (very effective)

-taking aspirin must be stopped 1 week prior to surgery

C. Clinical Uses of Aspirin

1. Analgesia

-for mild to moderate pain

-not for Visceral Pain

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-acts synergistically with OPIODS for cancer pain (Morphine + Aspirin)

2. Antipyresis

-may be contraindicated in some cases

-ex) Aspirin is not given to kids w/ viral infection because of “Rye’s Syndrome”

3. Anti-Inflammatory

-in high doses for treatment of Rheumatoid Arthritis, Rheumatic Fever, other inflammatory joint

diseases

4. Other Clinical Uses

Decreased Incidence of Transient Ischemi Attacts (which can cause strokes)

Unstable Angina

Coronary Thrombosis

Lower Incidence of Colon Cancer

**Prophylaxis -Aspirin is given to prevent stroke

-this is to thin-out the blood

D. Adverse Effects of Aspirin

o Gastritis

o Peptic and Duodenal Ulcers

o Upper GI Bleeding (Erosive Gastritis)

o Salicylism: vomiting, tinnitus, decreased hearing and vertigo

o Hyperpena: large doses respiratory alkalosis proceed into acidosis (because of accumulation of

Salicylate Acid Derivatives)

o ASA: < or =2gdaily = increased serum uric acid; >4g daily = decreased urate levels below 2.5md/mol

o Antiplatelet Aggregation

o Reye’s Syndrome: acute encephalopathy, exanthematous rashes, vomiting, fatty infiltration of internal organs following acute viral infections

o Elevation of Liver Enzymes (mild) and Hepatitis (Rare)

o Decreased Renal Function

o Asthma, Bleeding, Rashes

III. INDOMETHACIN

-potent, non selective COX-Inhibitor

-also inhibits Phosphoipase A & C, reduce PMN Migration, decrease T-Cell and B-Cell Proliferation

A. Pharmacokinetics

o Well absorbed after Oral Administration

o Hepatic Metabolism . .

o Excreted Unchanged: Bile and Urine

o Half Life: 2 hours, prolonged by Probenecid

B. Indications

o Rheumatic Arthritis, Gout, Ankylosing Spondylitis

o Patent Ductus . .(it closes the Patent Ductus Arteriosus in infants –replaced by Lbuprofen)

o Sweet’s Syndrome –READ!

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o Juvenile Rheumatoid Arthritis

o Pleurisy

o Nephrotic Syndrome

C. Adverse Effects

o GI Effects: Abdominal Pain, Diarrhea, GIT Hemorrhage, Pancreatitis

o Headache: 15-25% - dizziness, confusion and depression

o Psychosis with Hallucinations (Rare) –similar structire with Serotonin?

o Thombocytoplenia

o Aplastic Anemia

o Hyperkalemia (inhibition of Renal PGE2 Synthesis)

o Contraindications: Nasal Polyps, Angioedema

IV. DICLOGENAC

-Phenylacetic Acid resembling Flurbiprofen and Meclofenamate

-potent, relatively non-selective Cyclooxygenase Inhibitor; also decreases Arachidonic Acid Bioavailability

-has Anti-Inflammatory Effects, Analgesic and Antipyretic Properties

A. Pharmacokinetics

o Rapid Absorption

o Bioavailability: 30-70% due to first pass hepatic effect (this is the only amount used in the body)

o Half-life = 1-2hours

o Accumulates in Synovial Fluid: Half-Life = 2-6 hours in the joints

o Liver Metabolism = Inactive Metabolites

o Clearance: Bile = 30%

B. Adverse Effects

o GIT Distress: 20%

o Occult GI-Bleeding

o Gastric Ulceration

o Increased Serum Aminotransferases

**Opthalmic Preparation -for prevention of Post-Opthalmic Inflammation

V. MEFENAMIC ACID

-inhibits both COX and Phospholipase A2

-Peak plasma levels = 30 minutes

-Half Life = 1-3 hours

**Adverse Effects

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o Diarrhea and Abdominal Pain: same as other NSAIDS

o Enhances effects of Oral Anticoagulants

o Not to be used >1 week and for children

VI. IBUPROFEN

-99% or more is protein bound

-Rapid Renal Clearance

-Half Life = 1-2 hours

-extensive hepatic metabolism: CYP2C8 and CYP2C9 – little excreted unchanged

-2400mg = 4g ASA in antiflammatoy effect

-Oral preparation <2400mg = Analgesic NOT Antiflammatory (we must go above 2400mg to become Antiinflmmatory)

-Topical: absorbed in muscles and fascia

**Adverse Effects

o GI Bleeding and Irritation (If Topical, it will not cause GI Bleeding) NOTE: note used concurrently

with Aspirin = it will decrease Anti-inflammatory effect

o Rashes, Pruritus, Tinnitus, Dizzines, Headache, Aseptic Meningitis (SLE patients), Fluid Retention

o Contraindications: Nasal Polyps, Broncospastic Reativity to Aspirin, Angioedemao Kidneys: acute renal failure, interstitial nephritis, nephritic syndrome (rare)

VII. PYROXICAM

-no-selective COX inhibitor, also inhibits PMN Migration, decreased oxygen radical formation and inhibits

lymphocyte function

-Half Life = 50-60 Hours Once a day dosing

-Rapidly Absorbed: stomach and upper small intestines

-peak plasma concentration = 80% in 1 hours

-Hepatic Metabolism: inactive metabolites

-indicated for Rheumatic Conditions

**Adverse Effects:

o GIT (20%) Symptoms

o Dizziness, Tinnitus, Headache, Rashes

o Doses > 20mg/day = peptic ulcers . . .

VIII. CELECOXIB

A. Pharmacokinetics / Dynamics

-Highly Selective COX-2 Inhibitor

-Absorption: decreased 30% by food (do not eat anything before taking)

-Effective Half-Life = 11-12 Hours

-highly protein bound

-Hepatic Metabolisms: CYP2C9-clearance impaired by heptic impairment

-no increased efficacy: >1200mg

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B. Adverse Effects

o Dyspepsia: frequency of other adverse effects like those of other NSAIDs

o Interacts occasionally with Warfarin

o Less Edema and Renal Effects

o Does not affect platelet aggregation

IX. ROFECOXIB

-potent, highly selective COX-2 Inhibitor

-Well Absorbed; Limited by solubility characteristics in higher doses

-less protein bound

-Half Life: 17hours – once daily dosing

-Hepatic Metabolism: also metabolized by Intestinal CYP3A4

**Indications:

o Osteoarthritis

o Rheumatoid Arthritiso Analgesic, Antipyretic

o Does not inhibit Platelet Aggregation

o Fewer gastric/duodenal ulcers

o Recalled by FDA (because it causes heart failure, etc)

STEROIDS

I. BIOSYNTHESIS OF STEROIDS-Adrenal Cortex = Corticosteroids (21-C) + Androgens (19-C)

-Corticosteroids = Glucocorticoids + Mineralocorticoids

A. Glucocorticoids

-for CHO, CHON, Lipid Metabolism

-for Anti-inflammatory properties

-Cortisol = Hydrocortisone

NATURALLY OCCURING SYNTHETIC

Hydrocortisone

Cortisone

Prednisone

BetamethasoneTriamcinolome

Prednisolone

Dexamethasone

1. Hydrocortisone Prednisolone

-four times increase in Glucocorticoid Activity

-decrease in Na+ Retaining Activity

2. PrednisoloneMethylprednisolone

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-introduction of 16-a-Methygroup in Prednisolone yields Methylprednisolone

-further enhances Glucocorticoid Activity

-nullifies Mineralocorticoid Activity

B. Mineralocorticoids (Aldosterone)

-fluid and electrolyte balance

NATURALLY OCCURING SYNTHETIC

Desooxycorticosterone

Aldosterone

Fludrocortisone

1. Hydrocortisone Fludrocortisone

-introduction of the 9-a-Fluro group to Hydrocortisone yields Fludrocortisone

-there is 10x increase in Glucocorticoid activity

-there is greater in Mineralocorticoid activity

C. Structure of Corticosteroids = Pregnane Component-Pregnane is the basic backbone structure of Corticosteroids

-Pregnane + Cholesterol

II. GLUCOCORTICOIDS-prevents / suppress inflammation in response to multiple inciting events: Radiant, Mechanical, Infectious & Immunological

-BUT, it does not address the underlying cause of the disease: suppression of inflammation is of enormous

clinical utility

-of immense value in treating diseases that result from undesirable immune reactions

A. Multiple Mechanisms:

**Inhibit Production by Multiple Cells of Factors critical in generating Inflammatory Response

Decrease release of Vasoactive and Chemoattractive Factors

Decrease Secretion of Lipolytic and Proteolytic Enzymes

Decrease Extravasation of Leukocytes to areas of injury

Decrease Fibrosis

**Inhibition of Functions of Tissue Macrophages and Other Antigen-Presenting Cells (Immune response)

Limits ability of macrophages to Phagocytose, kill microorganisms, and to produce the tumor

necrosis factors

**Reduce Prostaglandin, Leukotriene & Platelet-Activating Factor Synthesis resulting from Phospholipase A2

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**Reduced Expression of Cyclooxygenase II (the inducible form of this enzyme in inflammatory cells

There is reduction of amount of enzymes available to produce Prostaglandins

**Causes Vasoconstriction (against Vasodilation) applied directly to skin

Done by suppressing Mast Cell Degranulation

**Reduce Capillary Permeability

Reducing Amount of Histamine released by Basophils

B. Single Dose, Short Acting Glucocorticoid

-there will be changes maximal in 6-hours

-Dissipates in 24-Hours

Concentration of Neutrophils increases

Lymphocytes (T & B Cells), Monocytes, Eosinophils, Basophils decrease in number

C. Principles in giving Glucocorticoids (has little Antipyretic Effect)

o Chronic Therapy: undertakedn with great care

o Use Short or Medium to intermediate acting glucocorticoids:; Prednisone & Prednisolone

o Do all ancillary measures to keep doses low

o Alternate-day theraby should be utilized

o Therapy should not be decreased NOR stopped Abruptly

o With prolonged treatment: obtain chest x-rays and a tuberculin test

o Considerable comcommitant diseases such as diabetes, peptic ulcer, osteoperosis, and psychological

disturbances; assess cardiovascular function

D. Supplemental Measures

o Diet rich in K+ and Na+

o Caloric Management

o High Protein Intakeo Appropriate Antacid Therapy

o Physical Therapy + Adequate Calcium and Vitamin-D

READING ASSIGNMENT: AUTACOIDS

INTRODUCTION

I. AUTACOIDS

-Autos (Self) + Akos (Medical Agent / remedy)

-this group refers to an array of substances that are normally present or may be formed in the body whose primary

function is Humoral Regulation (a lot are mediators of inflammation)-they participate in Physiological or Pathophysiological responses to injury

-local hormones; brief duration; act near site of synthesis; not blood borne

II. AUTACOIDS DISCUSSED

• Histamine

• Kinins: Bradykinin / Kallidin

• Serotonin (5-Hydroxytryptamine)

• Eicosanoids

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• Platelet Activating Factors (PAF)

• Slow-Reacting-Substance of Anaphylaxis (SRSA)

• Eosinophil Chemotactic Factor of Anaphylaxis (ECEA)

• Cytokoines / Lymphokines

• Nitric Oxide (EDRF)

• Immunosuppressants: Cyclosporin Inhibits Interleukin-2

HISTAMINE

I. BIOCHEMISTRY OF HISTAMINE

-Histamine is a Hydrophilic molecule comprised of an Imidazole Ring + Amino Group connected by two

Methylene Groups

-it is widely distributed throughout the animal kingdom and present in many venoms, bacteria, and plants

A. Synthesis of Histamine

-L-Histidine Decarboxylation Histamine

-Histidine Decarboxylase: the enzyme to Decarboxylate Histidine into Histamine

B. Storage of Histamine

-chief site of storage in most tissues is in the Mast Cells; in the blood, it is stored in the Basophils

-Mast Cells + Basophils synthesize Histamine and store it in Secretory Granules (along with Heparin,

ECF-A and NCF-A)

C. Degradation of Histamine

o Ring Methylation catalyzed by: Histamine-N-Methytransferase

o Oxidative Deamination catalyzed by nonspecific enzyme: Diamine Oxidase

II. RELEASE OF HISTAMINE

A. Immunologic Release

-this type of release requires Energy + Calcium

-Mast Cells and Basophils degranulate when exposed to the appropriate Antigen (if sensitized by IgE

Antibodies attached in their surface membranes)

-released in Allergic / Inflammatory Responses

B. Mechanical Release

-injury to mast cells

III. MECHANISMS OF ACTION OF HISTAMINE

RECEPTOR DISTRIBUTION EFFECTS BLOCKED BY

H1 Smooth Cells

EndotheliumBrain

Increase Phosphoinositol Hydrolysis

Increase Intracellular Calcium

Classical Antihistamine

H2 Gastric Mucosa

Cardiac Muscle

Mast Cells

Brain

Increase cAMP Ranitidine

H3 Brain

Myenteric Plexus

Other Mucosa

Negative Feedback Release Thioperamide

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IV. PHARMACOLOGIC EFFECTS OF HISTAMINE

-“Wheal and Flare” Phenomenon

-three responses (triple response)

o Localized Reddening

o Swelling (Edematous Wheal)

o Red Irregular Flare

BODY SYSTEM EFFECT ON SYSTEM

CVS Vasodilation and Increase Capillary Permeability (H1)

Increase Heart Rate (H2) – increased force of contraction in Cardiac Muscles

GIT Increase GIT Motility (H1)

Increase GI Secretion (H2)

Respiratory Bronchoconstriction (H1)

Uterus Pregnant women in Anaphylaxis may abort (Increase Uterine Contraction)

Nerve Endings Pain and Itching (H1)

Exocrine Glands Physiological Regulator of Gastric Acid Secretion mediated by H2-Receptors

V. ANTAGONIST OF HISTAMINE

-Physiological Antagonist = Epinephrine-inhibition of release: (-) Mast Cell Degranulation; (-) IgE-Ag induced increases in intracellular Ca+

A. H1 Receptor Antagonists

-these are the classical Antihistamine Drugs used for treatment of allergy

**Antihistamine Drugs:

Ethanolamines – Diphenhydramine

Ethylenediamine-Pyrilamine

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Alkylamines – Chlorpheniramine Maleate

Phenothiazines – Promethazine Hydrochloride

Piperazine – Chlorcyclizine

Piperidines – Cyproheptadine

Miscellaneous – Mebyhydrolin

B. H2 Receptor Antagonists

-drugs used for Gastric Problems (ex. Gastric Ulcer)

-act predominantly on Gastric Mucosa

**H2 Receptor Antagonists:

Cimetidine

Rantidine

Famotidine

Nizatidine

VI. NEW CLASSIFICATION OF H1 RECEPTOR ANTAGONISTS

A. First Generation (More likely to Block Autonomic Receptors)

o Chloropheniramine

o Hydroxyzine

o Diphenhydramine

B. Second Generation

o Acrivastine

o Astemizole

o Azelastine

o Cetrizine

o Levocabastine

o Loratadine

o Mequitazine

o Terfenadine

o Fexofenadine

SEROTONIN (5-HYDROXYTRYPTAMINE)-5-HT is: 3-B-Aminoethyl-5-Hydroxyindole

-like Histamine, it is widely distributed in the animal and plant kingdom

-about 90% of Serotonin is located in the Enterochromaffin Cells in the GIT; the others is in the Platelets in CNS

I. BIOCHEMISTRY OF SEROTONIN

A. Synthesis of Serotonin

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-synthesized from Tryptophan

-Tryptophan Hydroxylation Decarboxylated Serotonin

-synthesized Serotonin is then taken up into secretory granules and stored

B. Degradation and Excretion of Serotonin

-Serotonin undergoes Oxidative Deamination by MAO to form = 5-Hydroxyindoleacetaldehyde which is

further degraded by further oxidation into 5-Hydroxytryptophil

-this is now excreted in the Urine (5-HIAA)

II. SITES OF ACTION

A. Enterochromaffin Cells

-synthesize and store 90% of Serotonin

-Release: Mechanical Stretch; Efferent Vagal Stimulation

B. Platelets (no synthesis)

-possess 5-HT-Transporter

-Release: activation of platelets

III. PHARMACOLOGICAL EFFECTS

BODY SYSTEM EFFECTS:

CVS Vasoconstricion (arteries and veins)

Indirect Vasodilation

Bezold-Jarisch Reflex

Smooth Muscles Contraction

Relaxation

Bronchial Smooth Muscles Bronchoconstriction

GIT Increased Motility

CNS Regulation of Sleep and Wakefulness

Anxiety and Depression

IV. PHARMACOLOGICAL MANIPULATION OF 5-HT LEVELS

-Diet Low in Tryptophan decreases Serotonin

-P-Chlorophenylalanine Irreversibly blocks Tryptophan Hydroxylase

A. Agonists:

o D-Lysergic Acid Diethylamide

o Buspirone

o Sumatripan

o Cisapride

B. Antagonists

o Ondansetron

o Clozapine

o Methysergide

o Cyproheptadine (Periactin)

VASOACTIVE PEPTIDES

I. CONSTRICTORS

• Angiotensin II

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• Vasopressin

• Endothelins

• Neuropeptide-Y

II. DILATORS

•Bradykinin and Related Kinins

• Natruiretic Peptides

• Vasoactive Intestinal Peptides

• Substance-P

• Neurotensin

• Calcitonin Gene-Related Peptides

KININS

• Bradykinins (Plasma Kallikerin)

• Kallidin / Lysyl-bradykinin (Glandular Kallikerin)

• Methionyl-Lysylbradykinin (Pepsin and Pepsin Like Enzymes)

I. BIOCHEMISTRY OF KININS

-they are formed by the action of enzymes known as Kallikreins or Kininogenases acting on Kininogen

-Kallikreins: glycoprotein enzyme produce in the liver as Prekallikreins and present in plasma

-Kininogens: precursor of Kinins and substrates of Kallikreins

II. PHARMACOLOGIC EFFECTS

SYSTEM / EVENT EFFECT

CVS Vasodilation in Arteries

Vasoconstriction in Veins

Endothelial Cell ContractionInflammation Edema and Bronchospasm in Asthmatics

Pain Chronic and Acute Pain

Neonate: Bradykinin Closure of Ductus Arteriosus

Constriction of Umbilical Cord

Dilation of Fetal Pulmonary Artery

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EICOSANOIDS-Precursor = Arachidonic Acid (polyunsaturated fatty acids with 20-carbons (Eicosa = Twenty)

-biologically active lipid and peptolipid acid derivatives of Arachidonic Acid

-extremely potent, endogenous, regulatory substances synthesized and released from immediate, autacoid action

I. BIOCHEMISTRY

-Arachidonic Acid = Leukotrienes + Prostaglandins + Thromboxanes

-Cyclooxygenase Pathway yields to Prostaglandins (by COX-1 and COX-2)

o COX-1 or PGH Synthase-I: always present with a House-Keeping Function

o COX-2 or PGH Synthase-II: immediate response in inflammatory and immune cells

A. Products of Cyclooxygenase + Lipooxygenase

CYCLOOXYGENASE LIPOOXYGENASE

Prostaglandins (PGs)

Prostacyclins (PGI2)

Thromboxane (TXA2)

Leukotrienes (LTs)

Hydroxyperoxyeicosatetraenoic Acid (HPETE)

Hydroxyeicosatetraneoic Acids (HETE)

B. Biosynthesis of Eicosanoids

o Arachidonic Acid is released from Cellular Phospholipids by: Phospholipase A2 OR Phospholipase AC

o Arachidonic Acid can enter: Cyclooxygenase or Lipoxygenase Pathways

1. Cyclooxygenase Pathway

Arachidonic Acid becomes PGG and PGH (unstable intermediates)

These rapidly undergo Synthesis to Prostaglandins by PGD, PGE, PGF2-A, PGI2 or TXA2 Synthases

Two isoforms of Cyclooxygenase: COX-I and COX-2

COX-1 is expressed in most cells, COX-2 is inducible

2. Lipoxygenase Pathway

Arachidonic Acid is converted to HPETE by 5-, 12-, 15-Lipoxygenases

HPETE are unstable intermediates – converted to corresponding 5, 12, 15-HETE

SRSA-A: “Slow-Reacting Substance of Anaphylaxis”” composed of LTC4 and LTD4

**5-Lipooxygenase -important because it leads to synthesis of Leukotrienes

-Leukotrienes are Peptidolipic Acids

C. Inhibitors of Biosynthesis

1. Phospholipase A2 (PLA2): Glucocorticoids (Inhibitor)

-synthesis of Lipocortin inhibits PLA2

-Dexamethasone suppresses Cytokine-Induced COX-2 Expression

2. Cyclooxygenase (COX-1 and COX-2): Aspirin / NSAIDs (Inhibitor)

-inhibited by Aspirin and NSAIDs

-Acetylsalicylic Acid (ASA) results in irreversible acetylation of COX-1 and COX-2

-leads to increase in Leukotrienes by shunting Arachidonic Acid to Lipoxygenase Pathway

3. COX-2 Selective Antagonist (Celecoxib, Rofecoxib)

-COX-2 Expression is regulated by Pro-Inflammatory Factors

-COX-2 is involved in local inflammatory response but not GIT or Kidney (selective antagonist

would afford protection from Ulceration and Reduced Renal Function

4. Thromboxane Synthase (Dazoxiben, Primagrel)

-selective Inhibition of Thromboxane (TXA2)

-promotes platelet aggregation and vasoconstriction

-Therapeutic Advantage as yet undemonstrated

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-Ridogrel: blocks both Thromboxane Synthase and Thromboxane Receptors

5. Lipoxygenase: Zileuton blocks 5-Lipoxygenase

-effective in trials of Asthma, Ulcerative Colitis, Allergic Rhinitis

II. PHARMACOKINETICS OF EICOSANOIDS

A. Distribution

-Eicosanoids are NOT stored, but synthesized and released as needed-distribution depends on tissue

-ex) Prostacyclin – metabolized and released by Endothelial Lining of the Vasculature

Thromboxane – synthesized and released by Platelets

B. Metabolism

-most Prostaglandins (95%) destroyed during one passage through pulmonary circulation

-PGI2 (Prostacyclins) NOT Metabolized in the lungs

III. PHARMACODYNAMICS

A. Mechanism of Action

**Receptor Diversity

-there are five main types of Prostaglandin Receptors corresponding to PGD, PGE, PGF2-A,PGI2 and TXA2

-Receptor subtypes have been identified for the PGE and TXA2 Receptors

-similarly, these receptors have been identified for Leukotrienes

**Signaling Pathways

-all are G-Coupled Receptors

RECEPTOR EFFECT

PGD2 & PGI2 Adenylyl Cyclase

PGE Activate / Inhibit Adenylyl Cyclase

PGF-2 & TXA2 Activate Phospholipase-C DAG + IP3 Increase Ca2+

LTD4 Activate Phospholipase-C

B. Effects on Tissues

BODY SYSTEM EFFECT

CVS *PGE2 & PGI2: Vasodilators (no effect on veins)

*PGF2A & TXA2: Vasoconstrictors in Pulmonary Arteries especially in Veins

*Leukotrienes (LTC4 & LTD4): Lower Blood Volume by Endothelial Contraction

and Exudation of Plasma into EVS (1000x more potent than Histamine)

Blood *PGE1 & PGI2: Inhibitor of Platelet Aggregation (in Endothelium)

*TXA2: Inducer of Platelet Aggregation (Aspirin inhibits synthesis of TXA2)

*LTB4: Chemotactic Agent

Renal *PGE1 & PGI2: diuresis and secretion of Renin

*PGE: inhibits water reabsorption by Antidiuretic Hormone

*PG Synthesis required for diuretic action of loop diuretics

GIT *PGE2 & PGF2A: contract longitudinal muscles

*PGF2A: contracts; PGE2 Relaxes circular muscles

*Leukotrienes contract GIT Smooth Muscles

*PGE & PGI2: inhibit gastric secretion

*PGE: increase mucus secretion in stomach

*PGE & PGF: stimulate water movement into intestinal lumen (Diarrhea)

Bronchial Smooth M *PGE1, PGE2, PGI2 relax Bronchial Muscle

*PGF2A & TXA2: Contract

*LTC4 & LTD4: 1000x potent than Histamine in Bronchoconstriction & Edema

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Uterus *PGE1, PGE2, PGF2A & TXA2: contract human uterus; PGI2 Relaxes

*PGE2 & PGF2A: increase in uterine tone in pregnant

CNS *Fever: PGE1 and PGE2 increase temperature (prevented by Aspirin)

*Pain: PGE & PGI2: sensitize afferent nerves to noxious stimuli

*PGD2 induce natural sleep though receptors around 3rd Ventricle

*LTB4: produces Hyperalgesia

IV. CLINICAL IMPLICATIONSA. Female Reproduction

**Abortion in Females

1. Dinoprost Tromethamine

-derivative of PGF2A withdrawn in US

-it can cause circulatory collapse resulting from Pulmonary Hypertension

2. Carboprost Tromethamine (Prostine/15M)

-derivative of PGF2A

-long duration action

3. Dinoprostone (Prostin E2): Analog of PGE2

**Facilitation of Labor

-PGE2 and its derivatives

-PGE2A is less used as it can cause Bronchoconstriction in Asthmatics and GI distress

**Dysmenorrhea

-excessive endometrial synthesis of PGE2 and PGF2A

-NSAIDs relieve 75-85% (Aspirin is less effective – has low potency)

B. Cardiovascular System

1. Aspirin

-Thrombosis: low dose of Aspirin reduces risk of death due to infarction

2. Alprostadili (Prostin)

-Patent Ductus Arteriosus: Alprostadili (Prostin VR Pediatric), PGE1 to maintain patency (Apnea

occurs in 10% especially low birth weight)

-delayed closure of Ductus Arteriosus can be treated with NSAIDs (in utero, NSAIDs can result

in premature closure in fetus)

3. Alprostadili

-Impotence or Erectile Dysfucntion: Alprostadil administered as intracavernosal injection

C. Respiratory System

-Peptidoleukotrienes probably are the dominant bronchoconstrictors in allergic reactions

-Zileuton (Lipoxygenase Inhibitor) has a Bronchodilator Effect

D. Renal System

-Cyclooxygenase inhibitors in elderly can result in Renal Dysfunction

-response to Furosemide (Lasix) diminished with concurrent NSAIDs administration

-Bartter’s Syndrome associated with Renal Overproduction of Prostaglandins and associated diuresis

and loss of sodium and potsddium (NSAIDs are used to treat it)

E. Gastric Cytoprotection

-Analogs of PGE1: Rioprostol, Misoprostol (Cytotec)

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-Analogs of PGE2: Enoprostil, Arbaprostil, Trimoprostil

-given orally to treat gastric ulceration, especially that associated with NSAID use (caution in pregnant)

V. ADVERSE EFFECTS OF EICOSANOIDS

• Vomiting

• Diarrhea

• Hyperthermia

• Abortion

• Bronchoconstriction

PLATELET ACTIVATING FACTORS-different family of phospholipids derived from fatty acids resulting after the release of Arachidonate from

cellular phospholipids

-restricted to blood cells, mast cells, renal medullary cells, endothelial cells

-PAF stimulates G-Protein Activate Phospholipase C, D, A2

I. PHRAMACOKINETICS

A. Distribution

-restricted to blood cells (platelets, neutrophils, monocytes, eosinophils), mast cells, renal medullary cells,

and vascular endothelial cells

B. Biosynthesis

-the precursor of PAF is: 1-O-Alkyl-2-Acyl-Glycerophosphocholine

-Phospholipase A2 releases Arachidonic Acid and resulting lyso-PAF is acetylated by lyso-PAF

Acetyltransferase, which is the rate limiting step

-PAF is either released or acts as an intracellular autacoid

II. PHARMACODYNAMICS

**Mechanism of Action

-PAF stimulates G-Protein coupled receptors which then activate Phospholipase C,D,A2

SYSTEM AFFECTED EFFECT

CVS Vasodilator

Increase Vascular Permeability

Platelet Aggregation

Chemotactic Factor for WBC and causes PMN to aggregate

Smooth Muscles Contraction

Most potent ulcerogenic substance known

Reproduction Ovulation, Implantation, Parturition

(Ginkoglide B interfere with these process)

Inflammation & Allergic

Reaction

Increased Vascular Permability

Hyperalgesia

Infiltration of Neutrophils

Edema

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Bronchospasm

PHARMACOLOGY MODULE 1

LECTURE 1:

ANTI-AUTACOIDS: NSAID AND STEROIDS

READING ASSIGNMENT:

AUTACOIDS

pharma m-1

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