1. H. pylori
2. increased acid production
3. Reduced mucus layer
4. reduced bicarbonate
5. increase in type 1 pepsin
6. decreased mucosal blood flow
7. NSAID-induced erosion

Tx for PUD:

Antibiotics

Eradicates H. Pylori

-Metronidazole

-amoxicillin + clarythromycin

decrease form 80% to 5% when antibiotics are used in conjungtion with PPI to rid of PUD (1-2 week duration)

Tx for PUD:

PPI

Inhibit H+/K+ dependent ATPase

-decreases H+ secretion from parietal cells (>90%)

-improves function of antibiotics by improving stability and absorption

PharmacoKinetics:

PPI

Pro-Drug

-activated by Low pH (should be taken with meal)
             -active sulfonamide in parietal cell caniliculi

-weak base unstable at low pH so given in eteric coated capsule

Active metabolite

-reacts with sulfhydryl group on the proton pump

-irreversible inhibition (long duration)

-Metabolized by CYPs (P450's)

-excreted in urine or feces

Theraputic uses:

PPI

promote healing of gastic and duodenal ulcers and to treat GERD that is unresponssive to H2 antags

Duodenal Ulcer: pH 3

GERD: pH 4

H. Pylori eradication (w/antibiotics): pH 5

Side Effects:

PPI

GI complications: Nausea, abdominal pain,

         constipation, flatulence and diarrhea

H2 antagonists

(names)

Cimetidine

Ranitidine

Famotidine

Nizatidine

Inhibit acid secretion by 60%

-blocks histamines role in acid secretion (other factors

      still promote secretion: ACh, gastrin)

-PPI's are more effective in promoting healing

Synthetic Prostaglandin E1 analog

Inhibits acid secretion

exerts "cytoprotective" effects on gastric mucosa

            (NSAID's decrease the protection)

PharmacoKinetics:

Misoprostol

Rapid absorption (orally)
Extensive first pass-->active metabolite

Effects seen within 30 min and can last 3 hour

Food and antacids delay absorption (empty stomach)

Therapeutic uses:

Misoprostol

decreases basal acid production by 85-95%

decreases food-stimulated acid secretion by 75-85%

Approved by FDA in preventing NSAID induced musosal

     injury (usually coadministered)

Side Effects:

Misoprostol

GI complications

Uterine contractions

Polysaccharide

-undergoes crosslinking and polymerization in acidic

      enviornments

-forms a sticky gel that adheres and protects the

      epithilial cells

PharmacoKinetics:

Sucralfate

Adheres to ucler craters for 6 hours

-taken four times daily

-empty stomach one hour prior to meals

-aboud antacids withing 30 min of dose

Therapeutic uses:

Sucralfate

Approved therapy for duodenal ulcers and other GI complications

Prophylaxsis for stress ulcers

Decline use over the years

Side Effects:

Sucralfate

Constipation- due to Aluminum content

Pt. with renal failure can have aluminum overdose

-toxicity leads to drowsiness and convulsions

can also alter absorption of other drugs

-take 2 hours after sucralfate dosing

Gelusil II, Maalox, Mylanta, Rolaids, Tums-EX

Basic substances that neutralize acid in stomach

Inhibit conversion of pepsinogen to pepsin (protease

       that aggravates ulcers)

usually salts of aluminum, Mg, Na, Ca

Used for Dyspepsia and GERD

Minimall SE

Toxicity in pt. with renal impairment

Gastric and duodenal contents reflux into the esophagus

Esophagitis---> barrett's metaplasia (10%)

   ---> esophageal cardinoma (rarely)

defects in GI tone: Lower esophageal sphinctor relaxes more often then normal

common in pregnant women

After 2 weeks of self-treatment and symptoms are not better must see physician

Tx approaches for:

GERD

1. PPI: drug of choice
2. H2 antag: less effective than PPI, good for symptomatic relief
3. antacids and alginic acid: form a 'floating raft' over the stomach content, reducing reflux
   -pt. must consume water and remain upright
4. Prokinetic drugs: Metoclopramide, reduce symptoms but does not promote healing
   -used in adjunct with PPI and H2 antags

15% population affected, more common in women

abdominal pain, bloating and altered bowel movements (constipation/diarrhea)

Thought to be caused by visceral sensitivity to noxious substances

Does not cause permanent harm just discomfort

Therapeutic approaches:

IBS

1. 5-HT3 antag:  Alosetron, has some effects but has 

              severe SE so only used when all else failed

2. 5-HT4 partial agonist:  Tegaserod maleate, IBS

             w/constipation,  SE of severe diarrhea and 

             ischemic colitis

3. Calcium channel activator:  Lubriprostone, IBS

             w/constipation, PGE1 analog, Laxative product

             increases fluid secretion in small intestine

             SE: N/D and ab pain CI pregnency

IBD

inflammatory bowel disease

Group of inflammatory deseases that affect the intestines

Ulcerative colitis: confined to colon, inflammation is superficial, involves the distal portion in continuous fashion

Crohn's disease:  Affect small and large bowel, focal inflammation affecting all layers of wall

Bothe pathologies not well understood therory that it is antigen driven response

Therapeutic approaches:

IBD

Tx IBD:

5-aminosalicylates

Sulfasalazine cleaved in th colon by bacterial enzymes into two components:

1. sulfapyridine: prevents absorption of 5-ASA before it

                        reaches colon

2. 5-ASA: inhibits both COX and 5-lipoxygenase

Positive response rate of 60-80%

also used to prevent relapse of ulcerative colitis

Not used for Crohn's disease

SE: Common: fever, malaise, N/V

-Megaloblastic anemia and low sperm count (folate given)

-most SE are caused by the sulfapyridine, other dirivitives have been created

Tx for IBD:

Mesalazine (5- amino salicylic acid)

The active moiety of sulfasalazine which avoids SE of the sulfapyridine

-must be taken 3-4 times daily

SE: rare but seious effects on kidney and liver and blood disorders: blood tests recomended b4 and after thereapy

Lialda (once a day)

Tx for IBD:

Glucocorticoids

Major therapy for sivere IBD and induce remission of chron's disease

Dexamethasone is the classic treatment

Tx for IBD:

Infliximab

Immunoglobulin given IV which binds to and neutralizes TNFalpha

-approved for severe crohn's disease, promotes healing

Tx for IBD:

Other agents

6-mercaptopurine and Azathioprine are second line agents for severe IBD

Methotrexate is effectev in crohn's disease

Cyclosporine is used for severe ulcerative colitis that is unresponsive to glucocorticoids

emisis center in the brainstem contains the Chemoreceptor Trigger Zone (CTZ) which monitors blood and receives neural input from the gut

1. GI irritation: mechano- chemo- receptors

2. Motion sickness

3. pregnancy- morning sickness 80% pg women,

     greatest in first trimester "hyperemeisis gravidum"

4. intracranial pathology- hemorrhage and inflammation

5. metabolic disorders- hyperglycemia, uremia

6. psychogenic- anxiety, nervouse stomach,

      andticipatory

7. pain

8. drugs and radiation

9. postoperative

Therapeutic approaches for N/V:

5-HT3 antagonists

Ondansetron- used to conteract emesis due to chemotherapy

Therapeutic approaches for N/V:

Dopaminergic antagonists

Phenothiazines- reduce nausea via D2 recepters in the emesis center, useful in motion sickness

Therapeutic approaches for N/V:

H1 antag

Cyclizine used for motion sickness and postoperative nausea

Therapeutic approaches for N/V:

Cholinergic antagonists

Scopolamine transderma patches redcue motion sickness and postoperative nausea

Therapeutic approaches for N/V:

Cannabinoids

Dronabinol- prophylaxis of chemo induced emesis when other drugs are ineffective, stimulates appetite

-given 1-3 hours prior to chemo then every 2-4 hours up to six doses

-ADR- sympathomimetic effects, CNS effects

-can displace other drugs

-subject to abuse

Therapeutic approaches for N/V:

Glucocorticoids

Dexamethasone- used to reduce nausea in patients with widespread cancer by reducing inflammation

Therapeutic approaches for N/V:

Bensodiazepines

results from disorders of intestinal water and electrolye transport

-Rehydration thereapy

- drugs used for pt. with persistent and severe symptoms

Therapeutic approaches for Diarrhea:

Bulk-forming agents

colloids (metamucil)- absorb water to increase stool bulk

Clays- bind water and enterotoxins

Kaopectolin is a popular OTC agent

Therapeutic approaches for Diarrhea:

cholestyramine

anion-exchange resin binds bile acids and bacterial toxins

-used to treat bile-salt induced diarrhea

-binds other drugs and vitamins

Therapeutic approaches for Diarrhea:

Bismuth

Mineral with mild antibiotic activity and ahnt inflammatory effects

-MOA unclear

-Excreted bismuth sulfide causes blackening of stools and tongue

Therapeutic approaches for Diarrhea:

Opioids

inhibit GI motility

Loperamide: is more potent than morphine in treating Diarrhea

avalible OTC and effective for travellers diarrhea

overdose can cause CNS depression and toxic effects on colon

Hard dry stool three times or fewer per week

can lead to significant problems

common cause is poor diet and lack of exercise

Change in diet (adding fiber) and increasing fluid intake often fix problems

Therapeutic approaches for constipation:

Laxatives

3 Classifications:

1. softening of feces (1-3 days)

 -bulk-forming lax- bran, psyllium, methylcellulose

 -sufactant lax- docusates, poloxamers

2. Cause soft or semifluid stool (6-8 hours)

 -Stimulatn laxatives- diphenylmethan derivatives (bisacodyl), anthraquinon derivative (senna)

 -cause mild inflammation and can damage mucosa upon repeated use

3. cause watery evacuation (1-3 hrs)

 -osmotic laxatives

castor oil- seldom used do to toxin ricin that it contains

Therapeutic approaches for constipation:

Enemas

introduction of solution into the lower bowel with the goal of evacuating its contents.

NA posphates or mineral oil are often used

are used for certain diagnostic procedures

Serotonin Background

(5- hydroxy- tryptamine)

Neurotransmitter

-synthesized in a two-step process from tryptophan

   1. catalyzed by tryptophan hydroxylase to 5- 

       hydroxytryptophan (rate-limiting)

   2. catalyzed by L-amino acid decarboxylase

-degradation of 5-HT not stored is by MAO 

Fungal products with serotonergic activity found on contaminated grains

- have been used to treat migraines

LSD (lysergic acid diethylamide)-ergot alkaloid synthesized, induces hallucinations

Physiologica role of Serotonin:

Brain

NT very important from therapeutic perspective

(covered later)

Physiological role of Serotonin:

GI tract

In the mucosa:

released locally to initiate peristalsis

also effects electrolyte secretion

Neuronal gut:

complex, net result is inhibitory

OVERALL effect in the gut is prokinetic

-promotes and cordinates propulsion of material through GI tract

Physiological role of Serotonin:

Platelets

take up serotonin from cirrculation

-store it in secretory granules

-upon aggregation it releases 5-HT which is a mediator of vasoconstriction

Physiological role of Serotonin:

Carcinoid tumor

Tumors of the intestinal enterochromaggin cells

-excrete extraordinarily high amounts of 5-HT into circulation

-leads to psychotic behaviors

Types of Serotonin receptors:

5- HT1

G-protein coupled receptros that inhibit adenylate cyclase

-also regulate ion channels that inhibit neuronal 5-HT release

-expressed by neurons in CNS

Examples of agents: Buspirone (partial agonist), LSD (agonist), sumitriptan(agonist)

Types of Serotonin receptors:

5- HT2

GPCR that activat phospholipase C thus increasing intracellular Ca+

-Expressed in brain, gut and plattlets

Examples of agents:

        Methysergide (antag)

        ketanserin (antag)

        Cyproheptadine (antag)

Types of Serotonin receptors:

5- HT3

Ligand gated ion channels

-agonist cause cell depolarization

-expressed in particular areas of brain and GI tract

-Both locations the receptor participates in the emetic response

Examples of agents:

     Ondansetron (antag)

Types of Serotonin receptors:

5- HT4

GPCR that activates adenylate cyclase

found in the CNS and GI tract

in gut these mediat secreation and peristalsis

Examples of agents:

     Mosapride (agonist)

     Metoclopramide (agonist)

Uses for serotonergic agents:

5-HT_1A Partial agonist

Used to treat anxiety and depression and mood disorders

*will be discussed more in future courses

Uses for serotonergic agents:

5- HT_1B/1D Agonists

Pharmacokinetics

SQ sumatriptin reaches peak [plasma] in 12 min.

-97% bioavalibility

oral administrations results in peak [plasma] in 1-2 hours

-15% bioavalability (nasally too)

Metabolism is predominatly via MAO-A

-half-life is 1-2 hours

Uses for serotonergic agents:

5- HT_1B/1D Agonists

Therapeutic uses

Used for acute treatment of migraine (not prophylaxis)

Vascular therory: thought vasodilation of vessels on outer surface of brain

neurovascular therory: affect of synaptic transmission that impacts pain circuitry

Pt. serotonin levels drop during migrane

oral dosage is more convient but impractical if migrane is acompanied by N/V

Uses for serotonergic agents:

5- HT_1B/1D Agonists

Side Effects

Acute increase in Blood Pressure, therefore CI with pt. cardiac or cerebrovascular disease

Serotonin syndrome: fatal situation that can result from serotonin excess

-cognitive effects (confusion, agitation, hallucinations, coma)

-autonomic effects (shivering, sweating, hyperthermia, tachycardia, hypertension)

-somatic effects (tremors)

co-administration of SSRI can exacerbate the toxicity

Uses for serotonergic agents:

5- HT_2A/2C Antagonists

Kinetics: methysergide's effects takes 1-2 days to develop

Tx uses:

cyproheptadine has stron antihistamin activity

Methysergide is used prophylactically to prevent migraine attacks and vascular headaches

-also used to treat GI effects of cardinoid tumors

SE: mild GI and CNS effects

prolonged use can, rarely, lead to inflammatory fibrosis

  -most serious can form in cardiac valves

Innerruptions of 3-4 weeks every 6 months is mandated to allow fibrosis to regress.  Valve damage can be permanent

Uses for serotonergic agents:

5- HT₃ Antagonists

kinetics: once daily

Tx uses:

Ondansetron: treat nausea induced by a variety of situations

-not effective against motion sickness

Alosetron useful in treatment of IBS (slows motility)

-start on low dose and discontinue if constipation develops

SE: minor: constipation, diarrhea, headache, ligh headedness

Uses for serotonergic agents:

5- HT₄ Agonists

metoclopramide, mosapride

Tx uses:

Metoclopramide: acts in uper digestive tract enhancing gastric emptying

-major indication is for relieving nausea caused by GI

dysmotility syndromes (chronic constipation in parkinson's disease)

-anti dopaminergic effect is key to relief of N/V

mosapride is more specific for 5-HT4

SE: rare but portentially dangerous

-extrapyramidal effects

Histidine converted to histamine by L-histidine decarboxylase

stored in mast cells released by allergens

important mediator of allergic response in upper respiratory, skin, eyes

responses to histamine

1. smooth muscle relaxation (small blood vessels)

2. smooth muscle contraction (broncial, GI)

3. Increased capillary permeability

Lewis triple response: vasodilation, wheal, flare

Types of histamine receptors:

H1

GPCR

agonists cause increase in intracellular Ca+

Expressed: Brain, smooth muscle, heart, and edothil

Action: bronchoconstriction, vaso -constriction/-dialation and increased vascular permeability

    *heart effects are + ino and chronotropic

Other actions:  CNS stimulation or depression, and motion sickness

H1 antagonists

Anti-histamines

Mepyramine, Chlorpheniramin, Triplodine

Types of histamine Receptors:

H2

Agonists cause an increase in intracellular cAMP

Expressed: Brain, stomach, smooth muscle, heart, and mast cells

Action: stimulates gastric secretions by parietal cells, regulation of BP, and acts on CNS

H2 antagonists

Cimetidine, Ranitidine, Famotidine, Nizatidine

Used to reduce acid secretion in GI disorders

Types of histamine Receptors:

H₃

agonists decrease influx of Ca+ into cells

expressed: Brain, heart and stomach

Action: involved in feedback inhibition of NT release

Thioperamide, Clobenpropit

considreable interest in the potential use for the treatment of ADHD, alzheimer's disease and Schizophrenia

Types of Histamine Receptors:

H₄

Agonists cause eosinophil and mast cell chemotaxis

Expressed: Bone marrow, white blood cells, and low levels in most tissues

actions: mediate inflammation

Thioperamide, VUF-6002

Have anti-inflammatory effects

Used to treat allergy

treat RA and IBD

Classes of histamine receptor antagonists:

H₁ blockers

all H₁-antihistamines are Invers Agonists

Work by decreasing basal activity by stabilizing there inactive conformation

Compete with agonist for binding

Classes of histamine receptor antagonists:

H₁ Blockers

(1st Generation)

All Cause Drowsiness because it can pass BBB

Ethylenediamines (pyrilamin, tipelenamine)

Ethanolamines (benadryl, clemastine, dimenhydrinate)

Alkylamines (chlorpheniramine, dexchlorpheniramine,

                  triprolidine)

Piperazines (meclizine, cyclizine, hydroxyzine)

Phenothiazines (promethazine, Trimeprazine)

Cyproheptadine

Classes of histamine receptor antagonists:

H₁ Blockers

(2nd Generation)

More H1 specific

Reduced ability to cross BBB, reduced sedation

Alkylamines (acrivastine)

piperazines (cetirizine)

Phthalazinones (azelastine)

Piperidines (levocabastine, loratadine, fexofenadine)

Classes of histamine receptor antagonists:

H₁ Blockers

(3rd Generation)

Active enantimers of metabolites of 2nd gen

Desloratadine- non sedating, long-lasting (once daily)

                      *no clear advantage over loratidine

Levocetirizine- more rapid absorption, more H1 selective

                      *no clear advantage over cetirizine

Ebastine- once daily, pro-drug

Fexofenadine- metabolite of terfenadine

Classes of histamine receptor antagonists:

H₂ Blockers

Cimetidine

ranitidine

famotidine

nizatidine

Classes of histamine receptor antagonists:

H₃ and H₄ Blockers

Uses of Antihistamines:

H₁ antagonists

Kinetics: 1st gen rapid absorption, last 4-6 hours

             2nd gen rapid absorption, last 4-24 hours

     -both metabolised in liver and exreted in urine

Tx: allergic conditions, motion sickness, sedation(1st)

-histamine is only one of many mediators for allergic reaction; not drug of choice for asthma

-treats symptoms of mast cell release does not treat underlying cause of why it was released

-thought to have some anti-inflammatory effects

SE: sedation, GI complication, Dry mouth, CNS stimulation (overdose)

-2nd gen will cause sedation if taken too much

-cardiotoxicity: arrythmias (blocking of K channels)

-1st gen thought to effect motion sickness and parkinsons disease theraputically

-dry mouth is actually caused by the anti-muscurinic action 

Uses of Antihistamines:

H₂ antagonists

Kinetics: rapidly absorbed, peak at 1-3 hours

             10-35% first pass, excreted in urine

             reduce dose for pt. with impaired renal clear.

             all avalible oral some IV

Tx: Inhibit gastric acid production by competing for H2

     on parietal cells, reduce basal secretion

-once daily after dinner is best to decrease nocturnal

     acid secretion

-promotes healing of gastric and duodenal ulcers

cimetidine is also used to treat hives (H2 responsible for hives)

SE: diarrhea, constipation, headache, drowsiness, fatigue, and muscular pain,  CNS effects when given IV

-Cimetidine can disrupt estrogen metabolism by binding to androgen recepors

     -glactorrhea in women and gynecomastia in men

     -longterm effects are impotence and reduce sperm

       count

     -inhibit CYP's so lots of DDI

Uses of Antihistamines:

H₃ antagonists

under development, not yet approved for human use

potentially useful in gastroprotective, anti-inflammatory and anticonvulsant agents

H3 receptors serve as inhibitory feedback functions

chronic inflammatory process- reversible obstruction of bronhi and bronchioles

10% population (increasing), strong genetic component

Most common pediatric disorder

Mast cell degranulation -> hypersensitivity reaction

1. spasms of smooth muscle

2. impaired gas exchange

3. swelling of bronchial lining due to mucus secretion

4. wheezing, SOB, chest tight, coughing

Depends on person - varies from person to person

1. enviromental factors: antigens, respiratory infections, cold aire, pollutants

2. PG

3. Nocturnal asthma

4. Exercise induced asthma (EIA)

5. Gastroesophageal reflux

Expiration is compramized- decrease in FEV

Early Phase: up to one hour after triggering stimulus

Late Phase: 4-8 hours after exposure

       -due to recruitment of inflammatory cells --> more

         mediators --> dcrease in FEV

Asthma

Goals of Therapy

1. no ER visits (they are costly)

2. normal physical activity

3. no sleep disruption

4. minimize damage to lungs

Anti-inflammatory agents for prevention

Bronchodialators for breakthrough symptoms

EIA can be treated prophylacticly with Bronchodilator

Bronchodilators:

Beta-adrenergic agonists

non selective

Isoproterenol, EPI

Not reccomended

Bronchodilators:

Beta-adrenergic agonists

B₂ selective

Short acting: albuterol, terbutalin, fenoterol

Long acting: Salmeterol, Formoterol

MOA: Bronchodilation by direct B2 receptors action

Administration: Inhalation (↓SE) MDI, DPI, nebulizers

       -inhalation technique is important (50% incorrect

         use)

Clinical use: For all asthma pt. for breakthrough use

       -not advised for sole or first line treatment

SE: Tremor seen when given oral or IV or in large doses

           -B2 action in skeletal muscle

      Palpations

      Increased mortality if used as sole treatment

Bronchodilators:

Theophylline

MOA

Methylxanthine related to caffeine and theobromine

MOA: inhibits Phosphodiesterase  --> increase in cAMP

        -relaxes bronchi and inhibits mast cell

         degranulation

      mild anti inflammatory effect:

             -adenosine receptor antag on mast cells

              reducing cytokine production

             -activates histone deacetylase (HDAC) repacks

              genes and prevents binding of transcription

              factors induced by inflammation

Bronchodilators:

Theophylline

Administration, Tx and SE

Administration: Oral

Metabolism is influence by age, smoking, otherdrugs, and disease

Blood levels need to be monitored periodically (narrow TD)

sustained release has better control

Clinical use: used in combo with others, COPD, and sleep apnea

SE: arrythmias, + ino and chrono

      -diuresis

      -CNS: N/V, nervouse, insomnia, tremers, convulsion

pediatric percautions:

-fever interferes with clearance

-CNS stimulation

-seizures    

Bronchodilators:

Cholinergic antagonists

Ipratropium Bromide

MOA: Blocks M2 receptors in Bronchial smooth muscle

Admin: inhalation

Tx: alternative to B2 agonists

      -slow onset of action

      -useful in elderly becuase B-adrenergic receptor

       density decreases with age where as M2 does not

Anti-inflammatory Agent:

Cromolyn Sodium

MOA: 'mast cell stabalizer'

-inhibits antigen induced degranulation of mast cells

-does not relax bronch smooth muscle

-suppresses many inflammatory cells other than mast

Admin: inhalation powder, bad tasting (children use compliance effected)

Tx: Prophylactic for allergen-induced asthma

-slow onset of action

SE: minimal, used in children due to the low SE

Anti-inflammatory agents:

Glucocorticoids

Prednisone (oral), Beclamehtasone and fluticasones propionate (inhale)

MOA: reduce infiltration of inflammatory cells, mucus secretion and bronch constriction

-enhances effects of beta agonists

-inhibits cytokine production

effects are widespread and delayed onset (transcriptional)

Tx: oral is for short term use in refractory asthma

inhalation is first-line treatment

SE:

systemic: adrenal suppression, decrease bone mass,

               growth suppression (concern in children)

Local: oral candida infection (spacer)

         hoarseness

Leukotriene Modulators:

LTD₄ Receptor antagonists

Zafirlukast, Montelukast, Pranlukast

MOA: competitive inhibitors for the D₄ leukotriene receptor

 - receptor mediates mast cell releasing

TX: antigen-induced asthma, EIA, mild asthma

      allergic rinitis, COPD,

      -not antiimflammtory

SE: safe and well tolerated

taken orally once or twice daily

Steriod sparing

not recommended for sole therapy for asthma

Leukotriene modulators:

5- Lipoxygenase inhibitors

Zileuton

MOA: Blocks production of leukotrienes that induce bronchoconstriction

SE: liver toxicity due to toxic metabolites

Steriod sparing

Not recommended for sole therapy

Leukotriene modulators:

Omalizumab

Recombinant monoclonal antibody against IgE

Adjunctive therapy to demonstrate efficacy when added to high dosed inhaled corticosteroids plus long acting beta agonist in patients with severe persistant asthma

Expensive

Fifth leading cause of death in USA

Composed of two syndromes (usesually coexists)

1. Bronchitis: Mucosal inflammation and edema

          - excess mucus causes cough dyspnea and 

            sputum production

2. Emphysema: affects alveoli and airways, causes

    irreversible strucrual damage that impairs gas

    exchange

        - alveoli there is decrease in SA and recoil

        - Decrease in FEV

cronic irritation of the airways

asthma is often in association

COPD:

Drug Therapy

(general stratagy)

1. Remove causative factors

2. control symptoms

3. partial reversal of the pathological damage

Smoking cessation is the most effective, difficult to acheive

*pulmonary function decreases with age

COPD:

Drug Therapy

Bronchodilators

MOA: promote clearance of mucus

Admin: inhalation (same for asthma)

Tx: not as effective for COPD as asthma but offer some

     relief

- Beta adrenergic agonist: may stimulater cilary activity

     *long acting are particularly useful

-anticholinergic agents: first-line, more effective in

 COPD than asthma pt.

COPD:

Drug Therapy

Anti-inflammatory agents

Steroids: Help reduce inglammatory components of the

             disease, Efficacy remains controversial

Teophylline: demostrated ability to reduce

                  inflammation in COPD

COPD:

Drug Therapy

N-acetylcysteine

Mucolytic

MOA: splits disulfide bonds of mucopolysaccharides

Admin: by aerosol or tracheostomy

SE: bronchospasms, bad odor

*efficacy is guestioned

COPD:

Drug Therapy

Other Mucolytics/expectorants

1. Volatile oils: NH₄Cl, ambroxol

    -Not commonly used in US

    -given orally

    -expectorant

2. Iodinated glycerol- no longer aval. in US

3. Hypertonic saline: in clinical trials

COPD:

Drug Therapy

Oxygen

Used when chronic severe hypoxemia develops

MOA: reduces hypoxemia

Admin: Nasal

Chronic administration is required

COPD:

Drug Therapy

Antibiotics

COPD:

Drug Therapy

Alpha 1 - antitrypsin (AAT)

Glycoprotein produced in liver then goes to lungs

serine proteases inhibitor and Neutrophil elastase inhib

deficiency can casue emphysema

   - leads to destruction of connective tissue in alveolar

     walls

MOA: restors balance to the protease/antiprotease levels

admin: IV

Expensive, still being tested

COPD:

Drug Therapy

Others and Future

Other:

  - pulmonary rehab

  - lung reduction surgery

  - lung transplantation

Future:

  - protease inhibitors

  - PDE-4 inhibitors

  - anti-oxidants

reflex to clear airways

Triggers: environmental irritants, infections, allergens, asthma, postnasal drip, organic disease, ACEI

Cough receptors: nerve endings in airway epithelia and

      transmit via vagus nerve

Cough Center: medulla, intiats impulse to cough

Drug Therapy for cough:

Narcotic Antitussives

CODEINE

MOA: suppresses cough center (acts on CNS)

SE: sedation, GI disturbances

*addiction is rare due to lack of euphoria

Drug Therapy for cough:

Non-narcotic antitussives

DEXTROMETHORPHAN

D-isomer of codeine analog levorphanol

equieffective to codeine

Non addictive

subject to abuse

Drug Therapy for cough:

Antihistamines

DIPHENHYDRAMINE (and relatives)

Antitussive action central component

Anticholinergic effects may dry out respiratory tract thus worsening cough

Drug Therapy for cough:

Steam (vaporizers)

Drug Therapy for cough:

Glyceryl Guaiacolate (Guafenesin)

Widely used OTC

Promotes fluid secretions

Dosing effectivness not clear

High doses can cause GI distress and Nausea

Genitic disease: mutation in gene coding for CFTR (a chloride channel

defects disrupt electrolye transprot which causes a thicker mucus

multiorgan disease: lung and pancrease

Death is due to repiratory insufficiency

CF disease:

- abundant, purulent airway secreation

- inflammatory response to infections

- nuclei  from degenerating neutrophils relase DNA

- DNA compines with actin to form the thick secretion

1. Expectorants/Mucolytics

2. recombinant human deoxyribonucleases

    - aerosol admin

    - decrease dyspnea, and improve well being

    - efficacy varies, high cost

    - well tolerated

3. high-dose IBU

Inflammation of mucous membranes of nose

Type 1 immune reaction

Sneezing, rhinorrhoea, nasal itch, and nasal congestion

triggered by antigen binding to IgE in nasal mucosa causeing mast cell degranulation

Drug therapy for Allergic Rhinitis

1. Antihistamines

2. anti-inflammatory agents

         - steroids- nasal aerosols

         - cromolyn- inhaled, eye drops

3. Decongestants

         - alpha₁ agonists: pseudoephedrine

         - Ipratropium- intranasal; aerosol

Located in sn-2 position on the glycerol backbone

once released it is rapidly metabolized to other compounds

mediators derived from AA

Three major classes:

1. prostaglandins

2. thromboxanes

3. leukotrienes

Pathways for eicosanoid productions Page 3

Cleaves substituent from the 2 position of the glycerol backbone

cPLA₂ most studied

-dependent on Ca+

-activated by phosphorylation and Ca+ in response to

 extracellular signal

-selective for AA in sn-2

Fatty acid cyclooxygenases

COX

(prostaglandin edoperoxide H-synthases)

metabolize AA to Prostaglandin endoperoxides

Two coupled reactions:

1. cyclooxygenase reaction

2. peroxidase reaction

COX-1: constitutively expressed in most cells

      - involved in making eicosanoids involved in

        physiologic responses (TXA₂)

COX-2: Inducable enzyme

      - synthesized in inflammatory cells

      - produces eicosinoids  at sites of inflammation

      - expressed in non-inflammatory cells (vascular)

      - over expressed in cancers

further metabolize PGH to bioactive products

oxygenates AA at carbon-5 generating 5-HPETE which is a precourser to Leukotrienes

all are GPCR

5 main types

DP- binds PGD₂

FP- binds PGF₂

IP- binds PGI₂

TP- binds TXA₂

EP- binds PGE₂: several subtypes

CysLT1

CysLT2

   -Both 1 & 2 bind  LTC₄ LTD₄ and LTE₄

BLT1

BLT2

   -Both 1 & 2 are LTB₄ receptors

1. Dialte vascular smooth muscle, reduce BP

2. dilate bronchial smooth muscle

3. contract uterine smooth muscles

4. contract GI smooth muscle and inhib secretions

5. induce pain, sensitize nerve endings to nociception

1. contracts uterine smooth muscle, levels in amnioti gluid increase at parturition

2. contracts GI smooth muscle

1. Dialates vascular smooth muscle, IV admin induces prominant hypotension

2. constricts Bronch sm

3. inhibits plattlet aggregation

4. inhibits gastric acid secretions

5. sensitizes nerve endings to nociception

1. constricts vascular smooth muscle

2. constrict Bronch sm

3. induces platelet aggregation

1. contract most smooth muscle

2. Cysteinyl LTs mediate bronchoconstriction and chemokine production by mast cells (inflammation)

3.  LTB₄ is a chemotactic agent and increases capillary permeability promoting exudation of plasma

all are rapidly metabolized and excreted in the urine

PGE2 inactivated by oxidation (95% one pass)

PGI2 hydrolyzes in blood (short acting)

PGF_2a agonists:

15-methyl PGF_2a

Tx: induce abortion, post-partum hemostasis

Admin: IM

SE: N/V, D, and bronchoconstrictions

CI: asthmatic pt.

PGF_2a agonist:

IUD

MOA: acts indirectly through PGF_2a  

        - cause irritation of the uterine mucosa which 

          increases PGF_2a

         - creates hostile enviornment for implantation

copper containing IUD alter prostaglandin production to favor PGF_2a over PGE₂

PGE₁/E₂ Agonists:

Misoprostol

PGE₁ analog

Tx: prevents NSAID induced ulcers

CI: pregnant pt. because it causes uterine contraction

PGE₁/E₂ Agonists:

PGE₁

Alprostadil, caverject

Tx: Erectile dysfunction in men that do not respound to other treatments

SE: priapism when dosing is incorrect

Warning: should not be used when having intercourse with PG women

Other use: can be used in neonates with congenital heart disease prior to surgery

PGE₁/E₂ Agonists:

PGE₂

Dinoprostone, Prepidil

Tx: used to induce labor

Admin: cervical gel

also used as vaginal suppository to induce mid-trimester abortion

leukotrient receptor antagonists;

Zafirlukast

LTD₄/LTE₄ receptor antagonist

    -antagonizes the effects of LTC₄, LTD₄ and LTE₄

specifically targets CysT₁ receptors

Used to treat asthma (montelukast)

leukotrient receptor antagonists;

LY293111

LBT₄ receptor antag show promiss in therapy of pancreatic cancer

COX inhibitors:

Glucocorticoids

Prednisone

block induction of COX-2 at transcriptional level

COX inhibitors:

NSAIDs

all NSAIDs have:

1. anti-inflammatory: symptomatic releif of pain, does

                               not stop pathology

       - used for arthritis

2. analgesic: effective against low-moderate pain

       - used for memstrual cramps, inflammatory pain,

         chronic postoperative pain 

3. anti-pyretic: Reduce body temperature

*exception is Acetaminophen, lacks anti-inflam

     activity

COX inhibitors:

NSAIDs

Adverse Effects

Gastric bleeding and ulceration (less in COX-2 inhib)

shown to increase cardiovascular events (vioxx)

- inhibit production of PGI₂(GOOD) in endothelial cells but does not block TXA₂ (BAD)

Specific COX inhibitors:

Aspirin

Effective in inhibiting platelet function

used prophylactically to prevent thromboembolic disorders

Aspirin Intolerance: resemble anaphylaxis, due to increased production of 5-lipoxygenase products

Aspirin Toxicity: overdose (20-30 tablets >6.5 g)

GI symptoms, CNS stimulation followed by depression, tinnitus, increase body temp, Respiratory alkalosis, acidosis and dehydration

- Tx: give bicarbonate

Specific COX inhibitors:

acetaminophen

Suggested that it is the most effective in blockin COX-3

- may play role in inflammation in humans

Chronic treatment at high doses can cause HEPATOTOXICITY

Specific COX inhibitors:

Indomethacin

Pyrrole acetic acid derivative

not suitable for long term use

SE: 35-50% of pt.

- GI problems

- most common are frontal headaches

Specific COX inhibitors:

IBU and Naproxen

SE: GI complications

Naproxen is better tolerated than IBU

Naproxen has a longer half-life

Specific COX inhibitors:

Celecoxib

COX-2 selective NSAID

Less GI toxicity than IBU

CI in pt. with sulfa allergies

Supraphysiologic doses

Hydrocortisone are the endogenous glucocorticoid

bind to intracellular receptors to cause change in gene transcripton- onset is slow

Important targets:

1. COX-2 expression is inhibited

2. induce expression of phospholipase A₂ inhibitor

3. cytokine expression is inhibited

4. expression of leukocyte adhesion molecules is inhibited

Increase SE with prolonged use (use intermittened dosing to decrease SE)

Major SE: Cushing's syndrome

1. muscle Weakness

2. central fat deposition

3. atrophic skin

4. bone loss

5. adrenal suppression (mimics addison's disease)

6. growth supression in children

7. increasedd risk for atherosclerotic disease

8. clucose intolerance

9. neuropsychiatric disorders

10. infections (immune supression)

11. cataracts

Oral: Prednison, Prednisolone, Methylprednisolone, Dexamethasone

Inhaled: Beclomethasone, triamacinolone acetonide, flunisolide, budesonide, flutacisone

Topical: betamethasone, triamcinolone acetonide, dexamethasone, hydrocortisone

Signigicant Differences between synthetic Glucocorticoids:

Glucocorticoid vs mineralcoticoid

activities

mineralocorticoid activity is desirable (less side effects on electorlytes

hydrocortisone has both activites

Prednisone has alightly lower mineralocorticoid potency and four times higher glucocorticoid potency

dexamethasone has no mineralcorticoid activity but 20-50 times higher glucocorticoid potency

Signigicant Differences between synthetic Glucocorticoids:

Potency

Signigicant Differences between synthetic Glucocorticoids:

Rate of metabolism/duration

and action/time of onset

compounds with low mineralocorticoid activity is more slowly mtabolized

Shorter acting is perffered when tappering off or whne alternate-day dosing

tapering off is to avoid adreanl suppresion that emerges with abrupt withdrawl

Signigicant Differences between synthetic Glucocorticoids:

Absorption

compounds that are poorly absorbed are ideal for topical administration or local via Injection

more water soluble eompounds are useful for IV admin

overproduction or undersecretion of uric acid

symptoms are due to precipitation of uric acid in tissue

"crystal arthritis"

Treatments for Gout:

NSAIDs

used to treat acute attacks of gout

Treatments for Gout:

Colchicine

Anti-mitotic

MOA: binds to tubulin

- prevents migration of granulocytes and other inflammatory cells into the inflammed area

SE: GI problems (80%pt with high dose)

-discontinued once GI problems develop

Tx: acute attacks of gout and to prevent them while treating with xanthine oxidase inhibitors

Treatments for Gout:

Glucocorticoids

Treatments for Gout:

Probenicid

Uricosuric agent

blocks transport of organic acids across renal tubule

- results in increased excretion

given to prevent attacks of gout

should only be given to pt. with reduced uric acid clearance

orally, well tolerated

SE: Rash, GI problems

CI in pt. with uric acid kidney stones (exacerbate the stones)

Treatments for Gout:

Allopurinol

Inhibits xanthine oxidase

blocks production of the urric acid precourser xanthine

SE: skin rash, GI distress, hypersensitivity reactions