II. Specifics
 A. Epinephrine
  1. comes in a prefilled syringe or in ampoules
  2. for asthmatic attacks, the dose tends to be somewhat smaller (0.3mg), administered subcutaneously; there is a suspension form for this purpose that is frequently on backorder from the manufacturer (Susphrine)
  3. in cardiac arrest, 1.0mg is given IV and can be repeated every five minutes; experimental initial doses of up to 7mg have been given; the "intracardiac" injection has not shown to be more effective than the standard route— it is now thought that the “shock” of introducing a pointed metallic object  directly into the cardiac muscle (with the resultant conduction of a small amount of electrical charge) is what made the procedure effective, not necessarily the drug itself
  4. causes sympathetic/adrenergic effects:  elevation in blood pressure, increase in cardiac rate, but it is done in a very inefficient manner with great oxygen requirements (consider the angina patient)
  5. syringe is a 10mL dilution of 1mg; ampoules are 1mg/1mL

 B. Calcium carbonate/calcium gluconate
  1. syringes or vials, "a dose" is usually 1gm/10mL
  2. intent is to increase the force of contraction of the heart and thereby increase cardiac output
  3. less often used than in the past

 C. Atropine
  1. prefilled syringes of 1mg/10mL
  2. anticholinergic effect causes increased heart rate

 D. Nitroglycerin
  1. dosage forms
   a. sublingual tablets
   b. topical patch
   c. sustained release capsules
   d. injection
  2. for angina ("chest pain")
  3. causes vasodilation of cardiac vessels, thereby reducing pressure, increasing blood flow, and cutting down angina
  4. major side effect: HEADACHE; if given orally, it is a test for potency whether the tablets produce a “tingling” effect on the tongue; when dealing with the topical forms, care must be taken by the compounder since nitroglycerin is very readily absorbed through the skin
  5. dose
   a. sublingual: 0.3mg, 0.4mg
   b. patch: 0.2-0.6mg/hr
   c. capsules: 2.5-9mg (sustained release format, absorption is somewhat irregular)
   d. injection: 50mg, diluted in IV solution, administered at a rate to balance between desired effect— loss of chest pain-- and side effects (dizziness and headache)
  --note: an older version of nitroglycerin was "amyl nitrate," administered by nasal inhalation;   the solution came in glass vials surrounded by a gauze mesh, much like the  ammonia capsules used today

 E. Nitroprusside (Nipride)
  1. to reduce blood pressure
  2. note the prusside portion of the name:  the word root "pruss" indicates the presence of a cyano grouping, or namely, cyanide
  3. long term dosing can result in symptoms of cyanide poisoning
   --blue lips and fingernail beds
   --hypoxic states
   --there exists a real danger of nitroprusside being used as a poison
  4. IV only, wrapping required to protect from light
  5. trade name marketing anecdote: (Roche, the company that manufactured nitroprusside under the brand name Nipride heavily promoted the stability of the mixed product to be only 4 hours, after which the IV had to be replaced with a new mixture.  Once nitroprusside was available generically, then and only then did the company relate that the mixture could be stable for 24 hours, thus assuring that the generic manufacturers would sell only about  1/6 the amount that the original manufacturers had!)

 F. Lidocaine and Bretylium (ventricular arrhythmia)
  1. Lidocaine
   a. a nice topical anesthetic (which grouping?)
   b. given IV, reduces ventricular arrhythmia
   c. bolus with 100mg (prefilled syringe), then start a continuous drip
   d. long term use affects the CNS

  2. Bretylium (Bretylol)
   a. newer than lidocaine; often used when lidocaine fails
   b. usually bolus with 250-400mg, then start a continuous drip
   c. comes in ampoules or vials of 500mg/10mL

 G. Dopamine
  1. just like the neurotransmitter of the same name
  2. used in cardiogenic shock to maintain blood pressure
  3. replaced levophed as the drug of choice for this
  4. in low doses, it stimulates renal output
  5. in higher doses, it causes peripheral vasoconstriction which, in turn, elevates the blood pressure
  6. 800mg is diluted into a 500mL IV and the dose is run as a continuous infusion

 H. Sodium bicarbonate
  1. often, the patient will have stopped breathing for some time at an "unwitnessed" arrest
  2. this causes a buildup of carbon dioxide in the blood and a drop in the physiologic pH
  3. sodium bicarbonate helps "buffer" the blood and return the system to the proper pH
  4. not often used at a "witnessed" arrest these days
  5. prefilled syringes, 50mL of a 50% solution

And here’s a press release from WHO, from 1998:
“Some governments did not take WHO’s declaration of a global TB emergency seriously,” said Dr. Arata Kochi, Director of WHO’s Global Tuberculosis Program.  Half of the trouble spots are middle or upper-middle income countries--Brazil, Indonesia, Iran, Mexico, Phillippines, Russian Federation, South Africa and Thailand.  (An)other eight countries are low-income economies--Afghanistan, Ethiopia, India, Myanmar, Nigeria, Pakistan, Sudan, and Uganda.  In at least four of them, there has been a deterioration in their efforts to control TB, as shown by worsening treatment success rates.  A lethal combination of HIV and TB is leading to sharp increases in the TB epidemic, particularly in Africa.  Asia shoulders almost two-thirds of the burden of the epidemic, accounting for 64% of the world’s notified TB cases.  Without more effective action, 70 million people will die from TB between now and 2020.
       --WHO Home page, the Internet, 1998

I. Background
   A. History/terminology
 1. Once a major cause of death; "consumption"
 2. Sanitariums for long-term treatment
   a. Kimball Sanitorium on E. Michigan in Battle Creek
   b. Sunshine Sanitorium in Grand Rapids, now Metro Hospital
   c. many others, now all closed

 3. Better hygiene, improvement in living conditions after WWII, and antibiotic therapies virtually eliminated the disease in the US by the 1960s

 4. Increase in homeless population, AIDS, and increase in drug-resistant strains of tuberculosis have had the incidence of TB steadily increasing since 1986.
  Two physicians noted in New York that the city’s tuberculosis control program had a funding of $40 million in 1968; this was reduced to $2 million in 1988 (The Coming Plague p520).
  a. was on the decline by 5%/year since the 50s
  b. in 1990, there were 25,000 new cases in the US (largest increase since 1953)
   in 1991, 23,000 new cases
   in 1992, 32,000 cases
   in 1994, 24,700 cases were reported, leading to media speculation that the emergency had passed... pfah!
  c. drug resistant strains are emerging: 300 cases in New York City, 30 in Michigan as of July, 1992 (MP Journal report) ; during the first quarter of 1991, 42.5% of all new TB cases in New York City were caused by mutant strains that were resistant to the primary treatment drugs; 60% of relapse cases had multiple drug resistance (The Coming Plague,  p521)
  d. In Canada, approximately 10% of tuberculosis strains are resistant to antibiotic therapy, and a small percentage of these are resistant to more than one antibiotic.
  e. The W- strain is of particular concern, since it is resistant to ALL antibiotic therapy and is associated with 60-70% mortality rates in even the best health care facilities. (“Emerging and Resurgent Infectious Diseases,” IDRC report, 1996; from the Internet)

 B. Causative Organisms
1. Mycobacterium tuberculosis, an aerobic, non-spore forming, non-motile gram positive rod.
 --it contains a waxy coat which allows it to retain the red dye of the acid-fast smear, even after exposure to strong acids that normally leach the dye out of other bacteria

2. (rarely, in U.S.) Mycobacterium bovis (destroyed by Pasteurization of milk)

 C. Disease course/diagnosis
  1/3 of the world’s population is actively or latently infected by M. tuberculosis
  Transmission is by the respiratory route, with the infected person producing an infectious aerosol by coughing; a susceptible person inhales a droplet with the organism in it HISTORICALLY, ABOUT 90% OF INFECTED PEOPLE NEVER BECOME ILL.

  1. infection begins in lower or middle lung fields--the first line of defense is the alveolar macrophage; however, the macrophage can take up the bacteria without killing it--the organism makes it to the regional lymph nodes, the T-lymphocytes are activated, releasing cytokins
  2. spread thoughout the body via the lymphatic system; can rest in any organ
  3. initial phase can resolve itself within 6-10 weeks; domancy can reactivate at any time during the life of the host, usually in an atmosphere of waning immunity
   Of the 10% of those exposed who will develop TB, will do so within weeks or months of exposure; other may take MANY YEARS to develop symptoms, especially if the immune system is compromised.
 
    a. AIDS
    b. cancer/immunosupressive therapy
    c. alcoholism
    d. malnutrition
 
In New York City, more than a quarter of the patients were hospitalized for tuberculosis relapses, meaning that they failed to take drug therapy properly.  In addition, 89% of the patients disappeared sometime after hospitalization, never returning for their mandated checkups and drug prescriptions.  A subgroup of the patients--women who were addicted to crack cocaine— were 97% noncompliant with tuberculosis medication (The Coming Plague, p520).
 
  4. Symptoms include
   a. cough
   b. sputum
    i. yellow and mucoid (chronic)
    ii. green and purulent (caseous necrosis)
   c. hemoptysis — spitting up blood
   d. Pleural/chest wall pain
   e. Dyspnea — difficulty in breathing
 
  5. X ray diagnosis
  6. Culturing is slow-- 3 to 6 weeks
   a. morning sputum
   b. gastric contents must be suctioned and cultured
 
  7. PPD tuberculin test
   Not definitive!  Infected patients may still test negative!
   PPD is a cutaneous manifestation of cell mediated immunity to a protein derived from M. tuberculosis
 
 D. Disease spread
  1. infectious droplets
   --transmission by coughing
   --droplets can remain present for a long time, especially in poorly ventilated areas
  2. infected, non-pasteurized milk
   --milk scares in the 1920s
 
II.  Drugs used to treat Tuberculosis
  Rate of mutation of M. tuberculosis is VERY HIGH.  Active TB must NEVER be treated with single drug therapy!
  Drug therapy also cannot be tolerated with alcohol— compliance becomes another factor!
 
 A. Isoniazid (INH)
  1. standard therapy
  2. bacteriocidal
  3. 300mg daily
  4. of concern--isoniazid induced hepatitis
  THIS IS THE DRUG USUALLY USED FOR PROPHYLAXIS when exposure to TB is suspected
  DURATION OF PROPHYLAXIS: 6-12 months
   --HIV patients require 12 months
   --children need 9 months
 B. Rifampin
  1. often given as combination therapy with INH
  2. 600mg daily

 C. Ethambutol
  1. added if INH resistance is suspected
  2. 800-1600mg daily

 D. Para-aminosalicylic acid
  1. retreatment agent
  2. 12-16gm daily
  3. severe GI symptoms--heartburn, long term use causes ulcers

 E. Streptomycin
  1. IM only
  2. 750mg-1gm daily
  3. 8th cranial nerve damage can result

III. Duration of therapy
 A. "Short term" of 9 months
  1. 6 month therapy shows results, but has many relapse problems
  2. therapy often extended to 18-24 months
  3. goal is to "sterilize" the lesion

IV. Chemoprophylaxis
 A. Vaccine
  1. BCG vaccine– BCG does not prevent the establishment of infection in exposed subjects but does limit the multiplication and dissemination of the bacilli and the development of lesions following infection.

BCG vaccine stimulates the reticuloendothelial system (RES) to produce activated cells, especially macrophages, that prevent the multiplication of virulent mycobacteria.

BCG is indicated for persons who have negative tuberculin skin tests (PPD) yet are repeatedly exposed to sputum positive cases of pulmonary tuberculosis; for children of tuberculin infected mothers; for travelers to areas of tuberculin infestation.

   Coverage with BCG is not permanent and administration of the vaccine may have to be repeated.

 B. Drug Therapy
  1. INH, 300mg daily, for 6-12 months has been shown effective in preventing active tuberculosis and prevents the spread of the disease to uninfected persons
  2. however, must be cautious of isoniazid-induced hepatitis
  3. candidates for therapy:
   a. household members and others closely associated with a tuberculin-positive patient
   b. TB test positive, lesions on X-ray, no history of TB or drug therapy
   c. TB test positive within past 2 years
   d. immunosupressed patients
   e. TB test positive AIDS patients
   f. TB test positive and age>35 or <7 years

It can be drug-induced, as with acetaminophen (Tylenol), isoniazid (INH), methyldopa (Aldomet), indomethacin (Indocin), phenytoin (Dilantin), and the inhalation anesthetic halothane.

I. Specific Hepatitis Types/discussion
 A. Hepatitis A
  Transmission by oral fecal route, primarily via infected foods; an infected food handler can spread the disease, and people can contract the disease from water or shellfish from sewage-contaminated waters.  Casual contact, as in the usual office, factory or school setting, does not spread the virus.

  People at risk: people who share a household or have sexual contact with someone infected with Hepatitis A; people who use street drugs; travelers to countries where Hepatitis A is common and access to clean water and sewage disposal systems is lacking; child care centers with child or employee with Hepatitis A (especially if diapers are present!); persons with clotting factor disorders who receive factor concentrates.  Contaminated water or ice, raw shellfish, and contaminated fruits or vegetables can relay HAV (ie strawberries from Mexico)

  Patient may develop an aversion to cigarette smoke and other strong odors.

  Patients generally recover; the disease confers immunity unto itself.    A person can spread HAV about one week before symptoms appear and during the first week of symptoms.  Persons with no symptoms can still spread the virus.No carrier state exists, and no chronic hepatitis is associated with Hepatitis A.  Personal hygiene, handwashing, environmental sanitation are best preventions.

  It CAN happen here-- Marshall Public Schools in 1998 from imported Mexican strawberries (thank you NAFTA!).

  Administration of Immune Globulin may prevent the disease if given IM during the period of incubation (2 to 7 days following exposure).  It provides 6-8 weeks of passive immunity by bolstering the patient's own immune system.  (but watch for reactions to the immune globulin!)

  Approximately 100 deaths occur annually from HAV in the United States.

  Available Hepatitis A virus vaccines are:
   Havrix :  1ml (1440 EL U) IM with a booster in 6 to 12 months for adults,
    0.5ml IM with a booster in 6 to 12 months for ages 2 through 18

   Vaqta :  0.5ml (50 U) IMwith a booster in 6 months for adults,
    0.25ml (25 U) IM with a booster in 6 months for ages 2 through 17

 B. Hepatitis B
  The hepatitis B virus is a particle consisting of
   hepatitis B core antigen (HBcAg)
   hepatitis B surface antigen (HBsAg)
   an independent protein (HBeAg)
  Each antigen elicits its own specific antibody:
   anti-HBc: acute phase of disease; HBV may be in the liver at this point
   anti-HBs: late convalescence, usually indicates recovery
   anti-HBe: usually signifies reduced infectivity

  About 15% of American adults are positive for anti-HBs, indicating that they have had hepatitis B.  Anti-HBs may be present in up to 67% of IV drug abusers.

  Blood donations are automatically screened for HBsAg.  Blood and bodily secretions are means of transmission of Hepatitis B.

  Transmission is bloodborne, sexual, or perinatal; risk groups include injection drug abusers; sexual contacts with HAB infected patients, infants born to infected mothers, health care workers, and hemodialysis patients.

  Since 1993, increases observed among the three major risk groups: homosexual men, sexually active heterosexuals, and injection drug users.

  Incubation period is longer, mortality is higher than with Hepatitis A.

  Vaccines:
  Hepatavax-B is plasma derived and consists of inactivated human hepatitis B surface antigen (HBsAg) particles, obtained from plasma of screened healthy chronic HBsAg carriers.
  Recombivax HB, Engerix-B are derived from HBsAg produced in yeast cells.
  Antibody titers of 10 mIU/mL against HBsAg are recognized as conferring protection against Hepatitis B.  Duration of protective effect is unknown.  However, anti-HBs levels may fall below the protective level over 3 to 4 years.  There is no current recommendation for intervals at which individuals should be rechecked for antibody titers.  However, there are these booster recommendations:

   Adults and children with normal immune status:  protection should last 5 years; booster doses are not routinely recommended, nor is routine serologic testing
   Hemodialysis patients:  protection is less complete; assess titers semi-annually and give boosters when titers drop below 10 mIU/mL.
   Vaccinated persons who become innoculated with HBsAg positive blood:  test for titers unless serologic testing has shown adequate levels within the previous 12 months; if titers below 10mIU/mL, administer booster
   Nonresponders: injections in the buttock (er, "hip") rather than the deltoid area show a diminished effectiveness; 75% of nonresponders show a positive response upon revaccination.

  Postexposure prophylaxis:  Hepatitis B Immune Globulin (H-BIG) administered with Hepatitis B vaccine at separate sites does not interfere with induction of protective antibodies against hepatitis B virus.

  Interchanging vaccines and types:  It is possible to interchange the plasma-derived and recominant-produced vaccines; the antibody response to both is comparable.
  Administration intervals:  Three injections, one at "time zero," one at one month, and one at 6 months.

 C. Hepatitis Type C
  1. Viral infection of the liver, formerly called Non-A, Non-B Hepatitis--hepatitis C virus has been identified as the primary cause of parenterally transmitted non-A, non-B hepatitis.
  2. Not transmitted by casual contact: injection drug abusers, health care workers with occupational exposure to blood, hemodialysis patients, blood transfusion recipients.
  3. No known treatment to prevent infection
   --effectiveness of latex condoms is unknown
  4. Treatment is by interferon— specifically, INTERFERON ALPHA 2b
   --40% response
   --60% relapse
   --only 10-15% of patients treated with interferon have a sustained, long lasting remission
  5. Experimental use of ribavirin (Virazole), an antiviral and thymosin ?-1, an immune modulator, NSAIDs, and amantadine (Symmetrel)

 D. Hepatitis Type D
  Also known as delta hepatitis— it is a form of hepatitis that occurs only as a co-infection or super-infection with hepatitis B.  Presently it represents 1%of the cases of hepatitis endemic to the United States

 E. Hepatitis Type E
  Hepatitis E virus has been identified as the primary causative agent in enterally (ie oral-fecal route) transmitted non-A non-B hepatitis.
  Hepatitis E virus is more exclusively associated with contaminated drinking water, with nearly all US cases being traced to travellers returning from foreign areas with endemic infections.
  Incubation times run 15 to 60 days...there is no effective treatment; the best treatment is to avoid getting it.
 
 F. Hepatitis Type G
  Whoa! Where's Type F?  (diplomacy reigns, even in viral nomenclature)
  --Risk groups from this bloodborne pathogen are transfusion recipients, injection drug abusers, co-infection with Hepatitis C
  --very rare, estimated 900-2000 cases worldwide annually, most suspected to be asymptomatic

1. What is the usual dose of epinephrine for an adult in a cardiac emergency?
2. What are three routes of administration for nitroglycerin?
3. Which drug for hypertensive emergencies has the potential of causing cyanide poisoning?
4. What are five drugs used for the treatment of tuberculosis?
5. Which drug for tuberculosis therapy is usually used for exposure prophylaxis?
6. What is considered a “short term” therapy period for tuberculosis treatment?
7. What are the limitations of using BCG vaccine as chemoprophylaxis for tuberculosis?
8. What is the route of transmission for Hepatitis A?
9. What is the route of transmission for Hepatitis B?
10. Name two vaccines used for Hepatitis B.

End of Module Eleven
January 2002
Emergency Drugs, TB, Hepatitis
KCC Pharmacology for Dental Hygiene
Instructor and Contact: Jim Middleton