Section One:  DRUG TRANSPORT--Dental Hygiene Pharmacology--Jim Middleton, Pharmacist
Kellogg Community College, Battle Creek, Michigan

Lecture objectives:
By the completion of this section, you should be able to
 1. Define enteric coating
 2. Discuss the benefits and problems of using an enteric coating
 3. Contrast the concepts of pharmacognosy and pharmacodynamics.
 4. Be able to define ADME
 5. Be able to give examples of drugs with topical administration routes
 6. Be able to understand the concept of bioavailability
 7. Discuss the passage of drugs across the placenta or the possibility of their presence in breast milk of nursing mothers.
 8. Be able to discuss special areas of drug accumulation.

I. Preliminary discussion: the enteric coating
 A. Definition: a waxy coating around a tablet to prevent dissolution in the stomach
 B. Value: reduces stomach irritation
 C. Potential limitations: drug may pass through the GI sytem, unchanged, or the drug may pass its point of greatest absorption
  1. aspirin absorption is primarily in the: duodenum
  2. What if the patient has difficulty swallowing?  What if the patient has a colostomy or ileostomy?
  3. Should a tablet with an enteric coating be crushed?  Could food or drink interfere with the action of an enteric coated tablet?
        --in the case of an enteric coating, especially one for bisacodyl (Dulcolax), concurrent administration of milk or antacids could cause premature breakdown of the enteric coating....intense cramping and diarrhea...

II. Definitions
 A. PHARMACOLOGY: how chemical substances interact with living systems; subdivisions include
  1. PHARMACOGNOSY: "weeds and seeds"
      This was the original basis of pharmacy, and, for that matter, of medicine ("pharm" meaning drugs and "gnosis" meaning knowledge); while it has fallen out of favor over the past generation, it is re-emerging as a legitimate discipline as people seek alternative routes for their health care.  These lectures shall introduce such herbal therapies as they are appropriate to the subject.
  2. PHARMACY: compounding and dispensing "lick and stick"
  3. TOXICOLOGY: adverse effects, poisoning
  4. PHARMACOKINETICS: factors affecting concentration of a drug in the body or at its site of action
  5. PHARMACODYNAMICS: biological effects of a drug and the mechanism that produces these effects (the main thrust of these lectures)
  6. PHARMACOTHERAPEUTICS: how drugs prevent, control, or cure diseases

 B. Pharmacodynamic effects may be achieved by:
        1. stimulating or blocking the effect of chemicals already in the body
        2. directly stimulating or depressing cellular function
        3. exerting purely physical actions on the body
        4. replacing or augmenting actual body chemicals
        5. destroying parasites (tapeworms, amoeba, etc)

      A. Absorption
          1. movement of drug from the site of administration to the bloodstream
          2. affected by
              a. route of administration
              b. blood flow to area of administration
              c. physical state of drug
          3. Routes of administration
              a. enteral-- means the use of the GI tract; the most common route
                 i. oral, sublingual (abbreviated “SL”), rectal
                   (a) ease of administration
                   (b) sterility not necessarily an issue (you've put worse things in your mouth)
                   (c) once introduced, can be purged or flushed if necessary
                   (a) GI irritation (aspirin)
                   (b) food interactions (tetracycline and calcium)
                   (c) destruction of drug (insulin is not effective orally)
                   (d) absorption usually slow (except sublingually)

              b. parenteral– means introducing the drug to the body by non-enteral means
                 IM (intramuscular), IV (intravenous), SC (sub-cutaneous; sometimes abbreviated “SQ”), intrathecal, intra-arterial
                 --more rapid onset, but also
                --greater onset of side effects
                 --irritation at injection site
                 --increased avenue for infection
                –-also, once a drug enters the bloodstream, it is very hard to remove!

              c. inhalation
                 --anesthesia, respiratory drugs for asthma
                 – inhalation antivirals for influenza therapy (Relenza)

              d. via mucous membranes
                 --eye, nose, throat, vagina, bladder
                 --localized effect, but systemic absorption possible
                (blood pressures have been altered from long-term use of beta blockers to treat glaucoma or nasal sprays used      to treat congestion)

              e. skin
               --toxins may be absorbed via this route (insecticides "DDT", "agent orange" and chemicals such as carbon tetrachloride...and mercury to cure leather...the source of the madness of a "Mad Hatter")
               --therapeutically, some drugs are administered as topical patches:
                CAPSCACIN ("Mustard plasters"): for muscle aches
                SCOPOLAMINE (Transderm-Scop): for nausea
                NITROGLYCERIN (Transderm Nitro, Nitro-Derm): for angina
                CLONIDINE (Catapres TTS): for hypertension
                ESTROGEN (Estraderm): for menopausal syndromes
                FENTANYL (Duragesic): for pain
                NICOTINE (Nicoderm, Habitrol): for nicotine withdrawal
                TESTOSTERONE (Androderm): for hypogonadal conditions
                LIDOCAINE (Dentipatch): topal anesthesia for dental procedures

  4. Bioavailability-- "The amount and rate of entrance of a drug into the circulation"
                a. factors affecting bioavailability
                     i. rate of absorption; administration site
                     ii. lipid solubility--where it may be stored in the body
                     iii. physical state of drug has an effect
                    --compare tablets vs capsules vs solutions vs enteric coatings; "depo" administration of lipid soluble agents

                b. in a situation where you have two tablets containing the same drug, the higher strength tablet is more bioavailable.  For example:
   Ibuprofen (Motrin) 800mg is more bioavailable than ibuprofen 200mg

                c. Sometimes a drug company will use the relatively simple term bioavailability as a marketing method, implying “more is better.”  For example, for many years a combination product of hydrochlorthiazide and triamterene called Dyazide was available to treat hypertension.  Another company came along, took the same two ingredients but increased the amount by 50% and called their product Maxzide.  They then heavily marketed their product as being “more bioavailable.”  It worked.  It is something akin to saying “two apples are more bioavailable than one apple.”  CAVEAT EMPTOR!
                --remember that most doctors get their drug information not from college training in pharmacology, but from drug reps...and that's more marketing than medicine

      --The drug goes for its site of action via the bloodstream
          1. Factors that can hold up distribution
              a. binding to plasma proteins
                ALBUMIN is the major plasma protein
               --consider two drugs battling it out for the same plasma protein site-- warfarin and aspirin, for example
              b. storage in body fat
              c. other sites where material/drugs can accumulate

                   LIVER--quinacrine (anti-malarial drug)
                   BONE AND TEETH--tetracycline (antibiotic), lead (from paint, water, pollution)

A two-year old boy contracts an infection that requires antibiotic therapy.  With this information alone, which drug below would not be appropriate?
a. penicillin
b. erythromycin
c. tetracycline
d. cephalexin (Keflex)
Tetracycline can bind to developing bone and teeth.  This affinity for chelation with calcium can also have a detrimental effect on its therapeutic activity.  More on this in the section on antibiotics.

          1. metabolism primarily in liver
          2. excretion primarily by the kidneys (other routes possible)

         1. meninges are of high lipid concentration
         2. lipid soluble drugs can pass
            --anethetics, antiepileptics
         3. water soluble drugs are effectively blocked

              1. placental barrier is of limited effectiveness, and there is no guarantee that agents in the mother's blood will not reach the fetus
              2. first trimester generalization--since there are no real studies showing that anything is particularly safe during the first three months of gestation, the general rule is to be leery of any drug during this time

     C. Breast milk crossovers
         1. Several factors
                 a. fat content (lipid solubility)
                   breast milk is 2-3% fat
                 b. protein bound drugs less likely to pass
                 c. large size drug molecules less likely to pass
                 d. weakly acidic drugs less likely to concentrate in breast milk (milk pH is 6.7 to 7.4)

         2. Drugs involved
             a. antibiotics
                i. penicillins/cephalosporins
                   both safe for the nursing child
                ii. tetracycline/erythromycin
    should also be safe; evidently not enough tetracycline passes through the milk to be of concern
   --biggest possible side effect is loss of child's normal body flora even at the minute amounts digested, resulting in diarrhea
              b. asthmatic drugs
    i. theophyllines should be sustained release preparations--child can develop symptoms otherwise
              c. anticoagulants
    i. warfarin appears safe (high protein binding)
                ii. heparin appears safe (large molecule size)
              d. antihypertensives
                 i. thiazide diuretics--may decrease lactation
                ii. beta blockers--may cause beta-blocking effects in the child
              e. antiepileptics
                 i. phenobarbital will be passed on to the child (high lipid solubility)
                ii. phenytoin, carbamazepine, ethosuccimide will be passed on as well
                iii. valproic acid does not enter breast milk
              f. thyroid products
                 i. thyroid will pass in small amounts, but is considered safe
              g. narcotics will pass into breast milk--
   morphine and codeine are particularly likely to cause problems; meperidine is less likely, but child should still be monitored for sedation

Part Two of this section:  DRUG ACTIVITY AND TERMINATION
 At the completion of this section, you should be able to:

 1. discuss the interrelationship between dose and potency
 2. identify an enzyme by its suffix
 3. compare synergism with antagonism
 4. discuss the differences between a broad and a narrow therapeutic index
 5. list examples of antagonists
 6. to define agonist, affinity, and intrinsic activity
 7. define enzyme induction and give an example of a drug that can cause the condition.
 8. give examples of products that are astringents
 9. identify another name for the 8th cranial nerve and discuss what damage to it can cause

Consider a case study: if one tablet is good, isn't two always better?  Also, if you have 300mg of one drug, is it stronger than 0.25mg of another drug?

 Example #1: aspirin
   usual strengths: 81mg, 325mg, 500mg

 Example #2: digoxin (Lanoxin)
   usual strengths: 0.125mg, 0.25mg, 0.5mg

I. A matter of terms
 A. Drug Activity: what happens when a drug reacts with a responsive site
        1. specific sites
            a. cell receptors
            b. enzymes
   --Definition of enzyme: a compound that can make changes in another substance without changing itself; a catalyst
   --"ASE" suffix on all enzymes (with the exception of “renin”, enzymes, or substances that cause breakdown of chemicals that pass through the liver or other areas of the body, have the same suffix-- penicillinase, acetylcholinesterase, etc.)

        2. generalized activity (anesthesia)
        3. mechanical (antacids, sunblocking agents)

    B. Receptor Sites
        1. Jigsaw puzzle concept "the drug fits!"
            specific drug-to-receptor complex
            "opiate" receptors and pain

        2. Blocking the effect
            --a drug binds but does not produce an effect–  antagonism

                   --naloxone (Narcan)--pure narcotic agonist
                            use: to reverse the effects of an opiate analgesic

                   --naltrexone (reVia)
                            use: to control the symptoms of alcohol withdrawal

     C. Affinity and Intrinsic activity
         1. Affinity:
              --degree of attraction between a ____drug__________ and  its___receptor site________

         2. Intrinsic activity:
             if the drug-receptor complex produces an action

 D. Agonists combine the affinity with an intrinsic activity

 E. Antagonists, therefore...
  have affinity for a receptor but do not possess intrinsic activity

 F. Agonist/antagonist properties: partial agonists that initially stimulate, then block
       --nicotine is an example
  nicotine stimulates cholinergic receptors that are nicotine-specific; once on-site, the nicotine then blocks the receptors and further stimulation is no longer possible at that site.  The body eventually creates more nicotine-specific receptors, requiring more of the drug to get the same effect.  Open receptors send out signals for more drug in the form of withdrawal symptoms (usually within 20 minutes of the last delivery of drug) which escalate with the number of receptor sites.  A "refreshing smoke" is merely a relief of the withdrawal symptoms, a cycle which can  repeat indefinitely until the user chooses to quit by choice or by death. End of sermon.

II. Drugs and Enzyme Induction:  a drug's effect on the liver
  What is enzyme induction?  The stimulation of enzyme production that results in increased hepatic metabolism

 An example of a drug that can cause enzyme induction: phenobarbital

 What is the primary use of this drug? to treat epilepsy

III. Mechanical and Chemical Activity
     A. Localized activity
     B. many are OTC (over-the-counter)
         1. adsorbents
             --kaolin, pectin, activated charcoal

         2. laxatives
             a. bulk (psyllium colloid [Metamucil, Citrucel, et al])
                must have a lot of added fluid as part of the therapy

            b. saline--magnesium citrate or "purgative lemonade"
                   this product, like revenge,  is best when served: cold
            c. stimulant--cascara (from the Cascara sagrada plant) or senna (from the senna plant)
                 a favorite addition to "diet herb teas"

            d. emoillent--docusate (Colace)
                   literally, you are adding soap to the system (taste the liquid version sometime, eeuh)

        3. antacids--chemical neutralization
  --antacids are weak bases (magnesium HYDROXIDE, aluminum HYDROXIDE) to act as chemical neutralizers, or act as weak buffers, such as calcium carbonate

Antacids by ingredients:
Magnesium products:
   Milk of Magnesia (magnesium hydroxide)
Aluminum products:
   Alternagel (aluminum hydroxide)
Combined magnesium/aluminum products:
   Maalox, Mylanta
Calcium carbonate products:
   Tums, Rolaids

   Note: these antacids differ both in chemical composition and mechanism of action from the class of antacids known as the "H-2 antagonists" or "proton pump inhibitors."  These other classes will be discussed later.

        4. astringents
                   --aloe vera, tannins (found in teas and red wines), aluminum chloride (alum)
                   --cause protein precipitation
                   –example:  Witch Hazel (Hammemaelis virginiana) --Hammemaelis is noteworthy as being the first discovered medicinal in the "New World"

        1. determination of dose
            a. ADME (absorption-distribution-metabolism-excretion) characteristics
            b. LD50 or TD50
    LD means: “lethal dose” The # refers to the % of the test population affected (ie LD 50 indicates that 50% of the test population died with that specific dose)

    TD means: “toxic dose”

            c. clinical studies--   not required until the early 1960s after the disaster with Thalidomide

    B. POTENCY: relative to dosage

  --relates only to ability of drug to produce desired response
  --consider aspirin and dental pain vs aspirin and pain of bone cancer

VI. Factors affecting drug activity
    A. Drug Interactions
        1. Enhancement
            --potentiation SYNERGISM
   "one plus one equals three" (two antibiotics working together can sometimes have a greater spectrum of activity than either one working alone)
   i.e., Tobramycin (an aminoglycoside antibiotic) and carbenicillin (penicillin)

   Another example is where one drug inhibits the metabolism of another, resulting in increased drug levels.  Ciprofloxacin (Cipro), a quinolone antibiotic, can inhibit the metabolism of caffeine.  Coffee drinkers taking Cipro have often experienced tachycardia!

When the combined action of two drugs is greatern than the sum of their individual actions, it is known as
 a. additive
 b. idiosyncracy
 c. cumulative action
 d. synergy

        2. Antagonism
            a. pharmacologic antagonism
    --two drugs working against each other; can happen with antibiotic therapy
            b. chemical
                --IV drug mixtures; precipitation possible
    sodium bicarbonate and calcium chloride in an IV solution
    Chemistry results in calcium carbonate

            c. kinetic antagonism
               --hepatic enzyme induction and increased metabolism
   --drugs that can stimulate or inhibit the other enzyme pathways in the liver

     B. Drug-Food Interactions
         1. griseofulvin (an antifungal drug) and greasy foods:
  absorption is improved
         2. tetracycline and dairy products:
  absorption of tetracycline is diminished; chelates are formed with Calcium, Aluminum, Magnesium, Lithium, and Iron
         3. MAO (monoamine oxidase) inhibitors
  (used to treat depression or Parkinsonism--Parnate and Marplan are examples) and aged cheese or beer (foods high in the amino acid tyramine or tryptophan); even avocados and bananas

     C. Accumulation and Tolerance
         1. accumulation and sustained release
                        --lipid partitioning
                        --fat-soluble vitamins A-D-E-K
     mainly a concern with toxicity

FAT SOLUBLE VITAMIN INFORMATION--one of many digressions

I. Vitamin A–Patient information
    A.  “Avoid prolonged use of mineral oil and cholestyramine (Questran, a cholesterol-lowering agent) while taking this drug.  Do not exceed recommended dosage.  Notify your physician if nausea, vomiting, anorexia, malaise, dry or cracking skin or lips, irritability or hair loss occur.  These are symptoms of toxicity.”
 B. Beta-carotene (15mg = 25,000 IU of vitamin A)
  1. do not take with dairy products
  2. skin may appear slightly yellow-orange while on this therapy
  3. beta-carotene is a precursor to vitamin A and a naturally occurring pigment in dark green and yellow-orange vegetables
  4. a controversial role in lowering the incidence of cardiovascular disease and cancer, particularly lung cancer
  5. fat in the diet serves as a carrier for beta-carotene; low-fat diets will result in reduced absorption of beta-carotene

II. Vitamin D (“dihydrotachysterol or DHT” or “Hytakerol”)
A. Patient information
  “Not to be considered an alternative to a healthy diet.  Signs of toxicity include weakness, lethargy, headache, anorexia, weight loss, nausea, vomiting, abdominal cramps, diarrhea or constipation, vertigo, excessive thirst, excessive urine output, dry mouth, muscle or bone pain.”
B. General information
  1. Vitamin D is considered a hormone.
  2. Vitamin D metabolites promote active absorption of calcium and phosphorus in the small intestine and promote reabsorption of calcium and phosphorus in the kidneys.
  3. Vitamin D is involved in magnesium metabolism.
C. Deficiency
  1. deficiencies lead to progressive hearing loss, rickets in children, and osteomalacia in adults
  2. often referred to as the “sunshine vitamin” since it is synthesized in the skin through a reaction involving sunlight and cholesterol
D. Drug Interactions
  1. digitalis (Lanoxin): increased calcium levels with vitamin D can cause heartbeat irregularities
  2. mineral oil, cholestyramine (Questran), phenytoin (Dilantin), and phenobarbital can caused reduced blood levels of vitamin D, either through blocking its absorption or promoting its metabolism and excretion.

III. Vitamin E
A. Patient information
  “Swallow capsules whole, do not crush or chew.  Use cautiously with other anticoagulant drugs (ie, Coumadin or Plavix), since the effects of anticoagulant drugs may be enhanced, with potential bleeding occurring.”
B. General information
  1. Vitamin E has been used as an adjunct treatment (primarily for its antioxidant properties) in cancer, skin conditions, heart disease, sexual dysfunction, aging, PMS, and to enhance athletic performance.  Studies currently indicate that vitamin E may be effective in delaying onset of symptoms of Alzheimer’s disease.
  2. the RDA is 15 units/day.  Usual doses, however, for the above activities are generally 400 units up to three times a day.

IV. Vitamin K
A. Patient information
  “Avoid prolonged use of mineral oil, since mineral oil can decrease the absorption of vitamin K.  Anticoagulant drugs such as Coumadin or Plavix may be antagonized by concurrent use of vitamin K.”
B. General information
  1. synthesized in the intestine by bacteria; in addition, vitamin K can be found in the following foods:
   –cabbage, cauliflower, kale, spinach, fish, liver, eggs, meats, cereal grain products, fruits, and milk and dairy products
  2. Vitamin K, while it interferes with Coumadin, does not interact with heparin; Coumadin and heparin cause their effects on clotting by different mechanisms
  3. supplemental doses are usually given by injection, although a 5mg tablet is available

Which of the following vitamins is synthesized by the intestinal flora?
 a. A
 b. B-12
 c. E
 d. K

Protracted (ie “prolonged”) use of sulfa drugs may produce symptoms of vitamin K deficiency because sulfa drugs
 a. are detoxified in the liver
 b. combine chemically with vitamin K
 c. inhibit growth of intestinal flora (bacteria)
 d. interfere with the conversion of prothrombin to thrombin
 e. inhibit calcium absorption which is essential to enzyme systems
This argument can be used for ANY antibiotic, by the way.  If you are killing off pathogenic invaders of the human body, you generally run the risk of killing off the body’s natural “flora” along the way.  This “flora” is responsible for manufacturing most of the vitamin K that the body has, and it is mainly produced in the large intestine.  By the way, dead bacteria swell up in the colon, and since gravity is the LAW, they have no where to go but OUT, taking copious fluids with them.  This is the post-therapy diarrhea that many patients complain about when taking an antibiotic.IV. Vitamin K (phytonadione “Mephyton”)


D. Individual variations
  1. Genetics
  2. Weight
  3. Age
   a. hepatic immaturity in children
    --use of Ritalin for hyperkinesis (usually Ritalin or methylphenidate is considered a stimulant)
   b. elderly patients and decreased absorption

   4. Disease state
   5. Placebo effect
   The placebo effect has been getting more publicity of late; studies (November, 1995; Boston seminar on psychic healing) are showing higher than expected (60-90%) effectiveness rates of treating conditions such as hypertension and stress using placebo or "alternative" therapies vs the standard drug regimens

Which of the following factors determines the dose of a drug to be administered?
 a. patient’s age
 b. patient’s weight
 c. patient’s physical condition
 d. route of administration

Precautions must be taken when drugs are given to geriatric patients because elderly people
 a. may metabolize drugs less rapidly
 b. may not be able to excrete drugs as rapidly
 c. will usually require greater than average adult doses
 d. all of the above
The elderly population is hit with a double dose of bad luck, physiologically speaking– (1) their livers are not producing the same amount of metabolic enzymes as before, thereby slowing the rate of drug metabolism.  Therefore, drug levels rise.  Also, (2) their renal system is slower, thereby reducing the rate of elimination of drugs and their active metabolites once the liver has finished with them... thus, the drug hangs out longer in the body.

If a patient develops tolerance to a drug, that means he has
 a. had an unexpected side effect
 b. obtained maximum response to the drug
 c.  a need for an increase in dose to produce the usual effect of the drug

    A. Distribution, Metabolism, Excretion
        1. Distribution
        2. Metabolism
            a. enzymatic
            b. mainly in the liver
               (although sometimes in kidneys and lungs)
            c. enzyme induction

        3. Excretion
            a. Kidneys
                i. filtration
                ii. reabsorption
                   --nutrients and electrolytes are preserved

                iii. secretion
                    --active transport
    --penicillin (or ampicllin) and probenecid: given together to prevent excretion of the penicillin, increasing its duration of action, a "one dose" oral therapy for gonorrhea

               b. GI
                i. liver and bile
                ii. lungs and paraldehyde
    (alcohols,aldehydes and ketones--consider diabetics in ketoacidosis--ketones are exhaled with a resulting "fruity" breath)

    B. Adverse Reactions
        1. also "side effects," "toxic effects"
        2. concern lasting damage to the body
           --liver, kidney, bone marrow, 8th cranial nerve
              8th cranial nerve is also known as the  AUDITORY nerve
              damage to this nerve can cause: DEAFNESS

         3.  adverse reactions may be
            a. dose dependent
            b. dose independent--allergic reactions
            c. interchangeable with therapeutic effect
               --atropine and diminished salivation (an anticholinergic effect)
               --disulfram (Antabuse) reaction and nausea

    C. Therapeutic Index
        1. relationship between toxicity and effectiveness
       2. narrow: great care to prevent toxicity
        3. broad: generally safe over a wide dosing range

KCC Dental Hygiene Students: to send your homework, highlight the questions below, go to "edit," click on "copy," then click onto my email address below...when the email appears, go to "edit" in the email menu, click on "paste," and the questions will appear as the body of the email.  Answer the questions and then press "send." Your homework will be reviewed and returned via email within 72 hours.  Or just do it all on paper and bring your work to the next class session.

Review questions to ponder at this point:
1. What is meant by the term “pharmacodynamics?”
2. What is meant by the term “pharmacognosy?”
3. Discuss the benefits and limitations of using a drug with an enteric coating.
4. A patient is taking an enteric coated potassium supplement.  He decides he just can’t take tablets and begins crushing it up with two spoons and a lot of elbow grease.  Is this a good idea?  Why or why not?
5. What is the difference between parenteral and enteral routes?  What are the advantages and disadvantages of each route?
6. Name two chemicals besides fluoride that can accumulate in teeth and bone.
7. What is the suffix used to identify an enzyme?
8. What is affinity?
9. What is intrinsic activity?
10. What is an agonist?
11. What is an antagonist?
12. What is enzyme induction?  What is the name of a drug that causes enzyme induction?  What is that drug primarily used for?
13. What recommendation should be made to a patient taking a bulk laxative such as psyllium (Metamucil)?
14. What is the difference between an LD50 and a TD50?
15. List nine drugs that can be worn as a topical patch.
16. Name the four lipid soluble vitamins.
17. List the toxicities associated with the four lipid soluble vitamins.
18. Metabolism is performed primarily in the :
19. The major organ of excretion is the:
20. Damage to the 8th cranial nerve can result in:

End of Module One
Comments: Jim Middleton, Pharmacist and Instructor
KCC Pharmacology for Dental Hygienists