20% of the patients seen by a dentist over 50 years of age will be on some sort of drug to control blood pressure or cardiac irregularities.
DEFINITION TIME AGAIN!
These drugs may--

 Cardiovascular Contraindications to Dental Treatment Can Include:

       3. Early uses
           a. any form of edema
           b. pulmonary tuberculosis (sometimes combined with cocaine)
           c. neuroses--Van Gogh
       4. Proper dosing and toxicologic studies--1922
           --proper dosing did not become common until 20th century

        5. Positive inotropic effects--not found until 1938
 

    B. Importance in today's armamentarium
        1. one of the most prescribed cardiac drugs: generic name digoxin (brand name “Lanoxin”)
        2. foxglove imported from Northern Europe

II. Mechanism of action of cardiac glycosides
    A. Therapeutic doses produce two major actions
        1. Increase in force and velocity of cardiac contractions
           --positive inotropic action
                  (this increases perfusion through the kidneys, with resultant increase in diuresis)

        2. decrease in heart rate
           --negative chronotropic action
                 (this is helpful in reducing atrial arrhythmias)

    B. These actions result in
        1. increased cardiac output
        2. increased renal perfusion, therefore increased fluid elimination

III. Indications
    A. Cardiac Arrhythmias– atrial arrhythmia, paroxysmal atrial tachycardia (PAT)
    B. Cardiac failure (treatment), also known as congestive heart failure or “CHF”

    E. Calium-ion influx inhibitors
          1. used for hypertension or cardiac arrhythmias
          2. examples:
            (verapamil [Calan, Isoptin], nifedipine [Procardia], diltiazem [Cardizem])
          3. may also increase serum levels of digoxin
          4. additive effects possible (additive negative chronotropic effects)
          5. excessive bradycardia, as with: BETA BLOCKERS

 F. Beta-blockers
        --beta blockers slow the heart rate

VII. Signs of Toxicity with digoxin (Lanoxin)
 A. Mild
     1. Loss of appetite; n/v
     2. Lower abdominal pain
 B. Moderate to severe
     1. Unusual weakness or tenderness (possible electrolyte imbalance)
     2. unusually slow or irregular heartbeat (in children, may be a rapid heartbeat)
     3. Blurred vision
         --"halos"
         --confusion of blues/greens/purples (see “Starry Night” by VanGogh)

     4. Mental depression/confusion

VIII. Treatment of Overdosage--until the development of digoxin antibodies, digoxin was officially considered a poison and had to be labeled as such on its stock bottles (thought you'd like to know)

 A. Mild toxicity
       1. stop drug and wait
       2. lab monitoring

 B. "Orphan Drug" for major toxicity
       --Digoxin antibodies
       1. digoxin specific antibody fragments (Digibind)
       2. Sheep ("ovine" source) antidigoxin FAB (Digifab)

I. QUINIDINE, PROCAINAMIDE, LIDOCAINE
 A. QUINIDINE
  1. History
            a. very old drug; one of the CINCONA ALKALOIDS
            b. isolated in 1918
        2. Non-cardiac effects
            a. antimalarial
            b. antipyretic
            c. oxytocic
            d. anticholinergic

        3. Cardiac uses
            a. myocardial depressant
                --decrease excitability of the tissue

        4. Therapeutic uses
            a. ATRIAL FIBRILLATION AND ATRIAL FLUTTER

  5. Toxicity: cinchonism
            a. most frequent effect:
                --N/V; DIARRHEA
            b. tinnitus, vertigo
            c. orthostatic hypotension
            d. blurred vision

        6. Significant drug interactions
            a. other antiarrhythmics
            b. anticoagulants
            c. digitalis: consider effects of cinchonism
            d. enzyme inducing drugs
                --barbiturates, phenytoin, rifampin

    B. PROCAINAMIDE (Procan, Procan SR)
       1. history
  --CHEMICALLY RELATED TO PROCAINE, THEREFORE POTENTIAL FOR CROSSOVER ALLERGIES

       2. effects
          --similar to quinidine, but with fewer side effects

       3. uses
           a. ventricular tachycardia
           b. atrial arrhythmias

       4. Side effects/toxicity
           a. hypersensitivity
           b. fever
           c. diarrhea, n/v

    C. LIDOCAINE
        1. primarily for ventricular arrhythmias
        2. ineffective orally, must give by IV
        3. LIDOCAINE ("XYLOCAINE")
 

   D. Disopyramide (Norpace)
  1. used for ventricular arrhythmias
  2. contraindicated in cardiogenic shock or pre-existing second or third degree AV block
  3. Anticholinergic activity–not for patients with urinary retention, glaucoma or myasthenia gravis
  4. Xerostomia is major side effect (32%); followed by constipation and blurred vision

DISCUSSION OF HYPERTENSION
Prelude:
Most of the "traditional" treatment of hypertension has been based less on a true stepped approach than on a pile-on concept where the patient was progressively saddled with one drug after another in an almost historic progression.  Thiazide diuretics were not necessarily the best beginning--they were merely the first class of drug on the market.

 DIURETICS -->  BETA BLOCKERS -->  VASODILATORS

Given the nature of the population that requires antihypertensive therapy, the notion of draining off "excessive fluids" to manage blood pressure has been likened to tapping water from a prune, with the added stress to the patient increasing the possibility of treating side effects of the medication rather than the actual disease state.

This form of therapy is not exactly new; after all, it used to be common to bleed patients to treat headaches.

 Pathogenic Considerations in Hypertension
1. Sustained elevations of systemic blood pressure above "normal" ("breakthrough point" being systolic 140, diastolic 90)

2. Concerns of potential consequences:    cardiovascular disease,  stroke,  renal damage

3. Primary hypertension
    a.k.a. "idiopathic" or "essential"
    90% of all hypertension falls under the "cause unknown" category–HENCE, “the silent killer”

4. Secondary hypertension:  it follows that this is the remaining 10%--a cause can be documented--renal failure, pheochromocytoma, etc

2. What does this all mean?
 a. In the young hypertensive, ages 20-40, an increase in MAP is usually due to an increased cardiac output.

 b. in the middle-aged hypertensive, the cardiac output tends to fall back to "normal" limits, and the TPR is increased
      --consider causes of an increased TPR

 c. in the elderly (over 65), MAP increase is due to a TPR increase with an accompanying drop in cardiac output

      RESULT
       i. left ventricular hypertrophy
       ii. expanded extracellular fluid volumes
       iii. diminished intravascular fluid volumes
 --Consider what diuretic therapy would do at this point–it would cause dehydration!

 Therapeutic Considerations in the Treatment of Hypertension

1. The Targets

 --a reduction in CO (cardiac output) TPR (total peripheral resistance) or BOTH should lower blood pressure

2. Possible complications of monotherapy
     a. reflex tachycardia
     b. reflex fluid retention

3. But monotherapy does have its advantages:
    a. fewer multiple side effects
    b. better patient compliance

Examination of complications of monotherapy--the causes of reflex actions:
1. Arteriolar dilation --> decrease in arterial pressure--> reflex stimulation of the heart (reflex tachycardia)--> arterial pressure rises

2. Decreased renal blood flow--> decrease in renal blood pressure--> reflex increase in renin secretion --> kidneys retain fluid --> fluid volume expands --> arterial pressure rises

First, a refresher on terms...
 A. Beta receptors–2 types
  --BETA-1 : beta receptor found primarily in the heart
  --BETA-2: beta receptor found primarily in the lungs

  1. Stimulating BETA receptors in the heart: increases heart rate
  2. Stimulating BETA receptors in the lungs: bronchodilation
  these drugs, however, are beta blockers, so the effects we would expect are
  3. BETA blockade in the heart: decreased heart rate
   Also, decreases force of contraction (negative inotropic action), and decreases the rate of electrical conduction through the heart.
   Beta blockade also prevents reflex tachycardia that occurs whenever blood pressure drops.
  4. BETA blockade in the lungs: bronchoconstriction
  These drugs are supposed to be primarily ?-1 blockers, with their primary effect on the heart; however, some BETA-2 blockade also takes place, with many patients experiencing bronchoconstriction.
  This begs the question: Which patient population might have the greatest problem with taking BETA blockers?

 B. Beta blockade elsewhere in the body
  1. bronchoconstriction
  2. decrease the release of fat from adipose tissues
  3. decrease glucose production by the liver and skeletal muscle
  4. decrease insulin release from the pancreas

 C. Side effects and interactions
  1. withdraw therapy over a 2 week period to prevent rebound of symptoms
  2. ORTHOSTATIC HYPOTENSION, especially with aerobic exertion
  3. sedation
  4. may increase uterine contractions
  5. may cause reduction in intraocular pressure
  6. tingling in extremities, cold hands and feet (especially with propranolol [Inderal])

 D. Indications
  1. chronic angina
  2. hypertension
  3. prevent/treat arrhythmia
  4. prevent second MI
  5. prevent vascular headaches (migraine)
  6. stage fright, panic during air travel

  OTHER USES FOR BETA BLOCKERS
  --in addition, there are several “unlabeled uses” for the beta blockers, namely– vaginal contraceptive, gastric bleeding in portal hypertension, schizophrenic acute panic attacks, esophageal varices rebleeding, some types of glaucoma,  aggressive behavior, and alcohol withdrawal syndromes to name a few– propranolol is inexpensive and is available generically, so the experimentation is running amuck!

  E. Drug names

 OTHER ANTIHYPERTENSIVE DRUGS

I. Diuretics (“water pills")
    A. Thiazides and derivatives
           chlorothiazide (Diuril)
           hydrochlorothiazide (HydroDiuril) **most often used**
           metolazone (Zaroxolyn, Diulo)

  1. All are sulfonamide drugs –crossover allergies with sulfa drugs possible (ie “Bactrim”)
  2. Reduction of blood pressure by
   a. increasing fluid elimination by inhibiting sodium reabsorption
   b. decrease in peripheral resistance by relaxation of peripheral blood vessels
   Consider implications of orthostatic hypotension and the need to educate your patients about this condition while the body becomes accustomed to diuretic therapy.

  3. The body responds by
   a. increasing aldosterone levels
    -- this increases potassium loss
   b. potassium loss is seen in about 40% of patients

  4. Potassium loss is most often observed long term effect
   a. big concern when taking digitalis-based drugs (ie digoxin/Lanoxin)
   b. one of the first symptoms seen is leg cramps; elderly patients often request quinine to treat the leg cramps; ironically, this can result in diarrhea, further reducing potassium levels
   c. potassium supplements often get added to patient's drug regimen; foods rich in potassium are encouraged

  5. Other considerations
   a. increase in blood uric acid levels (reversible)
   b. increase in blood glucose levels
   c. increase in cholesterol and triglyceride levels
   d. alterations in calcium levels
    --discontinue thiazide diuretics before performing parathyroid labwork
   e. lithium therapy
    --concurrent treatment not recommended; thiazide diuretics can increase the levels of lithium to toxicity
   f. cholestyramine or colestipol (lipid lowering agents)
    --concurrent administration may decrease absorption of thiazide diuretics; separate dosing by at least 1 hour

  6. Poor candidates
   a. severe renal impairment (drug accumulation)
   b. hepatic impairment (poor drug metabolism, more accumulation)
   c. diabetic patients (glucose levels become elevated)
   d. patients with gout
   e. patients with elevated cholesterol

                                                                 FOOD                AMT                 K+ (MG)

                                                                 Apricots                   1                     105
                                                                 Avocado                  1                     1097
                                                                 Banana                     1                     451
                                                                 Figs                          1                     116
                                                                 Grapefruit               1cu                    322
                                                                 Melon, fresh              ½                    312
                                                                 Orange                      1                     237
                                                                 Peaches                     1                     171
                                                                 Pears                         1                     208
                                                                 Prunes                    1cu                     706
                                                                 Raisins                    1cu                     1089
                                                                 Beets                      1cu                     532
                                                                 Peanuts                   1oz                     200
                                                                 Potato, baked           1                       610
                                                                 Spinach                   1cu                     838
                                                                 Squash, acorn          1cu                     896
                                                                 Squash, Hubbard      1cu                     504
                                                                 Squash, Zucchini       1cu                     622
                                                                 Sweet Potato           1                         397
                                                                 Tomato                     1                        297
                                                                 Tomato juice             1cu                     535

  1. differences from the thiazide diuretics
       a. considered stronger than the thiazides since they work on the loop of Henle, where a greater percentage of filtered sodium is reabsorbed

       b. response to therapy increases with the dose; as a result high doses may be administered, especially in the hospital setting, and especially in IV form

       c. ototoxicity and tinnitus
    --concern with concurrent administration of aminoglycoside antibiotics (gentamicin, tobramycin) or the IV antifungal Amphotericin B, all of which can cause 8th cranial nerve damage

  2. useful when other diuretics have failed

  3. orthostatic hypotension will be more pronounced due to the greater strength of these agents
   --especially with dehydration present

  4. hypokalemia (low potassium) is still possible, hyperuricemia (elevated uric acid) is still possible
  --consider patient populations at greatest risk here--

    C. "potassium sparing" diuretics
           spironolactone (Aldactone)
          --in combination with hydrochlorothiazide (Aldactazide)
          triamterene (Dyrenium)
          --in combination with hydrochlorothiazide (Dyazide or Maxzide)
          amiloride (Midamor)
          --in combination with hydrochlorothiazide (Moduretic)

  1. Unique aspects of these agents
   a. spironolactone (Aldactone) is an aldosterone antagonist that prevents renin from converting angiotensin I to angiotensin II
   --also, the brand and generic versions are easily differentiated by their smells
   --its antagonism of aldosterone makes it useful in treating primary hyperaldosteronism

   b. triamterene (Dyrenium) is rarely used alone; it depresses the sodium transport at the distal tubule without great effect on potassium

   c. amiloride (Midamor) is also rarely used alone; it blocks the sodium-potassium exchange at the distal tubule

  2. These agents all have the potential of producing a hyperkalemic state in the patient; they can all inhibit the excretion of lithium

III. ACE INHIBITORS
    A. definition:    "angiotensin converting enzyme inhibitors"
    B. Activity
        --ACE inhibitors block PLASMA RENIN ACTIVITY
    C. Examples
          1. captopril (Capoten/Squibb)
          2. enalapril (Vasotec/MSD)
          3. quinapril (Accupril/Parke Davis)
          4. ramipril (Altace/Hoescht)
          5. moexepril (Univasc)
          6. fosinopril (Monopril)
          7. benzapril (Lotensin/Ciba)
          8. lisinopril (Zestril or Prinivil)

    D. Mechanism of action
        a. Angiotensinogen (a plasma substrate) + renin (an enzyme) ---> angiotensin I

        b. Angiotensin I + ACE --> Angiotensin II

        c. Angiotensin II leads to aldosterone release from the Adrenal cortex

        d. Aldosterone release results in

        e. inhibiting ACE reduces Angiotensin II formation and any of the results of that formation--THEREFORE WITH AN ACE INHIBITOR YOU GET

    E. Systemic effects
        1. inhibition of vasoconstrictor action of angiotensin II-- vasodilation results -- TPR reduced

        2. potentiation of vasodilator response to bradykinin --  TPR reduction

        3. decreased sodium/fluid retention by kidney

    F. Adverse effects of ACE inhibitors
        1. hypotension, particularly with a diuretic or volume depletion
        2. loss of taste leading to  anorexia
        3. rash
        4. cholestatic jaundice
        5. acute renal failure with bilateral renal artery stenosis or single kidney involvement
        6. angioedema
        7. hyperkalemia if the patient is also on a potassium supplement or potassium sparing diuretic (spironolactone/Aldactone)
        8. rare:
            i. blood dyscrasias
           ii. renal damage

IV. Calcium channel blockers
 EXAMPLES:
 amiodipine (Norvasc)
 diltiazem (Cardizem)
 felodipine (Plendil)
 isradipine (DynaCirc)
 nicardipine (Cardene)
 nifedipine (Procardia, Procardia XL, Adalat CC)
 verapamil (Calan, Isoptin)

 A. Mechanism of action
  1. decrease of calcium movement into heart and vascular smooth muscle cells
  2. calcium is vital to electrical current initiation and propagation
  3. decrease in calcium, decrease in muscle contraction
  4. decrease in contraction, less vascular tone
  5. vasodilation results
  6. blood pressure drops

 B. Systemic effects
  1. peripheral vasodilation and decrease in TPR
  2. general decrease in cardiac output and heart rate (exception is nifedipine which may cause tachycardia)

 C. Adverse effects
  1. headache, flushing, dizziness
  2. hypotension (esp. nifedipine)
  3. pedaledema
  4. constipation (esp. verapamil)
  5. gingival hyperplasia, esp. verapamil

 D. Benefits of Calcium blockers
  1. Broader effects upon the hypertensive heart than diuretic or beta blocker treatment
      2. effective, safe, convenient
       3. relatively few side effects
         --no thiazide side effects (hyperlipidemia, hypokalemia, hyperuricemia)
         --no beta blocker effects (lethargy, drowsiness; sexual dysfunction, bronchospasm; peripheral vasoconstriction)
         --better patient compliance
       5. clinical benefits of verapamil
              --seldom see orthostatic hypotension
              --normal BP response to exercise (esp when compared to a beta blocker)
              --no rebound hypertension after discontinuation of medication

V. Vasodilators
 A. nitroglycerin (Nitrobid, NitroStat, et al)
  1. patches; daily use
   Often the recommendation now is to remove the patch at bedtime
  2. sublingual tablets: 0.2, 0.3, 0.4mg
   --1 tablet under the tongue every 5 minutes for angina; if 3 doses ineffective, patient should report to emergency room
   –should cause a “tingling” on the tongue – if it doesn’t occur, regard the tablets as subpotent and replace
  3. sublingual spray–pricey alternative to the sublingual tablets
  4. paste–regaining popularity; used at Butterworth hospital (Spectrum Health) in Grand Rapids for post-op cardiac catheter/angioplasty patients
   –paste is applied first to glassine strip marked in inches, then placed on body
  5. injection
   –ER and ICU settings
   –dose based on patient response–in the case of plastic tubing, much of the NTG will stick to the tubing rather than stay in solution; an expensive alternative is to use special tubing

Occasionally, the term “amyl nitrate” appears on the boards.  This is in reference to a rarely if ever used form of nitroglycerin that was administered by breaking an ampoule containing the drug and inhaling the vapors, much as you would use an ammonia capsule today for episodes of syncope.

VI. Clonidine (Catapres)
 1. tablets: 0.1, 0.2, 0.3mg doses; usually a daily dose
  a. Must be weaned off over 2 to 4 days once therapy has been maintained to prevent dramatic “rebound” hypertension
  b. also used as additive therapy to methylphenidate (Ritalin) for ADHD and in cases of drug withdrawal protocols

 2. 7-day “TTS” patches

1. Amiodarone (Cordarone)-- liver toxicity, skin discoloration, photosensitivity, corneal damage– dental light
2. Calcium channel blockers– gingival hyperplasia (especially with verapamil [Calan])
3. Disopyramide (Norpace) – xerostomia
4. Procainamide (Procan) – CNS depression, xerostomia
5. Quinidine (Quinidex) – nausea, vomiting, diarrhea, xerostomia
6. Phenytoin (Dilantin) – (generally used as a treatment for seizures, but has antiarrhymic properties found useful when patients are allergic to lidocaine or procainamide) – gingival hyperplasia
 
 

VII. Nonpharmacologic Management of Hypertension
 From MEDSCAPE, November 1998 (connect to www.netscape.com)
 A. Weight reduction
  1. nearly half of patients with hypertension are obese
   –involves sleep apnea (30% of obese patients have sleep apnea) and insulin resistance with hyperinsulinemia
  2. among obese patients, a loss of as little as 7 pounds can be effective in lowering blood pressure
 B.Sodium restriction to 2.4gm/day
  –evidence suggests that approximately 10% of hypertensive African American adults ingest excessively large quantities of dietary salt, equivalent to over 9 grams per day
 C. Potassium supplementation
  –especially correction of hypokalemia; not necessary with proper dietary addition
 D. Calcium supplementation
  –1 to 2 gm/day helps some patients
 E. Magnesium supplementation; especially if taking calcium
 F. Moderation of alcohol
  –the antioxidant properties of wine
 G. Cessation of smoking
 H. Dynamic Exercise 20 to 30 minutes at least three times a week
 I. Relaxation therapy
  1. yoga
  2. biofeedback
  3. Transcendental meditation
  4. Qi gong (Chinese breathing techniques)
  5. Hypnosis

II. Coumarins-- Warfarin (Coumadin)
    A. Action
       --inhibits action of vitamin K in prothrombin formation
    B. forms
       --oral, injection
    C. side effects
       a. spontaneous bleeding
       b. hematuria
    D. interaction with salicylates
        THAT MEANS ASPIRIN! (however, also note that PeptoBismol contains salicylates)
    E. antidote: vitamin K and transfusion
    F. Coumadin is now monitored using the International Normalized ratio (INR); INR is prothrombin time (PT) corrected for the activity of the specific tissue thromboplastin used in the laboratory during analysis.

IV. Clopidogrel bisulfate (Plavix)
 A. inhibits platelet aggregation to lower stroke or recurrent myocardial infarction
 B. Dose is 75mg daily
 C. should be discontinued 7 days before surgery if its antiplatelet effect would pose an unacceptable bleeding risk

V.  Ticlodipine (Ticlid)
 A. Platelet aggregation inhibitor
 B. 250mg tablets, taken twice daily with food
 C. To reduce the risk of thrombotic stroke in patients who have experienced stroke precursors and in patients who have had a completed thrombotic stroke

1. You should be able to identify beta-blocking drugs by their generic name:
 A handy guideline:
 beta blockers have the suffix -olol --  propranolol --  atenolol

2. Thiazide diuretics generally contain "thiazide" or a similar derivative in their names:

 You should know which electrolyte is most greatly affected by thiazide diuretics and understand how this might affect digoxin (Lanoxin) therapy or toxicity.

3. You should be able to recognize calcium channel blockers.–can cause gingival hyperplasia
    THE MAIN SUFFIX HERE IS "PINE"

4. Angiotensin Converting Enzyme Inhibitors (ACE inhibitors):
   This newer class of drugs is gaining favor for initial treatment of hypertension.  You should be able to recognize them by generic name.  THE MAIN SUFFIX FLAG HERE IS "PRIL"

 5. Methyldopa (Aldomet) is a centrally acting antihypertensive, interferring with the effects of dopamine.  It can result in nightmares.

6. Some people with added oxygen demands may be poor candidates for beta blocker therapy.  You should be able to identify these people and understand why.

7. More drugs are being studied for topical use in the form of plastic patches that are to be worn for up to a week at a time.  There is one antihypertensive drug that is available in this form.  You should know its name...Catapres TTS (clonidine)

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.

1. Define (a) hypertension, (b) tachycardia, (c) hypotension, (d) diuresis
2. What is the name of the plant from which we get the drug digoxin (Lanoxin)?  What are two primary indications for the use of digoxin (Lanoxin)?
3. What electrolyte is of greatest concern regarding potential digoxin (Lanoxin) toxicity?  Which class of diuretics can cause a drop in this electrolyte in at least 40% of those who take it?
4. What are three good dietary sources of potassium?
5. Which antiarrhythmic drug is chemically related to procaine, making it a candidate for crossover allergies?
6. What is a common suffix useful in identifying a beta blocker?  What is the effect of a beta blocker on cardiac activity?  What is the effect of beta blocker activity in the lungs?
7. Which patients would have the greatest difficulty with taking a beta blocker for hypertension? Why?
8. Which patients would be poor candidates for thiazide diuretic therapy?  Why?
9. What are the uses for ACE inhibitors and calcium channel blockers?  Give three examples of each class of drug.
10. In what dosage forms is nitroglycerin available?  What is the most common side effect of nitroglycerin therapy?
11. What is the treatment for overdosage with heparin?  What is the treatment for overdosage with warfarin (Coumadin)?
12. What is a major drug interaction of concern regarding warfarin (Coumadin)?
13. What is the drug Plavix used for?
14. What side effect of calcium channel blockers such as verapamil (Calan) has a particular significance in dentistry?

End of Module Seven
Cardiac Drugs
DEHY34
January 2002
Contact and instructor: Jim Middleton