PHARMACOLOGY

1
PHARMACOLOGY Simplified, not Mystified

• The arrival of a good clown exercises a more
  beneficial influence on the health of a town than
  20 asses laden with drugs.
• Dr. Thomas Sydenham (1624-1689)

2
The Numbers

• 30 years ago there were 900 drugs to choose from
  in the PDR
• Today there are over 12,000
• Plus.

3
The numbers.

• Over 600 herbals products many of which interact
  with prescribed drugs including cardiac drugs and
  antidepressants
• St. Johns Wort is the number one herbal product
  that interacts with over 60 percent of all
  prescription drugs. The interaction is to make
  the drugs LESS effective Cyclosporine,
  tamoxifen, HIV Rx, and Combined Oral
  Contraceptives
• Side effect?

4
Im PREGNANT!!!

• CONFUCIUS say
• It take many nail to build crib only one screw
  to fill it.

5
Vitamins and herbal supplements.

• Vitamin supplementsexcess A (liver toxicity), B6
  (peripheral neuropathy), C (doesnt work to
  prevent colds but is an excellent way to help
  absorb iron when iron supplements are necessary),
  D for bones, balance, boosting immune system, E
  (no extra benefit on hearts, and in the very old
  may actually exacerbate heart failure)but
  vitamin E reduces fat in the liver in patients
  with fatty liver disease (800 IU/ day)
• Calcium supplements, iron supplements, soy
  supplements, and multivitamins interfere with
  levothyroxine (Synthroid)4 hour separation

6
Speaking of levothyroxine

• Nighttime dosing may be more efficacious than
  daytime dosing (better absorption)(Bolk)
• Most importanttake at the same time of day on
  empty stomach
• Adjust doses as the patient ageswhy?
• Levothyroxine RX can also cause atrial fib if the
  dose is too high levothyroxine doses DECREASE
  with aging some patients only need 0.5
  mcg/kg/day vs. younger adults with 1.7 mcg/kg/day
  (Prescribers Letter July 2011)

7
The Gs and platelet aggregation

• Decrease platelet aggregation increased risk of
  platelet bleeding the more you takestacking
  effect
• Garlic vs. garlic supplements (interfere with all
  sorts of drugs)
• Gingkonot beneficial for dementia, but is
  beneficial for PAD
• grapeseed extractEAT GRAPES
• ginseng whatever ails ya side effects?
• Glucosamineworth a try
• green tea (a potentially harmful interaction is
  with green tea and simvastatinthe higher the
  dose of simvastatin the greater the risk of
  rhabdomyolysis)

8
Another GGrapefruit juice

• When grapefruit juice or grapefruit inhibits an
  enzyme in the small intestine--CYP3A4.
• This enzyme normally initiates the metabolism of
  40-60 of all drugs
• when grapefruit juice inhibits this enzyme the
  drugs are absorbed in a higher bioavailability

9
Grapefruit juice and drugs

• Interaction with grapefruit/grapefruit juice may
  last up to 72 hourstakes this long for CYP3A4 to
  recover from as little as 8 ounces of GJ
• What is it in the grapefruit juice? The
  furanocoumarins
• (American Journal of Clinical Nutrition May
  2006)

10
Cardiovascular drugs that may interact with
grapefruit

• Very high riskdronedarone (Multaq)torsades de
  pointes lovastatin (Mevacor) and simvastatin
  (700 increase in bioavailability)
  (Zocor)rhabdomyolysis (check CK if c/o severe
  muscle aches and pains)
• High riskamiodarone (Cordarone)-- torsades de
  pointes atorvastatin/Lipitor rhabdomyolysis
  clopidogrel (Plavix)loss of efficacy increasing
  the risk of a blood clot following
  angioplasty/stenting eplerenone (Inspra)high
  serum calcium levels, serious arrhythmias,
  ticagrelor (Brilinta)GI or kidney bleeding

11
Cardiovascular drugs that may interact with
grapefruit

• Intermediate riskfelodipine (Plendil),
  nifedipine (Procardia)low BP, peripheral edema
  quinidine (Quinidine)torsades de pointes
  rivaroxaban (Xarelto)GI bleeding
• Canadian Medical Association Journal, November
  26, 2012 (online)

12
The proverbial caveat

• One important caveat to consider There is a
  large individual variation in the effect of
  grapefruit juice on metabolism. Consequently,
  someone with a high intestinal CYP 3A4 activity
  might tolerate a certain statin dose but have a
  marked increase in drug levels with inhibition
  via grapefruit juice. Unfortunately, at this
  time, pretreatment intestinal CYP 3A4 activity is
  not measured in patients commencing drug therapy.

13
Plus

• Over 10,000 over-the-counter (OTC) drugs that can
  wreak havocexamples
• 1) cimetidine (Tagamet)1st dose delirium in
  elderly multiple drug interactions
• 2) acetaminophen (Tylenol) is in over 300
  over-the-counter products (Tylenol)inadvertent
  overdoses (narrow therapeutic indextoxic dose is
  not much higher than therapeutic dose)
• .as well as numerous prescription analgesics
  Fioricet, Lorcet, Percocet, Propacet, Roxicet,
  Ultracet (limit cets to 325/mg per tab to
  reduce toxicity)

14
Acetaminophen/Tylenol

• itchy, sneezy, wheezy, snotty, achy, breaky
  products
• Vicodin for pain, Excedrin for headache, Theraflu
  for cold or flu, Sinutab for allergies,
  Robitussin for cough, Allerest for sleep
• 3,000 mg day is recommended total dose (McNeil
  Consumer Healthcare, bulletin on July 28, 2011 to
  reduce risk of acetaminophen liver toxicity)even
  less for people who have more than 3 adult
  beverages per day

15
Whats in a name???

• When you hear Bayer what do you think?
• ASPIRIN OF COURSE!
• Bayer Aspirin is aspirin but Bayer Select
  Maximum Strength Headache is acetaminophen and
  caffeine
• Bayer Select Pain Relief is ibuprofen
• Aspirins principal use today is in low doses as
  a platelet inhibitor and to inhibit colorectal
  polyps in high risk patients

16
Dont PANIC.

• Know the 30 or 40 drugs you use daily in your
  clinical practice as well as the most common
  drugs most likely used by your patients(age and
  gender specific)
• Helpful hints

17
Generics vs. Brand names

• As a general rule, classes of drugs have the same
  generic last name
• PrilsACE inhibitors (BP more)
• SartansARBs (angiotensin receptor blockers)BP
  more
• Triptanstreatment of acute migraine headache
• StatinsLower LDL-cholesterol
• Dipinescalcium channel blockers (BP)
• TidinesH2 blockers reduce nighttime acid
• PrazolesProton Pump Inhibitors, GERD
• Azolesantifungal
• AfilsErectile dysfunction
• The osins, mabs, the nibs, the setrons,
  etc, etc, etc

18
Lets talk about blood pressure

• First line therapy for blood pressure today can
  be either
• A thiazide diuretic (HCTZ) or chlorthalidone
  (Thalitone)
• ACE inhibitors
• ARBs (angiotensin receptor blockers)
• Calcium channel blockers
• (American Society for Hypertension, Spring 2013)

19
ACE inhibitors the prils

• Captopril (Capoten)(1981)
• Enalapril (Vasotec)(1983)
• Fosinopril (Monopril)
• Lisinopril (Prinivil, Zestril)
• Perindopril (Aceon)
• Moexipril (Univasc)
• Benazepril (Lotensin)
• Quinapril (Accupril)
• Trandolapril (Mavik)
• Ramipril (Altace)

20
A little refresher on the kidney

• At any given moment, the kidney is sensing the
  pressure and volume of blood flow
• Low volume or low BP, the kidney will release
  renin from a small area (the JGA) just inside the
  afferent arteriole
• Renin (the messenger)?(liver) angiotensin I
  ?angiotensin II? via Angiotensin Converting
• Enzyme (ACE) (primarily in the pulmonary
  circulation)

21
What does angie II do?

• She tenses your angiosvasoconstricts your
  arteries, BP increases
• She triggers release of ALaldosterone (from
  the adrenal cortex to save sodium H2O in the
  kidneyinncreases BP by increasing volume
  excretes potassium)
• She increases inflammation in the
  arteriesinflammation plaque rupture
• Shes prothromboticincreased clotting risk
• She increases tissue resistance to
  insulinresulting in hyperglycemia (T2DM,
  dementia)
• Shes a potent growth factor and remodels
  (enlarges) tissues
• Is remodeling a GOOD WORD?

22
But not in your heart, vessels, and kidneys

• Remodels myocardium and disrupts the conduction
  systemIncreases the risk of ventricular
  dysrrhythmias
• Remodeling increases vascular fibrosishypertensio
  n
• Remodeling increases intraglomerular blood
  pressure resulting in intraglomerular
  hypertension leading to CKD
• BOTTOM LINE?

23
So, lets get back to the original storyWho is
ACE and why do we want to inhibit him?
ACE --
24
So if you were an ACE inhibitor, what would you
do? Inhibit ACE? Inhibit the formation AT
angiotensin II

• Anti-hypertensive agent via vasodilation (due to
  inhibiting angiotensin 2) and inhibition of
  aldosterone (excrete SODIUM and H20 BUT you save
  POTASSIUM)
• (as many as 70 of hypertensive patients in U.S.
  and Canada may have elevated renin-angiotensin-al
  dosterone (RAA) systems Treatment of heart
  failure by inhibiting renin-angiotensin-aldosteron
  eCHF is a HYPER-RENINEMIC state
• Anti-inflammatory
• Anti-thrombotic
• Hypoglycemic (be careful when starting ACE
  inhibitors in diabetics)
• Prevents remodeling of the heart, vessels, and
  kidneys

25
What does Angie do in the healthy kidney?

• Afferent arteriole
• (vasodilated via
• (prostaglandins)
• Blood entering
• glomerulus
• Glomerulus?filter
• Efferent arteriole
• (vasoconstricted via
• (angiotensin II)
• Blood exiting
• glomerulus

PG
filter
AT II
Toilet
26
Angie, the prils and the Diabetic/hypertensive
Kidneyhyperglycemia/HTN

• Afferent arteriole
• ( ? vasodilation by
• ( ? prostaglandins)
• Blood entering
• glomerulus
• Glomerulus?filter
• Efferent arteriole
• ( ? vasoconstriction via
• ( ? angiotensin II)
• Blood exiting
• glomerulus
• PRILS inhibit ATII/vasodilate the efferent
  arteriole
• 
  

Microalbuminuria
27
To summarizeACE inhibitors are used for

• Hypertension (night time dosing of
  anti-hypertensive drugsdippers (10 decline _at_
  night) vs. non-dippers)
• (American Journal of Kidney Diseases
  December 2007)
• Prevention of diabetic nephropathy
• Decrease preload and afterload in the patient
  with CHF and decrease the remodeling of the heart

28
To summarizeACE inhibitors are used for

• Decrease the remodeling of the heart in post-MI
  patients (clearly beneficial in MI patients 65-74
  years of age, but not so clear in patients older
  than 75)
• Beneficial in patients with anterior ST-elevation
  MIs and in patients with MIs complicated by HF or
  significant LV systolic dysfunction with LV
  ejection fractions less than 40
• Decrease the risk of 1st and 2nd myocardial
  infarctions in high-risk patients due to
  anti-inflammatory effects
• Stroke prevention

29
Whats not to love about the ACE inhibitors?
30
Side effects, of course

• Hypotensionstart low and go slow
• Hypoglycemia (low blood sugar)only in diabetics
  on antiglycemic agents not a problem in
  normoglycemic patients

31
Side effects, of course

• Hyperkalemia (high potassium) (excreting sodium
  and water and retaining potassium)
• Add a thiazide diuretic to the ACE inhibitor
• Capozide (captopril thiazide)
• Prinizide (lisinopril thiazide)
• Zestorectic (as above)
• Lotensin HCT (benazepril hydrochlorothiazide)

32
Since ACE inhibitors conserve potassiumWhat
about K containing foods?

• May contribute to hyperkalemia and cardiac
  arrhythmias but usually only in patients with
  renal insufficiency or in patients who are also
  on K sparing diuretics such as spironolactone
  (Aldactone) and eplerenone (Inspra)
• Avoid excessive potassium intake when on the
  above drugs or with renal insufficiency
• Advise patients to decrease potassium intake
  until they can get their potassium checked
• Dont use Bactrim/Septra for UTIsit also
  increases K and can lead to life-threatening
  arrhythmias

33
High K containing foods

• Potatoes
• Prunes
• Raisins
• Apricots
• Bananas
• Halibut
• Canteloupe
• Oranges
• Pasta sauce
• Health.harvard.edu/heartextra for K content of
  1,200 foods

34
Side effects, continued

• Cough (gender differences with F gt M)
• ACE inhibitors block angiotensin converting
  enzyme but as ACE is inhibited, bradykinin goes
  UPbradykinin is a potent bronchoconstrictor
• Women have more bradykinin to begin with,
  therefore the gender disparity in the cough

35
Side effects, continued

• Life-threatening angioedema (Does my voice sound
  funny to you?)
• Usually within the first month (but not the first
  week) almost all cases within the first year
• An exception or two

36
And ONE OTHER THINGACE inhibitors (category D)
throughout pregnancy

• Why?
• Angiotensin 2 boosts growth factors
• ACE inhibitors inhibit AT2 and inhibit growth
  ACE inhibitors are teratogenic
• Cooper WO et al. Major congenital malformations
  after first-trimester exposure to ACE inhibitors.
  N Engl J Med 2006 Jun 8 3542498-500

37
SartansAngiotensin II Receptor Blockers

• Angiotensin receptor blockers (bypass ACE) and
  work by blocking the angiotensin II receptors on
  tissues
• Who are they? The Sartan Sisters
• losartanCozaar
• valsartanDiovan
• candesartanAtacand
• irbesartanAvapro
• telmisartanMicardis
• olmesartanBenicar
• azilsartan -- Edarbi

38
ARBs as a safe haven for the side effects of the
prils

• Are the sartans safe for patients with a
  history of angioedema from the prils?
• Appears to be about an 5 to 8 rate of
  cross-reactivity
• Given this limited percentage, switching to an
  ARB should not be considered an absolute
  contraindication in all patients with
  ACE-inhibitor induced angioedema
• Switch cautiously
• (Prescribers Letter 2004 11(7))

39
ACE inhibitors vs. ARBs

• New and important info from American Society of
  Hypertension Spring meeting 2013
• All ACE are in lowering BP
• ACE ARB and both relatively safe ARBs with
  less angioedema
• ARBs may be better after MI
• Both protect after strokes
• No evidence to support combing ACE ARB

40
Two other drug categories that influence the
renin-angiotensin-aldosterone system

• The direct renin inhibitors -- aliskirin
  (Tekturna)
• The aldosterone antagonists spironolactone
  (Aldactone) and eplerenone (Inspra)be careful
  with these drugs when used for CHF in combination
  with ACE inhibitors potassium levels can
  increase to dangerous levels and life-threatening
  cardiac arrhythmias can occur
• Keep checking the potassium levels
• Stacking diureticsspironolactone (K sparing)
  with chlorthalidone (Thalitone) or furosemide to
  decrease hyperkalemia (American Society of
  Hypertension, Spring 2013)

41
Olols, alols, ilolsBeta blockers

• atenolol (Tenormin) (NO, NO. Raises central
  pressure despite lowering brachial
  pressureincreased risk for CV events including
  stroke and MI)
• betaxolol (Kerlone)
• bisoprolol (Zebeta)Monocor
• carvedilol (Coreg)Beta Blocker PLUS (alpha one
  blocker)
• Esmolol (Brevibloc)
• labetalol (Trandate)(Normodyne)safe during
  pregnancy
• metoprolol succinate (Toprol XL,
  Lopressor)Betaloc
• nadolol (Corgard)
• nebivolol (Bystolic)Beta blocker PLUS (boosts
  NITRIC OXIDE)
• propranolol (Inderal)(1968)(nonselective)
• sotalol (Betapace)
• timolol (Blocadren)

42
Sympathetic Nervous System (SNS)fight/flight
system

• In order to understand the beta blockers, a quick
  review of the SNS is in order
• Lock and key theory
• Receptors (lock) and neurotransmitters (key)
• Receptors beta-1, beta-2, alpha-1, alpha-2
  receptors regulate the SNS
• Neurotransmitters are the catecholamines
  epinephrine, norepinephrine
• Scenario Visit Barb in Chicago

43
Fight/flight response

• Pupils dilate
• Heart rate goes up
• BP goes up
• Bronchioles dilate
• Increased blood flow to arms and legs
• Hair on arms and neck stands up
• Tremor
• What do your bowels WANT to do?

44
But you have a motheryour frontal lobe

• Dont even think about itif I have told you
  once, I have told you twice

45
SNS receptors beta 1

• Beta 1 receptorsfound on cadiac muscle
  epinephrine binds to B1 and increases heart rate
  and strength of contraction (chronotropic and
  inotropic)
• Beta blockers that JUST block the beta 1
  receptors are called cardioselective

46
Cardioselective beta blockers block the B1
receptors

• Cardioselective beta blockers reduce cardiac
  output, heart rate falls (10-15), blood pressure
  falls
• Workload of the heart decreasesused to treat
  angina, SVT, post-MI to protect the heart from
  remodeling and to reduce heart rate
• EXAMPLES atenolol (Tenormin), metoprolol
  (Lopressor), betaxolol (Kerlone) bisoprolol
  (Zebeta), nebivolol (Bystolic)_at_ doses lt10 mg)

47
SNS receptorsbeta 2

• B2 receptorsfound on skeletal muscle, the
  bronchioles, large arteries of arms and legs
  when epinephrine binds to B2 the bronchioles of
  the lugns dilate, the large arteries of the arms
  and legs vasodilate, and hands may exhibit a
  slight tremor (skeletal muscle tremor), and
  piloerection occurs (hairs stand up on back of
  neck and arms)

48
Non-selective beta blockers block both beta-1 and
beta-2 receptors

• Blocking beta-2?block skeletal muscle receptors
  and decrease the tremor, can cause
  bronchoconstriction (problem w/ COPD patients and
  asthmatics) can cause vasoconstriction of the
  large arteries of the legsproblem with diabetics
  or anyone with PAD
• Non-selective beta blockers-- propranolol
  (Inderal), nadolol (Corgard), timolol
  (Blocadren), carvedilol (Coreg)
• Use CARDIOSELECTIVE beta blockers for diabetics,
  asthmatics, and COPD patients

49
Beta blockersother properties

• Water-soluble? (low lipophilicity)
• atenolol (Tenormin), nadolol (Corgard),
  labetalol (Trandate), nebivolol (Bystolic)
• Lipid-soluble? (high lipophilicity--cross the
  blood brain barrier)CNS side effectsanhedonia
  (the Blahs)BUTthe lipid-soluble can also
  calm down the brain
• propranolol (Inderal), timolol (Blocadren),
  metoprolol (Lopressor, Toprol XL), pindolol
• All of the others are moderately lipophilic

50
Functions of beta-blockers

• Decrease palpitations during panic attacks
• Decrease heart rate in atrial fib
• Decrease essential tremors
• Decrease situational anxiety
• Decrease symptoms of PTSD
• Decrease HR in patients with Graves disease
• Decrease portal pressure in patients with
  cirrhosis and esophageal varices
• Decrease migraine headaches by 50 in 50 of the
  patients (mechanism unknown)
• Pre-operative beta-blockersnon cardiac
  surgerieshigh risk pts

51
Beta Blockers

• Beta blockers have become obsolete for CV
  protection. Their era did not include
  percutaneous coronary interventions (PCI),
  statins, antiplatelet therapies, ACE or ARBs.
• Adding beta blockers to current therapies does
  not improve outcomes (REACH registry, JAMA 2012
  3091340)
• EXCEPTION Beta blockers still used for
  decreasing remodeling of heart in patients with
  systolic HFuse the beta blocker PLUS drugs

52
Beta-blocker eye drops for glaucomasecond-line
therapy--Lower intraocular pressure by 20-25
with once or twice daily dosing

• timolol (Timoptic) Betimol, , levobunolol
  (Betagan), carteolol (Ocupress), metipranolol
  (Optipranolol)
• Highly lipid-soluble and cross the blood-brain
  barrier
• Can cause bradycardia and anhedonia
• So what can you use instead?

53
The oprostsfirst line therapy for glaucoma

• The oprostsbimatoprost (Lumigan)(Latisse for
  eyelashes), latanoprost (Xalatan), travoprost
  (Travatan)
• And, unoprostone (Rescula)
• Prostaglandin analogueslower Intraocular
  pressure by 25-30
• Latisse for thick, long eyelashes

54
Calcium Channel Blockers 2 categoriesthe
nondihydropyridines

• Verapamil (Isoptin SR, Verelan and Verelan PM,
  Calan and Calan SR, Covera-HS)block calcium
  channels primarily on the coronary vessels and
  the AV nodeincreasing blood flow to the heart
  and decreasing impulses through the AV nodeused
  to decrease workload of heart and slow the heart
  rate HTN, angina, atrial fib, renoprotective
• Negative inotropic effectavoid in
  patients with CHF
• Calcium channels in bowels (elderly)severe
  constipation

55
2nd drug in the non-dihydropyridine category

• DiltiazemCardizem LA and CD, Dilacor XR,
  Tiazacdilates calcium channels on the coronary
  arteries and peripheral vessel calcium channels
  decreases impulse transmission from atrium to
  ventricle
• Negative inotropic effectsavoid in CHF patients
• Clinical uses
• Atrial fibrillation, Hypertension, Angina,
  Vasospasm, renoprotective
• Less constipation than verapamil

56
2nd categorythe Dihydropyridines or the
DIPINESPeripheral vessel calcium channel
blockers

• Amlodipine (Norvasc)
• Felodipine (Plendil)
• Nifedipine (Procardia XL, Adalat)
• Nicardipine (Cardene)
• Isradipine (Dynacirc)
• Nisoldipine (Sular)
• Clevidipine (Cleviprex) for IV use vs. esmolol or
  IV nicardipine)

57
Clinical uses of the dipines

• Hypertension
• VasospasmPrinzmetals angina, Raynauds
  phenomenon, cocaine-induced vasospasms
• Ureteral spasms in patients with small kidney
  stones
• male contraceptive

58
Side effects of CCBs

• Verapamilsignificant constipation lots of drug
  interactions
• Dipinessignificant peripheral vasodilation with
  headaches hypotension, and peripheral edema
  (swollen feetpedal edema (Plendil)
• Diltiazemless significant constipation than
  Verapamil
• All CCBs inhibit calcium-induced contraction of
  the LES, resulting in sphincter relaxation and
  acid reflux

59
The Statin Sisters

• Who are they?
• lovastatin (Mevacor)
• simvastatin (Zocor)
• atorvastatin (Lipitor)
• fluvastatin (Lescol)
• pravastatin (Pravachol)
• rosuvastatin (Crestor)
• pitavastatin (Livalo)

60
The Statin Sisterswhat do they do?

• Inhibit an enzyme in the liver responsible for
  the production of the LDL-cholesterol works
  primarily at night to reduce LDL, so the
  statins work the best when taken before bedtime
  (exceptions to the ruleatorvastatin/Lipitor and
  rosuvastatin/Crestor)

61
LDL-cholesterol

• LDL (low density lipoprotein) is the most
  atherogenic of the cholesterol bunch and puts fat
  right smack dab into all of the arterial walls
  therefore, statins decrease LDL-cholesterol and
  reduce the risk of coronary artery disease,
  peripheral vascular disease, renovascular disease
  and cerebrovascular disease they also increase
  survival rates and improve the quality and
  quantity of life

62
LDL-lowering effects

• If so, how low should your LDL go?
• Atorvastatin/Lipitor 10 mg 39
• Fluvastatin/Lescol 40 mg BID 36
• Fluvastatin XL/Lescol 80 mg 35
• Lovastatin /Mevacor 40 mg 31
• Pitavastatin/Livalo 2 mg 36
• Rosuvastatin/Crestor 5 mg 45
• Simvastatin/Zocor 20 mg 38
• (Circulation 2004110227-239)

63
LDL guidelines

• Guidelineswith CAD or a risk equivalent (PAD,
  TIA, stroke, abdominal aneurysm), the LDL should
  be 70 mg/dL (2.0 mmol/L or even lower, perhaps
  1.8 mmol/L)
• For the rest of us with other risk factors100
  mg/dL (lt2.85 mmol/L)
• Unless youre perfect--130 mg/dL (lt3.37 mmol/L)
• Particle size is also important (LDL-P)small and
  dense (B pattern) vs. large and loose (A pattern)

64
What do the statins do?

• Decrease total cholesterol
• Decrease LDL-cholesterol
• Decrease oxidation of LDL-cholesterol
• Shrink plaques including plaques in the renal
  artery and improve blood flow to vital organs
• Stabilize fatty plaques and prevent plaques from
  rupturing (an inflamed fatty plaque ruptures in a
  coronary artery triggers the coagulation cascade
  and clot formation)
• Prevent the formation of new plaques in the renal
  and other arteries
• Decrease mesangial proliferation in glomerulus
  and reduce intraglomerular hypertension
• Decrease vascular inflammation
• Boost neurogenesis (more later)

65
Combinations with statins

• Atorvastatin and amlodipine for HTN Caduet
• Lovastatin and niacin (to lower TG)Advicor
• Simvastatin and ezetimibe (Zetia) which blocks
  cholesterol absorption in GI tractVytorin
• Simvastatin and niacine Simcor

66
SIDE EFFECTS

• Myalgias (other causes in elderly patients)
• About 1/20 patients experience muscle pain or
  weakness
• Myositis rhabdomyolysis (rare) (ASA is 100x more
  likely to cause a fatal side effect than taking a
  statin)
• Simvastatin at higher doses is the riskiest
  statin for rhabdomyolysisnever use the 80 mg
  dose lots of drug interactions do NOT drink
  green tea or eat grapefruit or drink grapefruit
  juice with this statin
• How about adding CoQ10 for muscle aches and
  pains? take 50-100 mg/day of CoQ10
• Either switch statins, lower the dose of
  statins, consider every other day dosing

67
The 1 oral drug for Type 2 DM

• Metformin (Glucophage, Glucophage XR, Fortamet,
  Glumetza, Riomet ) does not have any direct
  effect on insulin release from the
  pancreasdoesnt require insulin to work
• Primary action DECREASE hepatic glucose
  production also, decreases glucose absorption
  via the GI tract, and may increase sensitivity of
  insulin receptors
• Problem? GI blues (nighttime dosing/give with
  food), need functioning organs--kidneys and heart
  especially (check serum creatinine before
  starting metformin)
• Se Creatinine--Cut-off is 1.4 (50-90 mmol/L) in
  females and 1.5 (70-120 mmol/L) in males

68
Metformin (Glucophage)

• Cardiovascular benefits lowers BP, increases
  HDL, lowers LDL
• Metformin and breast and prostate cancer
  reduction (54)Diabetes Care December 2010
• Metformin and slowing the aging process
• Metformin and neurogenesis
• Metformin and anti-psychotic drugs
• Metformin and HD-Prednisone
• Metformin and PCOS

69
Downside to Metformin

• B12 deficiency
• Increase in BFR (basal flatal rate)
• Diarrhea (take with food switch to Glumetza)

70
Incretin mimetics the tides

• incretins are responsible for approx. 60 of the
  post-meal insulin secretion, but the action of
  the incretins is impaired in diabetics) Acts at
  the GLP-1 receptor, promoting insulin release
• Exenatide (Byetta)(2005)isolated from saliva of
  a Gila Monster
• Bydureon (Byetta once a week) Better than Byetta
  as it reduces HgA1C 1.6 vs. 0.9 for Byetta
  Nausea 14 vs. Byetta at 35
• Indications? Type 2 diabetics who are already
  receiving metformin, a sulfonylurea, or both and
  do not have optimal control
• Weight loss is a side effect (due to slowing of
  gastric emptying and feeling full)

71
Incretin mimetics

• 2nd generationliraglutide (Victoza)QD, less
  nausea
• PANCREATITIS!
• The old face of Victozathe BUTTER QUEEN, Paula
  Deenshe was dumped due to her legal problems

72
The gliptins

• Weight neutral
• inhibit enzymes in the intestine responsible for
  breaking down incretins incretins potentiate
  insulin release
• Sitagliptin (Januvia)
• Saxagliptin (Onglyza)
• Linagliptin (Tradjenta)
• Janumet (Januvia metformin)
• Kombiglyze (onglyza metformin)
• Pancreatitis!

73
OLD Drugs for Type 2 Diabetes

• Sulfonylureasglimepiride (Amaryl) glipizide,
  glyburide
• Major side effects? Weight gain and hypoglycemia
• Boost release of insulin from remaining islet
  cellshigh risk of hypoglycemiause with caution
  in the elderly

74
OLD Drugsare these even worth using anymore?
Considered third-line therapycheap drugs

• Oral sulfonylureasGlipizide (Glucotrol) and
  glyburide (Diabeta, Micronase, Glynase) and
  glimipiride (Amaryl)
• Increase the secretion of insulin from the
  pancreas and increase receptor sensitivity
• Problem? Weight gain, hypoglycemia, increased
  cardiovascular risk
• glimipiride (Amaryl)safest use in
  elderly--decreased incidence of hypoglycemia
  (glyburide is NOT safe in the elderlytoo much
  hypoglycemia)

75
The afilsthe Pfizer Riser aka sildenafil
(Viagra) and friends, for erectile dysfunction

• Prior to November 1998
• PDE5 inhibitors which in a round about way boost
  nitric oxidepotent vasodilator primarily below
  the belt
• What are the causes of ED?
• Athero, neuro, drugs, ?testo, psychological (the
  stamp test)
• Sildenafil (Viagra)(Revatio for pulmonary
  hypertension)
• Vardenafil (Levitra, Staxyn)
• Tadalafil (Cialis)the weekend warrior (Adcirca
  for PH)
• Can use in patients with stable CHD

76
Cant use with nitroglycerin

• When was your last dose of Viagra?
• Cant use Viagra or Levitra within 24 hours of
  receiving NTG Cialis within 36-48 hours
• Side effects
• Hypotension
• Headaches
• GERD
• Blue vision
• Priapism
• A surprise side effect of the afils

77
Sexually transmitted diseases have increased by
over 300 in the over 60 crowd since the release
of Viagra

• More sex
• No pregnancy worries
• Swingin singles
• Who cares what the neighbors think?
• Swimming pools and golf courses
• Can you have a heart attack during sex?
• Only if

78
Drugs and reducing the size of the prostrate

• Alpha one receptors are located on the smooth
  muscle cells of the prostate
• Enlarge with aging (BPH)
• Incessant testosterone stimulation over a
  lifetime also increases the size of the prostate
• Alpha-one blockers
• Tamsulosin (Flomax)
• Silodosin (Rapaflo)
• Doxazosin (Cardura)

79
Drugs and reducing the size of the prostrate

• 5-a reductase inhibitors to prevent the
  conversion of testosterone to dihydrotestosterone
  (DHT)a more potent agonist for prostate growth
  (not only reduce size of prostate but also
  decrease the risk of prostate cancer)
• Dutasteride (Avodart)
• Finasteride (Proscar)
• Vitamin D for the prostate

80
Tamsulosin (Flomax) in women

• NOT to be confused with Flonase
• Can use in women to improve symptoms due to
  bladder outlet obstruction
• Help increase urine flow by relaxing the bladder
  neck and urethra
• Avoid all decongestants which can lead to
  increase tone in the bladder neck and make
  symptoms worse urinary retention

81
Alpha-one blockers, cataract surgery, and floppy
iris syndrome

• Who wudda thunk? If you or your patients are
  going to have cataract surgery
• Let the ophthalmologist know if you have EVER
  taken an alpha-one blocker or if currently on one
  (Prescribers Letter, May 2012)
• A history of taking an alpha-one blocker can
  cause serious complications (even years later)
  during cataract surgery(atrophy of muscle that
  holds the iris)
• Procedure is much harder with a floppy iris
• Tamsulosin (Flomax) is the biggest offender
• Silodosin (Rapaflo), Doxazocin (Cardura XL),
  beta-blocker with alpha-one blocking properties
  (carvedilol/Coreg), labetalol (Trandate),
  risperidone

82
The bisphosphonates for osteoporosis

• The dronates for osteoporosis
• Alendronate Fosavance (Fosamax D),
  Risedronate (Actonel), ibandronate (Boniva)
• Zoledronic acid (Zometa) lower dose for
  osteoporosisbrand name Reclast Aclasta
• Trigger apoptosis of osteoclasts
• Osteoblasts continue to build bone matrix but
  without remodeling
• Any downside? Osteonecrosis of jaw
• Subtrochanteric femur fractures? Very low risk
• Can the patient FOLLOW directions with the oral
  bisphosphonates?

83
How long should a patient stay on
bisphosphonates?

• May 9, 2012 online New England Journal of
  Medicine
• Discuss w/ HCP about staying on longer than 5
  years
• May not offer much additional fracture protection
  beyond this time periodwomen who stayed on drugs
  had similar fx rates to women who switched to
  placebo
• Consider continuing drugs in women with low
  bone-mineral density at femoral neck of hip
  (T-score below -2.5) and in women w/ existing
  vertebral fx who have T scores below -2.0.

84
The prazolesProton Pump Inhibitors

• Omeprazole (Prilosec)(first released as Losec in
  U.S.)
• Lansoprazole (Prevacid)
• DeXlansoprazole (old-Kapidex)(new-Dexilant)
• Rabeprazole (Aciphex) Pariet
• Pantoprazole (Protonix) Pantoloc
• Esomeprazole (Nexium)-- the purple pill
• BIG Exception Aripiprazole/Abilifyantipsychotic
  a dopamine system stabilizer

85
The prazolesProton Pump Inhibitors

• MOAInhibition of the proton pump at the lumenal
  surface of the stomachespecially after a meal

H, Intrinsic Factor-B12
PPIs work here
Lumenal surface
Parietal cell
Basilar surface
H2
H2 receptors
H2 blockers work here
86
The prazoles

• Work within 4-7 days to reduce all acid in the
  stomach take 30-60 before the first meal of
  the day or before the dinner meal (especially if
  nocturnal GERD is a problem)
• BUT long-term suppression of acid has been shown
  to have significant side effects
• Increased risk of hospital-acquired pneumonia and
  community acquired pneumonia (PPI use might be
  associated with 33,000 preventable deaths due to
  pneumonia in hospitalized patients)(Herzig)
• Increased food-borne illness
• Increased risk of osteopenia/osteoporosis with
  long-term use (in smokers)
• Increased risk of B12 deficiency due to blocking
  the release of intrinsic factor
• Long-term use and iron deficiency anemia
• Drug interaction with clopidogrel (Plavix)
• Increased risk of Clostridium difficile

87
Use of PPIs and clostridium difficile

• Daily PPI use associated with an estimated 74
  increase in Clostridium difficile infection
• People using PPIs while being treated for C.
  difficile had a 42 increased risk of recurrence
  Archives of Internal Medicine 2010170784-790,
  772-778.
• Should all patients be put on PPIs upon admission
  to the hospital? NO, its NOT necessaryICU
  patients? YES, because they have been shown to
  have the highest risk for a GI bleed from
  stress-induced gastric ulcers but not for every
  bunionectomy, hemorrhoidectomy, or tonsillectomy

88
PPIs and Inappropriate subscribing in hospital
patients

• Reid M et all. Inappropriate prescribing of
  proton pump inhibitors in hospitalized patients.
  J Hosp Med 2012 May/Jun 7421
• Herzig SJ et al. Acid-suppressive medication use
  and the risk for nosocomial gastrointestinal
  tract bleeding. Arch Intern Med 2011 Jun
  13171991.

89
The tidines (H2 blockers)

• Best to give at nightdecrease vagally-induced
  histamine release in stomach (double the OTC dose
  for best results)
• Use PEPCID in patients taking low-dose aspirin
  therapy for heart disease prevention
• Cimetidine--Tagametcan cause delirium in the
  elderly increases the bioavailability of many
  drugsbeta blockers and bradycardia, morphine and
  bradypnea
• Other H2 blockersRanitidine (Zantac) Nizatidine
  (Axid) Famotidine (Pepcid)safest and most
  effective

90
The antifungals--the azoles

• 75 of all women will have at least one vaginal
  yeast infection in their life
• Miconazole (Monistat-7)
• Tioconazole (Vagistat)
• Clotrimazole (Mycelex)
• Fluconazole (Diflucan)
• Itraconazole (Sporanox)
• Ketoconazole (Nizoral)
• Voriconazole (Vfend)
• Posaconazole (Noxafil)newest of the bunch (HIV)
• DRUG INTERACTIONS
• You have a yeast infection

91
The antiherpeticsthe cyiclovirs

• Acyclovir (Zovirax)
• Famciclovir (Famvir)
• Valacyclovir (Valtrex)
• Ganciclovir (Cytovene) CMV retinitis in HIV
  patients CMV pneumonitis in transplant patients

92
The antiherpeticsVaricella Zoster Virus

• Acyclovir (Zovirax)(4000/d)
• Famciclovir (Famvir)(750/d)
• Valacyclovir (Valtrex)(3000/d)
• Tx must be started within 48-72 hours after the
  first signs of a rash appear.
• Prednisone
• PREVENTION?

93
Zostavax the SHINGLES vaccine

• Zostavax (Merck) to reduce the incidence of
  Herpes Zoster (shingles/Hells fire) in people
  over 50 (14 x stronger than Varivax)(risk
  reduction50) reduces severity and decreases
  post-herpetic neuralgia

94
DEPRESSION

• The FDA this week approved the first-ever
  transdermal patch for the treatment of
  depression. Simply remove the backing and press
  the patch firmly over your mothers mouth. Tina
  Fey, on Saturday Night Live (March 2006)

95
Drugs for depression

• Serotonin Reuptake Inhibitors (SRIs)fluoxetine
  (Prozac), sertraline (Zoloft), paroxetine
  (Paxil)(Seroxat), citalopram (Celexa),
  escitalopram (Lexapro)(Cipralax)
• Serotonin Norepinephrine Reuptake Inhibitors
  (SNRIs)venlafaxine (Effexor), desvenlafaxine
  (Pristiq), duloxetine (Cymbalta)

96
Drugs for depression

• The other categorymirtazapine (Remeron),
  buproprion (Wellbutrin)
• old antidepressants (used primarily for
  neuropathic pain)Tricyclic Antidepressants
  (TCAs) such as amitriptyline (Elavil),
  nortriptyline (Norpramin, Pamelor)are actually
  SNRIs as they inhibit the re-uptake of both
  serotonin and norepinephrine
• Drugs that block the reuptake of serotonin and
  norepinephrine can be used for neuropathic pain
  (duloxetine/Cymbalta and amitriptyline (Elavil)
  are commonly used for neuropathic pain
• Milnacipran HCl (Savella, 2009)SNRI approved for
  the management of fibromyalgia (not approved for
  kids)

97
Is there a better SSRI?

• Top two are sertraline and escitalopram (Lancet,
  Jan. 09)
• Sertraline/Zoloftshort half life great for use
  in the elderly few drug interactions(cheapest)
• Escitalopram/Lexapro/Cipralexfew drug
  interactions, not as many as Paxil
• Citalopram/Celexa (not to be confused with
  Celebrex)very few drug interactions
• Fluoxetine/Prozachalf-life is too long for
  elderly
• Paroxetine/Paxilmany, many drug interactions and
  not good for use in the elderly is the most
  anti-cholinergic of all (interferes with
  cholinesterase inhibitors used for Alzheimers
  disease) and can cause anti-cholinergic side
  effects in elderly

98
Anti-cholinergic drugsside effects

• Confusion
• Pupillary dilation (blurred vision, glaucoma)
• Tachycardia (angina, possible MI)
• Decreased salivation (dry mouth)
• Decreased peristalsis in GI tract (constipation)
• Tighten urinary sphincter (urinary retention)

99
SSRIsa major side effect

• Boost serotonin
• Makes ya happy
• Blocks dopamine though and dopamine in the brain
  is responsible for sexual functioning (among
  other things)
• Decreases libido, anorgasmia (50-75 of patients)
  
• However, if premature ejaculation is your
  problem, the SSRIs are for you

100
Im here for my SSRI prescription

• Low serotonin is part of the problem with
  patients with premature ejaculation

101
Other side effects of the SSRIs

• Bruxism (due to low dopamine)--morning headaches,
  jaw pain, a clicking sound in your jaw, sensitive
  teeth, and damaged teeth and crowns. Permanent
  long-term effects can include temporomandibular
  disorder, a painful condition affecting the jaw
  and facial muscles, and periodontal disease.
• RLS (restless leg syndrome) due to low dopamine
  (check iron levels) (Rx? Dopamine
  agonistsropinirole (Requip) or pramipexole
  (Mirapex) (p.s. dopamine and addiction)
• SSRIs inhibit platelet aggregationincreased risk
  for GI bleed
• SSRIs cause hyponatremiaincreased risk for
  delirium, confusion, and seizures in the elderly

102
A few more notes on antidepressants

• Give them at least 8 weeks to workWHY?
  Neurogenesis stay on them for 9-12 months after
  improvement in all activities of daily living
• Switching from one SSRI to another SSRI is an
  optionanother 25 can show benefit by a switch
  to another drug in the same class or another
  antidepressent in another class
• Augmentation strategiesadd buproprion
  (Wellbutrin) or buspirone (Buspar), Lithium,
  mirtazepine (Remeron)
• Add T3 thyroid hormone (Cytomel)
• Add aripiprazole (Abilify) or other
  anti-psychotics

103
The antibioticsthe fluoroquinolones, the
floxacins

• Ciprofloxacin (Cipro)(2) (? INR)
• Lomefloxacin (Maxaquin)(2)
• Norfloxacin (Noroxin)(2)
• Ofloxacin (Floxin)(2)
• uncomplicated UTI if resistance to TMP/SMX is
  20
• Levofloxacin (Levaquin) (3)too broad spectrum
  for UTI
• Gemifloxacin (Factive)(4)
• Moxifloxacin (Avelox)(4)effective against TB
• WARNINGS C. difficile after the quinolones
• Acute tendonitis in elderly and patients on
  corticosteroids

104
The antibioticsthe macrolides

• Erythromycindangerous with many other drugs due
  to prolongation of the QT interval low-dose
  increases bowel motility in patients with
  gastroparesis
• Azithromycin (Zithromax)Z-pack (dont take with
  food)
• Clarithromycin (Biaxcin)take with food!
• Clarithromycin and digoxin toxicity

105
Its a MAB, MAB, MAB (monoclonal antibodies)
worldimmune system

• Infliximab (Remicade)targeted against TNF-a, the
  culprit in Crohns disease, Ulcerative colitis,
  Rheumatoid Arthritis, psoriatic arthritis TB and
  Hepatitis B testing prior to use
• Adalimumab (Humira)as above
• certolizumab pegol (Cimzia)as above
• Golimumab (Simponi)as above
• Palivizumab (Synagis)RSV protection for
  developing lungs 34-week neonates have just 52
  of the calculated lung volume of full-term
  infants at birth)
• Omalizumab (Xolair)mab to IgE
• Belimumab (Benlysta)SLE (targets B cell
  activating factor)
• Tocilizumab (Actemra)

106
MABs for tumors

• Trastuzumab (Herceptin)HER2-neu Breast cancers
  when given in early stages, prognosis improves
  significantly
• Rituximab (Rituxan)targets CD 20 receptor on B
  lymphocytes used for Non Hodgkins Lymphoma
• Cetuximab (Erbitux)colon cancer (Martha Stewart)
• Alemtuzumab (Campath)
• more.

107
Its a MAB, MAB, MAB world

• Bevacizumab (Avastin)inhibits angiogenesis used
  to inhibit tumor growth used to decrease
  neovascular growth in the retina glioblastoma
  multiforme (with a tyrosine kinase inhibitor)
• Abciximab (Reopro)inhibits platelet aggregation

108
The tyrosine kinase inhibitorsthe nibs

• Tyrosine kinases act as growth-stimulating
  factors, and inhibiting them directly by
  inhibiting their signal is another way of zapping
  the growth of cancer cells
• Imatinib (Gleevec)(2001)CML (Philadephia
  chromosome t920)(complete cytogenetic
  remissions in 70)
• Gefitinib (Iressa)lung cancer (investigational
  for other cancers)
• Erlotinib (Tarceva)--NSCLC
• Crizotinib (Xalkori)NSCLC w/ specific gene
  mutation
• Dasatinib (Sprycel)CML
• Nilotinib (Tasigna)(2007)CML w/better results
  and for resistance to Gleevec)
• Vandetanib (Caprelsa) medullary thyroid cancer
• reduced cravings for alcohol (gene in fruit
  flies, called happyhour is reduced with erlotinib
  and gefitinib)

109
The tyrosine kinase inhibitorsthe nibs

• Sunitinib (Sutent)renal cell carcinoma
• Lapatinib (Tykerb)HER2/neu breast cancer if
  the breast cancer doesnt respond to trastuzumab
• Sorafenib (Nexavar)survival benefit in patients
  with hepatocellular carcinoma (Journal Watch
  Oncology/Hematology 23 Jul 2008) renal cell
  carcinoma
• Tofacitinib citrate (Xeljanz)moderate to severe
  RA that has not responded to methotrexate (test
  for TB before prescribing)
• Vemurafenib (Zelboraf)metastatic melanoma

110
5-HT3 (serotonin) receptors and N V

• 5-HT3 in the CTZ (chemoreceptor trigger zone of
  the brain stem) is responsible for vomiting from
  chemo and post-anesthesia
• 5-HT3 in the duodenum is responsible for nausea
  the organ of nausea

111
Serotonin antagonists for 5-HT3

• The setrons for chemotherapy, reduced risk of
  anticipatory nausea and vomiting,
  postanesthesia-induced, and migraine-induced
  nausea and vomiting, morning sickness, and oral
  rehydration in kids
• Granisetron (Kytril)
• Ondansetron (Zofran, and generic)also used for
  acute n and v
• Dolasetron (Anzemet)
• Tropisetron (Navoban) (add on to risperidone for
  chronic schizophrenia)(Noroozian )
• Palonesetron HCl (Aloxi)long acting

112
And last, but not least, an all in one pill for
the stress of being a wonderful nurse
113
THANK YOUand remember

• Never under any circumstances take a sleeping
  pill and a laxative on the same night.
• Barb Bancroft, RN, MSN, PNP
• www.barbbancroft.com
• BBancr9271_at_aol.com

114
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