Back-to-Basics

Practical Pharmacology

Marc Riachi, R.Ph.March 29, 2010

University of Ottawa

Topics to be covered in this lecture

Antibacterials Narcotic analgesics Antidepressants: MAOIs,

SSRIs, TCAs, NDRIs, SNRIs Agents used for anxiety and

sleep disorders Antidiabetics: alpha-

glucosidase inhibitors, biguanides, meglitinides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase inhibitors, insulins

Antilipemic agents: statins, cholesterol absorption inhibitors (ezetimibe), resins, fibrates, niacin, omega-3 fatty acids

ACEI’s, ARB’s, direct renin antagonists, Beta blockers, calcium channel blockers

Diuretics: loop, thiazide, and potassium-sparing

Agents used in heart failure Nitrates Antiasthmatics Agents for benign prostatic

hyperplasia Agents for Urinary

Incontinence Agents for Dementia Appendix I Appendix II

Which of the following is a macrolide antibiotic?

a. Clindamycin

b. Tobramycin

c. Vancomycin

d. Azithromycin

e. Gentamicin

Which of the following ABX most commonly causes skin photosensitivity manifested by an exaggerated sunburn reaction, commonly used to manage acne vulgaris and should not be taken with Al3+, Ca2+, Mg2+ or Fe2+ products?

a. Clindamycin

b. Minocycline

c. Penicillin

d. Ciprofloxacin

e. Metronidazole

Which of the following ABX is least likely to affect INR when a patient is on warfarin?

a. Amoxicillin

b. Levofloxacin

c. SMX+TMP

d. Erythromycin

Which of the following ABX most commonly affects drug metabolism at CYP3A4?

a. Cloxacillin

b. Cephalexin

c. Erythromycin

d. Clindamycin

e. Metronidazole

Which of the following groups is the least likely to prolong QTc interval?a. Macrolides

b. Penicillins

c. Fluoroquinolones

Antibacterial families and their members Penicillins: penicillin, cloxacillin, amoxicillin, ampicillin,

piperacillin, ticarcillin Cephalosporins: all the ABX starting with “Ceph-” or

“Cef-” Fluoroquinolones: cipro-, nor-, o-, levo-, and moxi-

floxacin Aminoglycosides: gentamicin, amikacin, tobramycin Macrolides: erythromycin, clarithromycin, azithromycin Tetracyclines: tetracycline, minocycline, doxycycline SMX/TMP Clindamycin, metronidazole vancomycin

Antibacterials-Site of action

Bactericidal vs. bacteriostatic

Bactericidal ABX Aminoglycosides Fluoroquinolones Penicillins Cephalosporins Nitrofurantoin Metronidazole SMX+TMP

Bacteriostatic ABX Tetracyclines Macrolides SMX TMP chloramphenicol Clindamycin

Bactericidal ABX are preferred when:• Host defences are poor• Infection involves heart, brain,

blood

Better not to combine with bacteriostatic ABX because bactericidals require bacterial cells to be actively growing/dividing.

Bacteriostatics give the immune system enough time to clear the offending organism. Therefore it is important to dose those ABX long enough. They also require a healthy immune system.

Pen V/GG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL G+,G-, B. fragilis, atypicals)

Cloxacillin AmpicillinAmoxicillin

Amoxicillin + ClavulanateAmpi + sulbactam

Piperacillin, ticarcillin

Piperacillin/tazobactamticarcillin/clavulanate

Add Enterococcus and “easy to kill” G- (non-BL’ase) coverage

Add MSSA, M. Catarrhalis, BL H. Flu

and B. fragilis

Add MSSA & BL resistance to “easy to kill” bacteria

Add MSSA coverage

Coverage for “hard to kill” G- & B.

Frag

Penicillins

Easy to kill G- bacteria: non-BL’ase H. Flu, P. mirabilis, salmonella, shigella, E. coli, Listeria monocytogenes

Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas, providencia

Pen V/GG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL G+,G-, B. fragilis, atypicals)

1st gen CephsEg: cephalexin,

cefadroxil

Develop agent Vs BL staph (MSSA) and “easy to kill” non-BL G-

2nd gen CephsEg: cefuroxime,

Cefaclor, cefprozil

Improve activity vs. H. Flu, Neisseria, M. Catarrhalis

3rd gen CephsEg: cefotaxime,

Ceftriaxone, cefixime

Add activity vs “hard to kill” G-, reduce staph coverage, retain strep coverage, loss of B. Frag coverage

3rd gen: Ceftazidime4th gen: Cefepime

Add activity vs pseudomonas

Cefoxitin

Add activity vs B. Fragilis, and “easy to kill” G-

None are effective against enterococcus, L. monocytogenes, MRSA. 3rd gen can cross BBB.

cefepime covers pseudomonas like ceftazidime and G+/hard to kill G- like cefotaxime and ceftriaxone

Cephalosporins

Pen V/GG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL G+,G-, B. fragilis, atypicals)

AminoglycosidesEg: gentamicin,

Amikacin,tobramycin

Develop agent Vs G- (including pseudomonas)

2nd genFluoroquinolonesEg: Ciprofloxacin,

ofloxacin

Add activity towards BL G+

3rd gen FQ’sEg: levofloxacin

Add atypical coverage and expand G+ coverage but lose good pseudomonal coverage

4th gen FQ’sEg: moxifloxacin

Add activity vs anarobes (B. fragilis)

Don’t cover strep well. Ofloxacin also does not cover pseudomonas

Fluoroquinolones & Aminoglycosides

Pen V/GG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL G+,G-, B. fragilis, atypicals)

Macrolides,Tetracyclines,

TMP/SMX

Develop agents Vs common G+, common G-, atypicals, unusual or non-bacterial organisms

TMP/SMX does not cover atypicals but it covers some MRSA strains

Macrolides,

Tetracyclines

TMP/SMX

Pen V/GG+ (strep), oral anarobes, T. Pallidum

(Lacks efficacy vs BL G+,G-, B. fragilis, atypicals)

Metronidazole

Develop agent Vs B. fragilis and other anaerobes

Clindamycin

Add activity vs BL staph aureus (MSSA)

Vancomycin

Develop agent vs Staph Epidermidis and MRSA

Note:

Use PO vancomycin or PO/IV metronidazole to treat C. difficile colitis

Vancomycin, metronidazole, clindamycin

Commonly prescribed ABX in the community setting Oral infections: penicillin, clindamycin, erythromycin, amoxicillin,

cephalexin UTI: ciprofloxacin, SMX/TMP, nitrofurantoin RTI’s. sinusitis: clarithromycin, azithromycin, 2nd or 3rd gen Cephs,

amoxi/clav and sometimes levo-/moxifloxacin Skin/nail/bites: cephalexin, cloxacillin, amoxi/clav Traveller’s diarrhea: azithromycin, ciprofloxacin, norfloxacin Bacterial vaginosis, trichomoniasis: metronidazole, clindamycin Chlamydia: single dose azithromycin, 7-day course doxycycline Gonorrhea: PO cefixime, ceftriaxone IM injection Acne: tetracyclines Acute otitis media: Macrolides, high dose amoxicillin, amoxi/clav,

2nd gen Cephs Patients with penicillin allergy: clindamycin or erythromycin (choice

depends on indication) Intraabdominal infections: ciprofloxacin+metronidazole, 3rd gen

Cephs C. difficile diarrhea: metronidazole

FQ’s are usually not used in prepubertal children or pregnancy due to fear of cartilage and tendon damage

Some clinicians have no problem using FQ’s (particularly ciprofloxacin) in prepubertal children particularly for : complicated UTI’s pyelonephritis typhoid fever G- meningitis Osteomyelitis

The concern with cartilage damage is slowly falling out of favor. Journal Watch Pediatrics and Adolescent Medicine August 12, 2002 says

“Fluoroquinolones in Children: Use Them, but Don't Abuse Them”. Journal Watch Emergency Medicine December 21, 2007 concluded

“arthropathy is usually reversible with drug withdrawal, and serious joint damage has not been reported; therefore, it is reasonable to prescribe a fluoroquinolone to a child (as is commonly done for cystic fibrosis) if other antibiotic options are unlikely to resolve the infectious process”

Based on experience and availability of safety data , cipro is probably the most trusted FQ for use in pediatrics

Fluoroquinolones in patients < 18 y

Antibiotics contraindicated in pregnancy (category X) Tetracyclines (also in children < 8 y.o.): are incorporated into fetal

skeleton/unerupted teeth and may cause reduced weight and malformations Fluoroquinolones (young dogs and neonatal mice given ciprofloxacin

developed arthropathy with permanent cartilage erosion in weight-bearing joints) no evidence that same results are observed in humans

Erythromycin estolate (may cause toxic liver reaction), clarithromycin TMP: in 1st trimester because it is a folate antagonist Sulfonamides: last trimester or if delivery is imminent because they

interfere with the bile conjugating mechanism of the neonate and may displace bilirubin bound to albumin which may lead to jaundice and kernicterus

Chloramphenicol (pregnancy at term or during labour): gray baby syndrome, ie, cyanosis and hypothermia, owing to the limited glucuronidating capacity of the newborn infant's liver

Nitrofurantoin (during labor and delivery only): can affect glutathione reductase activity and hence can cause hemolytic anemia (analogous to the problems it causes in patients with glucose-6-phosphate dehydrogenase deficiency) and hemolytic crises have been documented in newborns and fetuses

Aminoglycosides: nephrotoxic and ototoxic to the fetus High single dose metronidazole

Category B (no evidence of human fetal risk) ABX

Penicillins, including those in combination with ß-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam)

Cephalosporins Erythromycin base Azithromycin Clindamycin

ABX and warfarin

All antibiotics have the theoretical potential to increase INR

Penicillins, cephalosporins, azithromycin, aminoglycosides, clindamycin, nitrofurantoin and vancomycin are generally safe with warfarin and do not necessitate INR monitoring

Which of the following is least likely to be beneficial in treatment of opioid-induced constipation?

a. Bisacodyl (Dulcolax)

b. Senna (Senokot)

c. Docusate (Soflax)

d. Lactulose

Which of the following opioids is least suitable for chronic pain management?

a. Pentazocine (Talwin)

b. Fentanyl patches (Duragesic)

c. Morphine

d. Oxycodone

e. Codeine

Which of the following also inhibits reuptake of serotonin and norepinephrine

a. Tramadol

b. Morphine

c. Codeine

d. Oxycodone

e. Fentanyl

Narcotic analgesics These are the opioids (synthetic) or the opiates (naturally

occurring) Morphine is the prototype and the standard opiate Treatment of moderate to severe pain Neuropathic pain may respond to higher doses of opioids.

Standard treatment of this kind of pain is with antidepressants and anticonvulsants

All opioids have the same basic side effects: – Euphoria– Constipation– N&V– Somnolence– respiratory depression (especially important if patient is not

awake)– potential for addiction– Hypotension– skin itchiness– Seizures

Classes of opioids

codeine, hydromorphone, levorphanol, morphine, oxycodone, hydrocodone, and pentazocine

meperidine and fentanyl methadone and dextropropoxyphene If a person is allergic to codeine but he/she still requires

opioids for adequate pain control, consider an opioid from a different class such as:– meperidine– fentanyl (Warning: not for narcotic naive or narcotic

inexperienced patients)– methadone (not every physician is licensed to prescribe

it. Usually reserved for severe pain)– dextropropoxyphene

In all cases, monitor patient for possible cross-allergic reactions

General notes Considered to not have a “ceiling dose” (except for

pentazocine)

Have “ceiling dose” when combined with other analgesics (e.g., acetaminophen) in the same dosage form

“Contin” in the name of the medication means that the drug lasts 8 to 12 hours and therefore is dosed q8-12h

If the Contin wears off before the 8 to 12 hours have passed, the dose (NOT the dosing frequency) should be increased

Most patient should be able to tolerate very high doses if the dose is increased slowly– Note that fentanyl and hydromorphone are the opioids

of choice for use in renal or hepatic impairment. Use codeine, morphine, or oxycodone with caution in these patients

Most opioids are either contraindicated or not recommended for use with monoamine oxidase inhibitors (MAOIs)

Examples of prescription opioids Codeine:

– Available as a 5mg/mL syrup (NOT 5mg/5mL), codeine contin tablets, and in combination with other ingredients such as:

Tylenol #1 = 8 mg codeine + 15 mg caffeine + 300 mg acetaminophen (available to patients w/o a Rx)

Tylenol #2 = same ingredients as #1 but 15 mg codeine. Can be prescribed verbally.

Tylenol #3 = same ingredients as #1 but 30 mg codeine. Can be prescribed verbally.

Tylenol #4 = 300 mg acetaminophen + 60 mg codeine (NOTE there is no caffeine and therefore can’t be prescribed verbally)

Others include: Robaxacet-8, Robaxisal-C, Emtec, Mersyndol with codeine, Fiorinal-C, Dimetapp-C, CoActifed, Calmylin with codeine, Atasol-8, 222 tabs, 282 tabs, 292 tabs

– Converted to the active metabolite morphine by CYP2D6– Some Caucasian, Asians, and Arabs have poorly

functioning CYP2D6 while others may have more efficient CYP2D6

– CYP 2D6 inhibitors: bupropion, duloxetine, paroxetine, moclobemide, escitalopram, fluoxetine, citalopram, quinidine, terbinafine

– CYP2D6 inducers: rifampin, dexamethasone

Examples cont…

Morphine:– Statex: short acting– M-eslon, MS contin: long acting– The metabolite morphine-3-glucuronide may build up

in elderly and in those with renal insufficiency causing myoclonus and interfering with analgesia

Oxycodone: – Percocet, oxycocet, Endocet: short acting preparations containing 5

mg oxycodone + 325 mg acetaminophen– Percocet Demi: short acting preparation containing 2.5 mg oxycodone

+ 325 mg acetaminophen– Oxy-IR, Supeudol: short acting 5, 10, 20 mg oxycodone. Supeudol also

available as 10 and 20 mg suppositories– Oxycontin: long acting 5, 10, 20, 40, 80 mg oxycodone.– Trivia: Dr. House of the TV show “House MD” likes to take oxycodone

Hydromorphone:– Dilaudid: short acting– Hydromorph Contin: long acting

Examples cont… Fentanyl: many street names including “China White”, “Apache”, “Dance fever”

– Patch: worn continuously for 72 hours. In some patients for 48 hours. Available as:

12 ug/hr (actually is 12.5 ug/hr but is marketed as 12 ug/hr to avoid misreading the Rx as 125 ug/hr)

25 ug/hr 50 ug/hr 75 ug/hr 100 ug/hr

– Should not be prescribed to narcotic-naïve patients– Rate of drug reaching the circulation is directly proportional to body temperature

patients should treat fever and should avoid exposure to heating pads, sunbathing, hot showers, saunas, vigorous exercise, etc…

– Dose of patch is calculated from conversion tables– Patients with low fat tissue mass may need lower doses than those recommended by

conversion tables– May take up to 24 hours to attain adequate and stable

blood levels and pain control– Drug may still leech into circulation from fat depot even after patch is removed– Gel patch should not be cut– Patch should be flushed down the toilet upon removal– Fentanyl is metabolized by CYP3A4 and therefore should monitor

patients carefully if they receive CYP3A4 inhibitors (e.g., azole antifungals, erythromycin, clarithromycin, ritonavir) or inducers (rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort)

– If skin needs cleansing before applying the patch, it should be cleaned with water only (avoid soaps, oils, alcohol)

Examples cont… Methadone:

– Last resort for pain control– Dosed Q4-8H for pain control– Dosed QD for management of opioid dependence– Physician has to apply for and be granted permission to

prescribe methadone from the federal office of controlled substances

Having authority to prescribe methadone for pain ≠ authority to prescribe as part of methadone maintenance program (MMT) for opioid/heroin dependence and vice versa

– PO liquid used for treatment of opioid dependence as part of the MMT

– Produces less euphoria than heroin.– Patients start off by drinking methadone dose daily at the

pharmacy If urine tests show no use of illicit drugs, patient may be

allowed by prescriber to “carry” some doses home for convenience

– Pharmacist has the authority to deny patient his/her methadone dose if patient shows s/sx of intoxication

Examples cont… Hydrocodone: Tussionex, Hycodan, Ibucodon

Meperidine:– Brand name is Demerol– 10 times less potent than morphine with shorter duration of action– Should only be used for acute moderate to severe pain– Contraindicated for treatment of chronic pain– Risk of accumulation of toxic metabolite normeperidine which could lead to anxiety,

tremors, myoclonus, seizures with repeated doses– Limit its use to less than a day or two– Not useful for cough or diarrhea

Tramadol: Tramacet, Ralivia, Tridural, Zytram. Parent compound and its metabolite bind

to mu receptors AND inhibit reuptake of serotonin and NE. Contraindicated with MAOIs and may cause seizures if mixed with SRIs. Only partially antagonized by the opiate antagonist naloxone. Laws for prescribing narcotics do not apply to tramadol, ie, tramadol can be refilled for example.

Pentazocine: – Brand name = Talwin– Mixed agonist-antagonist at mu receptor and therefore has

“ceiling dose”– Exceeding maximum dose does not give added benefit– May cause withdrawal symptoms if given to patients

taking pure agonists such as morphine, etc…– Causes hallucinations, confusion and vivid dreams which renders it as an unacceptable

option in most patients– Absolute contraindication in chronic pain

Other uses of opioids Diarrhea

– Lomotil (diphenoxylate + atropine) Cough suppression

– Codeine At least 15 mg per dose required Syrup is 5 mg/mL NOT 5 mg/5 mL

– Hycodan or Tussionex (Hydrocodone)

Opioid dependence– PO Methadone: see next slides– Sublingual Suboxone (Buprenorphine + naloxone)

naloxone is an opioid antagonist but is not absorbed orally; purpose is to deter patient from injecting Suboxone

Notes on SR or “Contins”

Idea is to deliver drug “Contin”uously over a 12 or 8 hour period

Not for use in acute pain Not for use if short bowel, diarrhea, or renal failure Available for codeine, morphine, oxycodone, and

hydromorphone Codeine contin and MS Contin 200 mg tabs are the only ones

which could be split

Management of opioid side effects

Constipation– Tolerance does not develop with repeated doses of

opioid– Stimulant laxatives:

senna 8.6 mg tabs: 2 to 12 tabs bid or hs bisacodyl 5 mg tabs: 2 to 12 tabs bid or hs

– Cathartics such as 15 to 45 ml of milk of magnesia daily

– Osmotics such as 15 to 30 ml of lactulose qd to tid– Fiber will not help and in fact may compound the

problem and lead to impaction– Stool softeners such as docusate are generally not

helpful and may delay patient from getting proper laxative

Management of opioid side effects cont… Nausea & Vomiting

– Tolerance usually develops with repeated doses

– Seen mostly if the up-titration of dose is too rapid – Dimenhydrinate (Gravol) 25 to 50 mg q4-6h– Metoclopramide or domperidone 10 to 40

mg qid– Prochlorperazine 5 to 10 mg q4-6h– If N/V persistent, consider switching to

another opioid

Management of opioid side effects cont… Respiratory depression

– Seen mostly if the up-titration of dose is too rapid or in case of overdose

– Sudden, severe sedation often precedes respiratory depression

– Respiratory depression is due to decreased responsiveness of respiratory center in brain stem to increases of Pco2

– Death from opioid poisoning is usually due to respiratory arrest

– Serious respiratory depression is managed by naloxone injections

– From the LMCC exam objectives: "Contrast respiratory depression caused by opioids to

the respiratory rate of six to eight breaths per minute of the dying patient who is not receiving opioids (i.e., the respiratory depression is not caused by opioids but is actually a natural part of the dying process)."

Opioid prescriptions

The law prohibits adding refills for opioids– Eg: Oxycontin 20 mg q12h x60 tabs + 2 refills

pharmacist can only fill 60 tabs and the refills are ignored

Prescriptions can be written as part-fills– Eg: Oxycontin 20 mg q12h x180 tabs, dispense in

portions of 60 tabs every 30 days (indicating an interval is not mandatory but strongly recommended)

(Straight opioids) OR (opioids + one nonopioid in the same tablet) cannot be prescribed verbally; they can only be prescribed as written prescriptions and can be faxed to the pharmacy

Which of the following has the longest half-life?

a. Citalopram

b. Venlafaxine

c. Trazodone

d. Fluoxetine

e. Paroxetine

Which of the following antidepressants is particularly useful for management of insomnia?

a. Fluoxetine

b. Trazodone

c. Escitalopram

d. Bupropion

e. Venlafaxine

Which of the following combinations makes the most pharmacological sense?

a. Citalopram + venlafaxine

b. Bupropion + duloxetine

c. Escitalopram + bupropion

d. Nortriptyline + fluoxetine

e. Venlafaxine + duloxetine

Antidepressants

Classified as:– TCA’s: include amitriptyline, desipramine, imipramine,

nortriptyline– SSRI’s: citalopram, escitalopram, fluoxetine,

paroxetine, fluvoxamine, sertraline– NDRI’s: bupropion– SNRI’s: venlafaxine, duloxetine– Misc: trazodone, mirtazapine– MAOI’s:

Irreversible: phenelzine, tranylcypromine Reversible: moclobemide

TCA=tricyclic antidepressant

NDRI=NE and DA reuptake inhibitor

SNRI=serotonin and NE reuptake inhibitor

How to decide which agent to use? Factors to consider include:

– Differences in efficacy based on controlled studies– TCA’s in general are less well tolerated (anticholinergic

SE’s)– Try to avoid TCA’s and MAOI’s in elderly– Ingestion of 10 day supply of 200 mg TCA at once could be

lethal (avoid in patients at high risk of committing suicide)

– Use a sedating agent if patient also has insomnia (trazodone or mirtazapine)

– Moclobemide and bupropion have lowest rates of sexual dysfunction

– MAOI’s are usually reserved as last resort– With atypical features of depression (over-eating, weight

gain or over-sleeping), use fluoxetine, sertraline, moclobemide

– If patient has OCD, use SSRI’s or clomipramine– If hypertensive, avoid high dose venlafaxine or

duloxetine– If cardiac conduction abnormalities or dementia,

avoid TCA’s

Dosage

Start low and increase dosage slowly until optimal therapeutic dose is reached

Use lower doses in elderly and hepatic dysfunction

When do you see a response? Response could begin in the first 1-2 weeks

but would be optimal most probably after at least 3-4 weeks

If no response after 4 weeks, alter treatment in some way (raise dose, switch to another agent, combine two agents with different mechanisms of action)

Treat for a minimum of 9 months and may need to continue for at least 2 years

To avoid relapse D/C therapy gradually and not abruptly (venlafaxine is particularly difficult to D/C).

Switching between agents

With most agents, there is no need for a washout period

One option is to taper down one agent while tapering up its replacement

If switching from an IRReversible MAOI to another agent: 2 week washout of MAOI

If switching from a REversible MAOI to another agent: 3 day washout

If switching from one agent to an MAOI: washout the first agent for a period of 5 half-lives then start the MAOI (fluoxetine has a very long half life ~ 1 week)

Side Effects

TCA’s: anticholinergic, sedation (tolerance usually develops after 1-2 weeks), weight gain, orthostatic hypotension, dizziness, reflex tachycardia, prolong conduction time of electrical current in heart (avoid in heart block or MI), lower seizure threshold, sexual dysfunction

SSRI’s: diarrhea, N/V, insomnia, sedation (especially with fluvoxamine), headache, sexual dysfunction (especially with paroxetine)

Irreversible MAOI’s: constipation, anticholinergic, drowsiness (phenelzine), insomnia (tranylcypromine), orthostatic hypotension, hypertensive crisis (occipital headache, stiff neck, N/V, high BP) if combined with tyramine containing foods (aged cheese, cured meats, broad been pods, sauerkraut, soy, tap beer)

Reversible MAOI: dry mouth, N, sedation, headache, dizziness. NO FOOD RESTRICTION REQUIRED.

Side effects continued …

Venlafaxine (Effexor): – Doses < 150 mg: behaves like an SSRI

(N/V)– Doses > 150 mg: additional NE reuptake

inhibition which may lead to hypertension– Doses > 300 mg: additional DA reuptake

inhibition (it’s like adding bupropion to an SSRI)

– So, venlafaxine has the potential to inhibit the reuptake of serotonin + NE + DA

Side effects continued …

Trazodone (Desyrel): SEDATION, DRY mouth, orthostatic hypotension, priapism (1 in 6000 male patients)

Bupropion (Wellbutrin): stimulation (insomnia, agitation), headache, higher risk of seizures if daily dose > 450 mg or if >150 mg per single dose of the SR version– SR formulation is dosed BID (at least 8

hours between the two doses)– XL formulation is dosed QD

Mirtazapine (Remeron): SEDATION and WEIGHT GAIN

Duloxetine (Cymbalta):– Similar mechanism of action to venlafaxine, ie, it is

another SNRI– Also indicated for management of diabetic

peripheral neuropathy– Like venlafaxine, it may increase BP– May cause nausea, dry mouth, constipation,

fatigue, decreased appetite, somnolence or insomnia, increased sweating

– Twice the cost of venlafaxine (60 mg duloxetine vs. 225 mg venlafaxine) but not more effective

More SNRI’s

Final words

SSRI’s, bupropion, venlafaxine are usually used as first line agents

Fluoxetine’s half life is 1-3 days after acute administration and 4-6 days after chronic administration

With all AD’s watch out for suicide ideation or attempts especially in those < 18 y.o.

Paroxetine is sometimes used off-label as an agent to delay premature ejaculation

Medications for anxiety

Benzodiazepines:

for short term use/PRN

Rapid onset of action

Buspirone:

for long term use

Up to 3 weeks for response

Antidepressants:

For long term use

Up to 8 weeks for response

Benzodiazepines Long acting (less rebound when tapering off):

chlordiazepoxide, clonazepam, clorazepate, nitrazepam, diazepam, flurazepam.

Short-Intermediate acting: alprazolam, bromazepam, lorazepam, oxazepam, temazepam

Toxicity is due to decreased respiratory rate and decreased LOC often a problem when prescribed with opioids

Can also cause cognitive/memory impairment, confusion, hallucinations, sleep apnea

Ethanol enhances toxicity

Doses should be tapered down gradually if patient has been using them chronically

Benzos continued ...

Can cause physiologic dependence.

Levels increased by cimetidine, estrogen, erythromycin, fluoxetine

Levels decreased by carbamazepine, phenobarbital, rifampin, smoking.

Lorazepam, oxazepam and temazepam (LOT) do not accumulate due to shorter half-life and do not undergo hepatic microsomal oxidation and therefore are best options for elderly patients

Any BZ can cause falls

Avoid BZ in dementia

Medications for insomnia Benzodiazepines: generally are first line. Avoid triazolam

since it is associated with behavioural changes (cases of husbands killing their wives and blaming it on the drug)

Other BZ receptor agonists: zopiclone (like BZ’s, it can also be abused). Has short half life. Metallic taste.

Sedating antihistamines, aka, 1st generation antihistamines: diphenhydramine, dimenhydrinate, hydroxyzine, chlorpheniramine. Anticholinergic side effects are a problem.

Antidepressants: Trazodone, mirtazapine. Low doses are sufficient.

Chloral hydrate: hypnotic, sedative. Fatal with overdose. Almost never used now due to other safer agents.

Secobarbital, pentobarbital. Abuse potential.

Oral hypoglycemics-site of action

Which of the following is not associated with clinical hypoglycemia?

a. Glyburide

b. Repaglinide

c. Metformin

d. Insulin

Which of the following is associated with vitamin B12 deficiency?

a. Pioglitazone (Actos)

b. Metformin

c. Glyburide

d. Acarbose

e. Gliclizide

Insulin glargine and detemir are usually injected:

a. Once daily

b. Twice daily

c. Three times daily

d. With every meal

Oral antidiabetic agentsAgent MOA Dosage Avoid Side Effects Notes

Sulfonylureas:

glyburidegliclazideglimepiride

stimulate insulin secretion

-Once or twice daily-gliclazide extended release is QD

Severe hepatic /renal dysfxn

- hypoglycemia (esp glyburide) if elderly, poor meal schedules, worsening renal function- weight gain (esp glyburide)- nausea, anorexia

- take 30 min before a meal- Alcohol risk of hypoglycemia- β-blockers – mask hypoglycemia cardiac Sx’s

Biguanides:metformin

- Inhibits gluconeogenesis- insulin sensitivity

-Particularly suitable if overweight-500 mg qd up to 2250 mg daily in divided doses

- renal impaired (ClCR<60)- liver impaired- heart failure

- GI discomfort- weight loss (mild)- lactic acidosis (rare) **stop it before using iodinated contrast media**- B12 deficiency

- does not cause hypoglycemia- has lipid effect

-glucosidase Inhibitors:acarbose

delays CHO absorption from GI tract

50 mg qd up to 50-100 mg tid with first bit of each meal

- severe renal dysfunction/ liver cirrhosis- IBD

- GI discomfort- LFT’s – dose related (rare)

- does not cause hypoglycemia by itself - digoxin levels

Thiazolidinediones:PioglitazoneRosiglitazone

- PPAR-γ receptor agonist- insulin sensitivity

-Pioglitazone 15-45 mg qd-Rosiglitazone 2-8 mg qd

- caution in HF- Use with insulin may precipitate HF- Class 3,4 HF

- weight gain- edema- anemia- LDL but after 8 weeks- triglycerides

- 3 week onset, peak 8-12 weeks-with or w/o food-Should not cause hypoglycemia if used alone-Monitor LFT’s

Meglitinides:RepaglinideNateglinide

Stimulate insulin production like sulfonylureas

Repaglinide 0.5 to 4 mg tid ac Nateglinide 120-180 mg ac tid

-hepatic dysfunction

- weight gain- Hypoglycemia less than SU’s

-take immed. before meals. Skip dose if meal is missed.

Dipeptidyl peptidase-4 inhibitors (new class of antidiabetics) Incretins are hormones released from intestinal cells in

response to ingestion of food Glucagon like peptide 1 (GLP-1) and glucose-dependent

insulinotropic polypeptide (GIP) are examples of such incretins

Incretins increase insulin synthesis and release from pancreatic beta cells, decrease production of glucagon by pancreatic alpha cells, slow gastric emptying, and promote satiety

Type 2 diabetics have reduced post-prandial incretin levels Incretins have a short life span because they are broken

down by dipeptidyl peptidase-4 (DPP4) in circulation Sitagliptin prolongs the life of incretin hormones by inhibiting

the action of DPP4 and increases endogenous GLP-1 and GIP levels by 2 to 3 times

Mechanism of action of “gliptins”

Food ingestion

GLP1 and GIP from GI cells

Increased insulin and reduced glucagon secretion from pancreas

Inactive incretins

DPP4

Reduced hepatic glucose production and increased glucose uptake by adipose tissue and skeletal muscles

sitagliptin

Θ

Sitagliptin continued … Reduces HbA1C similarly to acarbose by about 0.5 to

0.8% on average (metformin, sulfonylureas, thiazolidinediones, meglitinides reduce HbA1C by 1 to 1.5%)

Adverse effects include URTIs and GI upset Since incretins stimulate insulin release in a glucose-

dependent manner, sitagliptin is not expected and does not cause significant hypoglycemia

Advantages: dosed once daily, no weight gain, low risk of hypoglycemia, does not appear to have significant drug-drug interactions

Disadvantages: post-marketing reports of serious hypersensitivity reactions, new class and therefore no known long term effects (good or bad), expensive, reduces HbA1C less than other established antidiabetics, requires functioning beta-cells capable of producing insulin

Insulins Rapid acting:

– Lispro & aspart: use immediately before meals Short acting:

– Regular insulin: inject up to 30 minutes before meals Intermediate acting

– NPH & Lente: inject bid Long acting:

– Ultralente, glargine (should never be mixed with any other insulin in same syringe), insulin detemir: inject qd

*** insulin is the drug of choice for use in gestational diabetes. Glyburide or metformin may also be used. ***

*** corticosteroids, atypical antipsychotics, thiazide diuretics, beta blockers, cyclosporine, and protease inhibitors, all may cause hyperglycemia ***

Relative duration of action of the various insulins

Which of the following statins reduces LDL and TG the most and increases HDL the most?

a. Atorvastatin (Lipitor)

b. Pravastatin (Pravachol)

c. Rosuvastatin (Crestor)

d. Simvastatin (Zocor)

e. Lovastatin (Mevacor)

How does ezetimibe (Ezetrol) reduce serum cholesterol?

a. Inhibits HMG CoA reductase

b. Reduces absorption of cholestrol from intestines leading to increased LDL clearance from circulation

c. Increases breakdown of serum cholesterol in the liver

d. Does not reduce serum cholesterol but reduces triglycerides

Which of the following may lower triglycerides but may raise LDL?

a. Nicotinic acid

b. EPA+DHA in fish oils

c. Fenofibrate

d. Ezetimibe

e. Bile acid sequesterants

Antilipemic agents

HMG Co A reductase inhibitors, aka, Statins: atorva-, fluva-, lova-, prava-, rosuva-, and simvastatin.

Cholesterol absorption inhibitors: ezetimibe

Bile acid sequesterants, aka, resins: cholestyramine & colestipol

Fibrates: gemfibrozil, beza- & fenofibrate

Niacin

Fish oils containing EPA and DHA

Cholesterol biosynthesis pathway

Statins They reduce cholesterol mainly due to upregulation of LDL

receptors S, A, and L are metabolized by CYP3A4 R is minimally metabolized by liver and is excreted by

kidneys and feces mostly unchanged R & S increase HDL the most A, R & S reduce TG the most A and R reduce LDL the most All are dosed up to 80 mg qd but R and P are up to 40 mg qd Statins prolong life and reduce cardiac morbidity in certain Statins are also used for secondary prevention of strokes SE’s: abdominal cramps, flatulence, LFT elevations, muscle

tenderness/stiffness/weakness/inflammation, CK elevation Avoid coadministration with fibrates if possible since the

combo increases risk of myositis and rhabdomyolysis

ezetimibe

Inhibits absorption of dietary and biliary cholesterol via an unknown transporter leading to increased LDL receptors on hepatocytes

Reduces LDL only Works synergistically with statins 10 mg qd SE’s: abdominal pain, diarrhea, fatigue,

increase in LFT’s (monitor LFT’s especially is combined with statins)

Resins

Bind anionic bile acids in GI tract and prevent their absorption, which stimulates liver to convert more cholesterol into bile acids which leads to more LDL receptors

Not absorbed systemically Reduce cholesterol only May RAISE TG’s Also used to clear leflunomide (an anti-rheumatic drug) from

body within 2 weeks. Otherwise, it takes years to clear leflunomide.

Cholestyramine 4-12 g bid and colestipol 5-15 g bid SE’s: CONSTIPATION, bloating, flatulence, dyspepsia, decreased

absorption of vitamins ADEK, warfarin, digoxin To avoid the possibility of reduced bioavailability, other

medications should be taken a few hours before or after the resin

Fibrates

Reduce VLDL and hence TG’s

MOA not completely understood

Patient should stop excessive alcohol consumption before treatment

Use with statins should be avoided if possible since the combo increases risk of rhabdomyolysis and myositis

Clofibrate predisposes to gallstones and is best used in those with a cholecystectomy. Not in common use anymore.

Niacin (nicotinic acid but NOT niacinamide)

Only nicotinic acid version has anti-lipemic activity

Lowers TG’s by up to 50% (same as fibrates)

Most effective agent in raising HDL (up to 35%)

MOA: reduces clearance of HDL, blocks mobilization of FFA’s from periphery to liver, and reduces synthesis of VLDL

0.5-2g daily in divided doses of SR or ER forms

0.5-4g daily in divided doses of IR form

Start at a low dose and increase slowly to prevent side effects

Niacin continued …

SE’s: N/V, diarrhea, hyperglycemia, hyperuricemia, flushing, hypotension, headache, hepatotoxicity, worsening of peptic ulcer disease

To reduce SE’s: take with food, avoid alcohol and hot beverages/food, take ASA 30 minutes before niacin dose

Available in 3 versions: immediate, extended and sustained release

IR is least hepatotoxic but causes most flushing. SR niacin was developed to reduce flushing but it turned out to be most hepatotoxic form of niacin. So, ER version (Niaspan) was developed to reduce flushing and hepatotoxicity.

Effect of niacin on lipoproteins

0 1 g/d 2 g/d 3 g/d

Baseline

-15%

12.5%

25%

-30%

HDL-C with Niaspan®

TG with Niaspan®

TG with crystalline niacin

LDL-C with Niaspan®

LDL-C with crystalline niacin

35%HDL-C with crystalline niacin

Fish oils

Used to reduce TG’s. TG’s may be lowered by as much as 50% in some cases

May raise LDL but studies have inconsistent results

Need 2 to 4 g of EPA+DHA daily to lower TG’s

MOA: may reduce hepatic VLDL synthesis and secretion and enhance TG clearance

SE’s: Nausea, fishy after taste, dyspepsia, raised LDL (up to 10% in some studies)

AB/CD of hypertension

A=ACEI and ARB (and Aliskiren?)

B=Beta blockers

C=Calcium channel blockers

D=diuretics

======================

A&B work better in young and Caucasians

C&D work better in elderly and African Americans

Renin-Angiotensin-Aldosterone system

ACEI’s and ARB’s (angiotensin receptor blockers) ACEI’s suppress the renin-angiotensin-aldosterone system by

inhibiting the conversion of Angiotensin I to Angiotensin II

Captopril is proto-type. Others include ramipril, lisinopril, enalapril, quinapril, trandolapril, and fosinopril. They all end with “-pril”

Renin (released by the kidneys) converts angiotensinogen to angiotensin I, which in turn is converted to angiotensin II by ACE (in the lungs primarily)

ATII is a potent vasoconstrictor and stimulates aldosterone secretion from adrenal cortex which in turn promotes sodium and fluid retention.

SE’s: angioedema, cough (absent with ARB’s; caused by increased bradykinin levels), hyperkalemia, increased serum creatinine, headaches (more with ARB’s)

ACEI’s and ARB’s continued … Benefits of ACEIs: reduce peripheral artery resistance,

increase CO, no change in heart rate, increase renal blood flow, GFR remains constant

Dosage: qd to bid (captopril is tid) To prevent hypotension when initiating ACEI therapy, stop

diuretics for 2-3 days first (if possible). After that, diuretic could be restarted.

Warn patients not to use potassium-based salt substitutes.

Stop ACEI if serum potassium goes above 5.5 umol/L. Check K+ and SCr in 1-2 weeks after starting the ACEI (particularly if combined with an ARB). If SCr increases by more than 30% from baseline value, then D/C the ACEI.

Contraindicated in pregnancy and bilateral renal artery stenosis in a patient with two kidneys or in unilateral renal artery stenosis in a patient with one kidney.

ACEI’s and ARB’s continued …

ACEI Θ

ΘARB

Θ

Direct Renin

Inhibitor

(aliskiren)

Θ

ACEI’s and ARB’s continued …

Lisinopril and captopril are the only ACEI’s which are not prodrugs

Enalaprilat is the only ACEI available for parenteral administration

All ACEI dosages need to be adjusted in renal dysfunction/failure except for fosinopril

ARB’s include candesartan, irbesartan, losartan, valsartan, telmisartan, eprosartan. They are contraindicated in pregnancy. May also cause angioedema.

Both ACEI’s and ARB’s are very useful in managing HF, hypertension, and proteinuria.

Direct renin antagonists (new class of antihypertensives) Rasilez or aliskiren is the first member of this class Blocks renin from converting angiotensinogen to angiotensin 1 ACEIs/ARBs increase plasma renin activity while aliskiren blunts it Once daily dosing Metabolized by CYP3A4 Currently indicated only for treatment of hypertension Currently can be combined with HCTZ, ACEIs, ARBs or DHPs Dose is 150 to 300 mg once daily Reduces blood levels of furosemide by 50% through unknown

mechanism Ketoconazole and atorvastatin increase aliskiren’s levels while

irbesartan decreases its levels Like ACEIs/ARBs, aliskiren may cause angioedema, hyperkalemia,

and is considered contraindicated in pregnancy Most common side effect is transient diarrhea

Beta receptors

Βeta-blockers All names end with “-lol” Cardioselective (B1-selective at low doses): metoprolol,

acebutolol, bisoprolol, esmolol (injectable only), betaxolol, atenolol. Could be safely tried at low doses in asthmatics who require beta blockade

Non-selective (B1 and B2 blockade): propranolol and nadolol. Also useful in treatment of esophageal varices due to their ability to block the B2 receptor in blood vessels.

Some have Intrinsic Sympathomimetic Activity (ISA) such as pindolol, acebutolol, and oxprenolol. This means that they are also partial agonists at the beta receptor

BB’s with ISA may have less negative effects on heart rate, blood lipids, and tiredness

The only BB officially regarded safe in pregnancy is labetalol (it is an alpha and beta blocker which is useful in treating hypertensive emergencies and hypertension due to a pheochromocytoma)

Carvedilol is also a beta and alpha blocker

Beta-blockers continued …

Esmolol has a short half life of about 10 minutes and is administered intravenously to treat intra- or post-operative hypertension, and to treat hypertensive emergencies.

Elderly have less functional beta receptors and so require smaller dosages compared to younger patients

BB’s typically reduce blood pressure by reducing vascular resistance, CO and renin production

Reduce angina symptoms at rest and during exercise (compare with digoxin which reduces heart rate only at rest)

Most BB’s are administered qd or bid and are used in management of hypertension, HF (“start low and go slow”), post-MI, atrial fibrillation, & thyrotoxicosis to mention a few.

They must not be stopped “cold turkey”. They must be tapered down slowly.

SE’s: bradycardia, tiredness, dizziness, mood disturbances (with the fat soluble agents such as metoprolol), may raise blood lipids, exacerbation of PAD, sexual dysfunction, worsening of asthma symptoms at high doses of B1 specific agents

Calcium Channels

Calcium channel blockers

Dihydropyridines: nifedipine and amlodipine act on arteries (including coronary arteries) to induce vascular relaxation. Therefore, they reduce afterload. All their names end with “-dipine”.

Non-DHP’s: diltiazem and verapamil act mostly on cardiac cells (verapamil more so than diltiazem) to depress contractility, AV conduction, and heart rate. They also relax coronary arteries.

MOA: block calcium channels from allowing entry of calcium into muscle cells which results in less contractility and vascular resistance

They do not act on veins. May cause swollen ankles and flushing (mostly DHP’s) and

constipation (especially verapamil). Swollen ankles may be resolved by using an ACEI or by lowering the dose of the CCB.

Use cardioselective CCB’s with caution or not at all in HF

CCB’s continued …

DHP’s cause sympathetic nervous system activation and reflex tachycardia and so they are best combined with BB’s.

Non-DHP’s depress heart rate and CO and must not be combined with BB’s if at all possible. They cause bradycardia, AV block, may precipitate HF, peripheral edema, constipation.

Indications: all 3 types of angina (stable, unstable and vasospastic or Prinzmetal’s), and hypertension.

Site of action of diuretics

Loop diuretics Most powerful of all diuretics E.g.: furosemide (sulfa moiety may NOT cause an allergic reaction in

patients allergic to sulfa antibiotics. Detailed sulfa allergy Hx required) 50% of furosemide oral dose is typically absorbed These agents have to be available inside the nephron tubule in order to

exert their action Their secretion into the tubule is reduced by NSAIDS and probenecid MOA: inhibit luminal Na+/K+/2Cl- transporter in the thick ascending limb

of Henle’s loop. This results in loss of Na+, K+, Mg++, and Cl-

Indications: pulmonary edema, other edematous conditions, acute renal failure

Side effects: hypokalemic metabolic alkalosis, dose-dependent hearing loss especially if patient is receiving the oto-toxic aminoglycosides, hyperuricemia

Use cautiously in heart failure Doses typically range from 10 to 200 mg daily given as qd or bid

Thiazide diuretics Eg.: hydrochlorothiazide (HCTZ), indapamide, chlorthalidone,

metolazone Indapamide and metolazone are more powerful than HCTZ and may

be as powerful as the loop diuretics Reduce NaCl reabsorption by inhibiting NaCl transporter mostly in

distal convoluted tubule Enhance Ca++ reabsorption which may unmask hypercalcemia due

to hyperparathyroidism, sarcoidosis, or carcinoma. They could be useful in the management of kidney stones caused by hypercalciuria.

HCTZ and chlorthalidone are not effective diuretics at GFR < 30 ml/min; loop diuretics or metolazone retain effectiveness GFR<30.

Compete with uric acid secretion which may translate into reduced clearance of urate leading to possible gout attacks

SE’s: erectile dysfunction, hypokalemia, hyponatremia, gout attacks, hyperglycemia and hyperlipidemia

Indications: hypertension and HF Dose of HCTZ for hypertension range from 12.5 to 25 mg qd

K+-sparing diuretics MOA

Spironolactone

ΘΘ

K+-sparing diuretics

Spironolactone and eplerenone: steroid competitive antagonists to aldosterone at the mineralocorticoid receptor

Triamterene and amiloride inhibit Na+ influx through ion channels in luminal membrane

Spironolactone requires several days for full therapeutic effect

All 3 drugs are very weak diuretics and are not used for purpose of diuresis; mostly used for K+-sparing properties

Indications: 1° or 2° mineralocorticoid excess (Conn’s syndrome, ectopic ACTH production, HF, hepatic cirrhosis, nephrotic syndrome), prevent or to treat hypokalemia caused by other diuretics

SE’s: hyperkalemia (especially if used with BB’s, NSAIDS, ACEI’s or ARB’s)

Spironolactone may cause gynecomastia, BPH, impotence and is dosed qd to qid

Agents for heart failure

ACEI: prolong survival. Slow down progression in all NYHA classes. Reduce Sx & hospitalization

BBs: should be used in clinically stable HF. Avoid if patient is symptomatic with dyspnea at rest or in decompensated HF. Prolong survival, decrease hospitalization and symptoms. Use carvedilol (alpha1, beta1 and beta2 blocker), metoprolol, bisoprolol

Diuretics: for patients with fluid retention. Loop diuretics are the preferred agents. Do not affect mortality.

+/- digoxin: useful if patient also has Afib. Improves QoL, Sx, functional capacity, exercise tolerance but not mortality. Used if Sx persist despite using BBs, ACEIs, and diuretics.

ARB: use if patient intolerant to ACEIs. May benefit some patients as add-on therapy to ACEIs.

Hydralazine/Isosorbide dinitrate: use only if patient is intolerant to ACEIs. Prolong survival and exercise tolerance but not as much as ACEIs. Not in common use.

Spironolactone: reduces mortality in NYHA class IV. May consider using in earlier NYHA classes.

Which agents to use Captopril 50 mg tid, enalapril 10 mg bid, lisinopril 10 mg qd,

ramipril 10 mg qd. Start at lowest doses possible and double doses every 7 days until target dose is reached

Start diuretics at 20 to 40 mg furosemide daily and increase dose daily until fluid retention resolves

Carvedilol 25 mg bid, bisoprolol 10 mg qd, metoprolol up to 200 mg daily. Start at lowest doses possible and double dose every 3 to 4 weeks until target doses are reached.

0.125 mg daily of digoxin or every other day if low body mass, CrCl < 50 ml/min or if > 70 y.o. Others 0.25 mg daily. Maintain digoxin blood levels at 0.5 to 0.8 ng/ml

ACEIs and BBs take 1 to 3 months to realize symptomatic improvement

Digoxin toxicity (N/V, diarrhea, headache, dizziness) and arrhythmias especially if patient experiences hypokalemia, hypomagnesimia, or hypercalcemia. Toxicity more commonly seen if digoxin blood levels > 2 ng/ml

Use BBs with caution in those with 2nd or 3rd degree heart block (if at all) and if HR < 50 bpm

Nitrates and nitroglycerin Indicated for treatment of acute angina attacks or prevention of exercise or

prinzmetal’s angina To treat an angina attack use: S/L nitroglycerin tablet or spray To prevent an attack use: S/L nitroglycerin tablet or spray, nitroglycerin patch, NTG

ointment, isosorbide dinitrate (ISDN) or isosorbide mononitrate. Nitrate patch can be cut but manufacturer does not recommend it. Patches range

from 0.2 to 0.8 mg/hour. NTG S/L tabs should not be taken out of their amber glass container unless they

will be stored in a stainless steel container. The NTG spray does not have to be applied under the tongue. Manufacturer

specifies that spray could be used over or under the tongue. To avoid nitrate tolerance, provide a nitrate-free period of 10 to 14 hours

daily To ensure 14 hour nitrate dose-free period, the recommended dosing frequency of

ISDN is 10 to 40 mg at 8 AM, 1 PM, and 6 PM. Alternatively it can be taken bid at 8 AM and 4PM. ISMN extended release preparation is dosed as 30 to 120 mg once daily.

Nitrates can cause headaches in as much as 50% of patients, flushing, dizziness, hypotension, reflex tachycardia (minimized if also using BB)

Other drugs used to prevent angina include BBs and CCBs (DHPs or non-DHPs). Verapamil is especially useful for Prinzmetal’s angina.

Nitrates are contraindicated for use with PDE5Is such as sildenafil, tadalafil, vardenafil due to risk of life-threatening hypotension

Asthma medications Symptom relievers: inhaled short/long acting B2 agonists

(SABA/LABA) & anticholinergics Symptom preventers: inhaled corticosteroids (ICS), PO

corticosteroids (0.5-1 mg/kg/day prednisone for exacerbations; can also use prednisolone or dexamethasone), Leukotriene receptor antagonists (LTRA), sodium cromoglycate & nedocromil (inhaled nonsteroidal agents)

For ICS to be effective, they would have to be used regularly and not PRN. To prevent oral candidiasis, use water to rinse mouth and spit after using the ICS. Ciclesonide is a prodrug activated in lungs and therefore is not supposed to cause oral thrush. ICS’s in large doses may worsen glaucoma, bone density, dermal thinning, growth suppression.

Ideal pharmacological therapy: ICS daily + SABA for exacerbations OR ICS daily + LABA bid ± SABA for exacerbations

Can also use ICS + LABA + anticholinergics + SABA Never use LABA’s without ICS

Escalation of pharmacological therapy for asthma

Targets for anti-inflammatory therapy in Asthma

Mast Cells

IL-5 Eosinophils

Leukotrienes

Cromolyn, nedocromil, ketotifen

Θ

corticosteroids

Θ

LTRA’s block LT receptors in airway

Θ

a) LTRA’s: montelukast & zafirlukast. Serve as alternatives or adjuncts to increased ICS or when ICS are not tolerated.

b) Use montelukast instead of zafirlukast since the latter is bid dosing, has to be on empty stomach, and interacts with other meds such as Eryc, ASA, and warfarin.

c) Mast cell stabilizers need a few weeks to work, have to be used regularly, excellent safety profile.

d) CS’s inhibit mast cells, MØ’s, T-cells, eosinophils, epithelial cells, as well as gene transcription of the cytokines/interleukins implicated in airway inflammation

Θ

Simple overview of steroid MOA

Asthma medications

ICS: beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide, ciclesonide. Use regularly. Not for rescue therapy. All are dosed bid except for ciclesonide (Alvesco) which is dosed qd in most cases.

PO CS: prednisone, prednisolone, dexamethasone. For exacerbations.

IV CS: hydrocortisone, methylprednisolone. For exacerbations.

SABA: salbutamol, terbutaline. Can be used up to 6 times daily in outpatient setting. For rescue therapy.

LABA: salmeterol, formoterol. Use qd to bid regularly. Not for rescue therapy (formoterol, however, could be used for rescue). Not for monotherapy; for use with ICS.

Anticholinergics: ipratropium (bid to qid), tiotropium (qd). Mostly reserved for COPD.

Asthma medications side effects

SABA/LABA: tachycardia, palpitations, nervousness, tremor, hypokalemia (at high doses)

Anticholinergics: dry mouth, urinary retention, increased IOP, pharyngeal irritation, cough.

ICS: oropharyngeal candidiasis, adrenal Insufficiency, skin thinning/bruising, cataracts, glaucoma, osteoporosis.

Benign prostatic hyperplasia

BPH symptoms are due to increased size of prostate gland and due to increased smooth muscle tone

5-alpha reductase inhibitors reduce size by inhibiting conversion of testosterone to dehydrotestosterone (DHT)

Alpha blockers reduce smooth muscle tone by antagonizing binding of norepinephrine and epinephrine to alpha-1 receptors

Medications Testosterone, OTC decongestants

(pseudoephedrine, phenylephrine), and anticholinergic drugs worsen symptoms

5-ARI’s: finasteride and dutasteride. Delayed benefit. Teratogens. Decrease PSA.

Alpha blockers: avoid if arrhythmia, angina

2nd generation: terazosin, prazosin, doxazosin. Titrate up due to hypotension and dizziness

3rd generation: tamsulosin, alfuzosin. Latter causes less sexual dysfxn.

Urinary incontinence

Normal physiology:

Acetylcholine causes contraction in bladder detrusor muscle

Norepinephrine and epinephrine cause contraction in sphincter muscle by binding to alpha receptors

Stress UI: decreased sphincter resistance. UI occurs with increased abdominal pressure. Tx is with alpha agonists. Alpha antagonists would worsen. PV estrogen therapy is helpful.

Urge UI, aka, overactive bladder: bladder detrusor muscle is overactive. Tx is with anticholinergics. Oxybutynin, tolterodine. Problem is anticholinergic side effects.

Overflow UI: Rare. Sphincter muscle overactivity and/or bladder underactivity. Alpha agonists would worsen. Anticholinergics would worsen.

Mixed UI: Urge UI and Stress UI

Functional UI: access to or getting to toilet is restricted

Urinary incontinence

Cholinergic hypothesis: Ach is one of the main neurotrnsmitters in the brain that serves to increase attention and facilitate learning

Antipsychotics are associated with increased mortality

Pharmacological treatment: No effective agents are available

Acetylcholinesterase esterase inhibitors (AChEI): all should be titrated upwards slowly. May decrease heart rate

Donepezil (metabolized by CYP450; causes insomnia; dose in AM), galantamine (metabolized by CYP450), rivastigmine

NMDA antagonists: NMDA stimulates glutamate which is implicated in neuronal damage and dementia

Memantine. May be combined with AChEI’s

Dementia

Appendix I: supplemental and more in depth information regarding antibacterial agents …

Antibacterial agents-MOA Beta-lactams: bind to PBP and inhibit formation of the bacterial cell wall by inhibiting

peptidoglycan synthesis Vancomycin: inhibits bacterial cell wall synthesis at a site different than beta-lactams FQ’s: inhibit DNA gyrase in G- bacteria, and inhibit topoisomerase IV in G+ bacteria Macrolides: inhibit protein synthesis by reversibly binding to the 50S ribosomal subunit Clindamycin: inhibits protein synthesis by binding to the 50S ribosomal subunit (close to

where macrolides bind. Note similarity in the name of clindamycin and the macrolides) Aminoglycosides: inhibit protein synthesis by irreversibly binding to the 30S ribosomal

subunit Tetracyclines: interfere with protein synthesis by inhibiting codon-anticodon interaction

on ribosomes Chloramphenicol: attaches to ribosomes and inhibits the formation of peptide bonds

between amino acids Metronidazole: is a prodrug which needs activation in the bacterial cell via a reductive

process carried out by anarobic bacterial ferredoxins. The donated electrons form reactive nitro anions which in turn damage bacterial DNA.

TMP/SMX: inhibit the formation of tetrahydrofolic acid. SMX is a structural analogue of PABA and inhibits the synthesis of dihydrofolate. TMP is a structural analogue of the pteridine portion of dihydrofolate and acts as a competitive inhibitor of dihydrofolate reductase. The combo blocks two consecutive steps in the synthesis of THF which is needed to synthesize nucleic acids.

Antibacterial agents-Penicillins β -lactams:

– Penicillins (1) Pen VK & Pen G: mostly for non β-lactamase producing G+ and oral anaerobes. Pen V

is PO while Pen G is by injection only. Commonly used for strep throat and mouth infections. Agents of choice for syphilis even if patient is allergic to penicillins (need to desensitize patient first!). Give Pen VK on empty stomach.

(2) Methicillin & cloxacillin: for what (1) covers + BL’ase producing staphylococcus (MSSA). Commonly prescribed for skin infections. Oral and parenteral. Give on empty stomach. No dosage adjustment in renal dysfunction. Think of them as anti-staph.

(3) Ampicillin & amoxicillin: for what (1) covers + non BL’ase producing “easy to kill” G- bacteria & for ENTEROCOCCUS. Ampi is PO/IM/IV and causes diarrhea while Amoxi is only PO.

(4) Amoxicillin+clavulanate & ampicillin+sulbactam: for what (3) covers + (2) + easy to kill BL’ase producing G- bacteria + B. Fragilis + E. coli. Amoxi/clav frequently causes diarrhea.

(5) Piperacillin & ticarcillin: for what (4) covers + Pseudomonas + non-BL’ase “hard to kill” G- (often used in combo with aminoglycosides). Given parenterally only. Adjust dose in renal impairement. Think of them as mainly anti-pseudomonal.

(6) Piperacillin+tazobactam & ticarcillin+clavulanate: for what (5) covers + MSSA Pen G, ticarcillin, and piperacillin contain sodium which should be taken into account

when injecting them into patients with HF or renal insufficiency

Easy to kill G- bacteria: non-BL’ase H. Flu, P. mirabilis, salmonella, shigella (L. monocytogenes is not a G- bacteria as was indicated here previously)

Hard to kill G- bacteria: klebsiella, enterobacter, citrobacter, serratia, morganella, pseudomonas

Antibacterial agents-Cephalosporins

Β-lactams continued …– Cephalosporins: divided into 1st, 2nd, and 3rd generations. 1st generation has mostly

G+ coverage while 3rd has mostly G- coverage. Non are effective for enterococcus, MRSA, L. monocytogenes. Cross allerginicity with penicillins is up to 10% (less with higher generations).

(7) 1st gen: cephalexin, cefazolin, cefadroxil. Used for (1) + (2) + E. coli, klebsiella. Do not cross BBB. Cefazolin is parenteral only. Cephalexin is PO only

(8) 2nd gen: cefuroxime (parenteral only), cefaclor, cefuroxime axetil, (PO version of cefuroxime), cefprozil. For (7) + H. flu + Neisseria + M. catarrhalis. Give cefuroxime axetil with food while cefaclor on empty stomach

(9) 3rd gen: ceftazidime, ceftriaxone, cefotaxime, cefixime (the only PO drug), ceftizoxime. Retain activity versus strep species but have reduced activity vs. staph species. For (8) + “hard to kill” G- bacteria + pseudomonas (only ceftazidime). Avoid ceftriaxone in neonates. All parenteral agents cross the BBB and so helpful in treating meningitis

(10) 4th gen: cefepime. Active vs pseudomonas. Used to treat UTI’s, skin infections, pneumonia. Not advantageous over 3rd generation agents such as ceftazidime.

– Carbapenems: imipenem and meropenem. Available parenterally only. Imipenem may cause seizures and N/V. These are less common with meropenem. They cover “everything” including C. difficile. BL ring is resistant to the BL’ases. Imipenem is renally metabolized to the stable open-lactam metabolite by a dipeptidase, dehydropeptidase I, located at the lumenal surface of the proximal tubular cells. To prevent this, imipenem is combined with cilastin.

Antibacterial agents-fluoroquinolones

Fluoroquinolones: – may cause nausea, diarrhea, photosensitivity, dizziness, agitation, cartilage

damage (based on studies of beagle puppies), glucose dysregulation (newer generation)

– Newer generation agents are almost 100% absorbed PO– Cipro is about 80% absorbed– Polyvalent cations (Ca, Fe, Al, Mg, Zn, antacids) prevent absorption of FQ’s which

requires these drugs to be spaced by a few hours– Divided into 3 generations:

1st gen: Nalidixic acid (not used anymore) 2nd gen: nor-, o-, and ciprofloxacin 3rd gen: levo-, gati-, and moxifloxacin. Gatifloxacin was discontinued Summer

2006. this generation of drugs is commonly referred to as the “respiratory quinolones”

– 2nd gen agents cover G- bacteria mainly.– Cipro is the only FQ with reliable activity against pseudomonas. It could also be

used against MSSA. Cipro does not cover strep species well. – Norfloxacin is pretty much only used to treat uncomplicated UTI’s– 3rd gen agents were designed to cover more G+ bacteria than 2nd gen. They are

very broad spectrum (including B. fragilis and atypical microorganisms) but do not cover pseudomonas reliably.

– FQ’s are currently not recommended to be given to pregnant women or to patients under 18 y.o.

Antibacterial agents-aminoglycosides

Only available for parenteral administration (tobramycin is available for inhalation to treat chronic pseudomonas infections in cystic fibrosis patients; brand name is called TOBI)

Gentamicin, amikacin, tobramycin All have very narrow therapeutic window (must monitor levels

and SCr) Toxicity: reversible nephrotoxicity (less with qd dosing),

irreversible ototoxicity, rare but potentially fatal neuromuscular blockade (interfere with ACh release and binding leading to weakness of respiratory muscles which can be reversed by administering calcium gluconate)

Since all are renally cleared, dose must be adjusted in renal impairment

Active against G- bacteria including pseudomonas Frequently used with other ABX (especially anti-pseudomonal

penicillins)

Antibacterial agents-macrolides

Erythromycin (E), clarithromycin (C), azithromycin (A) E and C inhibit CYP450 enzymes while A does not. All are hepatically

metabolized and cleared. Non are removed during hemodialysis. E and C stimulate GI motility causing diarrhea, cramps, and nausea All are PO but E and A are also parenteral All are poorly absorbed. E should be taken on an empty stomach but because

it causes GI side effects, it is recommended to be taken with food All may cause QT prolongation They cover common G+ (including MSSA), common G- bacteria (A>C>E),

mycoplasma, chlamydia, legionella, treponema pallidum. They are very helpful for respiratory tract infections. E is an important antibiotic to use in those allergic to penicillin.

A and C are active against mycobacterium avium-intracellulaire (MAC) E is dosed qid, C is dosed bid or qd, A is dosed qd A is not officially labeled as safe in pregnancy but it is often used in

pregnancy without reported adverse effects

Antibacterial agents-tetracyclines Minocycline, doxycycline, tetracycline All cause photosensitivities. Because they are often used in young

people to treat their acne, these patients should be warned against sun tanning

Because they depress bone growth and cause permanent grey-brown discoloration of teeth, they should not be given to children < 8 y.o.

Esophageal ulceration has been reported with doxycycline (should be taken with lots of fluids)

Minocycline has been reported to cause dizziness, ataxia, and vertigo All should be administered on an empty stomach and patients should

avoid concomitant ingestion of metal cations found in milk, multivitamins, antacids

Doxy and minocycline are dosed bid. Tetracycline is dosed bid to qid Active against many respiratory pathogens, strep pneumo, H. flu,

mycoplasma, chlamydia, legionella, moraxella catarrhalis

Antibacterial agents-metronidazole & clindamycin Clindamycin causes diarrhea (sometimes due to C.

difficile) Clindamycin is active against G+ bacteria (BL’ase

producing staph, strep) and anarobes (B. fragilis and C. perfringens)

Metronidazole causes a disulfiram-like reaction when taken with alcohol (N/V, abdominal cramps, hypotension, headache), metallic taste, stool and/or urine discoloration, peripheral neuropathy, seizures

Active against anarobes (B. fragilis, C. difficile). Agent used to combat C. difficile infection caused by clindamycin. Also active against trichomonas, giardia lamblia, and entamoba histolytica.

Antibacterial agents-TMP/SMX

Can cause skin reactions (rashes, Stevens-Johnson syndrome), N/V, diarrhea, hepatic necrosis, hemolytic anemia in those with G6PD deficiency, bone marrow depression

Advise patient to drink lots of fluids to prevent crystallization in kidneys Active against G+ (including MRSA!!), and G- bacteria (salmonella,

shigella, H. flu)

Antibacterial agents-vancomycin

Available for parenteral administration only Rapid infusion causes flushing of face, neck and upper thorax,

pruritis and hypotension (similar to side effects of nicotinic acid). This is known as the “red man” syndrome and is not an allergic reaction

High serum levels (> 80 ug/ml) may cause ototoxicity leading to deafness

May potentiate aminoglycoside nephrotoxicity Given PO to treat C. difficile pseudomembranous colitis or staph

enterocolitis Adjust dosage in renal dysfunction (trough levels should be 5-10

ug/ml) Not removed by dialysis Active against G+ bacteria mainly staph (MSSA, MRSA, and staph

epidermidis), strep, C. difficile

Appendix II: Guidelines on opioid dosing Opioid naïve patient:

– 10 to 20 mg morphine q4h– 1/3 to ½ dose for breakthrough pain q1h– Eg: 10 mg morphine q4h, 5 mg q1h prn– Elderly should get half the doses

Previously on opioids or poorly controlled:– Increase dose by 25 to 50% q4h– Eg: 10 mg * 1.5 = 15 mg q4h, 7.5 mg q1h prn

Converting from injection to oral:– Divide total 24-hour dose by 3 and dose q4h– Eg: morphine 30 mg SC q4h

Total daily injected dose = 30 * 6 = 180 mg The q4h dose = 180/3 = 60 mg The q1h dose for BT pain = 60/2 = 30 mg

Reassess pain control every 24 hours and make adjustments until patient is stable When you find the stable dose as outlined above, the patient could be switched from IR

to “Contin” or SR preparation for convenience:– Divide total daily dose of the IR by 2 for q12h dosing– Divide total daily dose of the IR by 3 for q8h dosing– Give 1/5 of the q12h dose for BT pain q4h– Eg: patient is stable on 120 mg/day of IR preparation. The q12h dose of MS Contin

would be 120/2 = 60 mg PLUS 10 mg of the IR q4h prn

Safe prescribing of opioids Before prescribing opioids, consider using:

– Non-pharmacological pain therapy– Non-opioid analgesics such as NSAIDs, acetaminophen and antidepressants or antiepileptics for

neuropathic pain If patient requires opioids:

– Prescribe small amounts– Tell patient what you expect from him/her– Be alert for scripts not lasting expected duration or if pharmacist contacts you for an early fill of a

part-fill– Be alert when patient reports stolen pills or lost scripts (you can ask patient for a police report)– Use prescription pads with security features– Spell out the amount of pills to dispense when writing a Rx because patients could alter digits more

easily than written words. Eg: 60 (Sixty) tablets instead of 60 tablets– Be alert for evidence of drug injections– Be alert for requests of other opioids by patient– Patient has to inform prescriber by law that he/she received a prescription for an opioid from

another prescriber within the last month: most patients do not know this and therefore may require reminding

– Be alert if patient is young and without identifiable pathology or if psychologically unstable– Try not to be pressured by patient to prescribe an opioid you do not agree with– Include intervals on part-fills to limit how often a patient fills the Rx– Consult with the pharmacist and ask if he/she can provide a good reference for the patient or if

he/she can vouch for the patient– Pharmacists are required by their licensing body to verify the legitimacy of questionable

prescriptions with the prescriber; most diverters will attempt to prevent the pharmacist from doing that and may voice their “concern” to you during the next visit

– Inform patient of his/her own responsibilities when entrusted with drugs that have a huge potential street value