back-to-basics practical pharmacology marc riachi, r.ph. march 29, 2010 university of ottawa
TRANSCRIPT
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