Exam 5 Flashcards
How much Morphine is metabolized on the “first pass” through the liver?
75% It is much less potent when taken orally than when given IV/IM.
How soon after injection does Morphine exert its maximum effect? How long does a dose typically last?
Max effect = 1 hour Lasts 4-6 hours, longer in the elderly sometimes.
Half-life of Morphine
2-3 hours
What is Morphine metabolized to?
Conjugated to Glucuronide (in liver)
Excreted mostly in urine, some in feces.
Effects of Morphine on fetus?
Crosses placenta. Respiratory depression and possible drug dependence with chronic use.
What can opioids + MAO inhibiters cause? Which opioid in particular?
Hyperpyrexia (high fever) Meperidine (but can occur with all opioids)
What is a “Speedball”?
Opioid + Amphetamines or Cocaine
What are 3 types of drugs sometimes used in combination with opioids to enhance analgesic effect?
Aspirin/tylenol Antihistamines (hydroxyzine) Tricyclic antidepressants
Triad seen with Opioid poisoning
CNS depression (coma/stupor)
Respiratory depression
Miosis (pinpoint pupils)
Miosis can become mydriasis if the patient becomes severely hypoxic and is close to death
Treatments for Opioid toxicity
Supportive respiration
Naloxone
Aside from pain management, what are 4 other common uses for opioids?
Antitussives (codeine)
Antidiarrheals
Dyspnea associated with left heart failure/pulmonary edema (makes them feel better)
Abuse
Standard dose of Morphine
10 mg IV/IM, 10-30 orally
Morphine
Opioid used for severe pain Can be given IV/IM/SC or orally.
Used in many types of spinal anesthesia
3 new developments in Morphine usage
Infusion/autoinjector systems
PCA (patient controlled analgesia)
Spinal anesthesia
Codeine
Opioid used for mild-moderate pain and as an antitussive.
Much less potent opioid than morphine.
Taken orally 30-60 mg.
Sensitivity can vary considerably due to genetic differences.
Ultrarapid metabolizers can convert codeine to morphine much faster than most people, causing opioid intoxication.
Hydromorphone
Like Morphine, but more potent. Dilaudid
Oxycodone
Like morphine, but taken orally.
Often used in combo with tylenol
Usually used for mild-moderate pain.
Sustained release preparation used for severe chronic pain.
Hydrocodone
Similar to morphine/codeine.
Used orally to treat mild-moderate pain.
Antitussive.
Used to be schedule 3, now it’s schedule 2.
Zohydro ER is extended release prep that does not contain tylenol.
Meperidine
Weaker opioid compared to morphine. Taken orally or IV.
May have less of an effect on smooth muscle (less constipation/ urine retention).
Used for moderate-severe pain.
May cause less respiratory depression in newborn (used in OB)
Short acting, and chronic usage creates buildup of toxic metabolites that may cause seizures.
Heroin
More potent/euphoria inducing than Morphine. Schedule 1 in USA. Smoked/snorted/injected.
Methadone
Like morphine/heroin but less euphoric and longer acting (12-24 hours). Used to treat opioid addiction and pain.
Dosing is tricky and patient needs to be monitored.
It has a shorter duration when used as an analgesic (4-6 hours) than when used chronically to treat opioid dependence (12-24 hours).
Can only be dispensed for opioid dependence from licensed clinics.
Good analgesic for severe pain, but there is a stigma associated with it.
Fentanyl
Very potent mu agonist (100x morphine).
Used IV during anesthesia.
Also used as a transdermal patch for chronic pain management.
Fentanyl + droperidol
Induces neuroleptic analgesia.
Used for endoscopy/minor surgical procedures where the patient may not completely lose consciousness.
Opioid Combination Preparations
Opioid + aspirin or tylenol or ibuprofen.
If too much is taken, patient is at risk for toxicity of aspirin/tylenol/ibuprofen.
Pentazocine
Mixed opioid agonist/antagonist
Kappa agonist.
Partial mu agonist at low doses, antagonist at high doses.
Not as effective as morphine for severe pain, but causes less sedation/respiratory depression.
Causes more CNS stimulation/hallucinations than morphine.
Less potential for dependence, but it’s still possible.
Can cause withdrawal syndrome in opioid addicts.
Buprenorphine
Partial mu agonist, maybe kappa too.
Less analgesic than morphine, but less abuse potential.
Used to reduce heroin cravings.
Can be given in combo with naloxone.
Primary agent for “office based” treatment of opioid addiction (since only special clinics can prescribe methadone).
Tramadol
Weak mu agonist.
Used to treat mild-moderate pain.
Also inhibits reuptake of serotonin and norepinephrine.
Supposedly is a good analgesic with low abuse potential, but we don’t really know how true that claim is.
Tapentadol
Like Tramadol but stronger agonist at mu receptors.
Also inhibits NE/5-HT reuptake.
May have special benefits for neuropathic pain.
More analgesia than Tramadol, but more likely to be abused.
Schedule 2, where as Tramadol is schedule 4.
Naloxone
Opioid antagonist used to treat toxicity.
Must be given parenterally.
Short duration (1-2 hours).
Can cause withdrawal symptoms.
Naltrexone
Longer acting opioid antagonist than naloxone (24 hours)
Used to prevent the high produced by opioids.
Risk of hepatotoxicity.
Addict must be detoxed before starting this drug.
Also used for alcohol dependence.
Methylnaltrexone
Quaternary analog of naltrexone.
Doesnt enter CNS
Used to treat opioid induced constipation.
Must be given parenterally, usually SC.
Only appropriate for serious opioid induced constipation.
Naloxegol
Treats opioid induced constipation.
Naloxone conjugated to a polyethylene glycol molecule
Taken orally, can be used in out-patients.
Few systemic effects.
Contrast acute withdrawal from short acting drugs vs from long acting drugs
short acting drugs (heroin)- intense symptoms, short duration (2-3 days).
long acting drugs (methadone)- moderate symptoms, long duration (4-7 days).
After acute withdrawal, prolonged withdrawal can last weeks-months.
3 Salicylic Acid Derivatives
Acetyl Salicylic Acid (Aspirin)
Mesalamine (5-amino salicylic acid)
Diflunisal
They all have SAL in their names
5 Acetic Acid Derivatives
Indomethacin
Etodolac
Diclofenac
Tolmetin
Ketorolac
DIET K
They dont have SAL or PRO in their names.
4 Propionic Acid Derivatives
Ibuprofen
Naproxen
Ketoprofen
Oxaprozin
All have PRO in their name
NIKO
2 Enolic Acid Derivatives
Piroxicam
Meloxicam
1 Nonacidic NSAID Compound
Nabumetone
1 Para aminophenol Derivative
Acetaminophen
1 COX-2 Inhibitor
Celecoxib
Aspirin Chemical Properties
Hydrolyzed to salicylate and acetate in vivo
pKa = 3.5
Aspirin Mechanism
IRREVERSIBLY inhibits COX1 and COX2 by acetylation
Leads to decrease in prostaglandin synthesis, leading to a decrease in inflammation.
Hematologic Affects of Aspirin
May prolong bleeding time
Irreversible COX1 inhibition on platelets result in lack of Thromboxane A2, inhibiting platelet aggregation
Effect lasts lifetime of platelet (4-7 days)
Can cause decrease in serum Fe and hematocrit (reduction in RBC life span)
Stop treatment 7 days before surgery to prevent bleeding
Contraindicated in people with bleeding disease (VWF deficiency)
Aspirin Pharmacokinetics
Rapidly absorbed in the GI tract Acidity of stomach aids in absorption (pKa), but the aspirin must dissolve first, which happens faster at higher pH
Less acidic small intestine favors dissolution, which is the rate limiting step
Absorption is still good in the small intestine (despite higher pH) because the large surface area (villi) make up for higher pH
Can go all over the body (highly albumin bound)
Crosses BBB and placental barrier
Conjugated in the liver to glycine or glucuronate
Excreted in kidney (ALKALIZATION OF THE URINE GREATLY INCREASES ITS EXCRETION RATE)
Aspirin Adverse GI Effects
Many GI disturbances, more common with aspirin than other salicylates
People with preexisting peptic ulcer diseases are especially vulnerable
Take them after meals or with lots of milk to help avoid these problems
Know how they cause gastric damage…
Can lead to occult bleeding, anemia.
Alcohol has a synergistic effect, making these problems worse
Misoprostol is a PG analog you can use to help combat the damage on the mucosa.
Misoprostol
PG analog used to prevent ulcers on patients on long term NSAID use Decreases stomach acid secretion
Aspirin Otic Effects
Can cause tinnitus and hearing loss
It is usually reversible Tinnitus occurs at >200 micrograms/mL
You need this concentration for really good anti-inflammatory affect, so it can be a sign that adequate plasma concentration has been reached
Aspirin Renal/Hepatic/Cardiac Effects
Potential hepatotoxicity, monitor liver function in patients on chronic or high dose aspirin.
This happens after 1-4 weeks of therapy
Can cause renal tubular necrosis, which is probably caused by ischemia due to decreased renal PG synthesis.
Can cause noncardiogenic pulmonary edema at about 400 micrograms/mL
Aspirin Triad
Aspirin sensitivity, asthma, and nasal polyps
Aspirin can cause bronchospasm in patients with asthma and nasal polyps
Other people can be allergic to aspirin too (urticaria and angioedema, IgE)
Aspirin Pediatric Cautions
Dont give it to a kid or teenager with a viral illness like chicken pox or the flu, they may get Reye’s Syndrome (Vomiting, headaches, coma, death)
You may use acetaminophen instead
Aspirin Pregnancy Cautions
It may be associated with negative outcomes for the fetus.
Large doses may cause hemorrhagic complications in mom/fetus
Especially avoid use during 3rd trimester
Use only if benefits outweigh risks.
Can be transferred in breast milk and cause platelet problems in baby, so use with caution in nursing mothers too (same with other NSAIDS)
Aspirin Toxicity
Can be chronic or acute, even fatal with one huge dose
Tinnitus/hearing loss are most common symptoms
Hyperventilation (resp alkalosis)and metabolic acidosis occur
Leads to dehydration, fever, electrolyte problems, glycemic issues, coma and death.
Treatment is largely supportive (correct imbalances).
Alkalization of urine (bicarb) helps speed elimination (this will almost definitely be on the test)
Aspirin Drug Interactions
Since it’s protein bound, it can mess with other protein bound drugs (oral anticoagulants WARFARIN)
Causes INCREASE in free anticoagulants and increases the risk of bleeding, same with thrombolytics.
Corticosteroids can speed aspirin’s renal clearance
Alcohol increases risk of GI problems (bleeding)
Dont use aspirin in conjunction with other NSAIDs.
Aspirin Uses
Inflammatory Diseases: RA, JA, OA (all of the arthritis types)
2.4/3.6 grams/day in divided doses. More may be needed. Less for kids.
Also used to treat mild/moderate pain, fever, and to prevent arterial and venous thrombosis.
Diflunisal
Salicylate derivative with analgesic and anti-inflammatory properties, but NOT antipyretic.
REVERSIBLE COX inhibitor (unlike aspirin, another salicylate)
Main side effects are GI, but aren’t as bad as with Aspirin.
Used to treat pain, inflammation, but NOT fever.
Mechanism of NSAIDS (not aspirin)
Reversible inhibition of COX1 and COX2
Decreased production of PGs
Anti-inflammatory and analgesic
NSAIDS used to treat Rheumatoid Arthritis
All of them EXCEPT Ketorolac, Meloxicam, and Mefenamic Acid
NSAIDS used to treat Osteoarthritis
All of them EXCEPT Ketorolac and Mefenamic Acid
2 NSAIDS Used to treat Juvenile RA
Tolmetin and Naproxen
NSAIDs (not aspirin) pharmacokinetics
Quickly absorbed.
Food helps prevent GI problems.
Highly protein bound.
pKa = 3.5-6.3 (higher than aspirin)
Metabolized by liver, excreted by kidney
Name an NSAID with an especially short half life and one with an especially long half life
Ibuprofen/Acetaminophen/Indomethacin are short Naproxen/Nambumetone are loNg
NSAID Consideration in Children
The only ones approved for JRA are Tolmetin and Naproxen
Hepatotoxicity is a concern with many NSAIDS
NSAID Cardiovascular Adverse Effect
Fluid retention, may be problematic for patients with heart problems (CHF)
Caused by COX2 inhibition in the kidneys leading to decreased Na excretion.
Which NSAID is associated with psych disturbances, Parkinsonism, epilepsy?
Indomethacin
Which 3 NSAIDS have been reported to cause headache?
Ketorolac, Indomethacin, Fenoprofen
What group is at increased risk of NSAID complications
elderly
NSAID GI Adverse Effects
Ulceration, bleeding.
Caused by COX1 inhibition decreasing synthesis of protective PGs
Smoking/drinking make this more likely
Taking with food/antacids decreases risk
Which NSAID is associated with Autoimmune Hemolytic Anemia
Tolmetin
NSAID Hematologic Effects
Increased bleeding time due to inhibition of platelet aggregation.
COX1 inhibits TXA2 production which prevents platelet aggregation.
This effect is less dramatic and shorter than with aspirin because non-aspirin NSAID effects are reversible.
Which NSAID is associated with severe reaction (rash, vomiting, headache) in patients with SLE/collagen disorders?
Ibuprofen
Ibuprofen Induced Hypersensitivity Syndrome
NSAID effects on pregnancy/lactation
Dont give them to nursing mothers, it will get in the milk and have negative effects on the infant’s CV system
Avoid NSAIDs during pregnancy, especially 3rd trimester
They can close the fetal ductus arterisus by inhibiting PGE2 synthesis
Which 2 NSAIDS can we use to close a patent ductus arteriosus in a premature infant?
Indomethacin and Ibuprofen
Mechanism is inhibition of PGE2 synthesis
NSAIDs Renal Effects
Decrease in renal PG synthesis, which are needed for normal function
can cause progressive renal functional decline.
Can lead to nephritis, necrosis, hyperkalemia, hypernatremia.
Fluid retention goes along with retention of Na
NSAID Drug Interactions
Like aspirin, they are highly protein bound and can interfere with other protein bound drugs like anticoagulants.
Celecoxib Mechanism/Kinetics
Selective COX2 Inhibitor
Anti-inflammatory, analgesic, and antipyretic
Serum concentration peaks after 3 hours, half life is 11 hours.
Highly protein bound Metabolized by P450 2C9 and excreted by the kidneys.
GI side effects are less severe than nonselectives
Celecoxib Contraindications
Patients allergic to sulfonamides.
It has a sulfonamide group
Patients allergic to NSAIDS Patients with Aspirin Triad (ASA sensitivity, nasal polyps, asthma)
Patients with heart or other vascular conditions
Celecoxib Uses
OA, RA, acute pain.
Dysmenorrhea
Familial Adenomatous Polyposis
Celecoxib Adverse CV effects
- PGI2 (prostacyclin) decreased production prevents vasodilation and makes the vessels more prone to injury.
- COX2 inhibition in the kidneys can increase BP.
This is a bad combination.
Acetaminophen Mechanisms
Acts directly on the hypothalamus to decrease fever.
COX inhibitor in the CNS, but not so much in the periphery.
It doesnt have systemic effects like NSAIDS
Acetaminophen Pharmacokinetics
Good bioavailability
Less protein bound than ASA/NSAIDs
Conjugated in the liver to glucuronate/sulfate and excreted in the urine.
If you take too much, more will be metabolized by P450 to produce NAPB, which is toxic to liver/kidney.
Acetaminophen Adverse Reactions
Allergies/rash, rarely hematological stuff
Hepatotoxicity in high doses.
No more than 4g/day, 2g/day in alcoholics.
Acetaminophen Toxicity
Major problem
Caused by NABP production in hepatic enzymes when normal metabolism is saturated
N-acetylcyeteine is the antidote (try to give it in the first 8 hours). It restores glutathione levels needed for conjugation.
Acetaminophen Uses
Antipyretic/analgesic when ASA is contraindicated
Pain, OA
Mesalamine
normal NSAID (COX1/2 reversible inhibitor)
Maintenance of remission of Ulcerative Colitis
What NSAID is used as a Tocolytic (prevent premature labor)?
Indomethacin
Remember this one can cause headaches and psych problems
DMARDs
Disease Modifying Anti-Rheumatic Drugs
4 nonbiological DMARDs
Hydroxychloroquine Sulfate
Methotrexate
Sulfasalazine
Leflunomide
HMS Leaf
2 TNF Inhibitors
Inflixamab
Etanercept
Non-TNF Inhibitory Biological DMARD
Anakinra
Conservative Therapy for Rheumatic Disease
Aspirin, other NSAIDs (NOT indomethacin), corticosteroids.
DMARDs are reserved for severe, progressive disease because they are pretty toxic.
What is a common combination therapy for rheumatic disease?
TNF Inhibitor (inflixamab, etanercept) plus methotrexate.
Combo therapy allows for lower doses, less toxicity, and possibly has synergistic effects.
Methotrexate
Nonbiological DMARD
Chemotherapy drug that is used in low doses to treat rheumatic/autoimmune diseases
DHFR inhibitor, decreases production of THF needed for nucleotide synthesis
Hydroxychloroquine
Nonbiological DMARD with unknown mechanism
Gets deposited in many tissues, including eyes
Can cause ocular toxicity/retinopathy leading to blindness (irreversibly damage).
“Bull’s Eye Maculopathy”
Dont give in pregnancy, can harm the fetus’ eyes.
Sulfasalazine
Nonbiological DMARD
Treats severe RA, Ulcerative Colitis
Has a 5-ASA group (like aspirin, has the SAL in the name)
Immunosuppressive with high affinity for connective tissues.
Metabolized by acetylation. Some people do this quickly, other do it slowly. Slow acetylators are at higher risk of toxicity.
Can cause neutropenia.
Leflunomide
Nonbiological DMARD
Inhibits pyrimidine synthesis (dihydroorotate dehydrogenase inhibitor) like methotrexate
Used to treat RA
Anti proliferative, antiinflammatory
Long half life, highly bound to albumin
Can cause hepatotoxicity (monitor liver enzymes)
Not safe during pregnancy
Etanercept
TNF Inhibitor
TFN receptor linked to Fc portion of human IgG
Inhibits TNF alpha or beta by binding to them
Treats RA, JRA (subcutaneous injections)
Adverse reactions involve immune suppression (tumors, infections/sepsis)
Infliximab
TNF Inhibitor
Used to treat RA and Chron’s
Chimeric IgG1 monoclonal antibody
Human Fc, murine variable region
Only inhibits TNF-alpha (unlike Etanercept)
Hypersensitivity is an issue because it’s partly made in mice.
Problems involve immunosuppression (TB, fungal, other infections)
Treatment Algorithm for RA
Early RA= less than 6 months
Established RA= more than 6 months.
Early Mild RA = Monotherapy with a DMARD (methotrexate)
Early Severe RA = Combo of DMARD + TNF Inhibitor
Late Mild RA = DMARD Combination
Late Severe RA= DMARD Combo + TNF inhibitor or non TNF Inhibitor
Juvenile Rheumatoid Arthritis
Diagnosed before age 16 Good prognosis, most will have remission without joint damage
Tx = Aspirin maybe (Reye’s), other NSAIDS (only Tolmetin or Naproxen). Then Methotrexate. Then Sulfasalazine. Then Hydroxychloroquine.
Move down this line if the treatment doesnt work.
Etanercept is approved, but no other biologicals.
Dont give oral corticosteroids. You can do injections, but limit them to less than 4 a year.
Osteoarthritis Treatment
All NSAIDS EXCEPT Ketorolac and Mefenamic Acid
Corticosteroid Effects on Blood Cells
PMN concentration in blood increases, but amount sent to site of injury decreases.
Lymphocytes, basophils, eosinophils, monocytes decrease in number.
Immunosuppressive Effects of Corticosteroids
Reduce response to antigens.
Inhibit COX1 and phospholipase leading to decreased lipocortin and PGs
Decrease production of many cytokines (IL1, IL2, TNF alpha)
Reduce complement activation, reduce antibody production
Adverse Effects of Corticosteroids
Immunosuppression
Peptic Ulcers
Cushings
Obesity
Adrenal suppression
Dyslipidemia
Cyclophosphamide
Cytotoxic agent that kills B and T lymphocytes.
Treats severe rheumatic conditions (RA) and some malignancies.
Must be activated by P450
Alkylating agent that inhibits nucleotide synthesis.
Non Cell cycle specific
Makes patient more prone to infection
Azothiprine
Immunosuppressive by inhibiting proliferation of B and T cells
Used to prevent rejection of renal transplant
Also can be used for RA, maybe for Chrohn’s too.
Suppresses T cells more than B cells
S phase specific antimetabolite that prevents nucleotide (purine) synthesis
Not safe for pregnancy
Increases likelihood of infection and neoplasm
Methotrexate
DHFR Inhibitor, prevents THF synthesis needed for DNA synthesis.
Used to treat RA, JRA, and cancer.
Same list of adverse effects as every other drug ever: hepatotoxic, infective risk, GI upset, nephrotoxic, Interstitial pneumonitis, obstructive pulmonary disease.
Cyclosporine
T cell suppressant
Used to prevent kidney, liver, heart transplant rejection
Used to treat RA in conjunction with steroids.
Also treats psoriasis.
Inhibits Signal 1 by inhibiting calcineurin phosphatases.
Mostly suppresses CMI (allograft rejection)
P450 metabolism
All kinds of side effects… Dont give to pregnant patient.
Mycophenolate mofetil
B and T cell Inhibitor (cytostatic)
Used with steroids and cyclosporine to prevent issue rejection in transplants.
Inhibits proliferation of lymphocytes in response to mitogen.
Inhibits B cell Ab production
Can prevent allograft rejection and reverse rejection in progress.
Hydrolyzed to MPA which inhibits inosine monophosphate dehydrogenase, which prevents guanosine nucleotide synthesis.
Can cause leukopenia (duh) including neutropenia (not so duh) Risk of infection (duh)
Muromonab
Monoclonal Ab that block T cell receptors
Blocks Signal 1
CD3+ cells are removed from circulation somehow.
Used to prevent heart, liver, kidney, and pancreas transplant rejection
Lymphocyte Immune Globulin
Ig from horses immunized with human T cells
Causes reduction of T cells
Used to prevent renal transplant rejection.
Used in combo with steroids, antimetabolites.
Can cause hypersensitivity reaction because it comes from horses.
Daclizumab
Humanized (90% human) IgG1 Antibody to the IL2 receptor
Since IL2 causes lymphocyte activation, this drug prevents lymphocyte activation.
Used to prevent heart, kidney transplant rejection
Rho Ig (Rhogam)
Human plasma containing a bunch of Rho abs
Dont give to someone who is Rho positive
Used to prevent hemolytic disease of the newborn
Give to Rho neg mom within 72 hours of giving birth to a Rho positive newborn
Prevents sensitization by mom to the Rho abs. Signal 1
Immune Globulin
A bunch of IgG and some IgM derived from many human hosts.
Used in hypogammaglobulinemia, pediatric HIV, ITP, and Guillou Barre
Can potentially transmit diseases (rare?)
Can cause allergic reaction
Interferon Beta-1b (Betaseron)
Recombinant DNA immunomodulator with anti proliferative properties.
used to treat relapsing remitting MS
Can cause depression, suicide, other more normal reactions (injection site reactions)
IFN Gamma 1b
Recombinant DNA product, immunomodulator
Phagocytic activating effects (activated generation of oxygen free radicals used to kill bugs)
Used in Chronic Granulomatous disease to help the immune system kill Staph aureus
Also treats osteoporosis somehow.
Generalities associated with allergies to drugs
Allergic reactions only account for less than 20% of drug reactions.
Anaphylaxis
cutaneous urticaria
glomerulonephritis
Cytopenias of various types
Gender, age, genetics, current illness, previous drug administration, many other factors can participate in drug reactions.
Type I Hypersensitivity
Immediate Hypersensitivity
Initial exposure causes IgE production, which then become fixed to mast cells/basophils.
Reexposure causes these cells to degranulate and cause anaphylactic reaction.
Tx with prednisone, isoproterenol, epinephrine, and theophylline
Type II Hypersensitivity
Ab mediated (IgG, IgM)
Antibodies cause complement activation
Example is hemolytic anemia of the newborn
Tx= corticosteroids
Type III Hypersensitivity
Serum sickness/arthus reaction
IgM/IgG Involved, form immune complexes which get deposited in tissues (often blood vessels and cause damage)
Tx= corticosteroids
Type IV Hypersensitivity
Cell mediated (delayed)
Mediated by sensitized T cells and macrophages
Ex is contact dermatitis
Tx is corticosteroids.
Name 3 corticosteroids. What are 2 mechanisms of immune suppression?
Prednisone, methylprednisolone, dexamethasone
- Decrease leukocytes and macrophages
- Inhibit Phospholipase A2 and COX2
Which cytotoxic/antiproliferative agent is particularly hepatotoxic?
Methotrexate
Which nucleic acids are broken down to Uric Acid? What enzyme is involved in both pathways?
Adenine and Guanine (Purines)
Xanthine Oxidase
What are two ways Uric acid is eliminated from the body? Which one eliminates more?
Filtration through the glomerulus and secretion in the renal tubules.
90% filtration
Reabsorption also occurs in the tubules
Describe the pathogenesis of gout
Too much uric acid, precipitation as crystals
Uric acid crystals are phagocytosed by macrophages and neutrophils
Severe inflammatory reaction occurs.
2 oral NSAIDS especially useful in Gout
Indomethacin and Ibuprofen (propionic acid derivatives)
2 Corticosteroids used in treatment of Gout
Prednisone, methylprednisolone
2 Drugs that inhibit the formation of uric acid
Allopurinol, Febuxostat
Why should aspirin be avoided in gout?
It has a biphasic effect on uric acid secretion
Injectable NSAID used to treat Gout?
Ketorolac
Colchicine
Unique anti-inflammatory effect that is specific for gout As a LAST RESORT
Treats acute gout and low doses can be used to prevent attacks.
Binds tubulin, prevents polymerization of microtubules, preventing leukocyte migration, phagocytosis, and proliferation.
Also prevents release of inflammatory glycoproteins from neutrophils.
Side effects are Nausea, vomiting, diarrhea (can be pretty serious, which is why it’s more of a last resort drug)
Also leukopenia, agranulocytosis
NSAIDS and steroids are often used first because GI side effects can be pretty severe.
Allopurinol
Xanthine oxidase inhibitor.
Prevents Uric acid production
Not useful for acute attacks, used to prevent attacks.
Keeps Uric acid levels low.
Can cause an increase in attacks early in treatment
May elevate liver enzymes and cause allergic attacks.
Increases half life of some drugs metabolized in liver (probenecid, theophylline)
Febuxostat
Newer xanthine oxidase inhibitor.
Prevents uric acid production
May be better and have fewer side effects than allopurinol.
Not good evidence of this yet.
Probenecid
Inhibits secretion and reabsorption of uric acid in the renal tubules (net increase in excretion because more reabsorption occurs than secretion normally).
Lowers uric acid levels.
Increased risk of kidney stones.
Dont give to people who have kidney stones.
Make sure they maintain adequate urine flow.
Not effective for acute attacks.
May even precipitate attacks.
Sulfinpyrazone is a similar drug
Rasburicase
Converts uric acid to allantoin.
Used to prevent hyperuricemia in patients undergoing chemo (tumor lysis syndrome)
Pegloticase is a similar drug
Guideline for Use of Migraine Abortive Drugs
Dont use them more than about twice per week or you run a risk of rebound headaches.
Which drug is effective at relieving medication overuse headaches?
Botox
How do NSAIDS help treat migraines?
Inhibition of PG synthesis helps decrease inflammation in the trigeminal system
Butorphanol
Opioid taken by nasal spray that is used to treat severe migraines
Ergotamine tartrate
Vasoconstrictor that used to be first line against migraines. Now, not so much.
Activated 5-HT receptors causing vasoconstriction and reduction of neurogenic inflammation (decreases release of Sub P, NKA, and CGRP)
it’s a powerful vasoconstrictor, so don’t give it to people with vascular disease.
Dihydroergotamine
Like ergotamine, but causes less vasospasm
Must be given IV
Sumatriptan
Treatment of acute migraine
Agonist at type 1 serotonin receptors
Relieves N/V, photophobia
Can cause vasospasm..MIs
Metabolized by MAO, don’t give to pts on MAIOs
Zolmitriptan
2nd generation triptan
Like sumatriptan, but more lipid soluble
Acts centrally to inhibit pain transmission in the trigeminal nucleus.
Better oral absorption than Sumatriptan
Metacloperamide, Prochlorperazine, Chlorpromazine
Dopamine antagonists used to treat migraines that are unresponsive to triptans, DHE, or oral analgesics.
Relieve both headache pain and have antiemetic effect
Chronic Migraine Treatment protocol
Consider prophylactic drugs if they’re getting 3 or more migraines per week
Give the drug at least 2-3 months to work before giving up on it
If it works, keep them on it for 3-6 months before you consider trying to take them off.
The drug of choice is Beta blockers
Which two beta blockers are approved for migraine prophylaxis? Which two should be avoided?
Propranolol and Timolol are FDA approved.
Acebutolol and Pindolol should be avoided due to intrinsic sympathomimetic activity.
Mechanism of Beta blockers in treatment of migraines?
Unclear, possibly something to do with affinity for serotonin receptors.
Amitriptyline
Migraine treatment
Down regulates 5-HT2 and adrenergic receptors (dont ask me how this makes sense)
Has sedation and anticholinergic side effects
Verapamil
Calcium channel blocker
Sometimes useful in tx of migraines
Mechanism isn’t really clear (acts on smooth muscle or effects neurotransmitter release)
Valproic Acid, Topiramate, Gabapentin
Anti epileptic drugs also used for migraine prophylaxis
They facilitate GABA neurotransmission, modulate glutamate, and inhibit sodium and calcium channels
Botox
Injection used to treat migraines
Lasts up to 3 months
Useful for rebound headaches
L-DOPA
Converted to dopamine in the body. Must still be in L-DOPA form to enter the CNS.
Carbidopa prevents the conversion to DOPA in the periphery, allowing more to enter the CNS.
Most effective agent at controlling Parkinson’s symptoms
It may take 2-4 weeks for effects to begin.
It does not stop the progression of the disease, only fights symptoms
Most common side effects are N/V, which can be helped by carbidopa.
Also can have serious cardiovascular effects. they can also be reduced by carbidopa.
Choreaform movements are associated with long term use (kind of the opposite of parkinsonian symptoms)
Effectiveness can suddenly stop (end of dose phenomenon)
Can decrease release of prolactin
Selegiline
Inhibits dopamine metabolism by MAO (MAOI)
Specifically MAO B, which is found in the CNS
treats Parkinson’s
Used as a supplement to L-DOPA, may decrease “end dose effect”
They used to think it might slow progression of disease, but they don’t think that now. Still used though.
Cheese toxicity with tyramine (idk what that is)
Entacapone
Inhibits dopamine breakdown by COMT near the synaptic cleft
Used in conjunction with L-DOPA
Symptoms associated with increased dopamine and catecholamines
Can cause hepatotoxicity
Contraindications to L-DOPA
Cardiac arrhythmia
psychosis
melanoma
glaucoma
active peptic ulcer disease
L-DOPA Drug Interactions
Pyridoxine Antipsychotics (dopamine antagonists)
MAOI (hypertensive crisis)
Tricyclic antidepressants
Carbidopa
DOPA decarboxylase inhibitor
Prevents L-DOPA metabolism in the periphery
Increases L-DOPA effects in the CNS, decreases peripheral side effects
Sinemet
L-DOPA plus Carbidopa
Bromocryptine and Pergolide
Nonspecific DA receptor agonists
Useful, but not as good as L-DOPA.
Used in patients that can’t tolerate L-DOPA
Side effects similar to L-DOPA
Ropinirole and Pramipexole
Preferential D2 and D3 agonists
Similar but less severe side effects than L-DOPA
May help actually slow the disease
Amantidine
Antiviral agent used to treat Parkinson’s
Increases Dopamine release and decreases its reuptake
Less effective than L-DOPA but better than anticholinergics
May potentiate L-DOPA, used in combination
Excreted by kidney, dose needs to be adjusted in patients with renal diseases.
Benztropine, Trihexiphenidyl, Diphenhydramine
Anticholinergics used in treatment of mild Parkinson’s
Effective against tremor, not so much for rigidity.
Dont get confused about diphenhydramine, it is an antihistamine that contains anticholinergic properties.
Huntington’s Disease
Kind of opposite of Parkinson’s
Choreaform movements
Treatments decrease dopamine function or enhance GABA effects
Essential tremor tx
Beta blockers (propranolol)
Also, clonidine (alpha 2 agonist)
Ballismus tx
Dopamine antagonists (haloperidol)
Ballismus is involuntary jerking of the proximal musculature, usually unilateral. caused by a lesion in the contralateral subthalamic nucleus.
Dystonia tx
Anticholinergics, benzos
Dystonia is a movement disorder characterized by involuntary muscle contractions leading to twisting, repititve movements.
Chorea tx
dopamine antagonists (haloperidol?), cholinesterase inhibitors (i dont understand this one)
Tic disorders tx
Dopamine antagonist (haloperidol)
8 Benzodiazepines
Alprazolam
Chlordiazepoxide
Diazepam
Lorazepam
Midazolam
Oxazepam
Temazepam
Triazolam
All end in Pam or Lam except Chlordiazepoxide, which at least has “diaze” in there.
1 Benzodiazepine Antagonist
Flimazenil
4 Barbituates
Butalbital
Pentobarbital
Phenobarbital
Thiopental
5 Centrally Acting Muscle Relaxants
Baclofen
Cyclobenzaprine
Diazepam
Metaxalone
Tizanidine
3 Drugs Used to Treat Alcoholism
Disulfiram
Acamprosate
Naltrexone
4 Effects of Benzos
Anxiolytic
Sedative/hypnotic
Anticonvulsant
Muscle Relaxant
Benzodiazepines mechanism of action
Enhance the GABA mediated influx of Chloride ions, hyperpolarizing the neurons, making them less likely to fire
Benzo Side Effects
Drowsiness
Confusion
Memory impairment (anterograde amnesia)
Disinhibition of suppressed behavior
hangover
Rebound anxiety
Respiratory depression in large doses
If you can’t remember them, think of effects of booze…
To which effect of benzos is tolerance most likely to occur?
Sedation
What are effects of Benzos on sleep?
They help you fall asleep faster, but they decrease the amount of REM sleep.
The decrease in REM sleep isnt as bad as it is with alcohol or barbituates.
When patients stop taking the drugs, they may experience a rebound increase in REM sleep (lots of weird, vivid dreams)
Uses of Benzos
Anxitey disorders
Sedatives
Alcohol withdrawal
Anticonvulsants
Relief of skeletal muscle spasms
Preanesthetics
Induction of anesthesia (Midazolam)
How are benzos metabolized?
They are first oxidized, then conjugated, then excreted.
Major drug interactions of benzos
Additive effects with CNS depressants (alcohol)
Cross tolerance with alcohol
Cimetidine, disulfram, INH inhibit oxidation of benzos and prolong their action
They can increase serum levels of digoxin and phenytoin
1 Long active barbiturate
Phenobarbital
2 Intermediate-Short active barbiturates
Pentobarbital
Butalbital
1 Ultra short acting barbiturate
Thiopental
Mechanism of Barbiturates
Facilitation of the effects of GABA at the GABAA receptor chloride channel complex.
Very similar to benzo mechanism, but they work at a separate site
They can produce nonspecific effects on neuronal membranes at high doses (may explain ability to cause surgical anesthesia and pronounced CNS depression)
Barbiturate Effects
Sedative
REM sleep decrease (worse than with benzos)
General anesthetic
Respiratory depression (much more pronounced than with benzos)
Anticonvulsants
Euphoria (potential for abuse)
Barbiturate Pharmacokinetics
Well absorbed through GI tract
Penetrate the CNS due to lipid solubitily. The more lipid soluble, the faster it will act.
Metabolized by hepatic microsomal enzymes (potental for drug interactions, problems in patients with decreased liver function)
Induction of hepatic microsomal enzymes
Barbiturate Adverse Effects
Sedation
Hangover
resp depression
Disinhibition of suppressed behavior
Nausea GI upset
Allergic reactions
Aggravation of Acute Intermittent Porphyria due to induction of hepatic enzymes involved in porphyrin synthesis
Barbiturate Drug Interactions
Additive effects with CNS depressants
MAOIs enhance CNS depression
Decrease effects of Warfarin due to induction of hepatic microsomal enzymes
Buspirone
Drug similar to benzos but with fewer side effects
Eliminates anxiety without other benzo effects
Does NOT act on GABA mechanisms
Maybe it’s a partial 5-HT1A agonist
Low abuse potential (good for use in patients with history of alcohol/sedative abuse who have already been brought through the withdrawal phase)
Metabolized in liver, excreted by kidney
Interactions with MAOIs (HTN)
Interactions with other drugs metabolized by liver enzymes
General side effects similar to barbiturates but much less pronounced. CNS depression at high doses
Zolpidem, Zaleplon, and Eszopiclone
Non barbituate sedatives (sleep aids)
Ambien, sonata, lunesta
Influences the effect of GABA
Acts on a benzo receptor subtype
Less anxiolytic, anticonvulsant, muscle relaxant then benzos
The ones with ZO (Zolpidem, Eszopiclone) are longer acting, Zaleplon is shorter acting.
Mild side effects
Lower risk for abuse/dependence than benzos
Less reduction in REM sleep and less rebound insomnia than benzos
GHB
Gammahydrozybutyrate
GABA analog that crosses BBB
not approved for medical use
Abused by athletes, date rape
Effects kind of like super alcohol
Can cause seizures, CNS depression, coma, death
Hydroxyzine
Antihistimine with sedative properties
Also anxiolytic
Limited abuse potential
Promethazine and diphenhydramine
Antihistamines with sedative properties
Melatonin and ramelteon
Melatonin is a pineal gland hormone
RaMELteon is an agonist at MELatonin receptors
May have sedative properties and have limited abuse potential
Ramelton can have drug interactions due to hepatic metabolism.
it may also increase prolactin and decrease testosterone levels.
Flumazenil
Benzo antagonist, used to reverse CNS depressant effects of benzos, particularly those used for surgical anesthesia (midazolam)
Can trigger seizures, especially in people who are alcohol/depressant dependent.
Can cause withdrawl.
Diazepam
Centrally acting muscle relaxant
Increases GABAs inhibitory effect in the spinal cord
Baclofen
Centrally acting muscle relaxant
GABA analog at GABAB in the spinal cord
Treats spasticity caused by spinal cord injury, MS
Can cause CNS depression
Cyclobenzaprene
Centrally acting muscle relaxant
Inhibits gamma/alpha motor systems in the brainstem
Useful in treating muscle spasms of local origin (muscle strains, pulls, etc)
Can cause CNS depression
Tizanidine
Centrally acting muscle relaxant
Alpha 2 agonist
Can cause hypotension
Very sedating
Metaxalone
Centrally acting muscle relaxant
Similar to cyclobenzaprene
Carisoprodol
Centrally acting muscle relaxant
Similar to Cyclobenzaprene
High abuse potential. Probably shouldnt be prescribed, but still is.
Probably not a correct answer, unless he asks which drug SHOULD NOT be used or something.
Alcohol Metabolism
90% oxidized in liver and excreted by kidneys
Liver oxidation follows zero order kinetics, meaning that it reaches a constant rate at a low concentration.
Normal person can metabolize 7-10 grams/hour (challenge accepted)
Alcohol dehydrogenase pathway
This is how most alcohol is metabolized
EtOH gets converted to acetaldehyde by alcohol dehydrogenase
Acetaldehyde gets converted to acetic acid by aldehyde dehydrogenase (this is the step inhibited by disulfiram)
Disulfiram
Inhibits aldehyde dehydrogenase causing buildup of acetaldehyde when alcohol is consumed
This makes the patient very sick and less likely to drink
Pretty much causes really bad hangover symptoms
Can be hepatotoxic
MEOS
Microsomal Ethanol Oxidixing System
Some alcohol is metabolized through this instead of alcohol dehydrogenase
Chronic alcohol use induces these enzymes and may cause problems with drug interactions
How important is the amount of alcohol cleared through the lungs?
not very
1/2300 air concentration to BAC ratio
Breathalizers extrapolate this
Alcohol effects on sleep
Really bad decrease in REM sleep.
Major problem with heavy drinkers
Alcohol CNS mechanisms
Maybe disordering of membrane lipids
direct effects on neurotransmitters
Enhanhaced effects of GABA at GABA receptor chloride channel complexes. Like benzos, barbiturates. Explains cross tolerance/dependence.
3 ways alcohol can exacerbate Gout
- Drinks may contain purines
- alcohol induces metabolic acidosis
- Alcohol directly decreases uric acid solubility.
other effects of alcohol
CV effects (peripheral vasodilation, decreased cardiac performance)
Increase stomach acid production
ADH inhibition
tendency for heavy drinkers to become malnourished
large cause of pancreatitis
Alcohol effects on liver
Induction of enzymes
fat accumulation
inflammation, scarring, fibrosis (cirrhosis)
portal hypertension
Naltrexone
Opioid antagonist used to treat alcholism
Supposed to lower cravings
Can be hepatotoxic
Acamprosate
Decreases cravings for alcohol
Mechanisms involve GABA, glutamate receptors
Less potential for hepatotoxicity
Can cause diarrhea, depression, anxiety, insomnia
Naltrexone and acamprosate together may be better than either alone
Sulfinpyrazone
Similar to probenecid.
Treats gout
Decreases secretion, reabsorption of uric acid.
Dont give to someone with kidney stones
