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126 Cards in this Set
- Front
- Back
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the 3 processes that affect the plasma concentration of a given drug
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absorption
distribution elimination |
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Fick's Law
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the rate of absorption is proportional to the drug concentration gradient across the barrier and the surface area available for absorption at that site.
(applies to passive diffusion) |
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4 ways for drugs to enter cells
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1. passive diffusion
2. lipid diffusion (dissolves into lipid components of cell membranes) 3. aqueous diffusion (passage through aqueous pores in membranes) 4. active transport (against concentration gradient) |
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Henderson-Hasselbach equation
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log (protonated form / nonprotonated form) = pKa - pH
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types of proteins drugs are most often reversibly bound to
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**albumin**
lipoproteins, glycoproteins, beta globulins. |
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what are Pgps?
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p-glycoproteins. these are intestinal proteins that transport drugs in a blood to lumen direction, dumping drugs into the intestines, thereby serving a detoxifying function. these also work in other tissues to remove drugs.
Pgps can be inhibited by erythromycin, increasing the tissue levels of other drugs. . |
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most drug biotransformation takes place in the....
other sites include: |
liver.
other sites include: gut, kidneys, brain, lungs, skin. |
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prodrugs
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are administered as inactive compunds and then biotransformed to active metabolites.
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high first pass effect
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drugs that have a low bioavailability after first pass through the gut wall and liver (due to transformation to inactive metabolites).
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Phase I Biotransformation
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Phase I biotranformations include oxidative, reductive, and hydrolytic reactions.
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most common type of type I biotransformations?
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oxidation.
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what is needed for a CYP oxidation reaction?
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CYP, NADPH CYP reductase, NADPH, membrane lipids in which the CYp is embedded, oxygen atom from something else.
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the CYP____ subfamily hydrolyzes more than half of all microsomal drug oxidations.
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the CYP3A subfamily.
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common endogenous substances used in phase II biotransformation (conjugation)
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acetate, glucuronate, sulfate, glycine.
most conjugated drug metabolites are biologically inactive. |
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urine is the most common route for excretion of drugs. others are...
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bile, sweat, saliva, tears, feces, breast milk, exhaled air.
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what is the definition of bioavailability?
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the fraction (F) of the administered dose of a drug that reaches the systemic circulation in an active form.
F(oral) = AUC (oral) / AUC (IV) |
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what's the Vd?
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defined as the voume of fluid in which a drug would need to be dissolved to have the same concentration as it does in plasma.
it is an apparent volume that represents the relationship between the dose of a drug and the resulting plasma concentration of the drug. |
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a low Vd that approximates plasma Volume or ECF volume usually indicates...
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that the distribution is restricted to a particular compartment (the plasma or ECF).
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total body water is about...
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40 L
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2 possible reasons for a large Vd?
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1. intracellular ion trapping (weak bases are less ionized in plasma than in cells because of lower pH inside cells. This restricts its diffusion out of the cell, and results in a larger Vd)
2. sequestration into fat tissue. |
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definition of Clearance (Cl)
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Cl = the volume of body fluid (blood) from which a drug is removed per unit of time.
Cl = 0.693(Vd) / ke ke is elim constant |
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normal creatinine clearance in an adult?
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about 100 mL/min.
drugs eliminated primarily by glomerular filtration (i.e., little tubular secretion or reabsorption) will have a renal clearance that is approx. equal to the creatinine clearance. |
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calc. of renal clearance?
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renal excretion rate / plasma drug concentration
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calc. of hepatic clearance?
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hepatic blood flow x arteriovenous drug concentration difference.
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first order kinetics in drug elimination
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the scenario in which the rate of drug elimination is proportional to the plasma drug concentration and follows an exponential decay function.
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zero order kinetics in drug elimination
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the scenario in which the rate of drug elimination is constant and independent of plasma drug concentration. (e.g., ethanol).
a straight line, not exponential |
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definition of elimination half-life
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the time required to reduce the plasma drug concentration by 50%.
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does the time to reach steady-state depend on the dose of the drug? dose interval?
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No, the time it takes to reach steady-state is dependent entirely on the half-life of the drug.
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the steady-state drug concentration depends on...
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...the drug dose administered per unit of time and on the drug's clearance or half life.
so if either of these is doubled (dose administered or half-life, the steady-state concentration will be doubled. |
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why would you give a loading dose?
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to rapidly establish a therapeutic plasma drug concentration.
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how do you calculate a loading dose?
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loading dose = Vd * desired plasma drug concentration.
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how would you calculate a maintenance dose?
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1. determine rate of elimination (Cl * avg. steady-state drug concentration)
2. maint. dose = rate of elim.x dosage intervals. (if oral, bioavailability must be accounted for) |
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what is the time to steady state dependent on?
what is the time to steady state for any first-order process? |
the elimination rate of the drug.
first order process time to steady-state: about five half-lives. |
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if drug elimination mechanisms become saturated, what can happen?
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the drug can exhibit zero-order kinetics until the saturation is overcome.
in zero order kinetics, the rate of elimination is constant. |
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what is clearance?
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the volume of plasma from which a drug is eliminated per unit of time.
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name a selective cyclooxygenase-2 inhibitor
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Celecoxib
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name 4 non-selective cyclooxygenase inhibitors
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acetaminophen
aspirin ibuprofen naproxen indomethacin ketoprofen ketorolac |
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name a selective cyclooxygenase-2 inhibitor
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Celecoxib
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name 4 non-selective cyclooxygenase inhibitors
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acetaminophen
aspirin ibuprofen naproxen indomethacin ketoprofen ketorolac |
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what class reduces inflammation better than NSAIDs?
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steroids
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what 2 therapeutic properties does acetaminophen have?
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anti-pyretic
analgesic NOT a good anti-inflammatory |
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what 4 therapeutic properties does aspirin have?
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anti-pyretic
anti-inflammatory analgesic anti-platelet |
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briefly describe MOAs for aspirin
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1. non-specific inhibition of cyclooxygenase
irreversible inhibition of platelet aggregation. |
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so why does a low dose of aspirin achieve hemostasis?
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1) Relative Cox-1 selectivity
2) Irreversible binding to thromboxine |
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aspirin hypersensitivity and ____ seem to overlap a lot.
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asthma.
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tinnitus is a sign of _____ toxicity
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aspirin
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why should you take NSAIDs with food?
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less pain reported. Same amount of ulceration, though.
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NSAID adverse effects
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GI disturbances (Nausea, diarrhea, reflux, ulceration)
Take w/food Renal insufficiency/Fluid retention Bleeding Hypersensitivity CNS Hepatotoxicity - rare reports |
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describe misoprostol
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Prostaglandin E1 analogue
given with NSAIDs to protect GI, reduce risk of ulceration. Adverse effects: Diarrhea, abdominal pain Abortifacient (sometimes used to induce labor) |
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what protectants can you give to pt.s with an underlying GI risk?
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mistoprotol
PPI efficacy about the same. |
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describe Cox-2 inhibitors and how they differ from other NSAIDs
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e.g,, celecoxib
-less risk of GI ulceration -less interference with platelet aggregation - increase in CV related events, renal insufficiency |
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adverse effects of acetaminophen?
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Usually very well tolerated
Hepatotoxic - esp if high doses, alcohol use, liver disease Interaction with warfarin? (yes, with cox-1 inhibitors |
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what is the toxic intermediate we're afraid of with acetaminophen use?
how do we treat an overdose? |
benzoquinoimine
treat with glutathione N-acetylecysteine (Mucomyst) |
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what enzymes do liver function test measure?
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ASTs and ALTs.
these only come out when the liver is damaged. |
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treatment of salicylate overdose?
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1. induction of vomiting and gastric lavage to remove unabsorbed drug
2. IV administration of sodium bicarbonate. (counteracts metabolic acidosis, increase ionization of salicylate in kidneys thereby enhancing excretion. 3. admin. fluids, electrolytes, etc. |
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what is miosis?
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pupil constriction
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what effects do opioid agonists have in addition to anagesia?
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sedation
euphoria respiratory depression miosis peripheral vasodilation constipation drug dependence |
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what are the three types of opioid receptors?
which are primarily responsible for analgesic effects? |
mu
delta kappa. all mediate analgesia, but mu receptors are primarily responsible for analgesic effects, as well as respiratory depression and and opioid dependence. |
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where do opioid analgesics primarily act?
where do non-opioid analgesics primarily act? |
opioid analgesics act primarily in the spinal cord and brain to inhibit the neurotransmission of pain.
non-opioid analgesics act primarily in peripheral tissues to inhibit the formation of algogenic (pain-producing) substances such as prostaglandins. |
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describe somatic pain
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well localized to specific dermal, SC, or musculoskeletal tissue.
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describe visceral pain
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originating is thoracic or abdominal structures, is often poorly localized and may be referred to somatic structures.
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describe neuropathic pain
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neuropathic pain is usually caused by nerve damage (such as compression, inflammation, diabetes)
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which primary afferent fibers are responsible for sharp pain?
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A delta fibers.
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which primary afferent fibers are responsible for dull pain?
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C fibers.
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what are the two main anatomical-functional projections of the ascending pain pathways?
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the sensory-discriminative component, to the cerebral cortex, which alerts an individual to the presence of pain and location of pain.
the motivational-affective component, which goes to the limbic cortex, which enable the individual to experience discomfort, suffering, and other emotional reactions to pain. |
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what are the 3 major families of endogenous opioid peptides?
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enkephalins, beta-endorphins, and dynorphins.
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where do enkephalins act?
how do they act? |
enkephalins are released from neurons throughout the pain axis, including those in the PAG (Periaqueductal gray matter), medulla, and spinal cord.
enkephalins activate opioid receptors in these areas and thereby block the transmission of pain impulses. |
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3 classifications of opioid drugs?
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full agonists, mixed agonist-antagonists, and pure antagonists.
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talk through the descending inhibitory pathways and state why they're relevant here.
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1. arise from PAG (periaqueductal gray matter) in the midbrain
2. project to medullary nuclei that transmit impulses to spinal cord. medullary neurons include serotonergic nerves arising in NMR (nucleus magnus raphae) medullary neurons also include noradrenergic nerves arising in the LC (locus ceruleus.) when these nerves release serotonin and norepinephrine in the spinal cord, they inhibit dorsal spinal neurons that transmit pain impulses to supraspinal sites. takeaway: opioid analgesics activate the descending PAG-NMR-LC neuronal pathways and also directly activate opiod receptors in the spinal cord. |
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CV effects of morphine and other opioids?
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vasodilation.
2y to histamine release in mast cells in periphery. |
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GI effects of morphine?
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increases smooth muscle tone --> leads to inhibition of peristalsis and causes constipation.
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neuroendocrine effects of opioids?
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opioids stimulate the release of ADH and prolactin
and inhibit the release of LH. |
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immunologic effects of opioids
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suppress the activity of certain types of lymphocytes (NK cells).
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how do opioids cause nausea and vomiting?
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by stimulating the chemoreceptor trigger zone in the medulla, opioids cause nausea and vomiting.
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why does tolerance develop to opioids?
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down regulation of opioid receptors.
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primary uses for morphine?
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trauma-associated pain, cancer pain, MI pain.
in MI, morphine reduces pain and anxiety as well as dilating coronary arteries and reducing myocardial oxygen demand. |
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why is meperidine (demerol) an attractive opioid?
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less pronounced effects on smooth muscle in GI, uterus, bilary means less side effects.
used in obstetrics because it does not prolong labor. only short-term treatment because of a toxic metabolite. |
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symptoms of opioid withdrawal?
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Diaphoresis
Abdominal cramping, diarrhea Nausea, vomiting Tachycardia Agitation |
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example mixed agonist/antagonists
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Butorphanol (Stadol)
Administered as nasal spray Nalbuphine (Nubain) Administered parenterally Pentazocine (Talwin) Available for oral use Buprenorphine (Subutex, Suboxone) * Administered sublingually for withdrawal maintenance |
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what is tramadol?
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Not classified as an opioid*
Less tolerance/dependence than opioids? MOA: Weak m-opioid receptor agonist Also inhibits re-uptake of serotonin & norepinephrine (antidep.) |
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platelet aggregation appears to have a larger role in the formation of __________ thrombi
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arterial thrombi (white thrombi)
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coagulation appears to have a larger role in the formation of ________ thrombi
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venous thrombi (red thrombi)
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warfarin and other coumarin derviatives work by...
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inhibiting the synthesis of clotting factors II (prothrombin), VII, IX, and X. (2,7,9,10)
they also inhibit the synthesis of proteins C and S. |
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warfarin and other coumarin derviatives are structurally related to...
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vitamin K
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what are proteins C and S known for?
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these are endogenous anticoagulants.
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these anticoagulants can cross the placenta
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coumarins (warfarin.)
they can cause hemorrhage and malformations. |
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how are pts with acute thromboembolism usually treated?
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treated with a LMWH and warfarin.
the LMWH is d/c'd in 3-5 days when the warfarin finally exerts its effects on clotting factors. |
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can anticoagulants dissolve thrombi?
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nope. but they can keep an established thrombus from extending.
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name the major rate-limiting step in the coagulation cascade.
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factor X
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which test monitors the action of warfarin?
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PT - prothrombin time
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main indications for oral anticoagulant
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DVT, atrial fibrilation, artificial heart valve.
MI, in conjunction with heparin-type anticoagulant |
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as a general rule, the dosage of warfarin should prolong the PT of the patient so that it is _____ times the PT of the control.
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1.3-1.5
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what are the two basic parenteral anticoagulants?
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heparin and hirudin. (+related compounds)
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what category do enoxaparin, dalteparin, and tinzaparin belong to?
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Low-molecular-weight heparin
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briefly, how does heparin work?
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by potentiating the activity of AT-III (antithrombin III).
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describe AT-III
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AT-III is a powerful endogenous INHIBITOR of thrombin (IIa) and stuart factor (Xa).
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briefly, how do LMWHs work?
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by inactivating active factor X.
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how is heparin removed from the system?
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it's removed from circulation by the reticuloendothilial system and is eliminated by hepatic and renal mechanisms.
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how is the dosage of heparin calculated?
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by the results of the aPTT test. (activated partial thromboplastin time)
adequate dosage results in aPTT of 1.5 - 2 times normal. |
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do you have to order tests for LMWH efficacy?
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nope. it's predictable enough that you don't have to order aPTTs like you do for heparin.
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possible complications with heparin?
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1. HIT-1 - heparin induced thrombocytopenia - caused by platelet aggregation (25% of pts). usually reversible with continued heparin treatment.
2. HIT-2 - less common but more seriuous - Ig mediated platelet inactivation. Risk for thrombotic complications and mortality. Must d/c heparin immediately. 3. hyperkalemia. |
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indications for heparin?
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acute thromboembolitic disorders: PEs, DVT. Coagulopathies like DIC.
prophylactic clotting prevention in heart or arterial surgery. low dose SC for prevention of DVT and PE in high risk pts. |
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LMWH indications
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1. knee or hip replacements (prevent venous thromboembolism)
2. prevent ischemic complications in unstable angina or non-ST MI. |
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how do you treat bleeding in heparin or LMWH pt.s?
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give them protamine sulfate, which inactivates negatively charged heparin.
Severe bleeds may require FFP. (fresh frozen plasma) |
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how does hirudin work?
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it's a direct thrombin inhibitor.
(leech saliva) |
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indications for hirudin?
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HIT
prevent DVT - unstable angina, acute MI IV only. |
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what mediators do platelets release when they adhere to vascular endothelium that increase the expression of GP IIb/IIIa receptors that bind to fibrinogen and cause platelet aggregation?
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TXA2 (thromboxane A2)
ADP (adenosine diphosphate) 5-HT (5-hydroxytryptamine, or serotonin) |
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talk me through normal platelet aggregation
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vascular endothelium is ruptured --> collagen fiber touches platelet GPIa receptors --> platelet releases TXA2, ADP and 5-HT --> these mediators increase expression of GPIIb/IIIa receptors --> GP IIb/IIIa receptors bind fibrinogen, which binds other platelets.
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what is prostacyclin?
PGI2 |
a prostaglandin synth. by vascular endothelial cells, inhibits platelet aggregation.
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What is TXA2?
thromboxane A2 |
a prostaglandin synthesized by platelets and promotes platelet aggregation.
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how does low dose aspirin work?
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low doses of aspirin inhibits the synthesis of TXA2 without affecting prostacyclin.
high doses of aspirin inhibit both prostacyclin and TX2. |
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how are LMWHs cleared?
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kidney
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how do you correct an elevated INR?
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INR < 5 (and not bleeding)
Hold warfarin until therapeutic, then resume at lower dose INR 5-9 Hold warfarin ± vitamin K Phytonadione 1-2.5 mg by mouth INR > 9 Hold warfarin ± vitamin K Phytonadione 2.5-5 mg by mouth Profound overdose (INR > 20) / hemorrhage: FFP and vitamin K 10 mg IV |
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4 types of antiplatelet meds
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1. Inhibitors of cyclooxygenase - aspirin
2. Adenosine diphosphate inhibitors - plavix 3. Phosphodiesterase inhibitors –dipyridimol 4. Glycoprotein IIB/IIIA receptor blockers – aggrastat, 2 others. |
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what's the approx. life of a platelet?
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approx 1 week.
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how do ADP inhibitors work (e.g. plavix?)
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Block binding of ADP to platelet surface receptors (P2Y12)
Reduce ADP-induced platelet aggregation |
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what class are these?
Ticlopidine (Ticlid)* Clopidogrel (Plavix) Prasugrel (Effient)+ Ticagrelor (Brilinta)+ |
ADP inhibitors
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what is an integrin?
give and example |
intergrins are cell surface transmembrane glycoproteins that function as adhesion receptors to structurally link the cell surface to the cytoskeleton.
e.g., GP IIb/IIIa |
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how do phosphodiesterase inhibitors work? give an example
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Prevents inactivation of cyclic AMP
Increased intraplatelet levels of c-AMP Less release of granule constituents Modest reduction in platelet aggregation e.g. dipyridimole usually just used for myocardial perfusion but can be used for anti-stroke |
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what are these?
Abciximab (ReoPro) Chimeric monoclonal antibody Often produce alleric rxns on 2nd exposure. Tirofiban (Aggrastat) Non-peptide synthetic antagonist Eptifibatide (Integrilin) Patterned after snake venom peptides |
Glycoprotein IIb/IIIa antagonists.
These prevent platelets from attaching via fibrinogen. |
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major adverse effects of thrombolytics/fibrinolytics
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Antigenic
If derived from bacterial source Hemorrhage Due to lack of site specificity Arrhythmias Secondary to reperfusion |
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name the fibrolytic drugs
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1. recombinent t-PAs: alteplase, reteplase, tenecteplase
(tissue plasminogen activator) 2. urokinase - enzyme from human urine 3. streptokinase - protein from streptococci 4. anistreplace - complex of streptokinase and plasminogen |
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how do the fibrinolytic drugs work?
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they convert plasminogen to plasmin, which degrades fibrin and fibrinogen.
streptokinase has to first combine with plasminogen to then form an activator complex. |
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why are the t-PAs nice? (relative to streptokinase)
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they selectively activate plasminogen that is bound to fibrin. So they cause less bleeding than streptokinase.
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how do you stop a bleed in a pt who's taken fibinolytics?
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aminocapoic acid. competitively blocks plasminogen activation.
this is also used to treat hemophilia. |
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contraindications to thrombolysis
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Recent hemorrhage, trauma or surgery
Active peptic ulcer Coagulation defects Esophageal varices Recent CVA Severe, uncontrolled hypertension Coma |
