Pharmacology pt 2 Flashcards
Metabolic ALKALOSIS is common following the administration of which diuretics?
Loop and thiazide
- loss of extracellular volume with constant extracellular HCO3
What receptors do loop diuretics act on in the ascending LOH?
Na-K-Cl transporter
What receptors do thiazide diuretics act on in the distal convoluted tubules?
Na-Cl reabsorption
Metabolic ACIDOSIS is common following the administration of which diuretics?
acetazolamide (carbonic anhydrase inhibitor)
- inhibits the rxn btwn H2O, CO2, Carbonic acid, and bicarb -> bicarb builds up in urine
- d/t bicarbonate excretion
Potassium sparing diuretics (spironolactone, amiloride)
You should not use acetazolamide in Pts with what lung condition ?
COPD
- can also impair CO2 elimination (not just increase HCO3 excretion)
What two metabolic disturbances are associated with diuretics?
Metabolic ALKALOSIS
- loops
- thiazide
Metabolic ACIDOSIS
- acetazolamide
- spironalactone
What diuretics act at:
- distal convoluted tubule?
- collecting ducts
distal convoluted tubule
- thiazide
collecting ducts
- spironalactone
Which pain medication is associated with QT prolongation?
Methadone
- concurrent use with other meds that also inhibit CYP3A4 -> cardiac arrhythmia
Half-life of methadone
20-60 hours
Metabolism of most drugs occurs via 2 processes - Phase I and Phase II reactions
- What is Phase I?
oxidative and reductive reactions
- hydrolytic reactions
- catalyzed by cytochrome P450
Metabolism of most drugs occurs via 2 processes - Phase I and Phase II reactions
- What is Phase II?
Conjugation of drug or its metabolites w. substrates (ie. glucuronic acid)
- once metabolized -> eliminated from body
What reaction occurs after large and prolonged thiopental dosing?
desulfurization reaction
–> produces pentobarbital -> CNS depressant activity
Remifentanil is metabolized by:
ester hydrolysis in the blood by plasma esterases
- safe in pts with ESRD
Buprenorphine MOA
u-opioid partial agonist
k-antagonist
Buprenorphine potency vs morphine
- effects at high dose
24-40x potency of morphine, half life of 3 hours
High dose - partial agonist ceiling effect
- (less respiratory depression)
Spironolactone MOA
competitive aldosterone antagonist
- K sparing diuretic
- retention K
- excretion Na
_____ is the major counterregulatory hormone to insulin
Glucagon
Glucagon effects on the heart
Inotropic and chronotropic response
- activates G protein coupled receptors -> adenylyl cyclase -> increase cAMP
Glucagon is contraindicated in which 2 disease states?
Pheochromocytoma
- risk for hyperglycemia and severe HTN
Insulinoma
- risk of severe hypoglycemia
Glucagon resembles which vasopressors?
Epi
Norepi
*Inotropic and chronotropic response
Isoproterenol MOA
Nonselective Beta agonist
-> - activates G protein coupled receptors -> adenylyl cyclase -> increase cAMP
*Very similar to glucagon
How does ASA irreversibly inhibit platelet function?
Blocking formation of thromboxane A2
How many days does it take for your entire platelet pool to be replenished?
7 days
- 10% per day
What is the MOA of:
Clopidogrel (Plavix)
Ticagrelor (Brilinta)
Prasugrel (Effient)
Inhibit ADP receptor activation
What is the MOA of:
Eptifibatide (Integrilin)
Abciximab (Reopro)
Tirofiban (Aggrastat)
Blocks GP IIb/IIIa receptors
Example of antiplatelet agents
- Irreversibly inhibit plt function, so even if med no longer present, effect on plt still persists
- ASA
- Clopidogrel
- Ticagrelor
- Dipyridamole
- Abciximab
- Eptifibatide (integrillin)
*limited list
Examples of anticoagulation agents
- works via diff mechanisms, but can continue/hold perioperatively
- Warfarin
- heparin
- Fondaparinux
- Dabigatran (pradaxa)
- Rivaroxaban (xarelto)
- Apixaban (Eliquis)
MOA of:
Dabigatran (pradaxa)
Rivaroxaban (xarelto)
Apixaban (Eliquis)
Dabigatran (pradaxa)
- direct thrombin inhibitor
Rivaroxaban (xarelto)
Apixaban (Eliquis)
- direct factor Xa inhibition
NMBs are (hydrophilic/hydrophobic) w/t quaternary amine structure - importance?
Hydrophilic
- (cirrhosis, CHF, RF): an increase in body water -> increase volume of distribution -> DECREASES plasma [ ] of NMBs, so you need to INCREASE the intubating dose
Which NMBs will have INCREASED duration of action with impaired hepatic metabolism?
- Roc
- Vecuronium
- Pancuronium
Sodium nitroprusside toxicity is a direct side effect of ____ and ____ toxicity.
- Triad of:
1. Elevated mixed venous oxygen (PVO2)
2. Tachyphylaxis
3. metabolic acidosis
cyanide
thiocyanate
Sodium nitroprusside toxicity is a direct side effect of cyanide and
thiocyanate toxicity.
- What Triad is seen?
- Elevated mixed venous oxygen (PVO2)
- Tachyphylaxis
- metabolic acidosis
Antidote for cyanide poisoning
Amyl nitrate
- converts Hgb to Methgb (which binds cyanide)
In pts with biliary disease, how does morphine affect the common bile duct?
Induce Biliary colic
- Opioids inhibit efferent innervation (smooth m) to bile duct -> frequent muscle contraction
Max dose of neostigmine (acetylcholinesterase inhibitor)
- 07 mg/kg
- too much can INCREASE risk of developing weakness
Which anesthetic gas produces that largest [ ] of fluoride ions upon metabolism?
Methoxyflurane and Sevoflurane
- fluoride induced nephrotoxicity to the collecting ducts, inhibiting ADH
*Halothane causes HEPATOtoxicity
How does halothane decrease BP?
Mainly by reducing cardiac output
*the other inhaled anesthetics lower BP by decreasing SVR
How does nitrous oxide decrease BP?
It generally doesnt
Can nitrous oxide be used in laparoscopic or bariatric surgery?
Yes
- duration is more important than the type of surgery (>4 hours)
- but avoid if bowel is already distended or ischemic
How fast can nitrous oxide expand a pneumothorax?
double in 10 min
triple in 15 min
Which anesthetic drug below will cause the least dmg with local tissue extravasation (vesicant)?
propofol, diazepam, phenytoin, promethazine, thiopental
propofol
Can pts with PCN allergy with no h.o severe reaction (whether IgE or non IgE mediated) receive cephalosporin abx?
Yes
*rash does NOT count as a severe rxn
Difference btwn LMWH and UFH?
UFH: inactivate factor Xa and IIa
LMWH: inactivate factor Xa only
PTT is used to assess _____ pathway.
Used to monitor ____.
Intrinsic (VIII, IX, XI, XII)
and common pathway (II, V, X, fibrinogen)
Unfractionated heparin
PT is used to assess _____ pathway.
Used to monitor ____.
Extrinsic pathway ( Tissue factor and VII) and common pathway (II, V, X, fibrinogen)
Warfarin
Anti-Xa assay is Used to monitor ____.
LMWH
*PTT is used to monitor UF
Norepinephrine is a naturally occurring catecholamine secreted at the _________ synapses and is release from the _______
postganglionic sympathetic
adrenal gland
The ____ reflex mediates a decrease in HR secondary to increase blood pressure from an increase in SVR
baroreceptor
Beta 1 activity
increase HR, contractility, and cardiac output
Norepi has alpha 1 and beta 1 activity, which one predominates?
alpha > beta
- leads to more arterio/venoconstriction than increasing HR
- worsen renal and splanchnic blood flow
Dosing for NDMB prior to succinylcholine (1 mg/kg) to prevent fasciculations?
10% of ED95 dose
ie: roc 0.03 mg/kg
vecis 0.05 mg/kg
cis is 0.05 mg/kg
*ED is effective dose, NOT intubating dose
What does ED50 mean?
Median effective dose that will produce an effect in 50% of the population that it is administered to
What does ED95 mean?
Median effective dose that will produce an effect in 95% of the population that it is administered to
- different meaning with NMBDs
- 95% twitch suppression in 50% of the population
What happens when you mix propofol with lidocaine?
It decreases the stability of propofol w/in 30 min, inc risk of PE
- give immediately after mixing
Most effective way to reduce pain associated w/ injection of propofol
- injection in antecub vein
2. modified bier block
Anesthetic drugs associated with myoclonus
Etomidate Ketamine Methohexital Suxx Propofol
*pretreatment with midazolam helps
Transdermal fentanyl patch max plasma [ ] ? How long does it take to decrease [ ] by 50%?
30 hours
24hours
Following neostigmine administration, how does this affect succinylcholine?
Phase I augmentation
- prolonged DOA (~30 min)
- common after laryngospasm
Milrinone MOA.
WHere is it excreted?
PDE III inhibitor
- acts on cAMP -> inodilator
Kidneys /urine
- Lower dose if RF
Milrinone effect on:
cardiac index
systemic vascular resistance
pulmonary vascular resistance
Increase CI (without increasing myocardial oxygen demand)
Decrease both systemic and pulmonary vascular resistance
What doses of amiodarone are associated with bradycardia?
HIGH doses
Amiodarone MOA
- half life?
block potassium, calcium, and sodium channels
- lesser extent: alpha, beta
45 days
- risk of toxicity extends that long after d/c
What % of pts on amiodarone develop hypothyroidism?
20%
Clonidine MOA
alpha 2 agonist
- analgesic
- potentiates opioids (morphine)
Which drug lasts longer in an epidural, clonidine or morphine?
Which one causes more hypotension?
Clonidine
Clonidine
H2 blockers (Cimetidine, ranitidine, famotidine) oral vs IV onset time? WHich one reduces gastric volumes?
1 hour - PO
30 min - IV (ranitidine IV will be 1 hour)
Cimetidine, famotidine
*Ranitidine does NOT reduce gastric volumes
PPI MOA and onset time?
binds H+-K+ pumps
2-4 hours
Most common side effect of water soluble fospropofol (gets metabolized to propofol)
- parasthesias
- > 50% of pts - pruritus
- localized to genitals
(in propofol its 10%)
DOes phenylephrine affect splanchnic perfusion?
yes
- arterial and venous constriction
Aminoesters (procaine, chloroprocaine) are derivatives of ______
paraaminobenzoic acid (PABA_ - known allergen, hapten
If pts have an “allergic” rx to Aminoamides (lidocaine, bupivacaine, ropivacaine), what is it likely d/t?
preservatives
- methylparaben
If local anesthetics are stored with epi, and they have an “allergic” rxn, what could it be d/t?
metabisulfite
Volatile anesthetic effects on CBF and CMRO2
Increase CBF
Decrease CMRO2
- phenomenon known as “uncoupling”, as they usually parallel
*CMRO2 usually decreases with hypothermia and sleep
All volatile anesthetics (increase/decrease) CMRO2
decrease
*except nitrous oxide, it does NOT cause decoupling of CBF and CMRO2
Nitrous oxide effects on CBF and CMRO2
Increase both
All other volatile anesthetics Increase CBF
Decrease CMRO2
All IV agents except _____ decrease CMRO2 and decrease CBF
ketamine
- inc CBF and decrease CMRO2
*fentanyl has no effect
Which immunosuppressant PROLONGS NDMBs?
cyclosporine
- neurotoxic
- nephrotoxic
How does St. John’s wort affect drugs
CYP3A4 inducer
- metabolizes drugs -> subtherapeutic drug levels
Hydromorphone dosing should be (increased/decreased) in pts with ESRD
decreased
- accumulates in kidneys
- Hydromorphone-3-glucuronide is toxic metabolite
Meperidine, a synthetic opioid for post op shivering, dosing should be (increased/decreased) in pts with ESRD
decreased
- accumulates in kidneys
- Normeperidine is toxic metabolite
Morphine dosing should be (increased/decreased) in pts with ESRD
decreased
- accumulates in kidneys
- Morphine-6-glucuronide is active metabolite -> prolong sedation and respiratory depression
Why do you need to be careful using meperidine, a synthetic opioid for post op shivering, in pts using MAOIs (ie. selegiline)?
Opioid that also has weak SNRI
–> serotonin syndrome
All opioids except remifentanyl is metabolized in the _____
liver
- biotransformation in liver by phase I –>
- phase II conjucation
Cytochrome ______ is responsible for metabolism of most anesthetics, lidocaine, and dexamethasone
P450 3A4
CYP3A4
Cytochrome ______ is responsible for metabolism of PPI (omeprazole) and antidipressants
P450 2C19
CYP2C19
Cytochrome ______ is responsible for metabolism of phenytoin, warfarin, ibuprofen
P450 2C9
CYP2C9
*Cytochrome ______ is responsible for metabolism of codeine, BBs, antiarrhythmics, diltiazem, tramadol
P450 2D6
CYP2D6
P450 3A4
(CYP3A4)
is responsible for metabolism of _______
most anesthetics, lidocaine, and dexamethasone
P450 2C19
CYP2C19
is responsible for metabolism of _______
PPI (omeprazole) and antidipressants
P450 2C9
(CYP2C9)
is responsible for metabolism of _______
phenytoin, warfarin, ibuprofen
P450 2D6
(CYP2D6)
is responsible for metabolism of _______
codeine, BBs, antiarrhythmics, diltiazem, tramadol
Where is the Na/K/Cl transporter located for antihypertensives?
In the LOH
*Na/Cl transporter is in the distal conv tubule
Most common GABA B receptor agonist
baclofen for “B”
- B receptors are linked to K+ channels
*A is Cl-
Most anesthesia drugs are GABA (A / B) activators?
A for “anesthetics”
- allows Cl’ to enter neuron and hyperpolarize cell
How does NMDA receptor activation work?
Inc intracellular calcium -> second messenger
- both voltage gated AND ligand gated
2 conditions must be met for NMDA receptor to become activated
- GLutamate or glycine must be bound (ligand gated)
- Cell must be depolarized (voltage gated)
Insulin and glucagon use which receptors as a second messenger system?
cAMP
Nitroglycerin, sodium nitroprusside, nitric oxide, sildenafil use which receptors as a second messenger system?
cGMP
Tirofiban, abciximab, eptifibatide MOA
Glycoprotein (GP) IIb-IIIa receptor inhibitor
- prevent platelet aggregation and thrombus formation
Clopidogrel, prasugrel, ticagrelor, and ticlopidine MOA
ADP receptor inhibitors
- impair ADP dependent activation of GP IIb-IIIa complex
What type of shunt is formed with a foreign body in the R mainstem bronchus?
R -> L INTRApulmonary shunt
Prevent ventilation to a lung that is perfused, creating a SLOWER induction
- rate of rise for arterial concentration of gas will DECREASE (more obvious with LESS soluble agents, desflurane and nitrous oxide)
How do R -> L intracardiact shunts (ie. eisenmenger syndrome) affect IV induction?
Faster induction
- lungs are bypassed
*L to R shunts and intrapulmonary shunts will have minimum effect
Intrapulmonary or Intracardiac (R to L) shunt will affect inhalational and IV inductions how?
R to L Intrapulmonary
- Decreases inhalational induction
- No effect on IV induction
R to L intracardiac
- Decreases inhalational induction
- Increases IV induction
Intracardiac (L to R) shunt will affect inhalational and IV inductions how?
No effect on inhalational agents
No effect on IV agents
In the presence of an intrapulmonary shunt, the speed of induction will affect which gas (most to least)?
Nitrous Oxide > Desflurane > Sevoflurane > Isoflurane
*
Shunts typically affect insoluble agents more than soluble agents
Drug of choice in electroconvulsive therapy (ECT)
Methohexital (short acting barbiturate)
- Lowers sz threshold
- cause hiccups
BDZ effects on respiratory system
Decrease TV, which dec MV
Which commonly used BDZ (midazepam, lorazepam, diazepam) has the fastest onset of action and shortest DOA
Midazolam
How is the CO2 sensitivity affected with BDZ?
Sensitivity to CO2 is decreased
Chronic barbiturate admin (increases / decreases) the DOA of drugs metabolized by the CYP450 enzyme
DECREASES
- so you would need to increase the dose requirement
Commonly used anesthesia drugs metabolized by CYP450 34A
- Acetaminophen
- Statins
- Alprazolam, Diazepam, Midazolam
- Bupivacaine, Lidocaine, Ropivacaine
- Codeine, Fentanyl, Alfentanil, Sufentanil
- Warfarin
- Varapamil, Diltiazem, Nicardipine, Nifedipine
- Omeprazole
*Chronic use of barbiturates decreases DOA of these drugs, and you will need to INCREASE dose requirements
How does morphine and fentanyl affect the thoracic and abdominal wall?
In large doses over a short period of time = wall rigidity
Which CYP do SSRIs (fluoxetine and paroxetine) significantly inhibit?
CYP2D6
- converts codeine, hydrocodone, oxycodone to metabolites w/ greater potency (morphine, hydromorphone, oxymorphone)
- You have increased opioid requirements now bc active forms are reduced
When reversing NDNMB, which cholinesterase inhibitor should be paired with which anticholinergic?
Edrophonium - Atropine (onset 1 min)
Neostigmine / Pyridostigmine - Glyco (2-3 min)
*similar onset and DOA
Which is the only cholinesterase inhibitor that crosses the BBB?
Physostigmine
- great against anticholinergic overdose or organophosphate poisoning
The rate of rise in FA/FI ratio is a marker of ____
volatile anesthetic uptake by the blood
The greater the solubility of an inhaled anesthetic, the more ____ the uptake into the bloodstream
The _____ the uptake, the slower the rate of rise of FA/FI
Uptake into the bloodstream is the primary determinant of _____
The gases with the ______ solubilities in the blood (desflurane) will have the fastest rise in FA/FI
Rapid
Greater
FA (alveolar anesthetic concentration)
Lowest
If ventilation is fixed, an increase in cardiac output from 2 to 20L/min will (increase / decrease) alveolar anesthetic concentration (FA) .
DECREASE
- by augmenting uptake
This will slow the rise of FA/FI ratio.
More prominent w/ soluble anesthetics.
Factors that tend to INCREASE the rate of rise of FA/FI
- Low blood:gas partition coefficient (solubility)
- Low cardiac output
- High min ventilation
- Low (Parterial - Pvenous), meaning less blood uptake
Epidural 2-Chlorprocaine onset time? DOA?
6-12 min d/t high [ ] of LA
45-60 min plain
60-90 w/ epi
Butorphanol MOA
Synthetic mu agonist-antagonist
Partial agonist at K-opioid receptor
- relieves biliary colic
Which receptors do dopamine stimulate and at what doses?
D 1: low concentration
- vasodilation of renal, mesenteric, coronary vasculature -> inc GFR and blood flow
Beta 1 - high dose
- inc HR, SBP, pulse pressure
Alpha 1 - highest doses
- peripheral vasoconstriction
Side effects of dopamine
Tachyarrhythmias Dec splanchnic blood flow -> gut ischemia Dec TSH, prolactin, GH Dec Ventilatory response WOrsen V/Q mismatch in lungs
Opioid w/ fastest Onset of action
Alfentanil
- high unionized fraction d/t low pKa 6.5 (90% of drug in unionized form)
For opioids, ______ correlates with DOA the majority of the time
lipid solubility
- Hydromorphone lipid solubility of 2
- Morphine lipid solubility 1.4
*Fentanyl is 816
sufentanil is 1700
Eating tons of Natural licorice can lead to what abnormality?
It blocks 11-beta-hydroxysteroid -> hyperaldosterone effects -> all the sx of Conn syndrome
- HYPOkalemia
- activates Na-K-ATPase channels in renal proximal tubules
- Na reabsorption and K secretion - HTN
- HYPERnatremia
- FLuid overload
- Metabolic alkalosis
What describes a drug with a large volume of distribution?
*Vd = Drug dose / Plasma [ ]
Lipophilic
High amt of TISSUE protein binding
- Inversely proportional to unbound drug in the tissue
Low amt of plasma protein binding
- Directly proportional to unbound drug in the plasma
Lipophilic
High amt of TISSUE protein binding
- Inversely proportional to unbound drug in the tissue
Low amt of plasma protein binding
- Directly proportional to unbound drug in the plasma
*Does this describe a drug with large or small volume of distribution (Vd)?
LARGE Vd
*high affinity for tissue components (tissue proteins, tissue lipids)
Hydrophilic
High degree of PLASMA protein binding
Low degree of TISSUE protein binding
*Does this describe a drug with large or small volume of distribution (Vd)?
Small Vd
What do time constants refer to?
The volume or capacity of the circuit (Vc) / FGF
Time it takes to reach equilibrium
How do volatile anesthetics prolong NMBs?
Decrease the sensitivity of the postjunctional skeletal muscle
Two drugs associated with genital burning and itching
Fospropofol (prodrug of propofol)
Awake dexamethasone
3 major mechanisms for nitroprusside toxicity
- Cyanide ions bind cytochrome C oxidase and inhibits cellular aerobic respiration
- Formation of cyanmethemoglobin (unable to carry oxygen)
- Thiocyanate production (CNS events)
How does glucagon increase cardiac contractility?
Increases intracellular cAMP - > inc myocardial contractility (inotropic and chronotropic)
Glucagon physiologic effects
- Inhibit gastric motility
- Promote hepatic gluconeogenesis
- Relax sphincter of Oddi
- Inotrope and chronotrope
Which p450 enzyme is induced by St. Johns wort?
CYP450 3A4
- metabolizes drugs -> subtherapeutic drug levels
- Affects codeine, BBs, antiarrhythmics, diltiazem, tramadol, SSRI, MAOI
Metoclopramide MOA and its effects on:
- Gastric volume
- pH
Dopamine antagonist
- Inc lower esophageal sphincter tone -> enhance gastric emptying -> decrease gastric vol
- no change pH
Sodium citrate MOA and its effects on:
- Gastric volume
- pH
Weak base reacts w/ HCl
- no change vol
- increase gastric pH
How does Cytochrome p450 work?
heme protein that utilizes oxygen to OXIDIZE organic compounds
- part of Phase I metabolism
Phase I drug metabolism involves ____
Phase II involves ____
I: oxidation, reduction, hydrolysis
- inactivate drug
II: conjugation
- (either glucuronic acid or sulfate is added to drug to make it easily excreted from kidney/liver)
Chronic barbiturate use ______ cytochrome P450 activity.
Increases
- therefore, metabolism of drugs by P450 is increased. ie. BDZ
The blood:gas coefficient refers to the _________.
The oil:gas coefficient refers to the ____________.
The rate of rise of the FA/Fi and is related to the SOLUBILITY and the speed of inhalational induction
LIPOPHILICITY and is related to the anesthetic potency and MAC
Max allowable dose for: Lidocaine (plain): Lidocaine (w/ epi): Bupivacaine (plain): Bupivacaine (w/ epi): Ropivacaine (plain only): Chloroprocaine (plain only):
Lidocaine (plain): 5mg/kg Lidocaine (w/ epi): 7mg/kg Bupivacaine (plain): 2.5 mg/kg Bupivacaine (w/ epi): 3 mg/kg Ropivacaine (plain only): 3 mg/kg Chloroprocaine (plain only): 12 mg/kg
What does cAMP do in the heart vs in the peripheral smooth muscles?
Inc intracellular cAMP
Heart:
cAMP -> increased influx of intracellular calcium stores ->
enhance cardiac inotropy
Peripheral smooth muscles:
cAMP -> smooth muscle VASODILATION and decreased peripheral vascular resistance
*Milrinone is a PDE III INHIBITOR, which impairs cAMP breakdown
*Milrinone is a PDE III INHIBITOR, which impairs _____ breakdown
cAMP
- Inodilator
Adrenaline (epinephrine), isoprenaline (isoproterenol), and dopamine undergo (extensive / no) metabolism in the lungs
NO metabolism in lung
Effects of burns on:
- Pseudocholinesterase lvls
- ACh receptor numbers
- Protein binding
- Pseudocholinesterase lvls: decreased
- ACh receptor numbers: increased
- Protein binding: increased (meaning less free drug is available)
*Doses of most NDNMBs must be increased 2-5x in burn pts
Mivacurium metabolized by:
Pseudocholinesterase alone
*atracurium has some metabolism by pseudocholinesterase
*Doses of most NDNMBs must be increased ___x in burn pts
2-5x
*mivacurium needs the least increase (1-2x) b/c burn pts have decreased lvls of pseudocholinesterase and are more sensitive to it
What are the safest opioids to use in ESRD?
fentanyl and methadone
*no concern for metabolites accumulating
*but dose reduction still recommended