Pharmacology 1 Flashcards
What is primary site of anesthetic action?
membrane receptors
What are the three common properties of receptors?
specificity, sensitivity, selectivity
Arrange the bonds between drug and receptor from weakest to strongest.
van Der walls, hydrophobic, hydrogen, ionic, covalent
What are the prominent forces that help agonist drugs align with its receptors?
van Der walls and ionic bonding
How do volatile anesthetics bind to their cell receptors?
nonspecific hydrophobic bonding
Which proteins mainly bind acidic drugs?
albumin
What proteins mainly bind basic drugs?
a1-acid glycoprotein and beta-globulin
Acetylcholine and sodium transduce a _____ signal.
excitatory
GABA and chloride ions transduce a ____ signal.
inhibitory
What is the occupancy theory?
the magnitude of a drugs effect is proportional to the number of receptors it occupies.
When the therapeutic safety margin is ___ the risk of drug-induced death is ____, and the margin of therapeutic safety is ____.
When the therapeutic safety margin is large the risk of drug-induced death is small, and the margin of therapeutic safety is wide.
What value can be used to compare the potency of drugs in a class?
ED50
What phrase describes drug onset time and magnitude of drug response?
pharmacokinetic analysis
What phrase describes the duration of the tissue response of a drug?
drug elimination kinetic analysis
Antagonist drugs lack ___ but have ____
Antagonist drugs lack intrinsic activity or efficacy but have receptor affinity.
What type of antagonist can be displaced by the agonist?
competitive
What type of antagonist have a strong affinity for the receptor protein and cannot be displaced by an agonist.
noncompetitive
Continued stimulation of cells with agonists can result in what?
down-regulation
Chronic administration of an antagonist leads to what type of response to receptors?
up regulation
How does molecular size affect molecules crossing lipid bilayers?
the smaller the molecule the easier it crosses membranes and tissues
What range of molecular weights prevents molecules from crossing membranes?
100-200
What is antiport transportation?
exchange of one molecule for another agonist a concentration gradient
What is symport transportation?
transportation of two molecules together in the same direction against a concentration gradient
For a given pKa what part of the drug is charged and uncharged?
charged, ionized, water soluble
uncharged, nonionized, lipid soluble
What is the pKa formula for basic drugs?
pKa = pH = log (HA/A)
What is the pKa formula for acidic drugs?
pKa = pH = log (A/HA)
A acidic drug into a more acidic pH =
A acidic drug into a more basic pH =
A basic drug into a more acidic pH =
A basic drug into a more basic pH =
A acidic drug into a more acidic pH = nonionized
A acidic drug into a more basic pH = ionized
A basic drug into a more acidic pH = ionized
A basic drug into a more basic pH = nonionized
What plasma proteins bind to acidic drugs? To basic drugs?
albumin binds acidic drugs
alpha-1 acid glycoprotein, and beta globulin bind basic
What proteins bind cyclosporin and corticosteroids?
lipoproteins bind cyclosporin
transcortin binds corticosteroids
How does protein binding affect the drug acting on the tissues?
high protein binding prevents the drug from entering the tissues
How does ionization affect protein binding?
the more lipid soluble (nonionized), the more highly protein bound the drug will be.
What are drugs that have protein binding greater than 90%?
warfarin, phenytoin, propranolol, propofol, fentanyl and analogs, and diazepam
What type of drugs are highly absorbed in the stomach?
highly acidic drugs. Because They are more nonionized, so they are absorbed more.
somach pH is 1.5-2.5
What is pre systemic elimination?
when the drug is eliminated before it reaches the systemic circulation
What are the mechanisms that cause pre systemic elimination?
stomach acid hydrolyzes the drug, digestive enzymes deactivate the drug, liver biotransforms the drug
What is the first pass hepatic effect?
when the liver biotransforms the drug before it reaches its clinical effect site
What is the ideal route of administration of Nitroglycerin?
sublingual
Insertion of a drug into which part of the rectum leads to more predictable circulatory levels?
Distal rectum
What determines systemic absorption of intramuscular and subcutaneous injections?
capillary blood flow, and lipid solubility
Requirements for a transdermal medication include
molecular weight:
dosage:
pH:
molecular weight: < 1000
dosage: < 10mg
pH: 5-9
What impacts the bioavailability of a drug?
lipid solubility, solubility in aqueous and organic solvents, molecular weight, pH, pKa, blood flow
What is the volume of distribution
the amount of drug in the body compared to the serum concentration
How are drugs with a low Vd and high Vd described?
Low: < 0.6mL/kg or < 42L
high: > 0.6mL/Kg or > 42L
What affects a drugs Vd?
lipid solubility, plasma protein binding, and molecular size
What are some isomers?
cisatracurium, levobupivicaine, ropivicaine, dexmedetomidine
what occurs during phase 1 reactions?
oxidation, reduction, hydrolysis.
The molecule becomes more polar and ready for elimination
What occurs during phase 2 reactions?
conjugation.
a drug or metabolite is conjugated with an endogenous substrate like glucuronic acid, sulfuric acid, acetic acid, glycine, and a methyl group
What do you get when you add water to an ester?
acid and alcohol
What do you get when you add water to an amide?
acid and amide
What is another name for the P450 system?
mixed-function oxidase system
Genetic variation of CYP2D6 causes changes in metabolism of what class of drugs?
B-blockers
What are the enzyme inducers?
alcohol, phenobarbital, phenytoin, rifampin, and carbamazepine
What effect do enzyme inducers have on half life?
decrease half life
What drug does erythromycin inhibit the metabolism of?
theophylline
What is the context sensitive half time?
time required to decrease the drug dose by 50% after stopping an infusion
What is drug clearance?
the volume of plasma that is cleared of drug per unit time
What is clearance directly proportional to?
dose
extraction ratio
blood flow to the clearing organ
What is clearance inversely proportional to?
half life
drug dose in the central compartment
What are the two main clearing organs?
liver and kidneys
What determines rate of clearance?
blood flow to the clearing organ
the organs ability to extract the drug from the bloodstream
What is the formula for clearance?
Clearance = Q x E q= blood flow, e= extraction ratio
What are three examples of drug that undergo perfusion dependent elimination?
verapamil, morphine, lidocaine
How does protein binding effect capacity dependent drug clearance?
decreased protein binding increases clearance
increased protein binding decreases clearance
What are two drugs that undergo capacity dependent elimination?
diazepam and theophylline
The excretion of drugs involves:
____ glomerular filtration
____ tubular secretion
____ reabsorption
passive glomerular filtration
active tubular secretion
some reabsorption
What substances are actively secreted from the kidneys?
morphine, meperidine, furosemide, penicillin, and quaternary ammonium compounds
What determines the amount of drug available for renal elimination?
amount of free unbound drug
GFR
What induction agent is almost completely reabsorbed by the kidneys?
propofol
How does urine pH affect the elimination of drugs?
acidic urine eliminates basic drugs
basic urine eliminates acidic drugs
Are water soluble or lipid soluble agents more likely to accumulate in the elderly?
lipid soluble.
Their fat compartment is increased, therefore their Vd is larger.
Which gender is more sensitive to propofol?
Does should be reduced by how much?
males
30%
What is pharmacogenetics?
studies variations in genes suspected of affecting drug response
Does pharmacogenetics or pharmacogenomics aim to identify the genetic basis for variations in drug efficacy, metabolism, and transport?
genomics
What are polymorphisms?
Do polymorphisms affect phase 1 or phase 2 reactions more?
genetic variations in the DNA sequence
Phase 1
Functional polymorphisms occur in which four P450 isoenzymes?
2A6
2C9
2C19
2D6
Significant morbidity and mortality occur in which two patients populations receiving codeine, that are ultra rapid metabolizers of CYP2D6?
pediatric tonsillectomy
neonates of breast feeding mothers
What are two machine related factors that affect uptake of inhaled anesthetic?
solubility of anesthetic in the machine components
FGF
What gases are triggers for malignant hyperthermia?
all but N2O
How do you flush the anesthesia machine in a patient with a history or increased risk of malignant hyperthermia?
100% O2 at 10L/min for 20 minutes
What is an alternative to purging the AM to prevent malignant hyperthermia?
charcoal filters
blood:gas solubility and onset of anesthesia have what type of relationship?
inverse.
The lower the solubility the faster the onset of anesthesia
What is the ventilation effect?
The faster and deeper the patient breathes the faster the onset of an inhalation induction
What is overpressurizing or the concentration effect?
delivering higher concentrations of anesthetic needed for maintenance, to speed the initial uptake
Overpressurizing or the concentration effect is most effective with which agents?
Sevo and Iso, they are less soluble/ less potent
What is the second gas effect?
Adding a fast agent (N2O) to a slower agent during inhalation induction to sleep the onset of the slower agent
What relationship does oil:gas partition coefficient and potency have?
direct.
The higher the solubility the more potent the drug.
Iso has an oil:gas of 91, and its MAC is 1.4
Which anesthetic gas onset is most affected by increased cardiac output?
Iso
As the patients temperature falls, what happens to the anesthetic gases solubility and potency?
solubility and potency increase
How does temperature affect inhaled induction?
decreased temperature slows induction
What factors lead to a faster inhalation induction?
low B:G solubility, low CO, high Ve, high FGF, high concentration, second gas effect
What factors lead to a slow inhalation induction?
high B:G solubility, high CO, low Ve, low FGF, low concentration, V/Q mismatch, hypothermia
Arrange the gases from slowest to fastest emergence, when the anesthetic was delivered for 10 hours?
Iso, Sevo, Des, N2O
The longer an anesthetic is delivered the slower the patient emerges. Effect is greatest with most soluble Iso.
Why are children anesthetized faster than adults?
They have a high alveolar ventilation per weight
Are anesthetics more or less blood soluble in children compared to adults? What does this mean?
less blood soluble
they work faster
What inhaled agent is most likely to cause emergence reactions and agitation in children?
sevo
What are risk factors for children having increased agitation during emergence?
age 2-5
separation anxiety
anxiety and post-op pain
What agents are ineffective in decreasing emergence agitation in children?
midazolam, serotonin antagonists, parental presence
Effective: fentanyl, precedex, propofol, ketamine
How do right to left shunts affect inhalation induction?
Which agents is most affected by this?
slow induction
Desflurane
What is the structure of ethers?
R - O - R
What is the number of carbons used on the commonly used anesthetics?
maximum 4
What are the two categories of the commonly used anesthetics?
ethers or aliphatic hydrocarbons (straight chain or branched nonromantic hydrocarbons)
What is the consequence if the anesthetic molecule exceeds 4 or 5 carbons?
the anesthetic won’t produce immobility
Halogenation of hydrocarbons and ethers is the addition of what molecules?
Flourine, chlorine, bromine, iodine
How does potency affect MAC?
decreased potency, increase MAC
Des has a partition coefficient of 0.42 but a MAC of 6%
How does halogen atoms affect cardiac dysrhythmias?
the more halogens the more likely dysrhythmias will occur
what is the Meyer-overton theory?
lipid solubility is proportional to potency
where do volatile anesthetics produce immobility?
spinal cord and supraspinal
Where do inhalation agents produce unconsciousness?
cortex, thalamus, and brainstem
Where do inhalation agents produce amnesia?
amygdala and hippocampus
Where do inhalation agents produce analgesia?
spinothalamic tract
Where do inhalation agents produce immobility?
spinal cord central pattern generators
What MAC awake/MAC ratio is considered to be a potent anesthetic?
0.3-0.4
What is MAC-bar?
MAC that prevents adrenergic response to skin incision
What is the “triple low state” that increases 30 day mortality?
MAP of 75, MAC < 0.8, BIS < 45
How do volatiles affect CMRO2?
decrease
How do volatiles affect CBF and cerebral vessel diameter?
increase CBF by causing cerebral vasodilation
How does N2O affect CMRO2 and CBF?
increases both
How can we manipulate the increase in CBF that N2O causes if used on a patient with reduced intercranial compliance?
hyperventilation
How do volatiles affect EEG activity?
Overall decrease
Which evoked potential are the most and least affected by the volatiles?
Visual is most
Brainstem is least
Which volatile augments seizure activity?
Sevo
What did the PANDA trial determine?
Anesthesia in infants does not affect IQ score later in childhood
Which two anesthetic agents are most likely to cause emergence delirium in preschool children?
des and sevo
How do the volatiles affect hemodynamics?
Decrease MAP by decreasing SVR. Decreased CO and CI.
N2O increases SVR
Which volatile supports cardiac index the best in a wide range of MAC values?
Des
What mechanisms do anesthetics affect HR?
decrease SA node automaticity
modulate baroreceptor reflex
SNS activation
What is coronary steal? What is another name for coronary steal?
Blood flow is stunted from diseased cardiac tissue to more healthy tissue.
Reverse Robinhood effect
What is preconditioning caused by volatile anesthetics?
a cascade of intracellular events that help protect the myocardium from ischemic and reperfusion insult, potentially limiting infarct size.
How do the volatiles affect the Qt interval?
they increase the Qt interval
How do volatiles prolong the Qt interval?
inhibition of the delayed rectifier K current
How does N2O affect PVR?
increases
How do volatiles affect pulmonary artery pressure?
decrease
How do volatiles affect Vt and RR?
decrease Vt and increase RR
How do volatiles shift the CO2 response curve?
to the right. Less responsive to PaCO2
Impairment of the hypoxic ventilatory response by volatile anesthetics is not abated by what two mechanisms?
CNS arousal or acute pain
What serum concentration of methoxyflurane causes vasopressin resistant polyuric renal insufficiency?
50mmol/L
What are the FDA recommendations for Sevo to prevent formation of compound A?
Sevo exposure should not exceed 2 MAC hours at flow rates of less than 1-2L/min
N20 is an antagonist at ____ receptors, causing a potential decrease in ____ pain post-op.
NMDA, chronic
Which anesthetic gases is ok to use in a MH susceptible patient?
N2O
What is the chemical name of propofol?
2,6 - Diisopropyl phenol
What is the pH and pKA of propofol?
pH: 7-8.5
pKa: 11
What are the preservatives of branded and generic propofol?
branded: EDTA
generic: metabisulfite (bronchoconstriction, benzyl alcohol (avoided in infants)
What is the elimination half life of propofol?
1-2 hours
What are three factors that decrease protein binding?
decreased lipid solubility, increased drug concentration, competition to binding sites with other drugs
What are two factors that increase protein binding?
increased pH (<8.0), increased protein concetration
How does propofol work?
it stimulates the inhibitory GABA receptor. Causing Chloride to move into the cells and cause hyperpolarization.
What is one of the major inhibitory receptors in the CNS?
GABA, glycine, and K channels
How does propofol affect the CNS?
decreases CMRO2, ICP, CBF, and CPP
What is the effect of Propofol on EEG activity?
causes Delta waves, can cause burst suppression with higher doses
What are the predictors of hypotension from induction doses of propofol?
age > 50, ASA 3-4, baseline MAP < 70, high doses of fentanyl
What are the primary reasons for propofol induced hypotension?
decreases sympathetic tone and vasodilation
What are the preferred induction agents of the patient with asthma?
ketamine and propofol
One absolute contraindication to propofol is allergy to what?
sulfite. dont use generic
What is propofol infusion syndrome?
Metabolic derangements that occur from multiple days of high infusions of propofol. Common in the ICU not anesthesia.
What are risk factors for propofol infusion syndrome?
Dose > 4mg/kg/hr Duration > 48 hours critically ill high fat low carb intake catecholamine infusion steroid administration
What is one common denominator for propofol infusion syndrome?
impaired systemic microcirculation with tissue hypo perfusion and hypoxia
What drug is (1- [1-phenylethyl]-1H-imidazole-5-carboxylic acid ethyl ester)
Etomidate
What are some of the negative side effects of etomidate?
pain on injection, increase nausea, adrenal cortical suppression, myoclonia,
What is the pH and pKa of etomidate?
pH 8.1
pKa 4.2
How is etomidate metabolized?
hepatic enzymes and plasma esterases
What is the elimination half life of etomidate?
2-5 hours
How does etomidate affect CMRO2 and CBF?
decreases both
Pretreatment with which drugs can decrease the incidence of myoclonus from etomidate?
dexmedetomidine, midazolam, roc, and lidocaine
How does etomidate affect the evoked potential monitors?
BAEP: decreased amplitude, and increase latency
EEG: prolonged epileptic activity after ECT
SSEP: enhanced amplitudes
MEP: suppressed amplitudes
How does etomidate affect respiratory dynamics?
decrease Vt but increase RR
Which induction agents cause histamine release?
Propofol,
Adrenal cortical suppression caused by etomidate inhibits which enzymes?
11-B hydroxylase
17-A hydroxylase
causing a decrease in cortisol, aldosterone and corticosterone levels
What are porphyria?
a deficiency in the enzyme involved in the synthesis of heme
What is the rate limiting enzyme in the biosynthesis pathways of porphyrins?
ALA-synthetase
Which induction agents are contraindicated in poryphrias?
Etomidate and barbiturates
What drug is 2-(O-chlorophenyl)-2-(methylamino) cyclohexanone
Ketamine
What is the ph and pKa of Ketamine?
pH: 3.5-5.5
pKa: 7.5
What receptors does ketamine bind?
antagonist at NMDA receptors, blocking signals to the thalamus and cortex
How does ketamine exert its anti-inflammatory and antihyperanalgesic effects?
inhibits TNF-a and IL-6
How is ketamine metabolized?
P450 to norketamine
Intramuscular ketamine reaches peak plasma concentrations at what time interval?
22 minutes
How does ketamine affect the CNS?
increases CBF, CMRO2, ICP
How does ketamine affect EEG wave recordings and BIS?
produces theta waves, increases BIS
What should be given to reduce the incidence of emergence delirium from ketamine?
benzos- midazolam, lorazepam, diazepam
How does ketamine affect the cardiovascular system?
increases HR, CO, contractility, SVR, and CVP
What is the induction agent of choice in the patient with asthma?
ketamine
What are the mechanisms that ketamine causes bronchodilation?
increased catecholamines, bronchial smooth muscle relaxation, vagolytic actions
What antisialogogue is preferred to decrease secretions after ketamine administration?
atropine
What are some considerations when giving ketamine during eye procedures?
it causes nystagmus and increases IOP
Is ketamine safe to use in parturients?
yes, doses 0.5-1mg/kg do not compromise uterine tone, blood flow, or neonatal delivery status
What is the induction agent of choice for children with a difficult airway or reactive airway disease?
ketamine
How do benzos exert their action?
agonists of the GABA receptor. It increases the frequency of chloride channel opening causing hyperpolarization
Rank the benzos from shortest to longest acting?
shortest - Midazolam
lorazepam
longest- diazepam
Which benzo has the highest clearance rate?
midazolam
Which benzo is not affected by enzyme inhibition or induction?
lorazepam, undergoes phase 2 conjugation
How is diazepam metabolized?
hepatic microsomal enzymes. Demethylated to dimethyl diazepam
Although not an antiemetic, which benzo is used in reducing chemotherapy-induced N/V?
lorazepam
What is the most respiratory depressing benzo?
midazolam
What class of alpha-2 agonists does dexmedetomidine fall under?
imidazole
What are the primary effects of dexmedetomidine?
sedation, analgesia, anxiolysis, reduced post-op shivering and agitation, cardiovascular sympatholytic actions
What are the main sites of action of dexmedetomidine?
pontine noradrenergic nucleus and locus coeruleus
What is the effect of alpha-2 agonism on ions from dexmedetomidine?
inhibition of Ca channels, activation of K channels, modulation of the release of proteins. This leads to hyperpolarization of cells
What drug is (S)-5-(1-(2,3-Dimethylphenyl)ethyl)-1H-imidazole hydrochloride?
dexmedetomidine
What is the loading dose of dexmedetomidine?
1mcg/kg
How does dexmedetomidine affect the CNS?
increases CMRO2 and decreases CBF (cerebral vasoconstriction). This results in uncoupling.
Which IV anesthetic increases the analgesic effects of N2O?
dexmedetomidine
What are the main side effects of dexmedetomidine?
HoTN and bradycardia
Transient HTN can result, if dexmedetomidine induced bradycardia is treated with what medication?
glycopyrrolate
