Exam 1 Flashcards

1
Q

Pharmacokinetics

A

What the body does to the drug

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2
Q

Absorption

A

How the drug gets in

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3
Q

Bioavailability

A

Relative amount of drug that reaches systemic circulation

= 1 for parenteral (IV or IM)

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4
Q

First-pass metabolism

A

Occurs before drug reaches systemic circulation

Liver: very significant for enteral administration

Lung: fentanyl uptake, propofol metabolism

Plasma esterases/pseudocholinesterase

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5
Q

First-Pass of sublingual route

A

Direct absorption into systemic venous system, avoids portal circulation

NO FIRST-PASS

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6
Q

Distribution of cardiac output

A

VRG: 75% and is 10% BW
Muscle: 19% and is 50% BW
Fat: 6% and is 20% BW
VP: 0% and is 20% BW

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7
Q

Redistribution

A

Single doses of lipophilic drugs have short CNS DOA as they redistribute to peripheral tissues

Larger doses=longer apparent DOA
Decrease in plasma concentration becomes dependent on elimination from body instead of redistribution

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8
Q

Albumin

A

Carrier protein produced in the liver

Binds most acidic/neutral drugs, some basic(ex:benzos, SSRI’s)

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9
Q

Alpha-1-acid glycoprotein

A

Binds most basic drugs

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10
Q

Pt with low protein levels

A

Higher free drug levels

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11
Q

Cell Membrane make up

A

Lipid bilayer

Small lipophilic drugs pass freely

Hydrophilic drugs require channel (except in CNS, as they must undergo active transport)

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12
Q

Passive transport

A

Movement of drug down its concentration gradient

Generally limited by blood flow

Drug will diffuse as quickly as it can be delivered

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13
Q

Facilitated diffusion

A

Needs carrier proteins, NO ENERGY REQUIREMENT

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14
Q

Active transport

A

Carrier proteins use energy to move drug, even against concentration gradient

Both lipophilic and lipophobic drugs need active transport to deal with concentration gradients

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15
Q

Acid-Base

A

H(+) + A- HA

H(+) + B HB(+)

CHARGED SPECIES DONT CROSS MEMBRANES WELL

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16
Q

pKa

A

pH where ionization occurs
“50-50 point”

Ex: if pKa = 6 and pH = 2, excess protons will drive equation to RIGHT

If pKa = 6 and pH = 7.4, equation will shift to LEFT

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17
Q

Biotransformation

A

Alteration of the drug via a metabolic process (usually in liver)

Most drugs need to be HYDROPHILIC for excretion

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18
Q

Phase 1 Biotransformation

A

Oxidation, reduction, hydrolysis

Increase polarity of molecule to make the drug water soluble for excretion in urine

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19
Q

CYP

A

Enzyme that catalyzes most phase 1 rxns

Activity increases with ongoing drug exposure

Can be inhibited when drugs compete for same CYP subtype

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20
Q

CYP3A4/5

A

Subtype of CYP family

Metabolizes many opioids, benzos, LA’s

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21
Q

Phase 2 Biotransformation

A

Conjugation with a polar substance

(Attachment of glucuronate, acetate, glutathione group) –> water soluble for excretion in urine

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22
Q

Neonate Biotransformation

A

Neonates through 1 year have diminished phase 1 and 2 activities

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23
Q

Hepatic Drug Clearance

A

Volume of blood that the liver could cleanse of drug in given amount of time

Hepatic blood flow x extraction ratio

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24
Q

Hepatic blood flow

A

Dependent on CO and BP

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25
Q

Hepatic extraction ratio

A

Fraction of drug removed from the blood as it passes through the liver

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26
Q

High Extraction Ratio

A

“Flow-limited” (e.g. Etomidate, propofol)

Hepatic clearance nearly equal to hepatic blood flow

Low CO states will show diminished hepatic elimination

Clearance remains unchanged unless metabolic capacity (Vm) is severely compromised

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27
Q

Low extraction ratio

A

“Capacity limited” (e.g. Thiopental, diazepam)

Clearance NOT significantly affected by changes in hepatic blood flow

Clearance limited by fact that liver can only handle a fraction of the drug it sees

Changes in Vm will produce a nearly proportional effect on clearance

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28
Q

Renal drug clearance

A

Autoregulation maintains constant renal flow over wide range of CO

Renal clearance small fraction of renal blood flow, due to protein binding

Renal tubular active transporters allow renal clearance to approach RBF

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29
Q

Decreased Renal function and dosing

A

Altered drug dosing required to avoid accumulation of parent compounds and metabolites

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30
Q

Drugs with significant renal excretion

A
Aminoglycosides
Atenolol
Cephalosporins 
Digoxin
Edrophonium
Nadolol
Neostigmine 
Pancuronium
PCNs
Procainamide
Pyridostigmine
Quinolone
Rocuronium
Sugammadex
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31
Q

First-order kinetics

A

Fixed PERCENTAGE/FRACTION of existing drug removed per unit of time

AMOUNT depends on serum levels

FRACTION removed does NOT depend on serum levels

Ex: if 10% removed per minute, k=0.1min^-1

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32
Q

Zero-order kinetics

A

Fixed AMOUNT of drug removed per unit of time

INDEPENDENT of serum levels

Found in certain drugs (e.g. Phenytoin, alcohol)

Can occur at high serum levels of drugs (notably thiopental) especially when concentration exceeds body’s capacity to metabolize drug

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33
Q

Half-life

A

Time required for serum concentration to change by a factor of 2

= ln 2/k

After 5 half-lives, drug 97% reduced in serum

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34
Q

Volume of distribution

A

Quantifies extent of drug distribution

= amount given/serum concentration

Describes capacity of tissues for absorbing certain drug

Depends on tissue mass and the affinity of that drug for the tissue

Numeric index of extent of distribution, describing behavior of drug in body

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35
Q

Vd of lipophilic drugs

A

Generally larger Vd than other classes

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36
Q

Loading dose

A

Vd x target concentration

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37
Q

Elimination clearance

A

(ClE) theoretical volume of flood from which drug is completely and irreversibly removed in a unit of time

= dose given/area under concentration vs time curve

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38
Q

Elimination half-life

A

(t 1/2 beta) amount of time it takes for the amount of drug IN THE BODY to decrease by a factor of 2

Depends on both distribution and elimination

= ln 2 x (Vd/ClE)

Does not say anything about termination of EFFECT (which depends on SERUM concentration), only elimination of drug from the body

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39
Q

Two- compartment model

A

Central compartment (VRG + plasma) and peripheral compartment

Initial spike in serum concentration after injection

Quick decline = distribution phase (alpha phase)
Slower decline = elimination phase (beta phase)

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40
Q

Pharmacodynamics

A

What the drug does to the body

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41
Q

ED50

A

Does required to produce a specific effect in 50% of the population (like MAC)

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42
Q

LD50

A

Dose required to cause death (or toxicity) in 50% of population

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43
Q

Therapeutic index

A

LD50/ED50

Measure of safety

Our drugs often have two-tailed therapeutic index

There are both low (awareness) and high (overdose) toxicities to avoid

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44
Q

Receptor model

A

Drug + receptor Drug - Receptor –> Effect

Agonist (X) binds to receptor (R) and produces an effect

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45
Q

Potency

A

How much drug you need to get an effect

Usually due to differing affinity for receptor

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46
Q

Efficacy

A

Max degree of effect a drug can cause

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47
Q

Partial Agonist

A

Produces a lower maximal response than a full agonist

Lower efficacy

Competitively inhibits response produced by full agonist

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48
Q

Redundancy

A

Generally an excess of receptors

Max effect typically occurs at FAR BELOW MAXIMUM receptor binding

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49
Q

Tolerance

A

Diminished response to a drug dose due to chronic exposure

Cellular tolerance (adaptation)

Enzyme induction (change in metabolism)

Depletion of neurotransmitters

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50
Q

Tachyphylaxis

A

Acute tolerance after only a few doses

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51
Q

Antagonists

A

Bind to receptor without producing an effect

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52
Q

Competitive antagonist

A

(Y) Binds reversible to same binding site

Effect can be overcome by increasing concentration of agonist

Decreases agonist potency, but efficacy is not changed

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53
Q

Non-competitive antagonist

A

(Z) some bind irreversibly to receptor

Some bind to allosteric site

Reduce both potency and efficacy

Cannot be completely overcome by increasing concentration of agonist

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54
Q

TBW

A

Actual BW of PT

Can lead to drug overdose in morbidly obese pts

Especially inappropriate for dosing water-soluble agonists

Succinylcholine
Cisatracurium
Neostigmine

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55
Q

LBW

A

Fat mass subtracted from TBW

Correlates with better CO and drug clearance

Does not account for obesity-related cardiomyopathy

Males: 1.1 x weight -128 x (weight/height)^2

Females: 1.07 x weight - 148 x (weight/height)^2

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56
Q

IBW

A

Based on height

Useful in pts with BMI<40

Males: 50kg + 2.3kg for every inch over 60

Females: 45.5kg + same

Vecuronium
Cisatracurium 
Rocuronium
Morphine
Acetaminophen
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57
Q

Ideal IV Anesthetic

A

Water soluble and stable

Lack of pain on injection; no tissue damage with extravasation

Low incidence of histamine release or hypersensitivity

Rapid smooth onset

Rapid metabolism to inactive metabolites

Minimal cardiac/respiratory depression

Decreases ICP/CMRO2

Rapid smooth recovery

Minimal side effects

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58
Q

Propofol

A

Inhibitory transmission (GABA)

Emulsion in intralipid (soybean oil, glycerol, egg lecithin)

Lecithin is from YOLK, most allergies are to egg WHITE (protein)

Supports bacterial growth

Discard open vial & tubing after 12 hours

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59
Q

Fospropofol

A

Aquavan: prodrug, water soluble,

Side effect: perineal burning

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60
Q

Propofol pharmacokinetics

A

Absorption: IV

Distribution: highly lipid soluble; very fast redistribution (<8mins)

Biotransformation: exceeds hepatic blood flow - implies extrahepatic metabolism (lungs?)
Up to 10x faster than thiopental
Liver conjugation (inactive metabolites), but not affected by moderate cirrhosis

Excretion: renal (but not affected by CRF)

Dose: 1.5-2.5 Mg/kg
25-75 mcg/kg/min for sedation
100-200 mcg/kg/min for GA - target plasma concentration of 4-6 mcg/mL

Some risk of awareness when used as sole agent, higher risk of pt movement

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61
Q

Propofol Infusion Syndrome

A

Lactic acidosis usually after prolonged high-dose infusions (>75 mcg/kg/min, >24 hours)

Lipemia, rhabdomyolysis, metabolic acidosis, death

May reflect a genetic susceptibility

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62
Q

Effects of Propofol (CV)

A

CV: decreased SVR, contractility, preload –> hypotension

Worse with rapid injection, old age, LV failure

Potential for bradycardia, but often tachycardia with induction

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63
Q

Effects of Propofol (Respiratory)

A

Respiratory: depression, apnea; depresses hypoxic/hypercapnic drives

Profound depression of upper airway reflexes

Asthmatics - less wheezing than with thiopental

64
Q

Effects of Propofol (Neuro)

A

Decreased CBF, ICP, CMRO2

Anti-emetic, anti-epileptic

Occasional myoclonic twitches, hiccough

Euphoria on emergence, intense dreaming, amorous behavior

Potential for abuse and addiction

Little evidence of tolerance

65
Q

Burning on Injection (Propofol)

A

Lipid solvent (and propofol itself) produces bradykinin which vasodilates, increases contact between the aqueous phase of Propofol (phenol is irritating) and the free nerve endings

Prevention: lidocaine + tourniquet (bier block)
Pre-treat with IV opioid
Mix with lidocaine
Lidocaine inhibits bradykinin

66
Q

Barbiturates

A

Phenobarbital, methohexital, thiopental, thiamylal, secobarbital

Depress RETICULAR ACTIVATING SYSTEM - consciousness center in the brain stem

Suppress excitatory neurotransmitters (ACh), enhance inhibitory (GABA)

Water soluble, preparation is very alkaline (pH>10) and unstable (2-6 weeks in refrigerator)

Weak acid with pKa close to 7.4

Pain with extravasation, but usually painless on injection

67
Q

Intra-arterial injection of thiobarbiturate

A

Crystals –> thrombosis, necrosis

Treat with papaverine, lidocaine, stellate ganglion block, heparin

68
Q

Thiobarbiturates

A

Thiopental, thiomylal

Higher lipid solubility –> greater potency, rapid onset, shorter duration

Thiopental used by many states for lethal injection, not currently available in US

69
Q

Oxybarbiturates

A

Phenobarbital, methohexital

Lower lipid solubility –> less potency, slower onset, longer duration

Methohexital is an exception: more potent and shorter duration of action than thiopental

70
Q

Barbiturate Pharmacokinetics

A

Absorption: IV for GA; rectal/IM for premedication

Distribution: lipid soluble –> fast onset (30 sec) and rapid redistribution (10-20mins) after single dose
Higher plasma levels in hypovolemia, hypoalbuminemia, acidosis, elderly

Multiple doses: saturate peripheral compartments, slower redistribution
Poor choose for maintenance

Biotransformation: almost complete hepatic oxidation
Methohexital: high hepatic extraction
Perfusion-limited metabolism
Shorter elimination half-life

Thiopental: low hepatic extraction
Capacity-limited half-life
Longer elimination half-life
Liver dz unlikely to cause prolonged effect from single dose

Excretion: protein bound, lipid soluble –> difficult renal clearance until Biotransformation

71
Q

Barbiturate Elimination Half-life

A

3-12 hours (methohexital: 3.9, thiopental: 11.6)

72
Q

Barbiturate Dosing

A

Thiopental: 3-5 Mg/kg; 6-8 Mg/kg infants

2-4 Mg/kg/hr for treatment of intracranial HTN or intractable seizures

Methohexital: 1-1.5 Mg/kg

73
Q

Effects of Barbiturates (CV)

A

Decreased BP, increased HR (central vagolytic effect); venous pooling

CO maintained except in hypovolemia, CHF, beta-blockade –> decreased CO and BP

74
Q

Effects of Barbiturates (Respiratory)

A

Decreased hypoxic/hypercapnic dribe; airway obstruction; bronchospasm/laryngospasm

75
Q

Effects of Barbiturates (Neuro)

A

Decreased CBF, ICP, CMRO2 to burst suppression on EEG, antiepileptic; tolerance/dependence

Methohexital: neuron excitation (myoclonus, hiccoughs, seizures?)
Common drug of choice for electroconvulsive therapy (ECT)

76
Q

Effects of Barbiturates (Renal)

A

Decreased RBF due to hypotension

77
Q

Effects of Barbiturates (hepatic)

A

Decreased hepatic blood flow; induction of enzymes (CYP); porphyrin formation –> porphyria

Disorder of enzyme in the heme bio-synthetic pathway

Acute porphyria: overproduction and accumulation
Neuro: abd pain, vomiting, neuropathy, weakness, seizures, hallucinations, depression, anxiety, paranoia
Cardiac arrythmias, pain, constipation/diarrhea

Other: sulfur-containing (thio-) may evoke histamine release

78
Q

Etomidate

A

Depresses reticular activating system, mimics GABA

Disinhibition of motor activity –> myoclonus
Attenuated with premedication (benzos, opioids)

Highly lipid soluble: dissolved in propylene glycol –> burning on injection
Available in fat emulsion –> no burning

79
Q

Pharmacokinetics of Etomidate

A

Absorption: IV

Distribution: highly protein bound but highly lipid soluble; rapid redistribution

Biotransformation: hepatic hydrolysis and plasma esterases
Impaired in liver dz

Excretion: urine

Dose: 0.2-0.3 Mg/kg

80
Q

Effects of Etomidate (CV)

A

Minimal effects –> first-like induction agent used in unstable pts, trauma cases

81
Q

Effects of Etomidate (Respiratory)

A

Minimal effects

82
Q

Effects of Etomidate (Neuro)

A

Decreased CMRO2, CBF, ICP; myoclonus; enhances SSEP amplitude
Antiepileptic, but seizure-like EEG signals in epileptic pts (no motor activity)
May increase incidence of PONV

83
Q

Effects of Etomidate (other)

A

Inhibition of cortisol/aldosterone synthesis –> adrenal insufficiency
Can occur even after single dose
Prolonged hospital stay, ICU stay, time on ventilator
Subject of ongoing debate

84
Q

Etomidate Interactions

A

Fentanyl can increase levels and prolong action

85
Q

Ketamine

A

Dissociative amnesia

Dissociates thalamus from limbic cortex = “cataleptic state”

Profound amnesia/analgesia despite maintaining consciousness and protective reflexes

Phencyclidine (PCP) analogue –> hallucinations

Inhibition + excitation; NMDA antagonist

86
Q

Ketamine Pharmacokinetics

A

Absorption: IV/IM (water soluble)

Distribution: rapid uptake and redistribution

Biotransformation: liver metabolism (some active) with high extraction (hepatic flow dependent)

Excretion: urine

Dose: analgesia: 0.1-0.5 Mg/kg IV
Induction: 1-2 Mg/kg IV or 4-8 Mg/kg IM

Mixed with propofol infusion - ex: 1 Mg ketamine per 10 Mg propofol

87
Q

Effects of Ketamine (CV)

A

Increased HR, BP, CO (inhibits NorEpi reuptake)

88
Q

Effects of Ketamine (Respiratory)

A

Bronchodilator, salivation, minimal effect on ventilation

89
Q

Effects of Ketamine (Neuro)

A

Increased CMRO2, CBF, ICP (@high doses); enhances SSEP amplitude

Hallucinations and nightmares (minimize with benzos); analgesia, amnesia

Myoclonus (but probably anti-epileptic)

Infusion for treatment of chronic pain syndromes

90
Q

Benzodiazepines

A

Lorazepam (Ativan), diazepam (Valium), midazolam (versed), flumazenil (romazicon)

Enhance inhibitory neurotransmitters (GABA) in cerebral cortex

91
Q

Solubility of Benzos

A

Lorazepam/Diazepam insoluble in water - dissolved in propylene glycol (irritant)

Midazolam in aqueous solution

92
Q

Benzodiazepine Pharmacokinetics

A

Absorption: IV/IM, PO, nasally, SL; IV required for GA induction (poor choice)

Significant first-pass hepatic effect

Distribution: moderately lipid soluble (except diazepam), rapid redistribution; protein bound

Midazolam onset: 30-60 secs, peak effect ~ 5 mins - space doses appropriately
Duration of effect: 15-80 mins

Biotransformation: CYP

Diazepam: low hepatic extraction, long elimination half-life; active metabolites
Lorazepam: lower lipid solubility –> faster elimination
Midazolam: higher hepatic extraction –> fastest elimination

Excretion: Urine

93
Q

Versed Dosing

A

Premedication: 0.04-0.08 Mg/kg IV/IM; 0.4-0.8 Mg/kg PO

Induction: 0.1-0.3 Mg/kg IV (slow recovery)

Infusion: 0.02-0.1 Mg/kg/hr

USE LESS IN ELDERLY PTS

94
Q

Effects of Benzodiazepines (CV)

A

Minimal depression

95
Q

Effects of Benzodiazepines (Respiratory)

A

Small decreases in hypercapnic drive, esp with other meds

96
Q

Effects of Benzodiazepines (Neuro)

A

Decreased CMRO2, CBF, ICP but less than barbs; no burst suppression

Anterograde amnesia, anxiolysis; anti-seizure; muscle relaxation

Dependence: onset of physical or psychological symptoms after reduction in dose

Withdrawal symptoms: irritability, tremulousness, insomnia –> can be fatal

Synergy with volatiles, opioids, ethanol, barbs, CNS depressants

97
Q

Antagonism of Benzodiazepines

A

Flumazenil: high affinity for receptor with minimal activity (competitive antagonist)

Give 0.01 Mg/kg up to 0.2 Mg IV bolus

Repeat q1 minute up to 5 doses (1 Mg max dose)

Resedation is likely - reside at 20 minute intervals as needed

No effect on MAC of volatiles

Can cause withdrawal symptoms in chronically dependent pts

98
Q

Dexmedetomidine

A

Precedex: highly selective alpha-2 agonist - similar to clonifine but even more specific

Used for sedation of ventilated ICU pts; anxiolysis, MAC, anesthesia adjuvant, awake intubations

Dose: 0.2 - 0.7 mcg/kg/he

99
Q

Effects of Precedex (CV)

A

Hypotension, bradycardia

100
Q

Effects of Precedex (Respiratory)

A

Minimal

101
Q

Effects of Precedex (Neuro)

A

Calm sedation with rousability, anxiolysis, some analgesia

Reduces MAC of volatile anesthetics by as much as 90% - at high doses

EXPENSIVE

102
Q

Opioid

A

Any natural, synthetic, or endogenous substances with morphine-like properties

103
Q

Endogenous Opioids

A

(Met)-Enkaphalin, Bega-endorphin

104
Q

Mu

A

Most act here

Analgesia, respiratory depression, miosis, euphoria, physical dependence, constipation, urinary retention

105
Q

Kappa

A

Analgesia, sedation, miosis, hallucinations

106
Q

Delta

A

Analgesia, constipation, seizures, physical dependence

107
Q

Sigma

A

Dysphoria, hallucinations

108
Q

Opioid Mechanism

A

Inhibit release of and response to excitatory neurotransmitters in nociceptive neurons

Receptors exist throughout CNS as well as in peripheral nerves

109
Q

Opioid Absorption

A

Multiple Routes:
IV: most rapid and complete absorption
IM: morphine, meperidine -20-60 mins
PO: 15-30 mins

Transmucosal: fentanyl - 10 mins
Transdermal: fentanyl - 14-24 hours (reservoir in dermis)

Neauraxial: diffusion to opioid receptors in spinal cord - no sympathectomy, motor blockade, or loss of proprioception

  • specific visceral analgesia > somatic analgesia
  • Morphine: 10mg IV = 1mg epidural = 100mcg intrathecal
110
Q

Opioid Distribution

A

Distribution half-life of 5-20 mins

Crosses BBB; non-ionized, lipid soluble
First pass uptake in the lungs (fentanyl)
Redistribution of small doses

111
Q

Opioid Biotransformation

A

Mostly in liver

Morphine, meperidine have active metabolites

Fentanyl, sufentanil, alfentanil have inactive metabolites

Remifentanil: ester hydrolysis via plasma esterases

112
Q

Opioid Excretion

A

Mostly in urine

Morphine: (morphine-3-glucuronide, morphine-6-glucuronide) and meperidine (normeperidine) are renally cleared - CAUTION IN RENAL PTS

113
Q

Opioid Tolerance and Dependence

A

Acquired tolerance develops after 2-3 weeks

Tolerance to analgesia, euphoria, sedation, ventilatory depression, but often NOT constipation

Addiction (physical and psychological dependence) usually takes about 25 days to develop, but some degree occurs within 48 hours

114
Q

Opioid Withdrawal

A

Severe flu-like illness (“super-flu”): rhinorrhea, sneezing, yawning, lacrimation, abd cramping, leg cramping, piloerection, n/v, diarrhea, and dilated pupils

Not typically life threatening

115
Q

Morphine

A

Mu Agonist
The “template”

Dose 0.01-.01 Mg/kg OR 2-8 Mg every 5-10 mins

Can decrease MAC to 65%

Crosses BBB slowly - 5 min onset, but peak in 10-40 mins

35% albumin-bound

116
Q

Morphine Redistribution and Metabolism

A

Rapid: elimination half-life 1.7-3.3 hours

Age dependent: 7-8 hours in neonates; 4.5 hours for ages 61-80

High Hepatic extraction –> elimination affected by decreased hepatic flow

Active Metabolites (M3G and MG6) as well as morphine –> urine

Monitor carefully in renal pts

117
Q

Morphine Neuro Effects

A

Sedation, cognitive impairment, euphoria

Decreased CMRO2, ICP, CBF if normocarbia maintained

Muscle rigidity after large doses –> can even interfere with manual ventilation

Miosis and pruritis

N/V

118
Q

Morphine Respiratory Effects

A

Decreases response to CO2; hypoventialtjon, apnea but arousable; decreases cough reflex

Depression can be within minutes or delayed several hours

119
Q

Morphine GI Effects

A

Decreased motility, slower gastric emptying, increased bile duct tone, biliary spasm (sphincter of Oddi)

120
Q

Morphine GU Effects

A

Urinary retention

121
Q

Morphine Endocrine Effects

A

HA release –> hypotension, dilation of cutaneous blood vessels

Prevents stress response at high doses

Prevents inflammatory response during CPB

122
Q

Morphine CV Effects

A

Hypotension at higher doses (greater effect in pts with high sympathetic tone); can cause bradycardia at higher doses

123
Q

Hydromorphone

A

Dilaudid: similar efficacy as morphine (also a strong agonist)

5-10x more potent, 1.5 Mg dilaudid IV = 10 Mg morphine IV

No active metabolites

LOA: 3-4 hours

Dose: 2-8 mcg/kg or 0.2-0.4 Mg IV Q 5-10 mins

124
Q

Methadone

A

Long duration of action; treatment of opioid withdrawal and chronic pain

Mu receptor AGONIST and NMDA ANTAGONIST

125
Q

Heroin

A

Produced via acetylation of morphine

Rapid CNS onset w/o nausea

Not for medical use in USA

126
Q

Meperidine

A

Demerol: only opioid with some LA properties

Can decrease contractility at high doses

Similar effects as morphine: sedation, miosis, euphoria, N/V, dizziness; HA release

Active metabolite NOMEPERIDINE –> urine
High hepatic extraction

Max daily dose: 600-1000mg

No longer recommended for analgesia due to euphoria, renal clearance, toxic metabolites –> high doses especially dangerous in pts with renal dz

Effective in reducing shivering (kappa receptors), small doses ok in renal pts

127
Q

Meperidine Resistribution

A

4-16 mins; elimination 3.5 hours

128
Q

Meperidine Dosing

A

0.1-1.0 Mg/kg (10x that if morphine)

Use 12.5-50mg for SHIVERING

129
Q

Fentanyl (and sufentanil, alfentanil)

A

Synthetic mu agonist - 100x more potent than morphine

Can reduce MAC by 50-70%

Very lipid soluble; rapidly crosses membranes = rapid onset and redistribution to inactive sites

Highly protein bound: pH dependent acidosis –> unbinding –> more free drug

Rapid hepatic extraction - high extraction ratio

Short acting as a single bolus dose - onset 10s, recovery starts within 5 mins, complete by 60 mins

Clinical duration limited by redistribution

130
Q

High dose Fentanyl

A

100mcg/kg

Stable, but slow emergence and reports of awareness

Muscle rigidity –> use of muscle relaxant –> more awareness

Has been used in cardiac (“stress-free”) Anesthesia, but does not prevent inflammatory response

131
Q

Fentanyl Dosing

A

Premedication: 25-50 mcg IV

Adjunct to induction: 1-5 mcg/kg IV

Intraoperative: 0.5-2.5 mcg/kg intermittently up to 3-5 mcg/kg/hr

132
Q

Fentanyl Side Affects

A

Chest wall rigidity - hard to ventilate

Myoclonus/seizure-like activity

Pruritis, N/V

Respiratory depression, especially when given with versed

133
Q

Sufentanil

A

Synthetic - 1000x more potent than morphine (10x more than fentanyl)

Shorter redistribution half-life (30 mins)

134
Q

Alfentanil

A

Potency between morphine and fentanyl

Much faster elimination half-life

Lower pKa –> mostly nonionized –> rapid onset and redistribution

Short duration even in very large doses - commonly used as an infusion

Can reduce MAC by up to 70%

135
Q

Remifentanil

A

Ultiva: ultra-short acting opioid

ESTER HYDROLYSIS by blood and tissue esterases

Metabolism much faster than redistribution

Infusion (rigidity with bolus)

Can decrease MAC by up to 90% at high doses

Postoperative HYPERALGESIA, acute opioid tolerance, some nausea

EXPENSIVE

136
Q

Remifentanil Dosing

A

Induction: 0.5-1.0 mcg/kg over 30s (w/propofol)

Infusion: 0.1 mcg/kg/min with low-dose propofol infusion

MAC: 0.05-0.25 mcg/kg/min; even less if versed or propofol are also used

137
Q

Partial Agonists

A

Bind to mu receptor with lower efficacy

Compared with morphine, lower maximum effect at high doses when given alone

Good for control of mild-moderate pain

Full agonist + partial agonist: partial agonist usually acts as COMPETITIVE ANTAGONIST

  • Competes with full agonist for receptors
  • Net decrease in the clinical effect compared with full agonist alone, the CEILING EFFECT - lowers risk of respiratory depression

Also some risk of diminishing analgesia or even inducing a state of withdrawal

138
Q

Codeine

A

Partial Opioid Agonist

Good oral bioavailability; strong cough suppressant; mild-moderate analgesia

Converts to morphine - 10% of Caucasian school cannot convert it

Mix with acetaminophen to get Tylenol #2, #3, #4 (we see #3 most)

139
Q

Hydocodone

A

Partial Opioid Agonist

Lortab

Mix with acetaminophen to get Vicodin or Lorcet

140
Q

Oxycodone or OxyContin

A

Partial Opioid Agonist

Extended release

Mix with acetaminophen to get Roxicet, Percocet, Percodan

141
Q

Tramadol

A

Partial Opioid Agonist

Moderate mu activity - much less potent than morphine

Also inhibition of spinal norepinephrine and serotonin uptake

Side affects: nausea, seizures, possible interaction with Coumadin

142
Q

Propoxyphene

A

Partial Opioid Agonist

Darvon

Mix with acetaminophen to get Darvocet

Withdrawn from US market (arrhythmias)

143
Q

Opioid Dosing Conversions

A

IV: 100mg meperidine - 10mg morphine - 1mg dilaudid - 100mcg fentanyl - 10mcg sufentanil

144
Q

Equinalgesic Doses of Opioid Analgesics

A

REFER TO TABLE ON PAGE 4 OF OPIOID NOTES

145
Q

PCA

A

Typically electronic infusion pump that delivers an amount of IV Opioid when the patient presses a button

Can be used for both acute and chronic pain

Postoperative pain management

End-Stage Ca pts

146
Q

PCA Principles

A

Caregiver programs the PCA to allow only delivery (bolus) of an opioid dose after a set interval (lockout)

Continuous basal infusion can also be programmed into the pump

147
Q

PCA Advantages

A

Self-delivery of pain less

Faster alleviation of pain

Accurate monitoring of demand and doses administered, which can be used to convert pts to oral and longer-acting Opioid regimens

Pt protected from overdose because if the pt is too sedated they can’t press button

Tend to use less total medication compared with cases in which medication is delivered according to a set schedule

148
Q

PCA Disadvantages

A

Self-administering pain meds for euphoric effect

Under-dose or overdose if PCA device not programmed properly

Inappropriate for pts with learning difficulties or confusion, poor manual dexterity, critically ill, younger pts

149
Q

Mixed Agonist-Antagonists

A

Substances related to morphine - bind at multiple opioid receptors

When given with low dose of full agonist: additive up to the max effect of the partial agonist

Pretreatment with these drugs can reduce or prevent the euphoria associated with morphine use, since the mu receptors are competitively antagonized

Mixed Opioid Agonist-antagonists are believed to have less ABUSE POTENTIAL than full or partial Opioid agonists

150
Q

Nalbuphine

A

Nubain: strong kappa agonist and mu receptor antagonist

Similar analgesia to morphine

Less respiratory depression - ceiling effect similar to 30mg morphine
-Could reverse morphine-induced respiratory depression without compromise of analgesia

Antagonism of pruritis associated with intrathecal/epidural morphine or fentanyl

Can precipitate withdrawal in Opioid-dependent parents

Low abuse potential

Elimination half-life: 3-6 hours

151
Q

Buprenorphrine

A

Buprenex: partial my receptor agonist and kappa receptor antagonist

Often given sublingually to avoid significant first-pass effect

50x greater affinity for mu receptor compared with morphine

Prolonged duration of action due to slow dissociation from receptors
Resistance to antagonism with narcan

152
Q

Buprenorphine Uses

A

Used in management of chronic pain as well as opioid dependence

Binds more strongly to receptors than other opioids

More difficult for opioids to react when buprenorphine is in system

153
Q

Buprenorphine PostOp

A

Caution in surgical pts: UNCONTROLLED POSTOP PAIN

unless procedure will cause little pain or pain can be adequately managed with LA, there are 4 ways to deal with this situation:

(1) wean pt off drug at least 4 days prior to surgery
(2) switch pt from drug to another long-acting med like methadone
(3) with pt from drug to another opioid agonist like morphine
(4) anticipate the need for very large doses of opioids in the post op period, which may require additional monitoring and nursing care

154
Q

Suboxone

A

Buprenorphine + Narcan

Mixed with a pure mu receptor antagonism to prevent diversion for elicit IV use

155
Q

Naloxone

A

Narcan: Opioid Antagonist

Pure antagonist at mu, kappa, and delta receptors

Can reverse effects of endogenous opioids as well

Careful titration to prevent sudden, severe pain (HTN, tachycardia, pulm edema)

Opioid withdrawal in dependent pts

Dilute 1 coal 0.4mg in 10mL, and titrate 20-40mcg Q 1-2mins

Short duration of action, repeat dose or infusion may be required

156
Q

Context sensitive half-time/Context sensitive decrement time

A

Half time: time for amount of drug in the central compartment to decrease by 50%

Context: duration of the infusion prior to stopping it

Increases as a function of the duration of the infusion before it was stopped
Due to movement of drug stored in peripheral compartment back into central

Effect becomes more pronounced when trying to clear out a large percent of drug