Exam 1

Question 1

Pharmacokinetics

Answer 1

What the body does to the drug

Question 2

Absorption

Answer 2

How the drug gets in

Question 3

Bioavailability

Answer 3

Relative amount of drug that reaches systemic circulation

= 1 for parenteral (IV or IM)

Question 4

First-pass metabolism

Answer 4

Occurs before drug reaches systemic circulation

Liver: very significant for enteral administration

Lung: fentanyl uptake, propofol metabolism

Plasma esterases/pseudocholinesterase

Question 5

First-Pass of sublingual route

Answer 5

Direct absorption into systemic venous system, avoids portal circulation

NO FIRST-PASS

Question 6

Distribution of cardiac output

Answer 6

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

Question 7

Redistribution

Answer 7

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

Question 8

Albumin

Answer 8

Carrier protein produced in the liver

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

Question 9

Alpha-1-acid glycoprotein

Answer 9

Binds most basic drugs

Question 10

Pt with low protein levels

Answer 10

Higher free drug levels

Question 11

Cell Membrane make up

Answer 11

Lipid bilayer

Small lipophilic drugs pass freely

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

Question 12

Passive transport

Answer 12

Movement of drug down its concentration gradient

Generally limited by blood flow

Drug will diffuse as quickly as it can be delivered

Question 13

Facilitated diffusion

Answer 13

Needs carrier proteins, NO ENERGY REQUIREMENT

Question 14

Active transport

Answer 14

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

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

Question 15

Acid-Base

Answer 15

H(+) + A- HA

H(+) + B HB(+)

CHARGED SPECIES DONT CROSS MEMBRANES WELL

Question 16

pKa

Answer 16

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

Question 17

Biotransformation

Answer 17

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

Most drugs need to be HYDROPHILIC for excretion

Question 18

Phase 1 Biotransformation

Answer 18

Oxidation, reduction, hydrolysis

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

Question 19

CYP

Answer 19

Enzyme that catalyzes most phase 1 rxns

Activity increases with ongoing drug exposure

Can be inhibited when drugs compete for same CYP subtype

Question 20

CYP3A4/5

Answer 20

Subtype of CYP family

Metabolizes many opioids, benzos, LA’s

Question 21

Phase 2 Biotransformation

Answer 21

Conjugation with a polar substance

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

Question 22

Neonate Biotransformation

Answer 22

Neonates through 1 year have diminished phase 1 and 2 activities

Question 23

Hepatic Drug Clearance

Answer 23

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

Hepatic blood flow x extraction ratio

Question 24

Hepatic blood flow

Answer 24

Dependent on CO and BP

Question 25

Hepatic extraction ratio

Answer 25

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

Question 26

High Extraction Ratio

Answer 26

"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

Question 27

Low extraction ratio

Answer 27

"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

Question 28

Renal drug clearance

Answer 28

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

Question 29

Decreased Renal function and dosing

Answer 29

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

Question 30

Drugs with significant renal excretion

Answer 30

``` Aminoglycosides Atenolol Cephalosporins Digoxin Edrophonium Nadolol Neostigmine Pancuronium PCNs Procainamide Pyridostigmine Quinolone Rocuronium Sugammadex ```

Question 31

First-order kinetics

Answer 31

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

Question 32

Zero-order kinetics

Answer 32

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

Question 33

Half-life

Answer 33

Time required for serum concentration to change by a factor of 2 = ln 2/k After 5 half-lives, drug 97% reduced in serum

Question 34

Volume of distribution

Answer 34

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

Question 35

Vd of lipophilic drugs

Answer 35

Generally larger Vd than other classes

Question 36

Loading dose

Answer 36

Vd x target concentration

Question 37

Elimination clearance

Answer 37

(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

Question 38

Elimination half-life

Answer 38

(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

Question 39

Two- compartment model

Answer 39

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)

Question 40

Pharmacodynamics

Answer 40

What the drug does to the body

Question 41

ED50

Answer 41

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

Question 42

LD50

Answer 42

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

Question 43

Therapeutic index

Answer 43

LD50/ED50 Measure of safety Our drugs often have two-tailed therapeutic index There are both low (awareness) and high (overdose) toxicities to avoid

Question 44

Receptor model

Answer 44

Drug + receptor Drug - Receptor --> Effect Agonist (X) binds to receptor (R) and produces an effect

Question 45

Potency

Answer 45

How much drug you need to get an effect Usually due to differing affinity for receptor

Question 46

Efficacy

Answer 46

Max degree of effect a drug can cause

Question 47

Partial Agonist

Answer 47

Produces a lower maximal response than a full agonist Lower efficacy Competitively inhibits response produced by full agonist

Question 48

Redundancy

Answer 48

Generally an excess of receptors Max effect typically occurs at FAR BELOW MAXIMUM receptor binding

Question 49

Tolerance

Answer 49

Diminished response to a drug dose due to chronic exposure Cellular tolerance (adaptation) Enzyme induction (change in metabolism) Depletion of neurotransmitters

Question 50

Tachyphylaxis

Answer 50

Acute tolerance after only a few doses

Question 51

Antagonists

Answer 51

Bind to receptor without producing an effect

Question 52

Competitive antagonist

Answer 52

(Y) Binds reversible to same binding site Effect can be overcome by increasing concentration of agonist Decreases agonist potency, but efficacy is not changed

Question 53

Non-competitive antagonist

Answer 53

(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

Question 54

TBW

Answer 54

Actual BW of PT Can lead to drug overdose in morbidly obese pts Especially inappropriate for dosing water-soluble agonists Succinylcholine Cisatracurium Neostigmine

Question 55

LBW

Answer 55

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

Question 56

IBW

Answer 56

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 ```

Question 57

Ideal IV Anesthetic

Answer 57

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

Question 58

Propofol

Answer 58

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

Question 59

Fospropofol

Answer 59

Aquavan: prodrug, water soluble, Side effect: perineal burning

Question 60

Propofol pharmacokinetics

Answer 60

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

Question 61

Propofol Infusion Syndrome

Answer 61

Lactic acidosis usually after prolonged high-dose infusions (>75 mcg/kg/min, >24 hours) Lipemia, rhabdomyolysis, metabolic acidosis, death May reflect a genetic susceptibility

Question 62

Effects of Propofol (CV)

Answer 62

CV: decreased SVR, contractility, preload --> hypotension Worse with rapid injection, old age, LV failure Potential for bradycardia, but often tachycardia with induction

Question 63

Effects of Propofol (Respiratory)

Answer 63

Respiratory: depression, apnea; depresses hypoxic/hypercapnic drives Profound depression of upper airway reflexes Asthmatics - less wheezing than with thiopental

Question 64

Effects of Propofol (Neuro)

Answer 64

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

Question 65

Burning on Injection (Propofol)

Answer 65

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

Question 66

Barbiturates

Answer 66

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

Question 67

Intra-arterial injection of thiobarbiturate

Answer 67

Crystals --> thrombosis, necrosis Treat with papaverine, lidocaine, stellate ganglion block, heparin

Question 68

Thiobarbiturates

Answer 68

Thiopental, thiomylal Higher lipid solubility --> greater potency, rapid onset, shorter duration Thiopental used by many states for lethal injection, not currently available in US

Question 69

Oxybarbiturates

Answer 69

Phenobarbital, methohexital Lower lipid solubility --> less potency, slower onset, longer duration Methohexital is an exception: more potent and shorter duration of action than thiopental

Question 70

Barbiturate Pharmacokinetics

Answer 70

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

Question 71

Barbiturate Elimination Half-life

Answer 71

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

Question 72

Barbiturate Dosing

Answer 72

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

Question 73

Effects of Barbiturates (CV)

Answer 73

Decreased BP, increased HR (central vagolytic effect); venous pooling CO maintained except in hypovolemia, CHF, beta-blockade --> decreased CO and BP

Question 74

Effects of Barbiturates (Respiratory)

Answer 74

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

Question 75

Effects of Barbiturates (Neuro)

Answer 75

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)

Question 76

Effects of Barbiturates (Renal)

Answer 76

Decreased RBF due to hypotension

Question 77

Effects of Barbiturates (hepatic)

Answer 77

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

Question 78

Etomidate

Answer 78

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

Question 79

Pharmacokinetics of Etomidate

Answer 79

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

Question 80

Effects of Etomidate (CV)

Answer 80

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

Question 81

Effects of Etomidate (Respiratory)

Answer 81

Minimal effects

Question 82

Effects of Etomidate (Neuro)

Answer 82

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

Question 83

Effects of Etomidate (other)

Answer 83

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

Question 84

Etomidate Interactions

Answer 84

Fentanyl can increase levels and prolong action

Question 85

Ketamine

Answer 85

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

Question 86

Ketamine Pharmacokinetics

Answer 86

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

Question 87

Effects of Ketamine (CV)

Answer 87

Increased HR, BP, CO (inhibits NorEpi reuptake)

Question 88

Effects of Ketamine (Respiratory)

Answer 88

Bronchodilator, salivation, minimal effect on ventilation

Question 89

Effects of Ketamine (Neuro)

Answer 89

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

Question 90

Benzodiazepines

Answer 90

Lorazepam (Ativan), diazepam (Valium), midazolam (versed), flumazenil (romazicon) Enhance inhibitory neurotransmitters (GABA) in cerebral cortex

Question 91

Solubility of Benzos

Answer 91

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

Question 92

Benzodiazepine Pharmacokinetics

Answer 92

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

Question 93

Versed Dosing

Answer 93

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

Question 94

Effects of Benzodiazepines (CV)

Answer 94

Minimal depression

Question 95

Effects of Benzodiazepines (Respiratory)

Answer 95

Small decreases in hypercapnic drive, esp with other meds

Question 96

Effects of Benzodiazepines (Neuro)

Answer 96

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

Question 97

Antagonism of Benzodiazepines

Answer 97

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

Question 98

Dexmedetomidine

Answer 98

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

Question 99

Effects of Precedex (CV)

Answer 99

Hypotension, bradycardia

Question 100

Effects of Precedex (Respiratory)

Answer 100

Minimal

Question 101

Effects of Precedex (Neuro)

Answer 101

Calm sedation with rousability, anxiolysis, some analgesia Reduces MAC of volatile anesthetics by as much as 90% - at high doses EXPENSIVE

Question 102

Opioid

Answer 102

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

Question 103

Endogenous Opioids

Answer 103

(Met)-Enkaphalin, Bega-endorphin

Question 104

Mu

Answer 104

Most act here Analgesia, respiratory depression, miosis, euphoria, physical dependence, constipation, urinary retention

Question 105

Kappa

Answer 105

Analgesia, sedation, miosis, hallucinations

Question 106

Delta

Answer 106

Analgesia, constipation, seizures, physical dependence

Question 107

Sigma

Answer 107

Dysphoria, hallucinations

Question 108

Opioid Mechanism

Answer 108

Inhibit release of and response to excitatory neurotransmitters in nociceptive neurons Receptors exist throughout CNS as well as in peripheral nerves

Question 109

Opioid Absorption

Answer 109

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

Question 110

Opioid Distribution

Answer 110

Distribution half-life of 5-20 mins Crosses BBB; non-ionized, lipid soluble First pass uptake in the lungs (fentanyl) Redistribution of small doses

Question 111

Opioid Biotransformation

Answer 111

Mostly in liver Morphine, meperidine have active metabolites Fentanyl, sufentanil, alfentanil have inactive metabolites Remifentanil: ester hydrolysis via plasma esterases

Question 112

Opioid Excretion

Answer 112

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

Question 113

Opioid Tolerance and Dependence

Answer 113

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

Question 114

Opioid Withdrawal

Answer 114

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

Question 115

Morphine

Answer 115

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

Question 116

Morphine Redistribution and Metabolism

Answer 116

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

Question 117

Morphine Neuro Effects

Answer 117

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

Question 118

Morphine Respiratory Effects

Answer 118

Decreases response to CO2; hypoventialtjon, apnea but arousable; decreases cough reflex Depression can be within minutes or delayed several hours

Question 119

Morphine GI Effects

Answer 119

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

Question 120

Morphine GU Effects

Answer 120

Urinary retention

Question 121

Morphine Endocrine Effects

Answer 121

HA release --> hypotension, dilation of cutaneous blood vessels Prevents stress response at high doses Prevents inflammatory response during CPB

Question 122

Morphine CV Effects

Answer 122

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

Question 123

Hydromorphone

Answer 123

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

Question 124

Methadone

Answer 124

Long duration of action; treatment of opioid withdrawal and chronic pain Mu receptor AGONIST and NMDA ANTAGONIST

Question 125

Heroin

Answer 125

Produced via acetylation of morphine Rapid CNS onset w/o nausea Not for medical use in USA

Question 126

Meperidine

Answer 126

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

Question 127

Meperidine Resistribution

Answer 127

4-16 mins; elimination 3.5 hours

Question 128

Meperidine Dosing

Answer 128

0.1-1.0 Mg/kg (10x that if morphine) Use 12.5-50mg for SHIVERING

Question 129

Fentanyl (and sufentanil, alfentanil)

Answer 129

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

Question 130

High dose Fentanyl

Answer 130

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

Question 131

Fentanyl Dosing

Answer 131

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

Question 132

Fentanyl Side Affects

Answer 132

Chest wall rigidity - hard to ventilate Myoclonus/seizure-like activity Pruritis, N/V Respiratory depression, especially when given with versed

Question 133

Sufentanil

Answer 133

Synthetic - 1000x more potent than morphine (10x more than fentanyl) Shorter redistribution half-life (30 mins)

Question 134

Alfentanil

Answer 134

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%

Question 135

Remifentanil

Answer 135

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

Question 136

Remifentanil Dosing

Answer 136

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

Question 137

Partial Agonists

Answer 137

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

Question 138

Codeine

Answer 138

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)

Question 139

Hydocodone

Answer 139

Partial Opioid Agonist Lortab Mix with acetaminophen to get Vicodin or Lorcet

Question 140

Oxycodone or OxyContin

Answer 140

Partial Opioid Agonist Extended release Mix with acetaminophen to get Roxicet, Percocet, Percodan

Question 141

Tramadol

Answer 141

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

Question 142

Propoxyphene

Answer 142

Partial Opioid Agonist Darvon Mix with acetaminophen to get Darvocet Withdrawn from US market (arrhythmias)

Question 143

Opioid Dosing Conversions

Answer 143

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

Question 144

Equinalgesic Doses of Opioid Analgesics

Answer 144

REFER TO TABLE ON PAGE 4 OF OPIOID NOTES

Question 145

PCA

Answer 145

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

Question 146

PCA Principles

Answer 146

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

Question 147

PCA Advantages

Answer 147

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

Question 148

PCA Disadvantages

Answer 148

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

Question 149

Mixed Agonist-Antagonists

Answer 149

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

Question 150

Nalbuphine

Answer 150

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

Question 151

Buprenorphrine

Answer 151

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

Question 152

Buprenorphine Uses

Answer 152

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

Question 153

Buprenorphine PostOp

Answer 153

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

Question 154

Suboxone

Answer 154

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

Question 155

Naloxone

Answer 155

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

Question 156

Context sensitive half-time/Context sensitive decrement time

Answer 156

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