Pharmacology I Review

I. Pharmacokinetics – the body’s effect on the drug

a. Phase 1 reactions – hydrolyze, oxidize or reduce the parent compound

i. Catalyzed largely by the cytochrome P450 system

1. P450 system can be both induced by repetitive drug

administration

a. barbiturates

b. ETOH

c. antihistamines

d. phenytoin

2. P450 system can also be inhibited by competing drugs

b. Phase 2 reactions – conjugation of the parent compound to make it more

polar

i. Enzymes involved in conjugation can also be induced with repetitive

drug administration

c. Zero-order elimination – removal of a constant amount of drug per unit of

time

i. An uncommon method of drug elimination that implies saturation of a

metabolic or excretory pathway (ETOH removal)

d. First-order elimination – removal of a constant fraction of drug per unit of

time

i. Nearly all drugs administered during administration of an anesthetic

undergo first-order elimination

e. Volume of distribution (VD)– amount of drug administered divided by the

plasma concentration

i. Lipid soluble drugs (unionized, non-polar) have large volumes of

distribution

ii. Hydrophilic drugs (ionized, polar) have small volumes of distribution,

less than 1 L/kg

f. Clearance – the volume of blood from which the drug is completely

removed per unit of time

g. Half-life – proportional to the volume of distribution divided by the

clearance

i. Each half-life represents a 50% reduction in plasma concentration

1. After 4 – 5 half-lives most drugs lack clinical activity

h. Multi-compartment model – lipid soluble drugs will distribute first to those

organs receiving the greatest blood flow – brain, liver, lungs, kidneys and

heart (vessel-rich group)

i. This initial drug distribution causes a rapid decline in plasma

concentration

ii. As other less-well perfused organs continue to take up the drug

plasma concentration continues to decline and the vessel-rich group

begins to surrender drug to the plasma (A.K.A. α or redistribution

phase)

iii. Finally, plasma levels continue to decline as a result of drug

elimination (A.K.A. β or elimination phase)

II. Pharmacodynamics – the drug’s effect on the body

a. Most drugs exert their effect by a drug-receptor interaction

b. Agonists – bind to receptor and induce a response similar to that produced

by the endogenous ligand

c. Inverse agonists – bind to the receptor and induce a response opposite to

that produced by the endogenous ligand

d. Antagonists – bind to the receptor and inhibit the effects of the

endogenous ligand

i. Competitive inhibition – an increase in the concentration of the

endogenous ligand will cause reversal of the antagonist’s effect

ii. Non-competitive inhibition - an increase in the concentration of the

endogenous ligand will not cause reversal of the antagonist’s effect

1. This is often the result of covalent bonding of the drug to the

receptor site

e. Protein binding – most drugs are protein bound to some extent

i. Only the free-fraction of the drug (not protein bound) is

pharmacologically active

ii. Lipid soluble drugs tend to have extensive protein binding

iii. Drugs can compete for protein binding sites causing changes in the

free-fraction of the drug

iv. Albumin is the most common site of protein binding

1. Transcortin, globulins and alpha-1-acid glycoprotein

constitute other important sites of protein binding

a. Alpha-1-acid glycoprotein is especially important in

the protein binding of local anesthetics

f. Tachyphylaxis - diminished effect of a drug when used continuously or

repeatedly

g. Therapeutic index - LD50 divided by ED50

h. Margin of safety - LD01 divided by ED99

III. Autonomic Nervous System Physiology

a. Formed by two distinct systems that balance and control the visceral

functions of the body

i. Sympathetic system – triggered during times of stress to mobilize

resources for the flight-or-fight response

ii. Parasympathetic system – maintains bodily functions during non-

stressful time, such as digestion

iii. Functions maintained in balance by the autonomic nervous system

include blood pressure, cardiac output, vascular tone, thermal

regulation, digestion, bronchial tone, micturition, blood glucose levels,

and nasal, salivary and lacrimal secretions

b. Parasympathetic anatomy and physiology

i. Preganglionic nerves originate from the cranial and sacral nerves

1. A.K.A. as the craniosacral system

2. Cranial nerves III, V, VII, IX and X contain parasympathetic

fibers

3. Sacral nerves 2,3 & 4 contain parasympathetic fibers

ii. Preganglionic nerves are long with ganglia near the effector organ

iii. Autonomic ganglia use acetylcholine (ACh) as neurotransmitter and

nicotinic (NN) receptors

iv. Postganglionic fibers release ACh

1. Effector organs contain muscarinic receptors

a. 5 subtypes of muscarinic receptors are known

i. M1 – facilitate release of ACh

ii. M2 – found largely in cardiac tissue

iii. M3 – found in smooth muscle (eye, bronchi)

iv. M4 & M5 – found in CNS

2. Termination of effect of ACh result of acetyl or true

cholinesterase

c. Sympathetic anatomy and physiology

i. Preganglionic fibers originate from the thoracic and lumbar cord

1. Also known and the thoracolumbar system

2. Preganglionic fibers come from the intermediolateral column

from T1 to L2

ii. Preganglionic fibers are short, myelinated and run along both sides of

the vertebrae

iii. Sympathetic fibers commonly run with sensory fibers

iv. Autonomic ganglia use ACh as neurotransmitter and nicotinic (NN)

receptors

v. Postganglionic fibers are long and release norepinephrine

vi. Effector organs contain adrenergic receptors

1. Alpha1 - postsynaptic receptors at the effector organ

2. Alpha2

a. inhibitory presynaptic receptors

b. postsynaptic receptors found in CNS and oversee

platelet aggregation

3. Beta1 - cardiac receptors, juxtaglomerular apparatus

4. Beta2 - non-cardiac receptors (bronchioles, blood vessels)

5. Dopamine - vessels of mesenteric and renal beds

(vasodilation); CNS effects

a. Subtypes:

i. DA1 – most widespread and abundant; highly

expressed in basal ganglia; stimulation causes

increased adenyl cyclase activity

ii. DA2, 3, 4 - inhibitory; stimulation causes

inhibition of cyclic AMP

iii. DA5 – closely related to DA1; expressed in

nucleus of thalamus (? role in pain

transmission)

b. Distribution:

i. Cerebral cortex: D1,2,3,4,5

ii. Limbic system: D1,2,3,4,5

iii. Pituitary: D2

iv. Striatum: D1,2

v. CV, mesenteric beds: D1,2

vii. Termination of norepinephrine effect result of reuptake by

presynaptic nerve terminal

1. Monamine oxidase (MAO) is intraneuronal enzyme capable

of destroying norepinephrine and is used to regulate

neurotransmitter content in the presynaptic terminal

2. Circulating catecholamines are methylated and inactivated in

the liver by catechol-O-methyltransferase (COMT)

IV. Autonomic Pharmacology

a. Cholinomimetic agents

i. Acetylcholine - of limited pharmacological use as a result of rapid

hydrolysis. Used topically in the eye

ii. Methacholine - addition of methyl moiety reduces rate of hydrolysis

iii. Carbamylcholine - addition of carbamyl moiety reduces rate of

hydrolysis

iv. Bethanchol - contains both methyl and carbamyl moieties. Used in

the treatment of urinary retention

b. Anticholinergic agents

i. Atropine - causes peripheral muscarinic receptor blockade with slight

CNS effect at clinically used doses

ii. Scopolamine - readily crosses the blood-brain barrier and has

significant CNS effect. Also is a more potent antisialogogue and

mydriatic as compared to atropine

iii. Glycopyrrolate - synthetic quaternary amine that does not cross the

blood-brain barrier

iv. Ipratropium - inhaled anticholinergic agent used in the treatment of

bronchospastic disorders. Unlike atropine, it does not cause inhibition

of ciliary function

c. Sympathomimetic agents

i. Dopamine receptor agonists

1. Dopamine - endogenous catecholamine with dopaminergic,

and alpha- and beta-agonist activity

2. Fenoldopam - selective D1-agonist used in the treatment of

hypertension. Provides superior renal-protective effect as

compared to dopamine

3. Selective α1-receptor agonists

a. Phenylephrine - causes arteriolar and venous

constriction

b. Shown not to be detrimental to fetal oxygen delivery

when used to treat hypotension following neuraxial

blockade

4. Selective α2-receptor agonists

a. Effects largely secondary to CNS actions

i. Sedation and decreased sympathetic output

seen with use

b. Clonidine - used as an antihypertensive agent

i. Also effective in treatment of opioid withdrawal

ii. Should NOT be withheld prior to surgery

iii. lowers MAC requirements

c. Dexmedetomidine - useful in ICU setting to provide

sedation and analgesia while sparing respiratory drive

i. Hypotension and bradycardia are common side

effects

ii. exhibits slightly delayed onset

d. Non-selective β-receptor agonists

i. Isoproterenol

1. Produces positive inotropic,

chronotropic & dromotropic effects

2. Causes vasodilation of muscle bed

3. Produces bronchodilation

ii. Dobutamine

1. Synthetic catecholamine

2. Has potent β1-receptor agonistic activity

3. Causes less vasoconstriction than

dopamine

5. Selective β2-receptor agonists

a. Used to reduce bronchial airway resistance

b. Inhaled agents include: metproterenol, salmeterol,

albuterol & isoetharine

c. Terbutaline & ritodrine

i. Terbutaline is used primarily for the long-term

treatment of obstructive pulmonary disease

ii. Terbutaline & ritodrine are also tocolytic drugs

1. Significant hypokalemia has been

associated with the prolonged

administration of these drugs

2. May cause hyperglycemia

6. Non-selective adrenergic agonists

a. Epinephrine -

i. More pronounced beta-receptor activity and

beta effects predominate when lower doses

are used

ii. Alpha effects predominate when higher doses

are used

b. Norepinephrine

i. Principal endogenous mediator of SNS activity

1. Released by postganglionic SNS nerve

terminals

ii. Exogenously administered norepinephrine has

effects on alpha and beta1 adrenoreceptors.

1. No effect on β2-receptors clinically

2. Most often used therapeutically for the

treatment of profound vasodilation

c. Dopamine - see above

d. Ephedrine

i. Plant alkaloid with both direct and indirect

activity

ii. Competes with norepinephrine for local

reuptake

iii. Effects resemble those of epinephrine, but are

less pronounced and longer lasting

7. α-antagonists

a. Phenoxybenzamine - irreversible, non-competitive,

non-selective blocker

i. Used to manage pheochromocytoma and

neurogenic bladder

b. Phentolamine & tolazoline

i. Competitive, non-selective blockers

ii. Phentolamine can be infiltrated into tissues to

reduce the effects of extravasation of

norepinephrine

8. α1- selective antagonists

a. Prazocin, terazocin, tamsulosin

i. Causes vasodilation and decreased SVR

ii. α1- selectivity blunts reflex tachycardia

iii. Also used in treatment of BPH

9. β-receptor antagonists

a. Propranolol - prototype of non-selective β-receptor

antagonists

i. Side effects: bradycardia, CHF, inhibition of

gluconeogenesis, bronchoconstriction

ii. Rebound adrenergic state can occur with

discontinuation

10. Selective β1-receptor antagonists

a. Esmolol - rapidly hydrolyzed by red cell esterase

i. Half-life of 9 - 10 minutes

b. Metoprolol

11. Mixed α,β-receptor antagonists

a. Labetelol - predominantly beta effects (7:1)

i. Vasodilation tends to preserve cardiac output

b. Carvedilol - only available as an oral preparation

12. Direct vasodilators

a. Nitroprusside (SNP) - donates nitric oxide (NO)

directly resulting in vasodilation

i. Broken down in RBCs with release of cyanide

anion

1. Cyanide converted to thiocyanate in the

liver by rhodanase through

transsulfuration

2. Cyanide toxicity presents as

tachyphylaxis, metabolic acidosis and

increased PvO2

b. Nitroglycerine - requires active reduction to release

NO

i. Clinically causes greater venodilation and less

arteriolar dilation

c. Hydralazine - promotes influx of potassium into

vascular smooth muscle resulting in

hyperpolarization.

i. Prolonged effect as compared to nitrates

ii. Secondary reflex vasodilation may precipitate

myocardial ischemia

13. Phospodiesterase (PDE) inhibitors

a. Methylxanthines - theophylline, aminophylline

i. Cause an increase in cAMP activity that results

in vasodilation, positive inotropy and

bronchodilation

b. Milrinone & amrinone

i. Selective PDE-3 inhibitors which cause

increased inotropy and vasodilation

ii. Useful in low cardiac output states

iii. Amrinone causes platelet inhibition

14. Drugs affecting the renin-angiotensin-aldosterone (RAAS)

system

a. ACE inhibitior (enalapril is prototype)

i. Inhibit the conversion of angiotensin I to

angiotensin II

ii. Produce vasodilation and decrease effect of

aldosterone

iii. Cough a common side effect

b. Angiotensin-receptor blockers

i. Block angiotensin II from receptor site

ii. Cardiovascular effects the same as ACE

inhibitors

iii. Do not cause cough

V. Neuromuscular Physiology

a. Neuromuscular transmission

i. ii. Motor unit - the functional group of a terminal nerve fiber with muscle

fibers served by the terminal nerve fiber

iii. Release of ACh is associated with an influx of calcium into the nerve

terminal

1. ACh is synthesized in the nerve terminal by the enzyme

choline acetyltransferase

2. ACh is stored in the nerve terminal in packets called quanta

3. Each quantum stores about 5000 ACh molecules

4. About 200 quanta are released with each impulse

5. Two major pools of ACh are available for release

a. V1 - reserve pool, which is mobilized and used during

repetitive depolarizations

b. V2 - readily releasable pool, which is used with single

or infrequent depolarizations

iv. Approximately 50% of the released ACh reaches the target receptors

1. Remaining ACh is either hydrolyzed or diffused away

v. Postjunctional receptors

1. 2. Receptors traverse the muscle membrane

a. Receptors open and close allowing ion transfer

b. Alpha subunits contain ACh receptors

c. Fetal and extra-junctional receptors have greatly

increased sensitivity to ACh

i. Both fetal and extra-junctional receptors have

been found in patients with prolonged

immobilization, lower-motor neuron diseases

and burns

vi. Prejunctional receptors

1. Autoreceptors responsible for increased ACh release by

means of a positive feedback system

2. May be responsible in part for the fade seen with non-

depolarizing neuromuscular blocking agents (NMBAs)

vii. Acetylcholinesterase (ChE)

1. Hydrolyzes ACh into acetate and choline

a. Hydrolysis is very rapid, < 1 ms

2. ChE is secreted by muscle tissue

3. Choline created by ACh hydrolysis is taken up by nerve

terminal for re-use

VI. Neuromuscular blocking agents

a. Depolarizing NMBAs - succinylcholine (SCh)

i. Causes persistent depolarization of the neuromuscular junction

resulting in flaccid paralysis

ii. SCh is not hydrolyzed by ChE, but rather by plasma cholinesterase

1. Termination of effect is the result of diffusion away from the

junction as a result of the concentration gradient created by

drug destruction

iii. Adverse effects include:

1. Cardiac arrhythmias

2. Hyperkalemia

a. Usual potassium increase is 0.5 mEq/L

i. In patients with extrajunctional receptors,

potassium increase may exceed 9 mEq/L

3. Myalgias

4. Second-dose effect

5. Increased intragastric, intracranial, intrathoracic & intraocular

pressures

a. Trans-GE sphincter pressure unchanged

i. These effects can be attenuated (but not

completely prevented) by pretreatment with a

nondepolarizing blocker

6. Masseter spasm - up to 20% will go on to MH

7. Prolonged duration of action in patients with deficient or

defective plasma cholinesterase

a. Plasma cholinesterase activity can be assessed using

the dibucaine number (% inhibition of PChE)

i. Normal = 80% or higher

ii. Heterozygous abnormality = 40 - 60%

iii. Homozygous abnormality = 20% or less

8. Resistance noted in obese patients

a. Dosage based on TBW

9. MH

b. Nondepolarizing NMBAs

i. Benzylisoquinolinium compounds

1. Atracurium

a. Intermediate acting agent

i. Plasma half-life of 20 - 40 minutes

b. Modes of elimination

i. Hoffman elimination

1. Produces laudanosine and

pentamethylenediacrylate

2. Temperature & pH dependent (37° C;

7.4)

ii. Ester hydrolysis

iii. Renal elimination

iv. No drug accumulation

v. causes a modest histamine release

2. Cis-atracurium

a. Intermediate acting agent

b. Cis stereoisomer of atracurium

c. Approximately 3X more potent than atracurium

d. Does NOT release histamine

e. Elimination

i. 77% eliminated by Hoffman elimination

ii. 16% undergoes renal elimination

iii. Very little undergoes ester hydrolysis

ii. Steroidal compounds

1. Pancuronium

a. Long acting agent

i. Plasma half-life of 120 minutes

b. Elimination

i. 90% renal

ii. 10% hepatic

1. Metabolites - 17-OH, 3-OH & 3,17-

dihydroxy pancuronium

2. 3-OH pancuronium retains about half of

the neuromuscular blocking activity of

pancuronium

iii. Long half-life allow for significant drug

accumulation

2. Vecuronium

a. Intermediate acting agent

b. Chemically similar to pancuronium with the lack of

one methyl group at the quaternary amine

i. This reduces the charge and allows for greater

lipid solubility

c. Elimination

i. Increased lipid solubility allows for increased

hepatic extraction of up to 50%

ii. Hepatic metabolism results in 3,17 & 3,17-OH

compounds with the 3-OH metabolite having

blocking activity

iii. Increased lipid solubility allows for some

degree of drug accumulation

d. Thought to have the best autonomic margin of safety

of all NDMBs even @ 3X ED95; however there may

be vagotonic effect and occasional increases in

plasma [ ] of histamine without cardiac changes

3. Rocuronium

a. Intermediate acting agent

b. Structural changes result in a considerable reduction

of potency (1/5th)

c. Reduced potency requires increased dosage and

therefore more rapid onset of action

d. Elimination

i. Primarily hepatic

ii. No significant metabolism or metabolite

production

c. Monitoring the neuromuscular junction

i. Stimulator characteristics

1. Should be able to deliver 60 - 80 mA with varying

resistances (< 5 kΩ)

2. Pulse duration should be between 0.1 - 0.2 ms

ii. Monitoring modalities

1. Single twitch

a. Compare twitch height with control

b. Twitches at 10 sec intervals or greater

c. Of limited usefulness clinically

2. Tetanus

a. Stimulus of > 30 Hz (usually 50 Hz) applied

i. Higher frequencies result in greater fade

b. Stimulus usually applied for 5 sec

c. Post-tetanic facilitation may persist for up to 2 minutes

3. Train-of-four (TOF)

a. 2 Hz stimulus applied for 2 sec

b. c. During recovery

i. Second twitch reappears at 80% to 90%

single-twitch block

ii. Third twitch reappears at 70% to 80%

iii. Fourth twitch reappears at 65%

iv. TOF ratio > 0.7 relates to full twitch height of

T1

1. Significant blockade still exists at this

point

4. Post-tetanic count

a. During profound neuromuscular blockade, there is no

response to single-twitch, tetanic, or TOF stimulation

b. A 50 Hz tetanus is applied for 5 seconds, followed by

a 3-second pause and by a series of stimulations at 1

Hz

c. Facilitation produces a certain number of visible post-

tetanic twitches

d. For intermediate-duration drugs, the time from a post-

tetanic count (PTC) of 1 to reappearance of twitch is

15 to 30 minutes

5. Double-burst stimulation

a. It is difficult to detect TOF fade when actual TOF ratio

is 0.4 or greater

i. Residual paralysis can go undetected

b. Double-burst stimulation ratio correlates closely with

the TOF ratio, but is easier to detect manually

c. Double -burst is accomplished by applying two short

tetanic stimulations (two impulses at 50 Hz, separated

by 750 ms), and by evaluating the ratio of the second

to the first response

6. Newer techinques

i. EMG

ii. Accelerometry

d. Reversal of neuromuscular blockade

i. Anticholinesterase agents

1. Inhibit ChE at the junction and increases the concentration of

ACh

2. Agents have a low therapeutic index and can cause

neuromuscular blockade if overdosed

3. Significant increase in parasympathetic tone will occur if

agents not accompanied by anticholinergic drugs

4. Neostigmine & pyridostigmine

a. Forms covalent bond at esteratic site of enzyme

b. Although the block is non-competitive, recovery of the

enzyme does occur

c. Charged molecules that do not cross the BBB

5. Edrophonium

a. Inhibits enzyme by competing with ACh at the anionic

site of the enzyme

b. Does not require the formation of a covalent bond

allowing very rapid onset

c. Stimulates the presynaptic release of ACh from the

motor nerve

6. Physostigmine

a. Tertiary amine that crosses the BBB

b. Used for the reversal of central anticholinergic

syndrome, but not for reversal of neuromuscular

blockade

VII. Induction Agents

a. Most induction agents (except ketamine & dexmedetomidine) exert their

effects by enhancing inhibitory signaling vial GABAA receptors

i. GABAA receptors are pentameric transmembrane proteins with

multiple sites of drug binding

ii. Activation of the GABAA receptor enhances chloride conduction,

thereby inhibiting neuronal depolarization

b. Barbiturates

i. Produce a dose dependent depression of the CNS

1. Decrease in CMRO2 by 50%

2. Decrease in CBF

3. Decrease in ICP

ii. Produce venodilation with decreased preload and CO

iii. Produce dose-dependent ventilatory depression

iv. Barbiturates are acidic and require a pH > 10 to achieve aqueous

solubility

v. Thiopental

1. Thio analogue of pentobarbital with enhanced lipid solubility

2. 75 - 90% protein bound

3. Effects from induction doses terminated by redistribution

a. Elimination half-life reported at 6 - 24 hours

vi. Methohexital

1. Lipid soluble oxybarbiturate

2. May induce EEG seizure activity

3. Induction agent of choice for ECT

4. Shorter elimination half-life (2 hours)

c. Benzodiazepines

i. Act on a subset of GABAA receptors containing γ subunits

ii. Possess anxiolytic, sedative, hypnotic amnestic, central muscle

relaxant and anticonvulsant properties

iii. When used alone, benzodiazepines cause minimal ventilatory

depression

1. Significantly increase the ventilatory depressant effects of

other drugs such as narcotics

iv. When used alone, benzodiazepines cause minimal cardiovascular

depression

v. Diazepam & lorazepam

1. Highly lipophillic

2. Long duration of action

a. Elimination half-life of diazepam greatly prolonged in

the elderly

3. Formulated in propylene glycol, which causes pain with

injection

vi. Midazolam

1. pH dependent ring opening allows a water-soluble

preparation with no pain on injection

2. Elimination half-life shorter - 2 hours

3. Accumulation of metabolite, 1-OH midazolam can cause

prolonged sedation when midazolam is given as a

continuous infusion over time.

vii. Flumazenil

1. Competitive antagonist of benzodiazepines

2. Mild agonist effect

3. Can cause seizures in patients taking benzodiazepines

chronically

4. Short half-life creates possibility of resedation when used to

reverse long-acting benzodiazepines

viii. Etomidate

1. Minimal cardiovascular effects

2. Suppresses adrenocortical synthesis

a. Inhibits 11β-hydroxylase

b. Adrenocortical depression has precluded use for

continuous infusion in ICU setting

3. Formulated as the R(+) enatiomer

4. Metabolized in the liver by ester hydrolysis

5. High incidence of myoclonus with induction doses

ix. Propofol

1. Very poorly soluble in aqueous solutions

a. pKa = 11

b. Formulated in lipid emulsion

i. Supports bacterial growth

ii. EDTA or metabisulfite added to inhibit bacterial

growth

iii. Must be used within 6 hours of opening

iv. Pain with injection common

2. Metabolized in liver by conjugation to inactive metabolites

3. Recovery from induction doses is through redistribution

a. Elimination half-life is approximately 2 hours

4. Significant depressive effects on both cardiovascular and

respiratory systems

5. Causes decreased EEG activity

a. Decreases CMRO2

b. Decreases CBF

c. Decreases ICP

6. Propofol infusion syndrome

a. Seen with prolonged, high-dose infusions

b. Associated with:

i. Metabolic acidosis

ii. Rhabdomyolysis

iii. Renal failure

x. Ketamine

1. NMDA receptor antagonist

2. Has both central and spinal effects

a. Provides intense analgesia

3. Preserves airway reflexes and ventilation

4. Stimulates the sympathetic nervous system through a

central action

a. Increases blood pressure

i. Both CO and SVR increased

ii. In severely hypovolemic patients a fall in BP

may occur as a result of the direct depressant

effects on myocardium

b. Potent bronchodilator

i. Good choice for asthmatic patients

ii. Causes bronchodilation through direct effects

on bronchial smooth muscle and by increasing

sympathetic tone

c. Causes increased EEG activity

i. Increases CMRO2

ii. Increases CBF

iii. Increases ICP

iv. Poor choice in patients with increased ICP

d. Emergence delirium

i. Seen more commonly in children

ii. Attenuated with concomitant administration of

benzodiazepines or propofol

VIII. Inhalation Agents – refer to “Inhalational Fact Sheets” @

www.ynhhsna.com/student

IX. Opioid Agonists, Mixed Agonist/Antagonists, Antagonists, NSAIDs

a. Opioids are the drugs of choice for the control of moderate to severe pain

b. 3 subtypes

i. Phenanthrenes (morphine and codeine)

ii. Phenylpiperidines (meperidine, fentanyl and analogues sufentanil,

alfentanil, remifentanil)

iii. Benzylisoquinolones (papaverine and noscapine; lack

opioid/analgesic activity)

c. Opioids exert their effects by binding to opioid receptors:

Mu-1 -1 ° effect supraspinal analgesia -spinal analgesia -euphoria -miosis -urinary retention

Mu-2 -1 ° effect spinal analgesia -pruritis -respiratory depression -emesis -bradycardia -GI motility -physiologic dependence

**most clinically useful

opioids are highly specific

ligands for this receptor**

delta -supraspinal analgesia -spinal analgesia -respiratory depression -urinary retention -GI motility -physiologic dependence

kappa -supraspinal analgesia -spinal analgesia -sedation -dysphoria -miosis

d. pharmacokinetic differences between opioids is 2º variation in individual

agent’s lipid solubility

e. clearance of all opioids is principally via hepatic conjugation

i. exception is remifentanil; undergoes rapid ester hydrolysis by tissue

and blood esterases

f. cause depression of ventilation, shifting the CO2 response curve to the R

g. CBF, CMRO2

h. cross the BBB, placenta

i. cause sphincter of Oddi spasm

j. may cause skeletal muscle rigidity (particularly fentanyl and analogues)

i. thoracic and abdominal

ii. centrally-mediated effect

k. Opioid agonists (refer to chart on www.ynhhsna.com/student)

i. Morphine

1. Prototype for all opioids

2. causes arteriolar and venous dilation

3. causes histamine release

4. causes adrenocortical suppression at high doses

5. poor lipid solublilty

6. active metabolite-morphine-6-glucuronide

ii. Hydromorphone

1. Approximately 5-10X as potent as morphine

a. Shorter DOA

b. More sedation but less euphoria noted with use

c. Less emetogenic than morphine

iii. Meperidine (Demerol)

1. Approximately 1/10 the potency of morphine

2. Contraindicated in pts taking MAOIs, those with seizure

history

3. Has an atropine-like effect but decreases myocardial

contractility in large doses

4. Highly specific for the opioid receptors in the substansia

gelatinosa

iv. Fentanyl

1. 100X potency of morphine

2. Highly lipid soluble

a. Rapid onset

3. Context-sensitive half-time

a. DOA re: to initial bolus

i. 1-5 mcg/kg—low dose; DOA approximately 8-

30 minutes

ii. 6-10 mcg/kg—moderate dose; DOA

approximately 60-90 minutes

iii. > 10 mcg/kg—high dose; DOA longer than

morphine—approximately 16º

v. Sufentanil

1. Most potent of all of the opioids in relation to morphine

(1000X)

2. High lipid solubility

3. May cause profound bradycardia and chest wall rigidity

vi. Alfentanil

1. Lower lipid solubility than fentanyl and sufentanil

a. Smaller VD

2. Rapid onset due to LOW pKa

a. 90% of the drug exists in the non-ionized form at

physiologic pH

3. Short elimination half time

4. May ppt acute dystonic reaction in Parkinsonian pts

vii. Remifentanil

1. Rapid onset

a. Care with bolusing 2° the production of intense chest

wall rigidity; best administered as infusion

2. Short DOA, half times

a. ≤ 6 minutes

3. Clearance principally via plasma esterases

4. May produce hyperalgesic state after D/C

l. Opioid agonist/antagonists

i. displace opioid from the Mu2 receptor

ii. agonist at kappa receptors

iii. known for minimal production of respiratory depression

iv. “ceiling effect” – analgesia produced has limit 2° antagonist effect

v. Useful in the tx of pruritis from intrathecal opioids

vi. nalbuphine (Nubain)

1. antagonist @ Mu, agonist @ kappa

2. equipotent with morphine

3. 25% of activity of naloxone

vii. butorphanol (Stadol)

1. similar to nalbuphine with only 15% potency of naloxone

m. Opioid antagonists

i. fully reverse the analgesic effects and untoward side effects

associated with opioids by competitive inhibition of ligand effects at

the opioid receptor

1. naloxone

a. pure opioid antagonist

b. DOA short; pt may exhibit signs of re-sedation based

on opioid type/amount given

c. May ppt acute withdrawal in narcotic-addicted pts\

i. HTN

ii. HR

iii. dysrhythmias (VT, VF)

iv. pulmonary edema

v. from SNS stimulation 2º rapid reversal of

analgesic effect of opioids and abrupt onset of

pain

n. NSAIDs

i. Inhibit cyclooxygenase (COX)

1. Reduces prostaglandin mediators resulting in

a. analgesia

b. antiinflammatory

2. Antipyretic

3. Inhibition of platelet aggregation

a. increase bleeding tendency

4. Decreased renal perfusion

5. Gastric ulceration

6. May exacerbate asthma (theoretical)

7. Absent respiratory depression

8. Absent of dependence/addiction

9. Less n/v than opioids

10. Ceiling effect

ii. Refer to NSAID chart (www.ynhhsna.com/student) for specifics on:

1. ASA

2. Ketorolac

3. Acetaminophen

4. Indomethacin

5. Ibuprofen

X. Antimicrobials and Antivirals a.

Antimicrobial Anesthetic Implications

Cephalosporins 5 – 10 % cross-sensitivity with penicillin.

Aminoglycosides

(gentamicin)

Enhancement of neuromuscular blockade (neomycin most potent), ototoxicity, renal toxicity.

Macrolides

(erythromycin)

Inhibition of cytochrome P-450, clearance of benzodiazepines and narcotics.

Glycopeptides (vancomycin)

Potential for massive histamine release (Red-Man Syndrome) if infused too quickly. Rate of infusion < 1 gm/hr. Ototoxic & nephrotoxic.

Quinolones

(ciprofloxacin)

Do not use in children or pregnancy (arthropathy). May prolong QT interval.

Tetracycline Do not use in children or pregnancy (tooth damage).

Linezolid Reversible MAO inhibition.

b. Antivirals

i. Utilized primarily in the treatment of HIV 1. Ritonavir

a. Protease inhibitor b. Potent inhibitor of CYP3A4 c. Prolongs action of drugs metabolized by this

cytochrome (i.e. midazolam, fentanyl (decreased clearance by 67%), ?sufentanil, meperidine (specifically the metabolite normeperidine)

XI. Chemotherapeutic Drugs

limit FiO2 administration