PHARMACOLOGY NOTE: This is purely based on

Topic: Anesthesia & Muscle Relaxants Katzung 14th Ed. + Manual Info.
Chapter: 25, 26 & 27 Just add notes from PPT lecture

GENERAL ANESTHETICS TYPES OF ANESTHETIC AGENTS

History
General Anesthetics (G.A.) Local Anesthetics (L.A.)
 1842 – surgery was performed under ether anesthesia - Reversible loss of consciousness - No loss of consciousness
 1846 – first public demonstration of surgical general anesthesia - Loss of CNS activity - Reversible loss of pain sensation
It is generally accepted as the start of the modern era of
Types of G.A. Type of L.A.
anesthesia. For the first time, physicians had a reliable means to
keep their patients from experiencing pain during surgical Inhalation Intravenous Amides Esters
Volatile anesthetics Propofol Lidocaine Cocaine
procedures
Gaseous anesthetics Fospropofol Prilocaine Chloroprocaine
Barbiturates Bupivacaine Benzocaine
 30, September, 1846  William T.G. Morton administered diethyl Benzodiazepines Levobupivacaine Tetracaine
ether to Eben Frost for dental extraction Ketamine Ropivacaine
Etomidate Mepivacaine
Morton became the 1st to publicly demonstrate the use of diethyl
Dexmedetomidine
ether as a general anesthetic at Massachusetts General Hospital,
in what is known today as the Ether Dome
Inhaled General Anesthetics:
 5 Primary Effects (neurophysiologic state) produced by General Volatile Anesthetics Gaseous Anesthetics
Anesthesia:  Low vapor pressure  High vapor pressure
1. Unconsciousness  High boiling point  Low boiling point
2. Amnesia  LIQUID at room temperature or  GAS at room temperature
3. Analgesia sea level ambient pressure
4. Inhibition of autonomic reflexes
5. Skeletal muscle relaxation Examples: Examples:
None of the currently available anesthetic agents when used  Halothane  Nitrous oxide
alone can achieve all five of these desired effects well  Enflurane  Xenon
 Isoflurane
 Desflurane
 An ideal anesthetic drug:
 Sevoflurane
o Produces ALL the five primary effects
o Induce rapid, smooth loss of consciousness
MECHANISM OF GENERAL ANESTHETICS ACTION
o Be rapidly reversible upon discontinuation
1. Effect on the synapse
o Possess a wide margin of safety
o Presynaptic action – alter the release of neurotransmitters
o Postsynaptic action – may change the frequency or
 Other Techniques: amplitude of impulses exiting the synapse
1. Balanced Anesthesia The cumulative effect of these actions may produce
o Combination of IV and inhaled drugs strengthened inhibition or diminished excitation within key
This is to take advantage of the favorable areas of the CNS
properties of each agent while minimizing Studies have shown that:
their adverse effects Excitatory transmission is impaired more strongly by
anesthetics than inhibitory effects are potentiated
2. Monitored Anesthesia Care
o Oral or parenteral sedatives are be combined
with local anesthetics 2. Effect on the organ level (CNS)
o Usually done for minor superficial surgery or o Strengthened inhibition of:
invasive diagnostic procedure  Chloride channels
 GABAA Receptors
 These techniques provide:  Glycine Receptors
o Profound analgesia  Potassium channels
o Retain the patient’s ability to maintain a patent airway  K2P channels
o Retain the patient’s ability to respond to verbal  KV channels
commands  KATP channels
 For more invasive surgical procedures:
o Diminished excitation of ion channels activated by:
o Anesthesia may begin with a preoperative
 Acetylcholine:
benzodiazepine
 Nicotinic receptors
o Be induced with an IV agent
 Muscarinic receptors
eg, thiopental or propofol
 Glutamate:
 AMPA receptors
o And be maintained with a combination of:
 Kainate receptors
 Inhaled drugs
 NMDA receptors
eg, volatile agents, nitrous oxide
 Serotonin:
 5-HT2 receptors
 IV drugs
 5-HT3 receptors
eg, propofol, opioid analgesics

Page 1 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

This fractional rise of anesthetic partial pressure

during induction is usually expressed as a ratio of
alveolar concentration (FA) over inspired
concentration (FI)  FA/FI
The faster FA/FI approaches 1 (representing inspired-
to-alveolar equilibrium), the faster anesthesia onset
will be during an inhaled induction

 Alveolar Ventilation (Pulmonary Ventilation)

o It directly determines the rate of rise of FA/FI
o The anesthesiologist can increase the tidal volume and
respiratory rate to deliver larger amounts of anesthetic
agent faster
Figure Above: Putative targets of anesthetic action The magnitude of the effect is much greater for
inhaled anesthetics with high blood solubility than for
Anesthetic drugs may: those with low blood solubility
(A) enhance inhibitory synaptic activity or
(B) diminish excitatory activity o The tendency for a given inhaled anesthetic to pass from
ACh, acetylcholine; GABAA, γ-aminobutyric acid-A
the gas phase of the alveolus into the pulmonary capillary
blood is determined by the blood:gas partition
INHALED ANESTHETICS
coefficient
Pharmacokinetics
 Inhaled anesthetics, both volatile and gaseous, are taken up through
gas exchange in the alveoli of the lung
 Important determinants of the kinetics of inhaled anesthetics:
o Uptake from the alveoli into the blood
o Distribution and partitioning into the effect
compartments within the body
 As stated previously, an ideal anesthetic should have a rapid onset
(induction) and offset (emergence)
To achieve this, the effect site concentration within the CNS (brain
and spinal cord) will need to change rapidly

 Several factors determine how quickly the CNS concentration o As ↑ ventilation supplies more anesthetic molecules to
changes the alveolus, a more soluble anesthetic (blood:gas
partition coefficient >1) will traverse the alveolar
Uptake & Distribution capillary membrane more readily, preventing a rise in its
A. Factors Controlling Uptake alveolar partial pressure
1. Inspired Concentration & Alveolar Ventilation o Thus, ↑ ventilation will replenish the alveolar anesthetic
 The driving force for uptake of an inhaled anesthetic into the body is concentration for a highly soluble anesthetic but is NOT
the ratio between inspired and alveolar concentration NECESSARY for an anesthetic with low solubility
 Inspired Concentration or Partial Pressure o Therefore, an ↑ in ventilation produces only a small
o The most important parameter that can be controlled by change in alveolar partial pressure of an anesthetic with
the anesthesiologist to change alveolar concentration low blood solubility, BUT can significantly increase the
quickly partial pressure of agents with moderate to high blood
o It is the fraction of a gas mixture that a particular solubility such as halothane
component comprises
For example: Figure on Left:
A mixture of gases that may be delivered by an anesthesia Effect of ventilation on FA/FI and
machine—70% nitrous oxide, 29% oxygen, and 1% induction of anesthesia
isoflurane at normal barometric pressure (760 mm Hg)—
contains partial pressures of 532 mm Hg nitrous oxide, A fourfold increase in the
220 mm Hg oxygen, and 7.6 mm Hg isoflurane ventilation rate almost doubles
the FA/FI ratio for halothane during
o The partial pressure of anesthetic in the inspired gas the first 10 minutes of
mixture determines the maximum partial pressure that administration BUT increases the
can be achieved in the alveoli as well as the rate of rise of FA/FI ratio for nitrous oxide by only
the partial pressure in the alveoli 15%
Thus, hyperventilation increases
o To accelerate induction, the anesthesiologist increases
the speed of induction of
the inspired anesthetic partial pressure to create a
anesthesia with inhaled
steeper gradient between inspired and alveolar partial
anesthetics that would normally
pressure have a slow onset

Page 2 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27
Factors controlling Uptake continued…..
2. Solubility
 An important factor influencing the transfer of an anesthetic from the
lungs to the arterial blood
 Blood:gas partition coefficient  Solubility
o It is a useful index of solubility and defines the relative
affinity of an anesthetic for the blood compared to the
affinity for inspired gas
Low solubility
High solubility
Figure Above:
Desflurane & Nitrous Oxide  are relatively insoluble in blood, display low
partition coefficients
When an anesthetic with low blood solubility partitions between gas in the
lung and pulmonary capillary blood, equilibrium is quickly established and the
blood concentration rises rapidly
Conversely, for anesthetics with greater solubility, more molecules dissolve
in the blood before partial pressure changes significantly, & arterial
concentration of the gas increases less rapidly
 A blood:gas partition coefficient of 0.47 for nitrous oxide means that
at equilibrium, the concentration in blood is LESS THAN HALF the
concentration in the alveolar space (gas)
 A larger blood:gas partition coefficient (such as halothane) causes a
GREATER UPTAKE of anesthetic into the pulmonary blood flow &
therefore ↑ the time required for FA/FI to approach equilibrium
3. Cardiac Output
 Changes in the flow rate of blood through the lungs also affect the
uptake of anesthetic gases from the alveolar space
↑ pulmonary blood flow (e.g ↑ CO)
↓ unlikely to occur with most anesthetics during a typical 1-
↑ uptake of anesthetic
↓
Slowing the rate by which FA/FI rises and ↓ the rate of induction
of anesthesia
 Furthermore, one should consider the effect of CO in combination
with the tissue distribution and uptake of anesthetic into other tissue
compartments
The ↑ uptake of anesthetic into the blood caused by ↑ CO will
be distributed to all tissues
 Since cerebral blood flow is well regulated, the ↑ anesthesia uptake
caused by ↑ cardiac output will predominantly be distributed to
tissues that are NOT INVOLVED in the site of action of the anesthetic
Page 3 of 25
4. Alveolar-Venous Partial Pressure Difference
 The anesthetic partial pressure difference between alveolar and
mixed venous blood is dependent mainly on uptake of the anesthetic
by the tissues, including nonneural tissues
 Depending on the rate and extent of tissue uptake, venous blood
returning to the lungs may contain SIGNIFICANTLY LESS ANESTHETIC
than arterial blood
 Anesthetic uptake into tissues is influenced by factors similar to those
that determine transfer of the anesthetic from the lung to the
intravascular space, including:
1. Tissue:blood partition coefficients
 If your anesthetic is more soluble towards a
particular tissue = ↑ absorption
2. Rates of blood flow to the tissues
 ↑ perfusion = ↑ tissue uptake (eg, anesthetic
effect is greater in brain than in skeletal
muscle)
3. Concentration gradients
 ↑ concentration gradient = ↑ uptake
 The greater the difference in anesthetic gas concentrations, the more
time it will take to achieve equilibrium with brain tissue
 During the Induction Phase:
o The tissues that exert greatest influence on the
arteriovenous anesthetic concentration gradient are
those that are highly perfused (eg, brain, heart, liver,
kidneys, and splanchnic bed)
Combined, these tissues receive over 75% of the resting
cardiac output
 During Maintenance Phase:
o Drug continues to be transferred between various tissues
at rates dependent on:
 Solubility of the agent
 Concentration gradient between the blood
and the respective tissue
 Tissue blood flow
Although muscle and skin constitute 50% of the total
body mass, anesthetics accumulate more slowly in these
tissues than in highly perfused tissues (eg, brain) because
they receive only one fifth of the resting cardiac output
Although most anesthetic agents are highly soluble in
adipose (fatty) tissues, the relatively low blood perfusion
to these tissues delays accumulation, and equilibrium is
to 3-hour operation
Figure Above: Why induction of anesthesia is slower with more soluble anesthetic gases
In this schematic diagram, solubility in blood is represented by the relative size of the
blood compartment (more soluble = larger compartment) while relative partial pressures
of the agents are indicated by the degree of each compartment. For a given concentration
(ie, partial pressure) of the 2 anesthetic gases in the inspired air, it will take much longer
for the blood partial pressure of the more soluble gas to rise to reach alveolar partial
pressure  slower onset of anesthesia with halothane than with nitrous oxide
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

B. Factors Affecting Elimination of Inhaled Anesthetics Pharmacodynamics

 Major Route: Respiratory  MOA: interaction with neuronal membrane lipids leading to inhibition
 Factors that Govern Rate of Recovery: of ion influx
o Blood:gas partition coefficient (most important)  Mechanism of anesthesia can be considered two-fold:
 ↓ Blood:gas partition coefficient = ↓ solubility = ↑ o Inhibition of excitation
rate of elimination o Potentiation of inhibition
o Magnitude of ventilation
 ↑ ventilation = ↑ gas expulsion = ↑ rate of
 Minimum Alveolar Concentration (MAC) Value:
elimination
o Measure of anesthetic potency (similar to ED50)
o Pulmonary blood flow
 ↑ pulmonary blood flow = ↑ ventilation = ↑ rate of
o MAC (% of inspired anesthetic in air) at which 50% of
elimination patients do not respond to a surgical stimulus
o Tissue solubility o Reduced by drugs such as opioids, sedatives and
 ↑ tissue solubility (‘affinity’ to a tissue) = anesthetic hypnotics
stays there longer = ↓ rate of elimination o MAC Values (↓ MAC value = More Potent):
o Duration of Exposure
 ↑ duration = ↑ accumulation especially in adipose
= ↓ rate of elimination

 Differences between Induction & Recovery:

1st Difference:
o Induction  transfer of an anesthetic from the lungs to
blood can be enhanced by ↑ its concentration in inspired
air
o Recovery  transfer of an anesthetic from the blood to
lungs cannot be enhanced because the concentration in
the lungs cannot be reduced below zero
2nd Difference:
o Induction  At the start of induction of anesthesia, the
initial anesthetic tension is zero in all tissues
o Recovery  At the beginning of the recovery phase, the Factors Affecting MAC (Based on Manual)
anesthetic gas tension in different tissues throughout Increase Decrease No Change
the body may be quite variable Hyperthermia Hypothermia Duration of anesthesia
Hypernatremia Hyponatremia Gender
 Ventilation & Metabolism can be manipulated to facilitate ↑ CNS neurotransmitter Increasing age Chronic alcohol abuse
elimination levels Other CNS depressants PaCO2 – 95 mmHg
↓ CNS neurotransmitter PaO2 >38 mmHg
o Ventilation
levels
 Two parameters that can be manipulated by Acute alcohol ingestion
the anesthesiologist are useful in controlling α-2 agonists
the speed of induction of and recovery from PaO2 <38 mmHg
inhaled anesthesia: BP <40 mmHg
Pregnancy
1) Concentration of anesthetic in the
inspired gas
Organ System Effects of Inhaled Anesthetics
2) Alveolar ventilation
A. CNS Effects
o Metabolism
 General anesthetics ↓ cerebral metabolic rate (CMR) in general
 Metabolism may have important implications
o ↓ CMR causes ↓ cerebral blood flow (CBF)
for their toxicity
 General anesthetics can also cause vasodilation
 In terms of hepatic metabolism:
o ↑ vasodilation causes ↑ CBF
halothane > enflurane > sevoflurane >
o So ano na? Increase ba talaga or decrease ng CBF? Dyan
isoflurane > desflurane > nitrous oxide
na papasok and MAC…
NOTE:
Nitrous oxide is not metabolized by human Effect of MAC on CBF
tissues. However, bacteria in the GIT may be able Reduction in Net Change in
to break down the nitrous oxide molecule MAC Vasodilation
CMR CBF
0.5 Greater Less ↓
1* Balanced Balanced No change
1.5 Less Greater ↑
* Thus, MAC 1 = No change in CBF = Safest in patients with traumatic head injury

 Nitrous Oxide  can ↑ cerebral blood flow and cause ↑ intracranial

pressure
This effect is most likely caused by activation of the sympathetic
nervous system

Page 4 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27
 4 Stages of General Anesthesia (Guedel’s Sign) – levels of increasing
depth of CNS depression
o Stage I – Analgesia
 Early stage – patient experiences analgesia
without amnesia
 Late stage – both analgesia and amnesia are
produced
o Stage II – Excitement
 The patient appears delirious and may vocalize
but is completely amnesic
 Increased RR, HR, BP
 Duration and severity of this light stage of
anesthesia are shortened by rapidly increasing
the concentration of the agent
o Stage III – Surgical Anesthesia
 Target in surgical anesthesia
 Slowing of RR and HR
 Extends to complete cessation of spontaneous
respiration (apnea)
 4 planes of stage III are described based on
changes in ocular movements, eye reflexes,
and pupil size, indicating increasing depth of
anesthesia:
Plane I: from onset of regular breathing to loss
of eye movement
Plane II: from cessation of eye movement to
initiation of intercostal muscle paralysis
Plane III: from initiation of intercostal muscle
paralysis to completion
Plane IV: from complete intercostal muscle
paralysis to diaphragmatic paralysis
o Stage IV – Medullary Depression
 Deep stage of anesthesia represents severe
depression of the CNS
 Depression of the vasomotor center in the
medulla and respiratory center in the
brainstem
 Without circulatory and respiratory support,
death would rapidly ensue
B. Cardiovascular Effects
 All volatile anesthetics decrease MAP
o Halothane, Enflurane  greater decrease of MAP, mostly
due to myocardial depression (↓ CO) and there is little
change in SVR
o Isoflurane, Desflurane, Sevoflurane  lesser decrease of
MAP, with greater vasodilation with little effect on CO 
preferred in heart failure patients
 Nitrous Oxide also depresses myocardial function by activation of
sympathetic nervous system
 Baroreceptor changes
o Halothane, Enflurane, Sevoflurane  attenuates
baroreceptor input in the ANS  little effect on HR
o Desflurane, Isoflurane  less depression of
baroreceptors  ↑ HR
 Decrease myocardial oxygen consumption, produces coronary
vasodilation
 Sensitize the myocardium to epinephrine and circulating
catecholamines
o Halothane does this effect more than other volatile
anesthetics
Page 5 of 25
C. Respiratory Effects
 All volatiles have bronchodilating effects
 Airway irritation due to pungency
o Isoflurane, Desflurane – pungent, airway irritants
o Halothane, Sevoflurane – sweet, less airway irritation,
agents of choice for patients with airway problem
Nitrous Oxide – also nonpungent, facilitates inhalational
induction
 Dose-dependent ↓ tidal volume and corresponding ↑ RR up to a
certain limit (EXCEPT: Nitrous Oxide)
 All volatiles are respiratory depressants
o Isoflurane & Enflurane – have most effect
 Raises apneic threshold
o Apneic threshold – PaCO2 level below which apnea occurs
through lack of CO2-driven respiratory stimulation
o Inhaled anesthetics raises threshold, thereby there is less
tendency for patients to be roused from sedation even
when there is ↑ PaCO2
 Decrease response to hypoxia
 Depress mucociliary function  prolonged exposure results in mucus
pooling & plugging  atelectasis & postoperative respiratory
complications (hypoxemia & respiratory infections)
D. Renal Effects
 ↓ GFR & Urine flow
E. Hepatic Effects
 Concentration-dependent ↓ portal vein flow parallel to ↓ in CO
 Total hepatic blood is preserved
 Transient changes in liver function test may occur
F. Uterine Smooth Muscle Effects
 Potent uterine smooth muscle relaxant EXCEPT Nitrous Oxide
Toxicity
Acute Toxicity:
 Nephrotoxicity
o More seen in enflurane & sevoflurane (due to liberation
of fluoride ions)
o Metabolism of enflurane & sevoflurane are associated
with generation of nephrotoxicity vinyl ether compound
termed “Compound A”
It causes proximal tubule necrosis in rats
 Hematotoxicity
o Megaloblastic anemia is associated with prolonged
exposure to nitrous oxide due to ↓ methionine synthase
o All volatiles can produce carbon monoxide – desflurane
producing the most
Carbon monoxide is produced from their interaction with
strong bases in dry CO2 absorbers, binding hemoglobin
with high affinity leading to decreased oxygen delivery
 Malignant Hyperthermia
o Hereditary genetic disorder of skeletal muscle
 Associated with mutation in coding for RyR1
o Attributed to succinylcholine and general anesthetics
o Muscle rigidity, hyperthermia, hyperkalemia,
tachycardia, hypercapnia, metabolic acidosis
 Due to ↑ cytosolic concentration of Ca2+
o Treatment of dantrolene and supportive measures
o Most reliable diagnostic test is caffeine-halothane
contracture test
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Acute toxicity continued….. INTRAVENOUS ANESTHETICS

 Hepatotoxicity (Halothane Hepatitis)  Replaced inhalation (gas induction) as the preferred method of
o Fulminant hepatic failure when using halothane anesthesia induction in most settings except for pediatric anesthesia
 Development of life-threatening hepatitis (1 in  Provide sedation and has applicability in ICU
25,000-30,000)  Component of balanced anesthesia (mixture of local and IV
 Due to reactive metabolites causing direct anesthetics)
hepatocellular damage or Immune-mediated  Lipophilic  rapid onset of action
response  Termination of the effect of a single bolus is determined by
redistribution of the drug into less perfused and inactive tissues (eg,
Chronic Toxicity: skeletal muscle and fat)  similar duration of action of drugs
 Mutagenicity, Teratogenicity & Reproductive Effects
o Inhaled anesthetics including nitrous oxide are neither Intravenous General Anesthetics
mutagens nor carcinogens in patients - Propofol - Etomidate
o Apparent increase in miscarriages - Fospropofol - Ketamine
- Barbiturates - Dexmedetomidine
 Carcinogenicity - Benzodiazepines
o Some studies suggest ↑ risk of cancer for OR personnel
who were exposed to trace concentration of anesthetic
agents

 High plasma clearance  complete recovery with no “hangover”

Propofol
 Redistribution from highly perfused to less-well-perfused
 Most frequently administered drug for:
compartments
o Induction & maintenance of anesthesia sedation during
o Awakening after an induction dose of propofol usually
monitored anesthesia care, ICU, conscious sedation, &
occurs within 8-10 minutes
short-duration general anesthesia
o Important factor in the suitability of a drug for use as
 Alkyl phenol (2,6-diisoprophylphenol) with hypnotic properties maintenance anesthetic
 It is formulated as an emulsion:  Context-sensitive half time
o Soybean – 10% o Describes the elimination half-time after discontinuation
o Glycerol – 2.25% of a continuous infusion as a function of the duration of
o Lecithin – 1.2% the infusion
Lecithin is the major component of the egg yolk o The context-sensitive half-time of propofol is brief, even
phosphatide fraction  Hence, susceptible patients
after a prolonged infusion, and therefore, recovery
may experience allergic reactions
occurs relatively promptly
 The solution appears milky white and slightly viscous, has a pH of
approximately 7, and has a propofol concentration of 1% (10 mg/mL) Figure on Left: The context-sensitive half-
 MOA: Potentiation of the chloride current mediated through the time of common intravenous anesthetics
GABAA receptor complex Thiopental & Midazolam undergo slower
elimination due to longer context-sensitive
half-time
Pharmacokinetics:
Propofol’s half-time is relatively short, which
 It is rapidly metabolized in the liver makes it the preferred choice for IV
 Extrahepatic metabolism – lungs anesthesia
 Inactive metabolites excreted through the kidneys Ketamine & Etomidate have similar
characteristics, but their use is limited by
 Very rapid onset & recovery other effects

Page 6 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27
Propofol continued…..
Organ System Effects:
 CNS
o General suppression of CNS activity
 ↓ cerebral BF (CBF) & ↓ metabolic rate for
oxygen (CMRO2)  ↓ ICP and IOP
 ↓ cerebral BF + ↓ MAP  ↓ cerebral
perfusion pressure
o Acts as hypnotic but does not have analgesic properties
o Observed excitatory effects
o Studies support an anticonvulsant activity
o Large doses: neuroprotection, produces burst
suppression in the EEG
 CVS
o Arterial & venous vasodilation  ↓ BP  ↓ preload &
afterload
Produces most pronounce decrease in BP among IV
anesthetics
o Inhibition of baroreflex response
o Profound bradycardia & asystole after administration
 Respiratory
o Respiratory depression is apparent  apnea
o Reduction in TV & RR  ↓ minute ventilation
o Reduced ventilator response to hypoxia & hypercapnia
o Greater reduction in airway reflexes
Makes it well suited for instrumentation of the airway,
such as placement of a laryngeal mask airway
 Other Effects
o Propofol Infusion Syndrome  metabolic acidosis,
unexpected tachycardia
o Antiemetic activity
o Pain on injection is a common complaint
Clinical Uses & Dosage:
 Facilitate induction of general anesthesia by bolus injection of 1–
2.5 mg/kg IV
 Often used for maintenance of anesthesia either as part of a
balanced anesthesia or as part of a total intravenous anesthetic
technique
o Maintenance of anesthesia: 3-8 mcg/mL
 Used for sedation of mechanically ventilated patients in the ICU or
for sedation during procedures
 It can be used to treat postoperative nausea and vomiting
Fospropofol
 Water-soluble prodrug of propofol – 2,6-diisopropylphenoxymethyl
phosphate disodium salt  less pain on injection
 Rapidly metabolized by alkaline phosphatase producing:
o Propofol
o Phosphate
o Formaldehyde  metabolized by aldehyde dehydrogenase in
the liver & erythrocytes
 35 mg/mL single dose vial
 Onset and recovery are prolonged
Pharmacokinetics & Organ System Effects:
 Similar to that of Propofol but prolonged onset and recovery
 A/E: paresthesia (often in perianal region)
Page 7 of 25
Fospropofol continued…..
Clinical Uses & Dosage:
 For sedation during monitored anesthesia care
 Supplemental oxygen must be administered to all patients
 Initial bolus dose: 6.5 mg/kg IV
 Supplemental doses: 1.6 mg/kg IV
 Reduce dose by 25%:
o Patients >65 yrs. old
o Those with an American Society of Anesthesiologists
status of 3 or 4
Barbiturates
 Thiopental & Methohexital
 Enhance inhibitory & inhibit excitatory neurotransmitters
 Activation of GABAA receptor complex
 Absolute C/I: Acute Intermittent Porphyria
 Recovery: Redistribution
Pharmacokinetics:
 Undergo hepatic metabolism (mainly through oxidation)
 Methohexital: larger plasma clearance  faster and more complete
recover  shorter elimination half-time
 Recovery after a single bolus is comparable between propofol and
barbiturates
Organ System Effects:
 CNS
o Produce dose-dependent CNS depression (sedation to
general anesthesia)
o Do not produce analgesia but may increase pain
threshold resulting to hyperalgesia
o Thiopental has anticonvulsant properties
o Methohexital activates epileptic foci (useful in the
identification of epileptic foci during surgery)
o Potent cerebral vasoconstrictors  ↓ CMRO2 and ICP
(neuroprotective)
- Useful in the management of patients with space-
occupying intracranial lesions
- Provide neuroprotection from focal cerebral
ischemia (stroke, surgical retraction, temporary clips
during aneurysm surgery), but not from global
cerebral ischemia (eg, from cardiac arrest)
o ↓ electrical activity on EEG (EXCEPT: methohexital)
 CVS
o ↓ in systemic BP due to peripheral vasodilation
o Negative inotropic effects
 ↑ depressant effects on systemic BP in
patients with hypovolemia, cardiac
tamponade, cardiomyopathy, coronary artery
disease, or cardiac valvular disease
o Less pronounced baroreceptor and MAP effects
o Hemodynamic effects are more pronounced with larger
doses and rapid injection
 Respiratory
o Respiratory depressant  apnea (similar to Propofol)
o ↓ TV & RR  ↓ minute ventilation
o ↓ ventilator responses to hypercapnia & hypoxia  ↓
minute ventilation
o Suppression of laryngeal reflexes & cough reflexes
Suppression is not as profound as that of Propofol;
Therefore, inadequate depression of reflexes =
laryngospasm or bronchospasm
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Barbiturates continued…..
 Other Effects:
o Extravasation leading to gangrene during accidental
intra-arterial injection
o Rare barbiturate-induced histamine release may cause Etomidate
life-threatening allergic reactions  Carboxylated imidazole derivative
o Can precipitate porphyria due to stimulation of  Poorly soluble in water
aminolevulinic acid synthase  IV anesthetic with hypnotic effect
 No analgesic effect
Clinical Uses & Dosage:  MOA: Potentiation of GABAA-mediated chloride currents
 Thiopental (3-5 mg/kg IV)
 Methohexital (1-1.5 mg/kg IV) Pharmacokinetics:
 Used for induction of anesthesia in <30 seconds  Rapid onset & recovery (redistribution)
 May experience a garlic or onion taste after administration  Metabolism by ester hydrolysis
 Methohexital: rectal suppository  for mentally challenged patients  Excretion: Urine (78%) and Bile (22%)
& uncooperative pediatric patients  Highly protein bound, primarily to albumin
 Can be used as neuroprotection  Shorter elimination half-life than thiopental
 Use of smaller doses is less frequently associated with hypotension  Duration of action is linearly related to the dose
 easier to maintain adequate cerebral perfusion pressure  Minimal effects on hemodynamics
(especially in the setting of ↑ ICP)
Organ System Effects:
Benzodiazepines  CNS
 Midazolam, Lorazepam, & Diazepam (less frequently used) o Potent cerebral vasoconstrictor  ↓ cerebral blood flow
 Antagonist: Flumazenil and ↓ ICP
 Desired effects: Anxiolysis and anterograde amnesia o No neuroprotective effect
 No analgesic effect o May activate epileptic foci (similar with Methohexital)
o >50% of patients show myoclonus
Pharmacokinetics:
 Highly lipid soluble  easily enters CNS  CVS
 Rapid onset of action, followed by redistribution to inactive tissue o Cardiovascular stability
sites leading to termination of the drug effect o Absent or modest ↓ in systemic BP  ↓ systemic
 Midazolam: slower effect-site equilibration, shortest context- vascular resistance
sensitive half-time o Minimal changes in HR, CO & myocardial contractility
Short context sensitive half-time of Midazolam:
Makes it the only one of the three benzodiazepine drugs suitable  Respiratory
for continuous infusion o Less pronounced respiratory depression
o Apnea may occasionally follow rapid IV injection of drug
Organ System Effects: o Inhaled anesthetics or Opioids + Etomidate = Exaggerated
 CNS ↓ ventilation
o ↓ CMRO2 and cerebral blood flow
o Potent anticonvulsant for status epilepticus, alcohol  Endocrine
withdrawal, & local anesthetic-induced seizure o Dose-dependent inhibition of 11β-hydroxylase 
o No change in ICP adrenocortical suppression (↓ cortisol)
o Cannot product isoelectric EEG  no neuroprotection  Suppression lasts 4-8 hrs.
 CVS  Not given as an infusion
o Peripheral vasodilation  Midazolam greater decrease in
systemic BP than comparable doses of diazepam Clinical Uses & Dosage:
 Respiratory  Rapid IV induction of anesthesia, especially in compromised
o Minimal depression of ventilation  transient apnea myocardial contractility patients
with rapid IV injection  Standard induction dose – 0.2-0.3 mg/kg
o ↓ ventilator response to CO2  High incidence of pain on injection followed by venous irritation
o BDZ + Opioid  more severe respiratory depression (similar with Propofol)
 Other Effects  Involuntary myoclonic movements are common
o Pain during IV and IM injection and subsequent  Awakening is rapid with little residual depressant effects
thrombophlebitis (Diazepam)  Nausea & vomiting more common than with thiopental & propofol
o Allergic reactions  rare

Clinical Uses:
 Preoperative medication (amnesic, anxiolytic, sedative)
 IV sedation
 Suppression of seizure activity
 Induce general anesthesia

Page 8 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Ketamine Dexmedetomidine
 Phencyclidine derivative that has analgesic properties  Highly selective α2-adrenergic agonist
 Partially water soluble & highly lipid soluble  Water soluble
 Produces “dissociative anesthesia”  patient’s eyes remain open
with a slow nystagmic gaze (cataleptic state) Pharmacokinetics:
 MOA: Inhibition of NMDA receptor complex  Rapid hepatic metabolism
 Excretion: urine & bile
Pharmacokinetics:  High clearance, short elimination half-time (2-3 hrs.)
 Only IV anesthetic that has low protein binding  Long context-sensitive half-time (250 mins. after 8-hr infusion)
 Rapid onset & short context-sensitive half-time
 Metabolism: liver via N-demethylation Organ System Effects:
(active metabolite: Norketamine)  CNS
 Excretion: Urine o Hypnosis – stimulation of α2 receptors in locus coeruleus
o Analgesic effect – spinal cord level
Organ System Effects: o Sedative effect – resembles physiologic sleep
 Administered as a sole anesthetic o ↓ cerebral BF without significant changes in ICP and
 Amnesia is not complete CMRO2
 Reflexes often preserved o Potential development of tolerance & dependence
 Eyes remain open, pupils moderately dilated with nystagmic gaze  CVS
 Increased lacrimation & salivation o Infusion: moderate ↓ in HR and SVR  ↓ in systemic
BP
 CNS o Bolus: transient ↑ in BP & pronounced decrease in HR
o Cerebral vasodilator  ↑ cerebral BF and CMRO2  ↑ (peripheral α2 receptor activation)
ICP o Bradycardia  heart block, severe bradycardia,
o Myoclonic activity but may still be used as anticonvulsant asystole  require treatment
in status epilepticus  Respiratory
o Induces a euphoric state  potential for abuse o Small to moderate ↓ in TV & very little change in RR
o Unpleasant emergence reactions: o Ventilatory response to CO2 is unchanged
 Vivid, colorful dreams
 Hallucinations Clinical Use:
 Out-of-body experience  Used for short-term sedation of intubated & ventilated patients in
 Distorted senses ICU setting
o Unpleasant emergence reactions are usually reduced in  In operating room, it may be used as an adjunct to general
children or when in combination with benzodiazepines anesthesia or to provide sedation

 CVS Opioid Analgesics

o Transient but significant ↑ in SBP, HR, CO  presumably  Are routinely used to achieve postoperative analgesia &
due to centrally mediated sympathetic stimulation intraoperatively as part of a balanced anesthesia regimen
o Direct myocardial depressant  masked by sympathetic  When administered in high doses (eg, fentanyl), can cause chest wall
NS stimulation & laryngeal rigidity  impaired mechanical ventilation
 Large doses of potent opioids may speed up the development of
 Respiratory tolerance
o Do not produce significant respiratory depression
o Response to hypercapnia preserved and blood gases
remain stable
o Transient hypoventilation & apnea after rapid IV injection
o Preserve active airway reflexes – less risk of
bronchospasm especially in children
o Relaxes bronchial smooth muscles  helpful in patients
with reactive airways & management of patients
experiencing bronchospasm
Clinical Uses:
Desirable properties Disadvantages
Profound analgesia Hallucinations – visual & auditory;
Stimulation of sympathetic NS psychotomimetic effect
Bronchodilatation Euphoria – potential for abuse
Minimal respiratory depression Increase ICP, IOP
Reverse opioid tolerance Stimulation of sympathetic NS*
*Based on manual

 Administered in multiple routes (IV, IM, oral, rectal, epidural)

 Premedication in mentally challenged & uncooperative pediatric
patients
 Used as alternative to the other IV anesthetics

Page 9 of 25
PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Page 10 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

LOCAL ANESTHETICS 3) Drug-tissue binding

 Local anesthesia 4) Local tissue blood flow
o Refers to loss of sensation in a limited region of the body 5) Vasoconstrictor use
o This is accomplished by disruption of afferent neural o Vasocontrictors + LA = ↓ rate of systemic absorption &
traffic via inhibition of impulse generation or propagation diminishes peak serum levels
 Loss of sensation or localized analgesia is the primary goal 6) Physicochemical properties of the drug
 Has the ability to provide complete loss of all sensory modalities
 No loss of consciousness
 Drug is delivered directly to the target organ
 Used for local, peripheral and central neuraxial anesthesia

BASIC PHARMACOLOGY OF LOCAL ANESTHETICS

 Chemical structure:
o Aromatic acid (lipophilic/hydrophobic)
o Amine group (hydrophilic)  tertiary amine or
secondary amine
o Intermediate chain  Ester or Amide
 Weak bases  easily ionized upon injection
 Receptor site: inner vestibule of the sodium channel
o Uncharged form penetrates membrane easily
o Cationic form most active at the site
 Uncharged or Positively charged  governed by:
o pKa
o pH of fluids
 Chemical properties
o High pH of body fluids:
 Free base concentration ↑  ↑ penetration
o Low pH of body fluids:
 Free base concentration ↓  ↓ penetration

pKa of local anesthetics  7.5 to 9: mostly cationic EXCEPT benzocaine

(lower pKa of around 3.5)  exists solely as nonionized base
Figure Above: Comparative peak blood levels of several local anesthetic
agents following administration into various anatomic sites

Distribution
 Localized
o Distribution plays an essential role in achieving the clinical
effect of LA when directly injecting at the site of the target
organ
Example:
Injection into the subarachnoid space  pattern of
distribution dependent on specific gravity and
patient’s position

Figure Above: Paths of local anesthetics (LA) receptor sites Solutions are termed hyperbaric, isobaric, and
hypobaric, and will respectively descend, remain
Extracellular anesthetic exists in equilibrium between charged and relatively static, or ascend, within the subarachnoid
uncharged forms, with the uncharged form able to pass freely through the space due to gravity when the patient sits upright
membrane. Re-equilibration occurs intracellularly where the charged form
binds to the Na channel to elicit the anesthetic effect
 Systemic
o Concentration and speed of injection has minimal
PHARMACOKINETICS
affectation on peak blood levels
Factors Affecting Absorption
o Alpha vs. Beta
1) Dosage
 Initial Alpha phase:
2) Site of injection
 Rapid distribution in blood &
o Highly vascular area (i.e. Tracheal mucosa or tissue
highly perfused organs (e.g. brain,
surrounding intercostal nerves) = rapid absorption and
liver, heart, kidney)
higher blood levels
 Steep exponential decline in
o Poorly perfused (i.e. subcutaneous fat) = slower
concentration
absorption
 Beta phase:
o Serum peak levels when used for major conduction
 Slower decline reflecting
blocks:
distribution into less perfused
 Highest: Intercostal blocks
tissues
 Lowest: Sciatic and Femoral blocks
 Nearly linear rate of decline

Page 11 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27
Metabolism & Excretion
 Local anesthetics are converted to more water-soluble metabolites:
o Amides are processed in the liver, while esters are
converted in the plasma
Amide LAs undergo complex biotransformation in the
liver by cytochrome P450 isozymes (via hydroxylation
and N-dealkylation)
o Acidification of urine promotes rapid elimination of
amides while butyrylcholinesterase converts ester local
anesthetics
LA in uncharged form diffuse readily through lipid
membranes  little or no urinary excretion of neutral
form
o Rate of liver metabolism:
prilocaine > lidocaine > mepivacaine > ropivacaine =
bupivacaine & levobupivacaine
 Excretion: Urine
PHARMACODYNAMICS
Mechanism of Action
1) Membrane Potential
o Change in membrane potential by Na+ channel blockade
↓ entry of Na+ intracellularly  ↑ threshold of
excitation
2) Sodium Channel Isoforms can also be affected
3) Other factors affecting Channel Blockade:
o (-) RMP in rested fibers  Channels in the rested state
predominate  ↓ LA effectiveness
o (+) RMP in actively firing axons  Channels are in
inactivated & activated (open) state  ↑ LA
effectiveness
o ↑ intracellular Ca2+  ↑ in surface potential of
membrane  low-affinity rested state predominates 
↓ LA effect
o ↑ extracellular K+  depolarization of membrane
potential  ↑ LA effect
o Batrachotoxin from frogs, tetrodotoxin from pufferfish,
saxitoxin from dinoflagellates, etc.  When progressively
increasing concentrations of LA applied:
 ↑ threshold for excitation
 Slower impulse conduction
 ↓ in rate of rise of action potential
 ↓ AP amplitude
 Abolished ability to generate AP
 End effect: Same as local anesthetics but
different mechanism
4) Other effects on:
o K+ channels
o Enzymes (eg, adenylate cyclase)
o Receptors (eg, NMDA, G-protein, 5-HT3)
Structure-Activity Characteristics
 Smaller and more lipophilic local anesthetics have faster rates of
interaction with the Na+ channel receptors
 Lidocaine, procaine, mepivacaine are more water-soluble
 Tetracaine, bupivacaine, ropivacaine are more potent & longer
duration of local anesthetic action
They also bind more extensively to proteins and can be displaced
from these binding sites by other protein-bound drugs
Page 12 of 25
Neuronal Factors Affecting Blockade
1) Differential Block
o LA capability to block all nerves  actions not limited to
desired loss of sensation from sites of painful stimuli
o Neuraxial techniques (spinal or epidural)
 Motor paralysis  impairs respiratory activity
 Autonomic nerve blockade  promotes
hypotension
2) Intrinsic Susceptibility of Nerve Fibers
o Myelinated fibers are more easily blocked (as compared
to non-myelinated fibers of the same diameter)
o Rapidly firing vs. rested fibers
o LAs preferentially block smaller diameter fibers first (due
to shorter distance of passively propagating an electrical
impulse)
3) Anatomic Arrangement
o Anesthetic placed outside the nerve bundle – anesthetize
the proximal fibers in the outer potion of the bundle first
(thus, sensory block will occur from proximal to distal)
CLINICAL PHARMACOLOGY
 Usual routes of administration:
o Topical  Nasal mucosa, wound site/margins
o Local infiltration  injection in the perineural area
o Nerve blocks  injection near major nerve trunks
o Neuraxial  injection into epidural or subarachnoid space
Clinical Block Characteristics:
 The orderly evolution of block components (order of disappearance
of function):
1. Autonomics (Sympathetic) 4. Light touch
2. Temperature 5. Deep pressure
3. Pain 6. Motor function
Effect of Added Vasoconstrictors:
 Localized neuronal uptake is enhanced because of higher sustained
local tissue concentration that can translate clinically into a longer
duration block
o Adequate anesthesia for more prolonged procedures
o Extended duration of postoperative pain control
o Lower total anesthetic requirement
 Peak blood levels will be lowered as absorption is more closely
matched to metabolism and elimination, and the risk of systemic
toxic effects is reduced
 Epinephrine with spinal anesthetic  direct analgesic effect
mediated by postsynaptic α2-adrenoceptors within the spinal cord
 Addition of epinephrine can potentiate the neurotoxicity of local
anesthetics used for peripheral nerve blocks or spinal anesthesia
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Intentional Use of Systemic Local Anesthetics: Localized:

 Although the principal use of local anesthetics is to achieve  Neural
anesthesia in a restricted area, these agents are sometimes o Cauda equine syndrome associated with continuous
deliberately administered systemically to take advantage of spinal anesthesia (lidocaine)
suppressive effects on pain processing o Mechanism of LA neurotoxicity:
 Escalating doses of anesthetic appear to exert the following systemic  Conduction failure  Accumulation of IC calcium
actions:  Membrane damage  Disruption of axonal transport
o Low Concentration: may preferentially suppress ectopic  Enzyme leakage  Growth cone collapse
impulse generation in chronically injured peripheral  Cytoskeletal disruption  Apoptosis
nerves
o Moderate Concentration: suppress central sensitization
 Transient neurologic syndromes (TNS)
which would explain therapeutic benefit that may extend
o Syndrome of transient pain or dysesthesia or both
beyond the anesthetic exposure
(lidocaine)
o Higher Concentration: produce analgesic effects and may
culminate in serious toxicity
COMMONLY USED LOCAL ANESTHETIC AGENTS
Based on Manual: ESTERS
 Arrhythmia – Lidocaine  Class IB anti-arrhythmic agent  Relegated its application to topical anesthesia
Benzocaine  Pronounced lipophilicity
SYSTEMIC EFFECTS:  Induces methemoglobinemia
Dose-dependent Systemic Effects of Lidocaine  Epidural agent for obstetric anesthesia
Plasma concentration (µg/mL) Effect Chlorprocaine  Early reports of neuronal injury
1-5 Analgesia  Shorter onset & duration than lidocaine
Lightheadedness, Tinnitus,  Largely restricted to topical anesthesia for ear, nose,
5-10 Cocaine and throat procedures
Numbness of tongue
 Intense vasoconstriction
10-15 Seizures, Unconsciousness
Procaine,
15-25 Coma, Respiratory arrest
Tetracaine
>25 Cardiovascular depression
AMIDES (have 2 letter “i’s” in their names)
Management:  Mostly used for dental cases (dental anesthetic)
 Airway management  Unique in having a:
o Thiophene ring – enhanced lipophilicity thus
 Seizure suppression (benzodiazepine preferred) Articaine improved tissue penetration
 Management of cardiac dysrhythmias o Additional ester group (subject to plasma
 Lipid emulsion therapy esterase metabolism)
 Adverse Effect: persistent paresthesia
 Agent of choice for epidural postoperative pain
TOXICITY
control & labor analgesia
Systemic: Bupivacaine
 Concerns of cardiotoxicity
 CNS  Spinal anesthesia: long duration
o All local anesthetics have the ability to produce the  It has a tendency to produce an inverse differential
Etidocaine
following when high plasma concentrations result from block
rapid absorption or inadvertent IV administration:  S(–) enantiomer of bupivacaine with less cardiotoxic
Levobupivacaine and longer duration of action
 Sedation  More responsive to lipid resuscitation
 Light-headedness  High incidence of TNS with spinal administration
 Visual and auditory disturbances  Standard of comparison for most local anesthetics
Lidocaine
 Restlessness  Rapid onset, intermediate duration
o Early symptom of local anesthetic toxicity is:  Class IB anti-arrhythmic agent
 Comparable to lidocaine
 Circumoral and tongue numbness
 Slight vasoconstriction longer duration  choice of
 Metallic taste Mepivacaine major peripheral blocks
o At higher concentrations:  When used for spinal anesthesia: slightly lower
 Nystagmus incidence of TNS
 Muscular twitching  Highest clearance among amides
 Tonic-clonic convulsions  Induce methemoglobinemia, which results from
Prilocaine
accumulation of one of its metabolites, ortho-
o Seizures at 10 µg/mL plasma concentration toluidine, an oxidizing agent
 Management:  Chirality, with propyl group off the piperidine ring
 Benzodiazepines (1st line)  Reduced cardiotoxicity
 Propofol Ropivacaine  Control of labor & postoperative pain
 Neuromuscular blocker (for the  Might produce a more favorable differential block than
bupivacaine
motor activity)
 2.5% lidocaine + 2.5% prilocaine
 Cardiotoxicity – Bupivacaine EMLA  Permits anesthetic penetration of the keratinized layer
 Reversal of bupivacaine toxicity – lipid resuscitation (Eutectic Mixture of Local of skin, producing localized numbness
Anesthetics)  Commonly used in pediatrics to anesthetize the skin
prior to venipuncture for IV catheter placement

Page 13 of 25
PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Page 14 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27
SKELETAL MUSCLE RELAXANTS
 2 groups of drugs that affect skeletal muscle function:
1. Neuromuscular blocking drugs
 Produce muscle paralysis  used during
surgical procedures & in the ICU
 Interfere with transmission at the
neuromuscular end plate
 Lack CNS activity
2. Spasmolytics & Antispasmodics
 Used to reduce spasticity in a variety of painful
conditions
 Spasmolytics have been traditionally called
“centrally acting” muscle relaxants & are used
primarily to treat chronic back pain and
painful fibromyalgic conditions
NEUROMUSCULAR BLOCKING DRUGS
History:
 16th Century  Amazon natives use CURARE, an arrow poison that
produce skeletal muscle paralysis, to kill animals
o d-tubocurarine – active compound of curare
Its modern synthetic analogs have had a major
influence on the practice of anesthesia and surgery
It have proved useful in understanding the basic
mechanisms involved in neuromuscular transmission
Normal Neuromuscular Function:
Mechanism of Neuromuscular Transmission at the Motor End Plate:
Action potential at motor nerve terminal
↓ interruption of function at several sites along the pathway from the
Causes influx of calcium
↓ o
Release of neurotransmitter acetylcholine (ACh)
↓
ACh will diffuse across synaptic cleft
↓
Activation of nicotinic receptors at motor end plate
Page 15 of 25
Figure on Left:
Adult NM Ach receptor
Adult NM receptor is composed of 5
peptides:
o two α peptides
o one β peptide
o one γ peptide
o one δ peptide
The binding of 2 ACh molecules to receptors on the α-β and δ-α subunits
causes opening of the channel
↓
Movement of Na+ and K+ through the channel
↓
Graded depolarization of the end plate membrane
↓
Change in voltage (motor end plate potential)
 The magnitude of the end plate potential is directly related to the
amount of acetylcholine released
o If the potential is small, the permeability and the end
plate potential return to normal without an impulse being
propagated from the end plate region to the rest of the
muscle membrane
o If the end plate potential is large, the adjacent muscle
membrane is depolarized, and an action potential will be
propagated along the entire muscle fiber
Muscle contraction is then initiated by excitation-
contraction coupling
The released acetylcholine is quickly removed from
the end plate region by both diffusion and enzymatic
destruction by the local acetylcholinesterase enzyme
 It involves different types of acetylcholine receptors:
1. Presynaptic motor axon terminal
Activation of these receptors mobilizes additional
transmitter for subsequent release by moving more
acetylcholine vesicles toward the synaptic membrane
2. Extrajunctional
Not normally involved in neuromuscular transmission
It may proliferate sufficiently to affect subsequent
neuromuscular transmission under certain conditions
(eg, prolonged immobilization, thermal burns)
 Skeletal Muscle Relaxation & Paralysis  can occur from
CNS to:
Myelinated somatic nerves
o Unmyelinated motor nerve terminals
o Nicotinic acetylcholine receptors
o The motor end plate
o Muscle membrane
o Intracellular muscular contractile apparatus itself
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

 2 Basic Mechanisms of End Plate Function Blockade:  Another feature common to all currently used neuromuscular
1. Nondepolarizing blockers is the presence of one or two quaternary nitrogens, which
 Antagonist to acetylcholine makes them poorly lipid soluble and limits entry into the CNS
 These drugs prevent access of the transmitter
to its receptor and thereby prevent PHARMACOKINETICS
depolarization  All of the neuromuscular blocking drugs are:
 Prototype: d-tubocurarine o Highly polar compounds
o Inactive orally
2. Depolarizing Therefore they must be administered parenterally
 Produced by an excess of a depolarizing
agonist, such as acetylcholine Nondepolarizing Relaxant Drugs (Pharmacokinetics)
 Blockade when there is high  Rate of disappearance of a nondepolarizing neuromuscular blocking
concentrations of acetylcholine in drug from the blood is characterized by:
the synaptic cleft o Rapid initial distribution phase
 It also occurs at the ganglionic nicotinic o Slower elimination phase
acetylcholine receptor  Highly ionized
 Nicotine & Nicotinic Agonists  Do not readily cross cell membranes
 Prototype: Succinylcholine  Not strongly bound in peripheral tissues
Therefore, their volume of distribution (80–140 mL/kg) is only
BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUG slightly larger than the blood volume
Chemistry:
 All of the available neuromuscular blocking drugs bear a structural  Duration is strongly correlated with the elimination half-life
resemblance to acetylcholine o Drugs that are excreted by the kidney typically have
longer half-lives  leads to longer durations of action
 Metocurine
 Pancuronium
 Doxacurium
 Tubocurarine
o Drugs eliminated by the liver tend to have shorter half-
lives & durations of action
 Depolarizing Muscle Relaxant (DMR):  Rocuronium
o Succinylcholine  2 ACh molecules linked end-to-end  Vecuronium

 All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-

hydroxy, or 3,17-dihydroxy products in the liver
o Pancuronium
o Rocuronium
o Vecuronium
o Pipecuronium

 Atracurium
o Undergoes Hoffman elimination
 Nondepolarizing Muscle Relaxant (NDMR): o The main breakdown products are laudanosine and a
o Isoquinoline derivatives related quaternary acid, neither of which possesses
 Tubocurarine neuromuscular blocking properties
 Atracurium Laudanosine
 Doxacurium - Slowly metabolized by the liver
 Mivacurium - Has a longer elimination half-life (ie, 150 minutes)
- It readily crosses the BBB
o Steroid derivatives - High blood concentrations may cause seizures and an
↑ in the volatile anesthetic requirement
 Pancuronium
 Vecuronium
 Cistracurium
 Pipecuronium
o It resembles atracurium BUT:
 Rocuronium
 Less dependence on hepatic inactivation
 Produce less laudanosine
Figure on Left: Pancuronium  Less histamine release
 Clinical perspective: It has all the advantages
It conceal the “double- of atracurium with fewer adverse effects
acetylcholine” structure
(colored in blue) in one of two
types of bulky, semi-rigid ring
systems

Page 16 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

 Gantacurium
o It represents a new class of nondepolarizing
neuromuscular blockers, called asymmetric mixed-
onium chlorofumarates
o Can be degraded nonenzymatically by adduction of the
amino acid cysteine and ester bond hydrolysis
o Rapid onset & very short-acting
o Can be reversed by neostigmine or administration of L-
cysteine
o At doses above 3x the ED95: Cardiovascular adverse effect
(eg, hypotension)  due to histamine release
Based on Manual: (Also this is actually removed in Katzung 14th ed.)
 Mivacurium
o Shortest duration of action of all NDMR
o Slower onset than succinylcholine
Larger doses used to speed the onset  associated
with histamine release (hypotension, flushing,
bronchospasm)
o Prolonged duration of action in patients with renal failure

Depolarizing Relaxant Drugs (Pharmacokinetics)

 Extremely short duration of action of succinylcholine is due to its
rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase
in the liver and plasma, respectively
Plasma cholinesterase metabolism is the predominant pathway
for succinylcholine elimination

 The primary product is succinylmonocholine

o It is rapidly broken down to succinic acid + choline
 Neuromuscular blockade produced by succinylcholine can be
prolonged in patients with an abnormal genetic variant of plasma
cholinesterase
o Dibucaine number
 Measure of the ability of a patient to
metabolize succinylcholine and can be used
to identify at-risk patients
 Dibucaine inhibits the normal enzyme by 80%
and the abnormal enzyme by only 20%

Page 17 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

MECHANISM OF ACTION
Nondepolarizing Relaxant Drugs (MOA)
 d-tubocurarine  prototype neuromuscular blocker
 When small doses of NDMR are administered
o They compete with ACh at the nicotinic receptors
The least potent NDMR (eg, rocuronium) have the
fastest onset and the shortest duration of action

 In larger doses of NDMR are administered

o It can enter the pore of the ion channel to produce a
more intense motor blockade
o It also diminishes the ability of AChE inhibitors in
antagonizing the effect of NDMRs

 Nondepolarizers can also cause prejunctional Na+ channel blockade Figure Above: Action of normal agonist (Ach) in opening the end plate channel
o Causes interference to mobilization of Ach at the nerve
ending and cause fade of evoked nerve twitch
contractions
Fade – gradual decrease of Ach delivery from the
presynaptic neuron to the end plate leading to ↓
contractions

Depolarizing Muscle Relaxants (MOA)

 Phase I (depolarizing) block – succinylcholine binds to receptors and
are not metabolized as readily as ACh  sustained membrane
depolarization (flaccid paralysis)
o It is augmented (not reversed) by cholinesterase
inhibitors
 Phase II (desensitizing) block – membrane repolarization with
desensitization due to channels being in apparent prolonged closed
state
o May be reversed by cholinesterase inhibitors

Figure Above: Actions of NDMR and DMR

(Left) Nondepolarizing blocker prevents opening of the sodium channel (via
competitive inhibition)
(Right) Depolarizing blocker both occupies the receptor and blocks the
channel  normal closure of the gate is prevented causing persistent
depolarization and desensitization

Page 18 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS 3. Tetanic stimulation

Skeletal Muscle Paralysis  Very rapid (30–100 Hz) delivery of electrical
 Before the introduction of neuromuscular blocking drugs, profound stimuli for several seconds
skeletal muscle relaxation for intracavitary operations could be
achieved only by producing levels of volatile (inhaled) anesthesia  Two other modalities:
deep enough to PRODUCE profound depressant effects on the 4. Double burst stimulation
cardiovascular and respiratory systems  Three nerve stimuli are delivered at 50 Hz
 The adjunctive use of neuromuscular blocking drugs makes it followed by a 700 ms rest period and then by
possible to achieve adequate muscle relaxation for all types of 2 or 3 additional stimuli at 50 Hz
surgical procedures WITHOUT the cardiorespiratory depressant  Allows manual detection of residual
effects produced by deep anesthesia neuromuscular blockade
 The absence of fade in response to double-
Assessment of Neuromuscular Transmission burst stimulation implies that clinically
significant residual neuromuscular blockade
does not exist

Same principles with that of Train of Four

Figure Above: Peripheral Nerve Stimulator
 Monitoring of blockade is thru peripheral nerve stimulation
5. Post-tetanic count
 Three patterns that may be used:
 Several seconds of 50 Hz stimulation are
1. Single-twitch stimulation
applied, followed by several seconds of rest
 A single supramaximal electrical stimulus is
and then by single stimuli at a slower rate (eg,
applied to a peripheral nerve at frequencies
0.5 Hz)
from 0.1 Hz to 1.0 Hz
 Posttetanic count (PTC) – number of
detectable posttetanic twitch
2. Train-of-four (TOF) stimulation
 Four successive supramaximal stimuli given at
intervals of 0.5 second (2 Hz)
 TOF Ratio – strength of the 4th contraction
divided by that of the 1st contraction
TOF ratio >0.7  necessary for
resumption of spontaneous ventilation
TOF ratio >0.9  complete clinical
recovery from NDMR block

Figure Above:

No Drug
o Initial tetanic contraction  sustained
o PTC >6 (due to release of ACh built up during tetany)
o Posttetanic potentiation (*)  present

Nondepolarizer
o Initial tetanic contraction  fades over time (antagonist action)
o PTC less than normal
o Posttetanic potentiation (*)  present (↓ ACh after tetany is able to
Figure Above: surmount the blockade for a short period of time)
No drug – amplitude of twitch is sustained through the 4 stimuli
Depolarizer (Phase I block)
Nondepolarizer – Fade (decrease in amplitude of contraction over time due to ↑ ACh o Initial tetanic contraction  sustained but intensity of contraction is less
receptor blockade & ↓ delivery of ACh to the cleft); TOF decreased than normal (no fade because of agonist action)
Depolarizer (Phase I) – sustained amplitude but decreased intensity compared to o PTC less than normal
normal; Agonist (ACh-like) kasi ang effect ng succinylcholine during Phase I o Posttetanic potentiation (*)  absent
Depolarizer (Phase II) – same effect with nondepolarizer; Note: in most cases, phase II
Depolarizer (Phase II block)
depolarizing block has the same effect as a nondepolarizer
o Same effect with non-depolarizer

Page 19 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Nondepolarizing Relaxant Agents (Clinical Pharmacology)  Pancuronium

 In general, larger muscles (eg, abdominal, trunk, paraspinous, o Causes a moderate increase in heart rate and a smaller
diaphragm) are more resistant to neuromuscular blockade and increase in cardiac output
recover more rapidly than smaller muscles (eg, facial, foot, hand) o Little or no change in systemic vascular resistance
Diaphragm  last muscle to be paralyzed but 1st to regain o Pancuronium-induced tachycardia
function  Primarily due to vagolytic action
 May be secondary due to:
 Rocuronium – most rapid onset time (60-120 seconds)  Release of norepinephrine from
adrenergic nerve endings
Depolarizing Relaxant Agents (Clinical Pharmacology)  Blockade of neuronal uptake of
 Following administration of succinylcholine  transient muscle norepinephrine
fasciculations occur over the chest and abdomen within 30 seconds  Bronchospasm
 Paralysis develops rapidly (<90 seconds), the arm, neck, and leg o May be produced by neuromuscular blockers that release
muscles are initially relaxed followed by the respiratory muscles histamine (eg, atracurium)
 Duration of neuromuscular block typically lasts <10 minutes o Or it may be due to insertion of endotracheal tube
This is due to succinylcholine’s rapid hydrolysis by cholinesterase
in the plasma (and liver)  Succinylcholine
o Can cause cardiac arrhythmias with halothane
Adverse Effects administration
Cardiovascular Effects o It stimulates autonomic cholinoceptors, including the
 Minimal Effects: nicotinic receptors at both sympathetic and
o Vecuronium parasympathetic ganglia and muscarinic receptors in the
o Cisatracurium heart (eg, sinus node)
o Rocuronium o The negative inotropic and chronotropic responses to
o Pipecuronium Included based on Manual
succinylcholine can be attenuated by administration of
o Doxcuronium (but not mentioned in Katzung 14th ed.) an anticholinergic drug (eg, glycopyrrolate, atropine)
With large doses of succinylcholine, positive inotropic
 Slight-to-moderate block of muscarinic effect and chronotropic effects may be observed
o Pancuronium
o Bradycardia  happens when a 2nd dose of
 Hypotension due to systemic histamine release: succinylcholine is given less than 5 minutes after the
o Tubocurarine initial dose
o Atracurium This is due to direct myocardial effects, ↑ muscarinic
o Metocurine Included based on Manual stimulation, and ganglionic stimulation
o Mivacurium (but not mentioned in Katzung 14th ed.)
Prevented by:
Thiopental, Atropine, Ganglionic blocker,
Hypotensive effects of tubocurarine & mivacurium may be
Pretreatment with NDMR
attenuated with premedication of anti-histamine
Other Adverse Effects of DMR blockade (Succinylcholine):
 Hypotension in large doses due to ganglionic blockade:
 Hyperkalemia
o Tubocurarine
o Patients with burns, nerve damage or neuromuscular
o Metocurine – Included based on manual
disease, closed head injury, and other trauma may
develop proliferation of extrajunctional acetylcholine
receptors
o ↑ K+ release in the blood after succinylcholine
administration  risk for cardiac arrest
↑ Intraocular pressure
o Due to tonic contraction of myofibrils or transient dilation
of ocular choroidal blood vessels
o Succinylcholine is contraindicated only if anterior
chamber is open (“open globe”) due to trauma
↑ Intragastric pressure
o Increased risk for regurgitation and aspiration of gastric
contents
o It is more likely to occur in patients with delayed gastric
emptying (eg, those with diabetes), traumatic injury (eg,
an emergency case), esophageal dysfunction, and morbid
obesity
Muscle Pain
o Myalgias are a common postoperative complaint of
heavily muscled patients and those who receive large
doses (>1.5 mg/kg) of succinylcholine
o May be secondary to the unsynchronized contractions of
adjacent muscle fibers just before the onset of paralysis

Page 20 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Drug Interactions Effects of Disease & Aging on the Neuromuscular Response

Generally what happens is there is potentiation of blockade:  Myasthenia Gravis
 Anesthetics o Enhances the neuromuscular blockade produced by
o Inhaled (volatile) anesthetics potentiate the these drugs
neuromuscular blockade produced by NDMR in a dose-  Advanced Age
dependent fashion: o Is associated with a prolonged duration of action from
Isoflurane (most) > sevoflurane > desflurane > enflurane nondepolarizing relaxants as a result of decreased
> halothane > nitrous oxide (least) clearance of the drugs by the liver and kidneys
 Patients with Severe Burns & Upper Motor Neuron Disease
o Most important factors involved in the interaction: o Resistant to nondepolarizing muscle relaxants
1. Nervous system depression at sites proximal Desensitization is probably caused by proliferation of
to the neuromuscular junction extrajunctional receptors  which results in an ↑
2. ↑ muscle blood flow (ie, due to peripheral dose requirement for the nondepolarizing relaxant to
vasodilation produced by volatile anesthetics) block a sufficient number of receptors
3. ↓ sensitivity of the postjunctional membrane
to depolarization Reversal of Neuromuscular Blocking Drugs
o Malignant Hyperthermia  The cholinesterase inhibitors effectively antagonize the
 A condition caused by abnormal release of neuromuscular blockade caused by nondepolarizing drugs
calcium from stores in skeletal muscle o Neostigmine & Pyridostigmine
 A rare interaction of succinylcholine with  Antagonize nondepolarizing neuromuscular
volatile anesthetics blockade by ↑ the availability of ACh at the
 Treated with dantrolene motor end plate, mainly by inhibition of
acetylcholinesterase
 Antibiotics o Edrophonium
o Neuromuscular junction block is enhanced by antibiotics  Antagonizes neuromuscular blockade PURELY
(eg, aminoglycosides) by inhibiting acetylcholinesterase activity
o Antibiotics have been shown to cause a depression of It has a more rapid onset of action but may
evoked release of ACh similar to that caused by be less reversal in profound
administering magnesium neuromuscular blockade
Mechanism:  Sugammadex
Blockade of specific P-type calcium channels in the o A novel reversal agent recently approved for rapid
motor nerve terminal reversal of the steroid neuromuscular blocking agents
rocuonium and vecuronium
 Local Anesthesia & Antiarrhythmic Drugs
o Small doses  depress posttetanic potentiation via Uses of Neuromuscular Blocking Drugs
prejunctional neural effect  Surgical Relaxation
o Large doses  block neuromuscular transmission  Endotracheal Intubation
o Higher doses  block ACh-induced muscle contractions  Control of Ventilation
due to blockade of nicotinic receptor ion channels  Treatment of Convulsions
o Quinidine – a Na+ channel blocker antiarrhythmic drug
that can also produce similar effect as those of local SPASMOLYTIC & ANTISPASMODIC DRUGS
anesthetics  Spasmolytics & Antispasmodics are used to treat 2 conditions:
However, at the doses used for cardiac arrhythmias, 1. Antispasmodics  used for spasms from peripheral
this interaction is of little or no clinical significance musculoskeletal conditions
2. Spasmolytics  used for spasticity from upper motor
o Bupivacaine – high concentrations this local anesthetics neuron lesions
have been associated with cardiac arrhythmias  Spasticity:
independent of the muscle relaxant used o Intermittent or sustained involuntary contraction of
skeletal muscle, causing stiffness that interferes with
 Other Neuromuscular Blocking Drugs mobility and speech
o To prevent fasciculations associated with succinylcholine o It is characterized by an:
& postoperative myalgias  ↑ tonic stretch reflexes
 Pretreatment with NDMR:  ↑ flexor muscle spasms (ie, increased basal
 d-tubocurarine – 2 mg IV muscle tone) together with muscle weakness
 OR pancuronium – 0.5 mg IV o It is often associated with:
Although this dose usually  Spinal injury
reduces fasciculations and  Cerebral palsy
postoperative myalgias, it can  Multiple sclerosis
↑ the amount of succinylcholine  Stroke
required for relaxation by 50–
o The mechanisms underlying clinical spasticity appear to
90% and can produce a feeling
involve not only the stretch reflex arc itself but also
of weakness in awake patients
higher centers in the CNS, with damage to descending
pathways in the spinal cord resulting in hyperexcitability
of the alpha motor neurons in the cord

Page 21 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Spasticity continued….. Baclofen continued…..

o Pharmacologic therapy may ameliorate some of the Intrathecal Administration:
symptoms of spasticity by:  Control severe spasticity and muscle pain
 Modifying the stretch reflex arc  Partial tolerance may occur after several months of therapy 
May modulate excitatory or inhibitory increase dosage to maintain beneficial effect
synapses  Adverse Effects:
↓ o Excessive somnolence
Reduce activity of Ia fibers that excite the o Respiratory depression
primary motor neuron or enhance o Coma
activity of inhibitory internuncial neurons
 Disadvantage:
o Difficulty in maintaining drug delivery catheter
 By interfering directly with skeletal muscle
(ie, excitation-contraction coupling)
Other Uses of Oral Baclofen:
 Pharmacologic agents described as depressants of the spinal  Intractable low back pain
“polysynaptic” reflex arc:  Stiff person syndrome
o Barbiturates (Phenobarbital) used to treat these
 Trigeminal neuralgia
conditions of excess
o Glycerol Ethers (Mephenesin) skeletal muscle tone  Cluster headache
 Intractable hiccups
 Nonspecific depression of synapses involved in the stretch reflex  Tic disorder
could reduce the desired GABAergic inhibitory activity, as well as the  GERD
excitatory glutamatergic transmission  Cravings for alcohol, nicotine, and cocaine

CENTRALLY-ACTING SPASMOLYTIC
Tizanidine
Diazepam  A congener of clonidine that has been studied for its spasmolytic
 Facilitate the action of GABA in the CNS  acts on GABAA synapses actions
 Its action in reducing spasticity is at least partly mediated in the  Has significant α2-agonist effects, BUT it reduces spasticity in
spinal cord because it is somewhat effective in patients with cord experimental models at doses that cause fewer cardiovascular effects
transection than clonidine or dexmedetomidine
 Produce sedation at doses required to reduce muscle tone  Reinforces both presynaptic & postsynaptic inhibition in the cord
 Dosage: 4 mg/day up to a maximum of 60 mg/day o It also inhibits nociceptive transmission in the spinal
dorsal horn
Baclofen  Comparable efficacy to diazepam, baclofen, & dantrolene in relieving
 p-chlorophenyl-GABA muscle spasm
 Orally active GABA-mimetic agent  Dosage: 2-4 mg/day in divided doses
 Agonist at GABAB receptors  It is also effective in management of chronic migraine
 Activation of GABAB receptors results in hyperpolarization of 3
distinct actions: Adverse Effects:
1. Closure of presynaptic calcium channels  Drowsiness
2. Increased postsynaptic K+ conductance  Hypotension
3. Inhibition of dendritic calcium influx channels  Dizziness
Through ↓ release of excitatory transmitters in both the  Dry mouth
brain and the spinal cord, baclofen suppresses activity of Ia  Asthenia
sensory afferents, spinal interneurons, & motor neurons  Hepatotoxicity

 Baclofen may also reduce pain in patients with spasticity, perhaps by

OTHER CENTRALLY-ACTING SPASMOLYTIC DRUGS
inhibiting the release of substance P (neurokinin-1) in the spinal cord
Gabapentin
 It is as effective as diazepam in reducing spasticity but with less
sedation  Antiepileptic drug
 It does not reduce overall muscle strength as much as dantrolene  Spasmolytic agent in studies involving patients with multiple
sclerosis
Pharmacokinetics: Pregabalin is a newer analog of gabapentin that may also prove
useful in relieving painful disorders that involve a muscle spasm
 Rapidly & completely absorbed after oral administration
component
 Plasma T ½: 3-4 hrs.
 Dosage: 15 mg 2x daily  may increase as tolerated to 100 mg daily
Progabide
Adverse Effects:  It is a GABAA & GABAB agonist and has active metabolites, including
GABA itself
 Drowsiness  patients become tolerant to sedative effects with
chronic administration
 Increase seizure activity in epileptic patients  withdrawal of Glycine
baclofen should be done very slowly  An inhibitory amino acid neurotransmitter that appears to possess
pharmacologic activity when given orally and readily passes the BBB

Page 22 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Other Centrally-Acting Spasmolytic Drugs continued….. Botulinum Toxin

Idrocilamide & Riluzole  Therapeutic use: ophthalmic purposes, local muscle spasm
 Newer drugs for the treatment of amyotrophic lateral sclerosis (ALS)  Local injections:
that appear to have spasm reducing effects, possibly through o Facial  short-term treatment (1-3 months/treatment)
inhibition of glutamatergic transmission in the CNS of wrinkles associated with aging around the eyes and
mouth
DIRECT-ACTING MUSCLE RELAXANT o Generalized Spastic Disorders (eg, Cerebral Palsy) 
Dantrolene administer in 1 or 2 limbs  benefits persist for weeks to
 Direct acting muscle relaxant several months after a single treatment
 Hydantoin derivative related to phenytoin  It has virtually replaced anticholinergic medications used in the
 Reduces skeletal muscle strength by interfering with excitation- treatment of dystonia
contraction coupling in the muscle fibers  FDA approval was granted for:
 Normal contractile response: o Treatment of incontinence due to overactive bladder
o Involves release of Ca2+ from sarcoplasmic reticulum  o Chronic migraine
this activator Ca2+ brings about tension-generating  Type A botulinum toxin  more commonly used
interaction of actin with myosin But Type B botulinum toxin is also available
o Calcium is released from the sarcoplasmic reticulum via a
calcium channel, called the ryanodine receptor (RyR) Adverse Effects:
channel  Respiratory tract infections
It is called ryanodine receptor because the plant  Muscle weakness
alkaloid ryanodine combines with a receptor on the  Urinary incontinence
channel protein
 Falls
 Fever & Pain
 MOA: Interferes with the release of activator calcium through the
sarcoplasmic reticulum calcium channel by binding to the RyR1 and
ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL SPASM
blocking the opening of the channel
Centrally active drugs – promoted for the relief of acute muscle spasm caused
 Motor units that contract rapidly  more sensitive to the drug’s
by local tissue trauma or muscle strains:
effects than are slower-responding units
1. Carisoprodol 5. Metaxalone
 Cardiac muscle & Smooth muscle  minimally depressed because 2. Chlorphenesin 6. Methocarbamol
the release of calcium from their sarcoplasmic reticulum involves a 3. Chlorzoxazone 7. Orphenadrine
different RyR channel (RyR2) 4. Cyclobenzaprine

Pharmacokinetics & Dosage:  These drugs act primarily at the level of the brainstem
 Treatment of Dantrolene is initiated with 25 mg daily as single dose  Cyclobenzaprine
 Increase to a maximum of 100 mg 4x daily as tolerated o Prototype
 Only 1/3 of oral dose is absorbed o Structurally related to the tricyclic antidepressants and
 Elimination T ½: approximately 8 hrs. produces antimuscarinic side effects
o It is ineffective in treating muscle spasm due to cerebral
Major Adverse Effects: palsy or spinal cord injury
 Generalized muscle weakness o Adverse Effects:
 Sedation  Sedation
 Hepatitis  Confusion
 Transient visual hallucinations
Malignant Hyperthermia
This is due to its strong antimuscarinic side effects
 A special application of dantrolene
 A rare heritable disorder that can be triggered by a variety of stimuli,
o Dosage for acute injury related muscle spasm: 20-40 mg/d
including general anesthetics (eg, volatile anesthetics) and
orally in divided doses
neuromuscular blocking drugs (eg, succinylcholine)
 Patients at risk for this condition have a hereditary alteration in Ca2+-
induced Ca2+ release via the RyR1 channel or impairment in the ability
of the sarcoplasmic reticulum to sequester calcium via the Ca2+
transporter
 Pathophysiology:
Triggering agent
↓
Sudden & prolonged release of Ca2+
↓
Massive muscle contraction, lactic acid production, ↑ body
temperature

 Prompt Treatment:
o Control acidosis & body temperature
o Reduce calcium release  IV Dantrolene 1 mg/kg, repeat
as necessary to a maximum dose of 10 mg/kg

Page 23 of 25
 PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

Additional Antispasmodic Drug (Based on Manual):

Eperisone
 An antispasmodic drug
 Acts by relaxing both skeletal muscles and vascular smooth muscles

Clinical Effects:
 Reduction of myotonia
o Decreases pain, ischemia, and hypertonia in skeletal
muscle, thus alleviating stiffness and spasticity, and
facilitating muscle movement
 Improvement of circulation
 Suppression of the pain reflex
 Improves dizziness and tinnitus associated with cerebrovascular
disorders or cervical spondylosis
 Facilitates voluntary movement of upper and lower extremities
without reducing muscle power  useful during the initial stage of
rehabilitation and as a supporting drug during subsequent
rehabilitative therapy

 Low incidence of sedation when compared with other anti-

spasmodic drugs; this simplifies the clinical application of the drug
and makes it an attractive choice for patients who require anti-
spasmodic therapy without a reduction in alertness

Indications:
 Spastic paralysis in conditions such as cerebrovascular disease,
spastic spinal paralysis, cervical spondylosis, post-operative sequelae
(including cerebrospinal tumor), sequelae to trauma (eg, spinal
trauma, head injury), amyotrophic lateral sclerosis, cerebral palsy,
spinocerebellar degeneration, spinal vascular diseases and other
encephalomyelopathies
 Improvement of muscular hypertonic symptoms in conditions such
as cervical syndrome, periarthritis of the shoulder, lumbago

Dosage:
 Adults: 50-150 mg/day, in divided doses after meals

Other Effects:
 Skeletal muscle relaxation
 Relaxation of hypertonic skeletal muscles
 Improves intramuscular blood flow
 Suppression of spinal reflex potentials
 Reduction of muscle spindle sensitivity via motor neurons
 Vasodilatation and augmentation of blood flow
 Analgesic action and inhibition of the pain reflex in the spinal cord

Adverse Effects:
 Shock and Anaphylactoid reactions
 Steven Johnson Syndrome (Oculo-mucocutaneous syndrome)
 Toxic Epidermal Necrolysis

Other Side Effects:

 Anemia, rash, pruritus, sleepiness, insomnia, headache, nausea &
vomiting, anorexia, abdominal pain, diarrhea, constipation, urinary
retention or incontinence

Drug Interactions:
 Tolperisone hydrochloride & Methocarbamol  ocular disturbances

Page 24 of 25
PHARMACOLOGY
Topic: Anesthesia & Muscle Relaxants
Chapter: 25, 26 & 27

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