Critical Care Pharmacology

Critically ill patients present with complex hemodynamic, metabolic, and

biochemical derangements that significantly alter drug pharmacokinetics
and pharmacodynamics, posing a challenge for appropriate dose
optimization. Critical illness can lead to fluctuations in drug absorption,
distribution, metabolism, and excretion due to the patient's underlying
comorbidities, disease pathophysiology, resuscitation strategies, and
concurrent medications. These alterations necessitate individualized
dosing regimens tailored to each patient’s dynamic condition.

The physiological changes in critically ill patients can cause shifts in drug
protein binding, ionization, and volume of distribution. Additionally,
reduced oral absorption, impaired intestinal and hepatic metabolism, and
compromised renal clearance are frequently encountered, further
complicating therapeutic management. A deep understanding of these
changes and their implications on drug therapy is crucial to achieving
effective therapeutic outcomes.

This chapter provides a comprehensive overview of pharmacological

agents used in critical care settings, covering essential drug classes

intravenous Anesthetic Agents

Intravenous (IV) anesthetic agents are crucial in managing critically ill
patients for sedation, induction, and maintenance of anesthesia, as well
as for specific critical care interventions like rapid sequence induction and
sedation during mechanical ventilation. The choice of an IV anesthetic
agent is influenced by the patient's physiological state, underlying
pathologies, and comorbidities. In critical care the commonly used IV
anesthetics agents are propofol, etomidate, ketamine, thiopental, and
midazolam.

Propofol
Propofol is a versatile, short-acting intravenous (IV) anesthetic agent that
is widely used for induction and maintenance of anesthesia, as well as for
sedation in critical care settings. Due to its unique pharmacological
properties, including rapid onset and short duration of action, propofol has
become the agent of choice in various clinical scenarios.
Pharmacology and Mechanism of Action
Propofol enhances the inhibitory neurotransmission mediated by gamma-
aminobutyric acid (GABA) at GABA-A receptors, leading to
hyperpolarization of neurons and subsequent sedation, hypnosis, and
amnesia. Propofol’s rapid onset (30-45 seconds) and short duration of
action (3-10 minutes) make it an ideal agent for induction and
maintenance of anesthesia, as well as for procedural sedation. Propofol is
formulated as an oil-in-water emulsion containing soybean oil, glycerol,
and egg lecithin, giving it a milky white appearance, and it is available in
concentrations of 1% and 2% for intravenous use. (figure 6.1)

Figure 6.1: Propofol Vial (Note the white milky emulsion).

Propofol is primarily metabolized in the liver through glucuronide

conjugation, producing inactive metabolites that are excreted via the
kidneys. Less than 3% of propofol is excreted unchanged in the urine. A
unique feature of propofol is its extrahepatic metabolism, accounting for
up to 30% of its uptake and elimination via the lungs. This contributes to
its rapid clearance and short duration of action.
Dosage Recommendations:
 Induction of Anesthesia: 1–2.5 mg/kg IV bolus

 Maintenance of Anesthesia: 50–150 µg/kg/min IV, often

combined with nitrous oxide or an opioid

 Sedation: 25–75 µg/kg/min IV

Systemic Effects of Propofol

Propofol decreases intracranial pressure (ICP) and cerebral metabolic rate
of oxygen (CMRO2) by approximately 36%, providing cerebral protective
effects.

The most prominent effect of propofol is a dose-dependent reduction in

blood pressure (by 25-40%) due to vasodilation, which results from
decreased sympathetic activity and possible direct myocardial depression.

Propofol suppresses upper airway reflexes, allowing for laryngoscopy and

endotracheal intubation without the need for muscle relaxants in certain
cases. It has bronchodilatory properties, making it a suitable agent in
patients with reactive airway diseases.

ICU-Specific Applications of Propofol

1. Sedation in Mechanically Ventilated Patients: Propofol is the
agent of choice for sedation in intubated and mechanically
ventilated patients. Its rapid onset (30-45 seconds) and short
duration of action (3-10 minutes) allow for easy adjustment of
sedation depth. This enables clinicians to achieve targeted sedation
levels, facilitate neurological assessments, and expedite the
weaning process from mechanical ventilation.

o Dosing for Sedation: 25–75 µg/kg/min IV infusion.

o Advantages: Propofol offers quick recovery, minimal

hangover effects, and ease of titration. It also possesses mild
anti-inflammatory properties that may reduce systemic
inflammation in critically ill patients.

2. Induction and Maintenance of Anesthesia in the ICU: Propofol

is effective for inducing and maintaining anesthesia in critically ill
patients requiring short-term procedures. It can be used alone or
combined with opioids or benzodiazepines for balanced anesthesia.

o Dosing for Induction: 1–2.5 mg/kg IV bolus.

 o Dosing for Maintenance: 50–150 µg/kg/min IV infusion,
often combined with nitrous oxide or an opioid.

3. Management of Agitation and Delirium: Propofol’s sedative

properties help manage agitation and delirium in critically ill
patients. Its rapid onset allows for quick control of agitation, making
it ideal for patients with acute brain injury or those requiring
frequent neurological examinations.

Side Effects and Considerations

 Pain on Injection: This is a common side effect associated with
propofol administration.

 Propofol Infusion Syndrome (PRIS): A rare but potentially fatal

complication, PRIS is characterized by metabolic acidosis,
rhabdomyolysis, hyperkalemia, and cardiovascular collapse. It is
associated with prolonged high-dose infusions, especially in critically
ill patients

 Contraindications: Propofol should not be used in patients with

known hypersensitivity to the drug or its components, and in those
with severe hemodynamic instability or shock.
Mnemonic
P : Painful

R : Reflex suppressant

O : Oil containing

P : Pressure reducing (BP, intraocular pressure, decreasing ICP)

O : Onset is rapid

F : Fast action

O : Open injection not to be used again

L : Liver and lung metabolism

Etomidate
Etomidate is a rapid-acting intravenous anesthetic agent, introduced in
1972, known for its favorable hemodynamic profile and minimal
respiratory depression. It is primarily used for the induction of anesthesia
and short-term sedation in critically ill patients. Due to its ability to
maintain cardiovascular stability, it is particularly useful in patients with
compromised cardiac function or those who are hemodynamically
unstable.

Pharmacology and Mechanism of Action

Etomidate is an imidazole derivative that acts on the central nervous
system by enhancing the inhibitory effects of gamma-aminobutyric acid
(GABA) at the GABA-A receptors. It increases the affinity of GABA for its
receptors, resulting in depression of the reticular activating system, which
induces sedation and hypnosis. Etomidate is water-insoluble and unstable
in a neutral solution. To improve its solubility, it is formulated as a 0.2%
solution in 35% propylene glycol or a lipid emulsion.

Dose: For Induction: 0.2–0.6 mg/kg IV bolus. For Sedation: 5–10 µg/kg/min
IV infusion, limited to brief periods due to its endocrine effects.

Onset of Action: Rapid onset of anesthesia occurs within one arm-brain

circulation (approximately 30-60 seconds).

Duration: The effect lasts about 100 seconds after a single dose, allowing
for quick recovery.

Metabolism: Etomidate is primarily metabolized in the liver through

ester hydrolysis and is eliminated via the kidneys (85%) and bile (13%).

Important Systemic Effects of Etomidate

 Preservation of cardiac functions with hemodynamic stability
 Minimal effects on respiratory function, making it a safer option for
patients with compromised respiratory status.
 Etomidate reduces ICP and CMRO2, providing cerebral protection
while maintaining or increasing cerebral perfusion pressure (MAP-
ICP). However, it can be associated with grand mal seizures and
increased electroencephalographic (EEG) activity in epileptogenic
foci. It is also known for its high incidence of myoclonus, which can
be minimized by premedication with benzodiazepines.
 Etomidate is associated with transient adrenocortical suppression by
inhibiting 11-β-hydroxylase, the enzyme responsible for converting
11-deoxycortisol to cortisol. This suppression can last up to 6 hours
following a single dose and may lead to a reduction in cortisol levels,
impairing the body’s response to stress. Due to this effect,
etomidate should not be used for prolonged sedation in the ICU.

Limitations and Side Effects

 The most significant limitation of etomidate is its ability to cause
transient adrenocortical suppression, limiting its use for prolonged
sedation. The reversible inhibition of 11-β-hydroxylase can impair
 cortisol synthesis, which is a concern in critically ill patients,
especially those with sepsis. It is contraindicated for prolonged
sedation in the ICU due to the risk of adrenocortical suppression.

 Myoclonus and Pain on Injection.

ICU-Specific Applications of Etomidate

Induction and intbation in Hemodynamically Unstable Patients:
Etomidate is the induction agent of choice for patients with cardiovascular
instability, including those with valvular heart disease, ischemic heart
disease, and poor cardiac function. Under such conditions etomidate and
rocuronium makes the perfect combiation

Sedation for Short Procedures: Etomidate is effective for short-term

sedation in patients undergoing brief procedures or requiring sedation for
intubation. Its rapid onset and short duration of action allow for precise
titration and quick recovery.

Use in Neurocritical Care: Etomidate provides cerebral protection by

reducing intracranial pressure (ICP) and cerebral metabolic rate of oxygen
(CMRO2), while maintaining cerebral perfusion pressure. This makes it
particularly useful for patients with brain injury or increased ICP.

Cardioversion: Due to its quick recovery profile and ability to maintain

blood pressure, etomidate is a suitable option for cardioversion
procedures.

Table 6.1 : Summary of common induction agents in ICU

Agent Mechanism of Action Indications Common Side
Effects
Propofol Enhances GABA- General anesthesia Hypotension,
mediated inhibitory induction respiratory
neurotransmission depression
Etomidat Enhances GABA- Induction in patients Adrenal
e mediated inhibitory at risk of hypotension suppression, PONV
neurotransmission
Ketamin NMDA receptor Hemodynamically Hallucinations,
e antagonist unstable patients, increased cerebral
asthma blood flow
Thiopent Enhances GABA- Rapid sequence Prolonged
al mediated inhibitory induction (less recovery,
neurotransmission common now) accumulation
Midazola Enhances GABA- Anxiolysis, part of Amnesia,
m mediated inhibitory balanced anesthesia respiratory
neurotransmission depression
Thiopentone
Thiopentone (Thiopental) is an ultra-short-acting barbiturate used mainly
for refractory seizures in critically ill patients due to its potent
anticonvulsant properties. While its use in the ICU is limited because of
accumulation and prolonged sedation, it remains effective in certain
neurocritical care scenarios.

Mechanism of Action and Pharmacokinetics

Thiopentone enhances GABA-A receptor activity, causing CNS depression.
It has a rapid onset (15-30 seconds) and short initial duration (5-10
minutes) due to redistribution. However, repeated doses lead to drug
accumulation and delayed recovery. It is metabolized in the liver and
excreted in the urine.

ICU-Specific Applications

1. Refractory Seizure Management: Used when conventional

anticonvulsants fail.

2. Cerebral Protection: Reduces cerebral metabolic rate and ICP,

making it useful for neurocritical care.

3. Induction of Anesthesia: Rarely used due to cardiovascular and

respiratory depression but can be considered in specific scenarios
like neurosurgery.

Systemic Effects

 CNS: Decreases CMRO2 and ICP, but provides no analgesia.

 Cardiovascular: Causes hypotension and decreased myocardial

contractility.

 Respiratory: Induces central respiratory depression and can cause

laryngospasm.

Limitations and Side Effects

Prolonged sedation, delayed recovery, cardiovascular depression, and
respiratory complications limit its use in the ICU. It can also cause pain on
injection, tissue necrosis, and is contraindicated in porphyria and
hemodynamic instability.
Thiopentone’s primary use in critical care is for refractory seizures and
cerebral protection, with its adverse effects requiring cautious application
and monitoring

Note

Intubating a critically ill patient without an induction agent is a practice

seen in only a few centers and is highly contraindicated. Some physicians
may opt for awake intubation, particularly in hemodynamically unstable
patients, believing it prevents further compromise. However, this
approach is risky as induction agents not only provide loss of
consciousness but also decrease metabolic oxygen demand, reduce
sympathetic responses, and facilitate a smoother, faster intubation when
combined with muscle relaxants. Awake intubation increases the risk of
airway trauma, laryngospasm, and aspiration. Therefore, the safest and
most effective method is to use an appropriate induction agent followed
by a muscle relaxant, ensuring better control and minimizing
complications.

Ketamine
Ketamine is a phencyclidine derivative known for its unique ability to
provide analgesia and anesthesia without depressing cardiovascular or
respiratory function. It acts as an NMDA receptor antagonist, causing
dissociative anesthesia by selectively depressing the thalamus and cortex
while stimulating the limbic system. This makes it the induction agent of
choice for hemodynamically unstable patients, status asthmaticus, or
trauma cases.

Systemic Effects

 Cardiovascular: Increases heart rate, blood pressure, and cardiac

output, making it useful for shock but contraindicated in ischemic
heart disease.
  Respiratory: Minimal impact on respiratory drive and acts as a
bronchodilator, making it safe for asthma or COPD.

 CNS: Increases cerebral blood flow and ICP, limiting its use in
patients with head injuries.

Limitations and Side Effects

High incidence of emergence reactions (hallucinations), increased

salivation, muscle tone, and nausea. Contraindicated in head injuries,
increased ICP, or ischemic heart disease.

Dose
 Induction: 1–2 mg/kg IV or 4–6 mg/kg IM.

 Maintenance: Incremental IV bolus or infusion at 15-45 µg/kg/min

ICU-Specific Applications

ketamine’s hemodynamic stability and bronchodilatory effects make it

valuable for critically ill patients, with cautious use required to manage its
psychological and physiological side effects.

Benzodiazepines
Benzodiazepines (BZDs), including midazolam, diazepam, and lorazepam,
are widely used in the ICU for their sedative, anxiolytic, and
anticonvulsant properties. They act by enhancing GABAergic inhibition in
the CNS, producing sedation, hypnosis, and amnesia. Midazolam is the
preferred BZD in critical care due to its rapid onset, water solubility, and
shorter context-sensitive half-life.

Pharmacology and Mechanism of Action

Benzodiazepines enhance the binding affinity of GABA to the GABA-A
receptor, leading to increased chloride ion influx and neuronal
hyperpolarization, which results in CNS depression. BZDs differ in their
potency, onset, and duration based on their lipid solubility and
metabolism.

Dosing and Applications

 Sedation:
 o Midazolam: 0.05–0.15 mg/kg IV bolus; 0.5–1.0 mg IV repeated
as needed.

o Diazepam: 0.1 mg/kg IV bolus; 2 mg IV repeated as needed.

 Induction:

o Midazolam: 0.05–0.15 mg/kg IV.

o Diazepam: 0.3–0.5 mg/kg IV.

 Seizure Control: 0.1 mg/kg IV (midazolam) or 0.3 mg/kg IV

(diazepam) for anticonvulsant use.

ICU-Specific Applications of Benzodiazepines

1. Sedation and Anxiolysis:

Benzodiazepines are used for sedation in mechanically ventilated
patients and as premedication to reduce anxiety. Midazolam, due to
its rapid onset and short half-life, is the agent of choice for
continuous infusions and short procedures. Lorazepam is preferred
for longer sedation due to its intermediate duration.

2. Seizure Control:
BZDs are effective anticonvulsants and are used to control seizures,
particularly after local anesthetic toxicity or in status epilepticus.
Midazolam is often preferred due to its rapid action and ease of
titration.

Systemic Effects of Benzodiazepines

1. Central Nervous System:

Benzodiazepines decrease cerebral metabolic rate of oxygen (CMRO2) and
cerebral blood flow (CBF) while maintaining the normal ratio, providing
some degree of neuroprotection..

2. Cardiovascular System:
Minimal cardiovascular effects, making them safe for use in patients with
cardiovascular disease. Midazolam may cause a mild decrease in blood
pressure due to reduced systemic vascular resistance.

3. Respiratory System:
Dose-dependent respiratory depression is the most significant side effect,
especially when combined with opioids. Midazolam has a higher risk of
respiratory depression compared to other BZDs, and its effect can be
prolonged in patients with COPD or concurrent opioid use.

Limitations and Side Effects

  Respiratory Depression: Particularly with midazolam, which is
more pronounced in patients with chronic respiratory conditions.

 Venous Irritation: Diazepam and lorazepam can cause venous

irritation and thrombophlebitis due to the presence of propylene
glycol in their formulation.

 Reversal with Flumazenil: Flumazenil effectively reverses BZD-

induced sedation and respiratory depression, making it a valuable
tool in managing overdose or prolonged sedation.
Features Midazolam Diazepam Lorazepam
Physicochemical
Lipid solubility ++++Q +++ ++
Water solubility ++ (in acidic medium)
Pharmacokinetics
Onset (after IV) 30–60 sec 30–60 sec 1–2 min
Duration Short Long Intermediate
Elimination t1/2 2–3 hours 20–50 hours 10–20 hours
Context sensitive t1/2 70–90 minQ Very high (not used Very high (not used for
for infusion) infusion)
Dose
0.05–0.15 mg/kg 0.3–0.5 mg/kg 0.1 mg /kg
Induction
0.05 mg/kg prn 0.1 mg/kg prn 0.02 mg/kg prn
Maintenance
0.5–1.0 mg repeated 2 mg repeated 0.25 mg repeated
Sedation
Receptor affinity +++ ++ +++(max)Q
(Potency)
Metabolism Oxidation Oxidation Oxazepam,Q Conjugation None
Active metabolite Hydroxymidazolam Desmethyldiazepam

Disadvantages
Pain on injection –Q ++ ++
Hypotension + –/+ –/+
Flumazenil reversal Effective Effective Poor (due to high affinity)
Table 6.3: Benzodiazepines at a glance.

Opioids:

Opioids are a cornerstone in critical care for managing pain and providing
sedation in mechanically ventilated patients. Commonly used opioids in
the ICU include morphine, fentanyl, remifentanil, and sufentanil, each
varying in potency, duration, and side effect profile. They act primarily as
agonists at the mu-opioid receptors, producing analgesia, sedation, and
respiratory depression.

Opioids are chosen based on their pharmacokinetic properties: fentanyl

and remifentanil, with their rapid onset and shorter half-lives, are
preferred for acute pain management and sedation due to easy titration
and quicker recovery. Morphine, with a longer duration of action, is often
used for sustained pain control. While opioids are effective analgesics,
their potential for respiratory depression, constipation, and tolerance
requires vigilant monitoring and dose adjustment.

For detailed descriptions of individual opioids and their specific uses in

critical care, please refer to the appendix.

Muscle Relaxants
Muscle relaxants, or neuromuscular blockers, are commonly used in the
ICU to facilitate endotracheal intubation, optimize mechanical ventilation,
and provide muscle relaxation during procedures or in critically ill patients
with severe respiratory failure. They do not possess any analgesic or
amnesic properties and should only be administered to anesthetized or
deeply sedated patients to avoid the distressing experience of being
awake and unable to move or breathe voluntarily.

Neuromuscular blockers act by inhibiting the transmission of nerve

impulses at the neuromuscular junction, resulting in paralysis of skeletal
muscles. Their use in the ICU must be carefully monitored with
appropriate sedation and analgesia to ensure patient comfort and safety.
For ICU patients, muscle relaxants are chosen based on their onset,
duration, and hemodynamic profile, with agents like rocuronium,
cisatracurium, and vecuronium being commonly used.

Succinylcholine
Succinylcholine (Sch) is a depolarizing neuromuscular blocker and
remains the most commonly used muscle relaxant to facilitate intubation
in many third-world countries due to its rapid onset (60 seconds) and
short duration of action (3-5 minutes). Despite its popularity in emergency
airway management, the widespread use of SCh in advanced setups is
limited due to its numerous side effects, especially when alternatives like
rocuronium paired with sugammadex are available.

Mechanism of Action
Succinylcholine mimics acetylcholine (ACh) and binds to nicotinic
receptors at the neuromuscular junction, causing persistent
depolarization, leading to muscle paralysis. It is rapidly hydrolyzed by
butyrylcholinesterase in plasma, which results in its ultrashort duration of
action.

Dose
  Intubation: 1 mg/kg IV produces complete paralysis within 60
seconds.

 Maintenance: Typically avoided due to risks of prolonged paralysis

and side effects.

Common Side Effects

 Cardiovascular: Bradycardia, especially in children, dysrhythmias,
and potential for junctional rhythms.

 Hyperkalemia: Due to the efflux of potassium from muscle cells, it

can be life-threatening in patients with neuromuscular diseases,
burns, or prolonged immobility.

 Increased Intraocular and Intracranial Pressure: Pre-treatment

with non-depolarizing muscle relaxants can help mitigate these
effects.

 Myalgia: Common post-use, especially in ambulatory patients.

Succinylcholine’s rapid onset makes it ideal for rapid-sequence induction;

however, its use is limited in the ICU due to risks of hyperkalemia, its
ultra-short duration, and increased intracranial pressure, restricting its
application primarily to intubation in difficult airway scenarios.

Non-Depolarizing Muscle Relaxants

Non-depolarizing muscle relaxants (NDMBs) such as vecuronium,
rocuronium, atracurium, and cisatracurium are commonly used in ICU
settings to facilitate endotracheal intubation, maintain muscle relaxation,
and optimize mechanical ventilation in critically ill patients. Each agent
varies in terms of onset, duration, metabolism, and side effect profile,
making selection patient-specific based on underlying conditions and
desired effects.

Vecuronium
Vecuronium is an intermediate-acting steroidal muscle relaxant commonly
used for maintenance of perianesthetic muscle relaxation due to its
cardiovascular stability. It is primarily metabolized in the liver, producing
an active metabolite, 3-desacetylvecuronium, which can accumulate in
patients with renal impairment and prolong neuromuscular blockade.
Dose: 0.08-0.1 mg/kg IV.

Rocuronium
Rocuronium is a steroidal NDMB with a rapid onset of action (60–90
seconds), making it suitable for intubation, particularly in rapid-sequence
induction. It is metabolized mainly by the liver and lacks active
metabolites, making it preferable for continuous infusion compared to
vecuronium. Dose: 0.6-0.9 mg/kg IV.

Atracurium
Atracurium, a benzylisoquinolinium muscle relaxant, is unique in its
metabolism through Hofmann elimination and ester hydrolysis, making it
independent of renal or hepatic clearance. However, its use is associated
with histamine release, which can cause bronchospasm, especially in
asthmatic patients. Dose: 0.3-0.6 mg/kg IV.

Cisatracurium
Cisatracurium, a more potent isomer of atracurium, is metabolized
primarily by Hofmann elimination, making it ideal for patients with renal or
hepatic impairment. It lacks histamine release, making it safer in
asthmatic and cardiovascularly compromised patients. It is the muscle
relaxant of choice in conditions such as renal or hepatic failure and
myasthenia gravis. Dose: 0.15-0.2 mg/kg IV.

Table 6.5: Summary of neuromuscular blockers in ICU

Initial Onset Durati Excretion Histamin Ganglio Vagal

dose (min) on e n block block
Kidne Liver
Drug (mg/kg) (min) Metabolism release
y
Vecuronium 0.08–0.1 2–4 20–40 Liver (30–40%) 40% 40% – – +
(bile)
Atracurium 0.3–0.6 2–4 20–35 Hofmann elimination 20% – + – –
Ester hydrolysis
Cisatracurium 0.15–0.2 4–7 20–40 Hofmann elimination 15% – – – –
Rocuronium 0.6–0.9 1–2 25–40 None 10–15% 70% – – –
Succinylcholine 1–1.5 0.5–1.5 3–6 Pseudocholinesterase <2% – ++ Stimulate Stimulate
s ganglia s vagii