Pharmacology of Sedatives and Analgesics

2. PHARMACOLOGY OF
SEDATIVES AND
ANALGESICS
Prepared by :
Muhammad Umar Hafeez
Pharm D
Inpatient Pharmacist
Nation Hospital Managed by MUVI Abu Dhabi UAE.

3. Learning
Objectives:Upon completion of this course learners will be able to
 Gain knowledge, key concepts, and skills that promote safe and effective
use of medicines in Procedural Sedation.
by
 Defining and understanding different levels of sedation (minimal,
moderate, deep, and general).
 Pharmacological Classification
 Pharmacokinetics
 Pharmacodynamics
 Choices for safe medicines in procedural sedation based on
Pharmacological actions

4. SEDATION COMES FROM THE LATIN WORD SEDARE.
SEDARE = TO CALM OR TO ALLAY FEAR
Analgesic
Hypnosis
± Muscle
relaxation
Sedative Medications:
A sedative is defined as a drug that
• decreases activity,
• moderates excitement
• calms the patient
• depress central nervous system

5. Common definitions of Sedative
medications:
Hypnotics:
A hypnotic produces
drowsiness and
facilitates the onset and
maintenance of sleep
Analgesics:
An analgesic relieves
pain by altering
perception of
nociceptive stimuli.
Anxiolytics:
An anxiolytic relieves
apprehension and fear
due to an anticipated
act or illness.
Amnestic:
An amnestic agent
affects memory
incorporation such that
the patients unable to
recall.

6. WHY SEDATION IS
NECESSARY?
improve
patient
comfort.
Reduce stress.
Facilitate
interventions.
Allow
effective
ventilation.
Encourage
sleep.
Prevent post-
ICU psychosis

7. Levels of Sedation:
• Minimal Sedation
(Anxiolysis)
There are four Levels of Sedation :
• Moderate Sedation
A drug-induced state in which
patients respond normally to
verbal commands.
• Deep Sedation:
A drug-induced depression of
consciousness during which
patients respond purposefully to
verbal commands
• General Anesthesia:
A drug induced loss of consciousness
during which patients cannot be easily
aroused but may respond purposefully
following painful or repeated
stimulation.
This is a medically induced state
of unconsciousness with loss of
protective reflexes.

8. UPTODATE
Classification of Sedative and
Analgesics:
Intravenous
Anaesthetics:
Propofol
Thiopental
Ketamine
Etomidate
Sedative-
Hypnotics :
Midazolam
Diazepam
Lorazepam
Quality
Management
Systems

9. Classification of Sedative and
Analgesics:
Opioid Analgesics :
• Morphine
• Fentanyl.
• Remifentanil
α-2 receptors
agonists:
• Dexmedetomidine
Others:
• Chloral Hydrate
• Inhalation anaesthetics
(Sevoflurane)
UPTODATE

10. Pre-Sedation Assessment:
Allergies and previous adverse drug reactions
Current medications including over the counter medications.
Previous sedation/anesthesia history
Review of systems: focus on pulmonary, cardiac, renal and hepatic
function

11. Choice of sedative agents:
The choice of
drug depends
upon
Short-term Vs
long-term
sedation.
Degree of Pain
Organ problems
(Renal, hepatic,
brain, CVS).
Procedure Position
and duration
Procedure Location
(availability of
rescue resources)
Procedure Anxiety-
Distress

12. Goal:
The goal is to administer the sedative drug that
achieves the desired clinical effect (“right” drug)
(pharmacodynamics) at the “right” time
(pharmacokinetics).

13. Route of administration:
1. DESIRED CLINICAL EFFECTS
2. HOW FAST the effects desired?- Onset of action
3. HOW LONG the effects desired?- Duration of action
4. What is NOT DESIRED or
CONTRAINDICATED?
The selection of Route of
administration depends upon

14. Route of administration:
1 ) ORAL : It is
convenient and easy
method of administration.
DISADVANTAGES :
a) Include first pass
hepatic metabolism
b) Inconsistent onset of
clinical effect
c) Inability to titrate.
EXAMPLES : Midazolam ,
Chloral Hydrate
2) RECTAL : ADVANTAGES
a) Used in patients who
refuse to take medications
by mouth
b) Patients with nausea &
vomiting
C) Partial first Pass effect
d) Lower no. of doses
Examples : Diazepam
3) INTRANASAL
ADVANTAGES:
Intranasal absorption
occurs directly into the
systemic circulation
No first pass hepatic
metabolism.
Required doses are less
than the oral or rectal
route
Clinical effect is more
rapid.
DISADVANTAGES:
Not well tolerated by
some patients due to a
burning sensation (e.g.
Midazolam)
Examples :
Midazolam, Ketamine
and
Dexmedetomidine.

15. Route of administration:
4)INHALATION :
ADVANTAGE:
Onset of
action is
rapid and
very well
tolerated by
children.
DISADVANTS:
Acceptance
of the mask
by younger
children (less
than 3 years)
EXAMPLES:
Nitrous
Oxide,
Sevoflurane

16. Pharmacokinetics of Sedative and analgesics: General
Concept
Pharmacokinetic of a drug is “ its concentration at the target tissue which is
determined by combined influences of absorption, metabolism, distribution,
and elimination (excretion).”
Bioavailability refers to the portion of an administered dose that reaches the
systemic circulation in active form, and is thereby available for distribution to
target tissues.
Anesth Prog. 2011 Winter; 58(4): 166–173.

17. Pharmacokinetic Considerations while choosing
an agent:Drug Half Life
(hour)
Protein
Binding
(%)
Metab
olism
Hydrophili
c/lipophili
c
Eliminatio
n
Active Metabolite Cont.Infusion
/
Bolus
Midazolam 1 - 2.5 97 Hepatic Lipophilic Urine 1-hydroxymethylmidazolam Infusion prefer
Bolus*
Diazepam P^= 33 – 45
M^^= 87
90 Hepatic Highly
lipophilic**
Urine Desmethyl-diazepam,
oxazepam,hydroxydiazepam
Intermittent
infusion/Bolus
Lorazepam 10-20 91-93 Hepatic Lipophilic** Urine 88 %
Feces 7%
Bolus prefer
Fentanyl 2 - 4 80-86 Hepatic Highly
lipophilic
Urine 75 %
Feces 9%
Bolus/
Infusion case
dependent
Remifenta
nil
3 - 10 min 70 Hepatic/
plasma
esterase
Lipophilic Urine Infusion /
Avoid Bolus due
to side effects
Morphine
sulphate
1.5 - 4.5 20-30 Hepatic Less lipophilic Urine Morphine-6-glucuronide
Morphine-3-glucuronide
Bolus/Infusion
Case dependent
Dexmedet
omidine
2 94 Hepatic Highly
lipophilic
Urine (95%);
feces (4%)
Bolus not
recommended
*patients not requiring deep sedation to ensure optimal wake up times.
**Psychopharmacology (Berl). 1990;102(3):373-8.
^ Parent , ^^ Metabolite

18. Onset and Duration: General Concept
Anesth Prog. 2011 Winter; 58(4): 166–173.
Onset and duration of sedation : Following absorption, serum concentrations are high
and drug distributes to tissues in proportion to their degree of perfusion; brain, muscle, and
finally adipose tissues. As distribution proceeds, serum level declines and high concentrations
in brain redistribute into the bloodstream. These processes occur more rapidly with highly
lipid soluble drugs and account for rapid onset but shortened duration of sedation. Drug
elimination follows subsequently.

19. EFFECT OF METABOLISM : GENERAL
CONCEPT
BIOTRANSFORMATION OF VARIOUS BENZODIAZEPINES:
Parent drugs and their active metabolites vary in their
elimination half-lives: L, >24 hours; I, 6–24 hours; and S,
<6 hours (derived from Mihic and Harris7).
MIDAZOLAM:
water soluble state while in
formulated solutions for parenteral
injection. When subjected to
physiologic pH it becomes highly lipid
soluble.
Anesth Prog. 2012 Spring; 59(1): 28–42.doi: 10.2344/0003-3006-59.1.28

20. Circulation and
distribution:
Circulation and distribution: Drug (D) circulating in the bloodstream can distribute
easily through systemic capillaries into most body tissues. Distribution through central
nervous system capillaries (blood-brain barrier) requires lipid solubility. Notice that a portion
of the total drug circulating may be temporarily bound to plasma protein but readily
dissociates to distribute into tissues. See text for further explanation.
Anesth Prog. 2011 Winter; 58(4): 166–173.

21. Distribution and Elimination General Concept:
Pharmacokinetic compartments : Following an IV bolus, drug introduced into the bloodstream (central
compartment) distributes into peripheral tissues (peripheral compartment). In the 3-compartment model these
tissues are divided into those highly perfused (shallow) and less perfused (deep). As the serum conc. reduces
due to distribution or elimination, drug in the peripheral compartments will equilibrate by redistribution into the
central compartment. The time-concentration curve illustrates the decline in serum concentration attributable to
rapid distribution into highly perfused tissues, intermediate distribution to less perfused tissues, and a slow
decline due to drug elimination. Anesth Prog. 2011 Winter; 58(4): 166–173.

22. The Ideal Sedative Agent:
Sedative, analgesic and anxiolytic properties easy to titrate
Minimal cardiovascular and respiratory side-effects
Rapid onset and offset of action
No accumulation in renal/hepatic dysfunction
Inactive metabolites
No interactions with other drugs
cost-effective by improving quality of care
Crit Care. 2008; 12(Suppl 3): S4.Published online 2008 May 14. doi: 10.1186/cc6150

23. Commonly Used Sedative and
Analgesics:
Br J Anaesth (2001) 87 (2): 186-192 ⁴
0%
20%
40%
60%
80%
Midazolam Propofol Loraepam Diazepam Morphine Fentanyl Sufentanyl Others
63%
35%
0.50%
0.30%
33% 33%
24%
1%
Percentage
Sedative and Analgesics
MOST COMMONLY USED SEDATIVE AND ANALGESICS IN EUROPE, UK
AND NORWAY.

24. Combination Regimens:
The ideal
Sedative/Analgesic which
have deep to light
sedation and from
hypnotic-based to
analgesic-based sedation
does not exist.
The most commonly used
agents are
• Intravenous anesthetic
agents( Ketamine,
Etomidate, Propofol) or
benzodiazepines
(Midazolam, Diazepam,
Lorazepam) often in
combination with opioids (
Fentanyl ,Morphine ,
Remifentanil )
• Other options to control
agitation, delirium and
pain in the ICU include
alpha 2 agonists(
dexmedetomidine)
• non-opioid analgesics and
antipsychotic agents.
There is insufficient evidence
to recommend one regimen
over another, and so the
agents chosen should be
individualized to the patient’s
requirements, characteristics
and the clinical situations
Crit Care. 2008; 12(Suppl 3): S4.Published online 2008 May 14. doi: 10.1186/cc6150

25. MIDAZOLA
M : ROUTE : IV, IM ,SUB Q,
ORAL
Medication Safety:
LASA, HIGH ALERT(ISMP)
Mechanism of action :
Binds to GABA-A
receptors,
ADVANTAGES :
•Producing sedation, anxiolysis, amnesia and
anticonvulsant actions
•Water-soluble  lipid soluble in the body.
•Produces sedation, anxiolysis and amensia.
•It is the only IV benzodiazepine that is not
delivered in propylene glycol.
UPTODATE

26. MIDAZOLA
M :
DISADVANTAGES :
• Active metabolites may
accumulate and cause prolonged
sedation if delivered long-term.
• Half-life may be prolonged in
critically ill patients with hepatic
or renal impairment.
• Risk of delirium.
Role:
• A good choice for short-term
anxiolysis and treatment of acute
agitation.
• Dose adjustment needed for
patients with renal / hepatic
impairment.

27. DIAZEPA
M :
ROUTE :
IV,IM,RECTAL
Medication
Safety : LASA,
HIGH ALERT(
GERIATRIC)
Advantages :
Rapid onset with
potent sedative
and muscle-
relaxant effects.
Disadvantages:
• Half-life may be
prolonged with
hepatic/renal
impairment.
• Risk of delirium.
• Injection solution
contains propylene
glycol solvent and
cannot be delivered
as a continuous
infusion.
• Injection site pain
and risk of phlebitis
limit usefulness of IV
injections.
Role: Seldom
used for sedation
of critically ill
patients.
May be useful
for critically ill
patients at risk of
alcohol
withdrawal or
seizures

28. Sedative-hypnotics: General
Dosing
Benzodiazepine Initial Dose (loading
dose) iv
mg/kg
Maintenance
mg/kg
Onset
(Minutes)
Duration of intermittent
dose
Diazepam 0.05 - 0.2*** 0.03-0.1**
(1 - 7 mg)*
2-5 ½ - 6 hours
Midazolam 0.01 - 0.05 ***
(0.5 – 4 mg)*
0.02 -0.1
mg/kg/hour
(2-8 mg/hour)*
2-5 30 min
Lorazepam 0.02 – 0.04 ***
(1-2 mg)*
0.02-0.06 (1-4
mg) *
15-20 2-6 hrs.
*Dosing in Obese
**Continuous infusion not recommended
*** One/more loading dose may be necessary

29. Sedative-hypnotics:
Summary of enteral Midazolam administration – route, dosing, clinical onset and positive (+) and
negative (-) attributes.
Route Dose
mg/kg
Clinical Onset
(minutes)
(+) Attributes (-) Attributes
Intranasal 0.2-0.4 10-15 min fast onset irritating
Rectal 0.3-0.75 15-20 min. age < 3 year not older children
Oral 0.3-0.75 15-30 min easy delivery variable onset, bad taste

30. IV Anaesthetics –
Ketamine:Phencyclidine derivative.
High lipid solubility (5–10 times >
thiopental) crosses BBB faster.
Non-competitive antagonism at
NMDA receptor, also binds to
opioids mu and sigma receptors
Medication Safety : LOOK A LIKE SOUND A LIKE

31. IV Anaesthetics –
Ketamine:
Advantages:
A potent dissociative
sedative-anesthetic
with marked
analgesia
maintains CO and
MAP without
inhibition of
respiratory drive.
Disadvantages:
 HR, BP.
 CBF, ICP &
CMRO2.
Importance :
An alternate choice
for Postsurgical pain
management,
Severe Agitation
Adjunctive analgesic
in patients with
severe refractory pain
in clinical settings.

32. Summary of IV
Anesthetics :Anesthetic
Agent
Initial Dose
(loading dose) iv
Maintenance Onset Duration of
intermittent
dose
Elimination
Half life
Propofol Bolus dose is not
recommended in
ICU
5-50
mcg/kg/min
titrate every 5-
10 min in
increments of
5-10
mcg/kg/min
< 2
min
3-10 min* 3-12 hour
Ketamine 0.1-0.5 mg/kg 0.05-0.4
mg/kg/hour
≤1
min
10-15 min 2.5 hours
*It is for initial dosing. It is prolonged after repeated dosing/continuous infusion due to
accumulation of drug in adipose tissue.

33. α2-Adrenergic agonists
Dexmedetomidine

34. α2 – agonists
Sedation-
hypnosis:
by an action on α2-receptors in
the locus ceruleus.
• α2-receptors within the locus
ceruleus
• spinal cord
Analgesia:
by action
on

35. α2 – agonists;
Dexmedetomidine
94% protein bound.
Narrow therapeutic range (0.5 - 1.0 ng/mL)
It undergoes conjugation & N-methylation.
Approved only for sedation ≤ 24 h.

36. α2 – agonists; Dexmedetomidine
Haemodynamic Effects:
 heart rate.
Initial  then  BP.
 Systemic Vascular Resistance.
 Cardiac Output

37. α2 – agonists;
DexmedetomidineMedicine
Name
Initial Dose
(loading dose) iv
Maintenance Onset Duration of
intermittent
dose
Elimination
Half life
Dexmedet
omidine
Optional:
1 mcg/kg over 10
minutes if
hemodynamically
stable
Usually not given
Initiate 0.2 to 0.7
mcg/kg/hour
and titrate every
30 minutes
Some patients
require doses up
to 1.5
mcg/kg/hour
5 to 10
min
60 to 120 min 120 min

38. α2 – agonists; Dexmedetomidine
Advantages:
Sedative sympatholytic
(central alpha2 agonist)
with moderate
anxiolysis and analgesia
no clinically significant
effect on respiratory
drive.
Disadvantages:hypotension and
bradycardia,
loading dose associated
with cardiovascular
instability, tachycardia,
bradycardia, or heart-
block.
Role :
A good choice for short-
and long-term sedation
in critically ill patients
without relevant cardiac
conditions.

39. Opioids; Morphine
Isolated in 1803 by the German pharmacist Friedrich Adam.
Named it 'morphium' after Morpheus, the Greek god of dreams.

40. Opioids - Morphine
Plasma levels do not correlate
with clinical effect.
Low lipid solubility causes slow
equilibration across BBB.
Metabolized in the liver by
conjugation.
Morphine-6-glucuronide (active).
ALERT: US Boxed Warning

41. Fentanyl
: Fentanyl is 50-100 times as potent as morphine,
Piperidine derivative
Absence of histamine-releasing
properties; fentanyl is appropriate for patients
with bronchospasm
rapid penetration of the
blood-brain barrier and rapid
onset of action (4-6 minutes)
ALERT: US Boxed
Warning
Lipophilic

42. Remifentanil:
Piperidine derivative. Highly lipophilic.
Selective mu-receptor agonist.
potency is one to two times that of fentanyl
Terminal half-life < 10 min.
Rapid blood-brain equilibrium.
Ultra short acting 10 min.

43. Comparison of Opioids:
Opioids Initial Dose (loading
dose) iv
mg/kg
Maintenance
mg/kg
Onset
(Minutes)
Duration of intermittent
dose
(min)
Fentanyl 1 to 2 mcg/kg*
(25 to 100 mcg)**
0.35 to 0.5 mcg/kg every
0.5 to 1 hour
intermittent (25 to 35
mcg)¶
AND/OR
0.7 to 10 mcg/kg/hour
infusion
< 1-2 min 30 to 60***
Morphine 2 to 10 mg* 2 to 4 mg every
1-2 hour
intermittent
and/OR
2 to 30 mg/hour
infusion
5 to 10 240 to 300
Remifentanil Optional:
1.5 mcg/kg**
0.5 to 15
mcg/kg/hour
infusion
1 to 3 5 to 10 min
*One or more loading doses may be needed
** Obese Patients
***Duration for initial dosing UPTODATE

44. Unwanted side-effects of
opioids :
Respiratory
depression
ConfusionVasodilation
Gut motility
depression
Opioids

45. Unwanted side-effects of sedative
agents:
Propofol
Hypertriglyceridemia
CVS depression
Hypotension
2-agonists
Hypotension
Bradycardia
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
Ketamine
Hypertension
Secretions
Dysphoria
General
Over sedation
Delayed awakening

46. Case
StudyHistory :
Patient J is a young girl, 2 years of age, with a history of hydrocephalus since birth. She has been brought to
the hospital with complaints of continuous vomiting, lethargy, and inappropriate behavior for her age. The
pediatric neurologist orders the MRI to evaluate the current status of her cerebral spinal fluid circulation.
The neurologist orders the procedure to be performed under moderate sedation, She is not taking any
current medications at home, either prescribed or over-the-counter. She had previously been on
anticonvulsant medication, which was discontinued more than a week prior to the procedure.
Upon arrival of Patient J in the radiology suite, the nurse performs a pre-sedation assessment. Currently, her
vital signs are 92/64 mm Hg; pulse, 100; and respiratory rate, 30 breaths/minute. She has an IV line infusing
5% dextrose in 0.25% normal saline at a rate of 45 cc/hr. Her admission weight was 25 pounds
(approximately 11 kgs).She has not taken anything by mouth since admission.
Question: What are the medicines of choice ???
a) Midazolam 0.02 mg/kg IV
b) Midazolam 0.5 mg/kg orally, intranasal
c )fentanyl 0.5 mcg/kg
d) Both midazolam .02 mg/kg iv and fentanyl 0.5 mcg/kg

49. References :
1. Pharmacokinetic Considerations for Moderate and Deep Sedation
Anesth Prog. 2011 Winter; 58(4): 166–173. doi: 10.2344/0003-3006 -
58.4.166
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237326/
2. Medications for analgesia and sedation in the intensive care
unit,an overview.Critical Care200812(Suppl 3):S4 Published:
14 May 2008, https://doi.org/10.1186/cc6150
3. https://www.uptodate.com/contents/sedative-analgesic-
medications-in-critically-ill-adults-selection-initiation-maintenance-
and-withdrawal
4. BJA: British Journal of Anaesthesia, Volume 87, Issue 2, 1 August
2001, Pages 186–192, https://doi.org/10.1093/bja/87.2.186