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PHARMACOLOGY OF
SEDATIVES AND
ANALGESICS
Prepared by : Muhammad Umar HafeezPharm DInpatient PharmacistNation Hospital Managed by MUVI Abu Dhabi UAE.
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
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
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.
WHY SEDATION IS
NECESSARY?
improve patient
comfort.Reduce stress.
Facilitate interventions.
Allow effective
ventilation.
Encourage sleep.
Prevent post-ICU psychosis
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.
UPTODATE
Classification of Sedative and
Analgesics:
Intravenous Anaesthetics:
Propofol Thiopental Ketamine Etomidate
Sedative-Hypnotics :
Midazolam
Diazepam
Lorazepam
Quality
Management
Systems
Classification of Sedative and
Analgesics:Opioid Analgesics :
• Morphine
• Fentanyl.
• Remifentanil
α-2 receptors agonists:
• Dexmedetomidine
Others:
• Chloral Hydrate
• Inhalation anaesthetics (Sevoflurane)
UPTODATE
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
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
Goal:
The goal is to administer the sedative drug that achieves the desired clinical effect (“right” drug)
(pharmacodynamics) at the “right” time (pharmacokinetics).
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
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.
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
Pharmacokinetics of Sedative and analgesics: General
ConceptPharmacokinetic 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.
Pharmacokinetic Considerations while choosing
an agent:Drug Half Life
(hour)Protein Binding (%)
Metabolism
Hydrophilic/lipophilic
Elimination
Active Metabolite Cont.Infusion/Bolus
Midazolam 1 - 2.5 97 Hepatic Lipophilic Urine 1-hydroxymethylmidazolam Infusion preferBolus*
Diazepam P^= 33 – 45M^^= 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
Remifentanil
3 - 10 min 70 Hepatic/plasmaesterase
Lipophilic Urine Infusion /Avoid Bolus due to side effects
Morphine sulphate
1.5 - 4.5 20-30 Hepatic Less lipophilic Urine Morphine-6-glucuronideMorphine-3-glucuronide
Bolus/Infusion Case dependent
Dexmedetomidine
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
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.
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
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.
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.
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
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%
Per
cen
tage
Sedative and Analgesics
MOST COMMONLY USED SEDATIVE AND ANALGESICS IN EUROPE, UKAND NORWAY.
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
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
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.
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
Sedative-hypnotics: General
DosingBenzodiazepine Initial Dose (loading
dose) iv mg/kg
Maintenancemg/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
Sedative-hypnotics:
Summary of enteral Midazolam administration – route, dosing, clinical onset and positive (+) and
negative (-) attributes.
Route Dosemg/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
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
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.
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.
α2-Adrenergic agonists
Dexmedetomidine
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
α2 – agonists;
Dexmedetomidine94% protein bound.
Narrow therapeutic range (0.5 - 1.0 ng/mL)
It undergoes conjugation & N-methylation.
Approved only for sedation ≤ 24 h.
α2 – agonists; Dexmedetomidine
Haemodynamic Effects:
heart rate.
Initial then BP.
Systemic Vascular Resistance.
Cardiac Output
α2 – agonists;
DexmedetomidineMedicine Name
Initial Dose (loading dose) iv
Maintenance Onset Duration of intermittent
dose
Elimination Half life
Dexmedetomidine
Optional:1 mcg/kg over 10 minutes if hemodynamically stableUsually not given
Initiate 0.2 to 0.7 mcg/kg/hour and titrate every 30 minutesSome patients require doses up to 1.5 mcg/kg/hour
5 to 10 min
60 to 120 min 120 min
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.
Opioids; Morphine
Isolated in 1803 by the German pharmacist Friedrich Adam.Named it 'morphium' after Morpheus, the Greek god of dreams.
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
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
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.
Comparison of Opioids:
Opioids Initial Dose (loading dose) iv mg/kg
Maintenancemg/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/OR0.7 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 intermittentand/OR2 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
Unwanted side-effects of
opioids :
Respiratory
depression
ConfusionVasodilation
Gut motility
depression
Opioids
Unwanted side-effects of sedative
agents:
PropofolHypertriglyceridemia
CVS depression
Hypotension
2-agonists
Hypotension
Bradycardia
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
Ketamine
Hypertension
Secretions
Dysphoria
General
Over sedation
Delayed awakening
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, intranasalc )fentanyl 0.5 mcg/kgd) Both midazolam .02 mg/kg iv and fentanyl 0.5 mcg/kg
References :
1. Pharmacokinetic Considerations for Moderate and Deep SedationAnesth Prog. 2011 Winter; 58(4): 166–173. doi: 10.2344/0003-3006 -58.4.166https://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/cc61503. https://www.uptodate.com/contents/sedative-analgesic-medications-in-critically-ill-adults-selection-initiation-maintenance-and-withdrawal4. BJA: British Journal of Anaesthesia, Volume 87, Issue 2, 1 August 2001, Pages 186–192, https://doi.org/10.1093/bja/87.2.186