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