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NSU AA Denver: Summer 2025 (2nd Semester) > Pharmacology I: Lecture 3 - Induction Agents > Flashcards

Pharmacology I: Lecture 3 - Induction Agents Flashcards

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1
Q

What is induction in the context of anesthesia?

A

The process of initiating anesthesia using specific agents.

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2
Q

What are the ideal characteristics of an IV induction agent?

A
  • Rapid onset
    Steep dose-response curve
  • Minimal CV/Resp depression
  • Decreases ICP/CMRO2
  • Short duration
  • Highly lipid-soluble
  • Minimal metabolism
    Non-active metabolite
  • Effect terminated by redistribution
  • Freely eliminated
  • Minimal side effects: PONV, etc.
  • Produce hypnosis, amnesia, analgesia and immobility
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3
Q

Name a commonly used IV anesthetic agent.

A

Barbiturates
Sodium thiopental (Pentothal)
Methohexital (Brevital)… this is the one to pay attention to

Isopropyl phenols
Propofol (Diprivan)

Carboxylated imidazole
Etomidate (Amidate)

Phencyclidine
Ketamine (Ketalar)

Alpha-2 Adrenergic Agonis
Dexmedetomidine

Benzodiazepines

  • 5 Classes of Drugs for the Induction… Benzos would need to be used at really high doses, so becomes an adjunct
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4
Q

What is the mechanism of action of barbiturates?

A

Enhances the inhibitory effects of GABA by potentiating the duration of openings of the Cl- channel.

Depresses in the reticular activating system (RAS) in medulla oblongata

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5
Q

Structure of Barbiturates

A

Formed through combination of Urea + Malonic acid to form barbiturate ring

4 Main Groups:
Oxybarbiturate

Thiobarbiturates
Thiopental

Methylbarbiturates
Methohexital

Methylthiobarbiturates

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6
Q

Structure & Activity Relationship

A

The ring structure is the key to their specific activity

Substitutes on the ring dictate pro- or anti-convulsant properties

Induction drug

Sedative/hypnotic

Cerebral protection
Barb ‘coma’

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7
Q

Barbiturates and Recreational Use

A

The sedative/hypnotic properties of these oral drugs have led to a high abuse potential

Effect are similar to EtOH intoxication and have been described as a ‘relaxed and euphoric state’

Risk is respiratory arrest

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8
Q

What is the primary role of the Reticular Activating System (RAS)?

A

Arousal and alertness.

Poorly defined network of neurons near the medulla
Primary importance has to do with arousal and alertness

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9
Q

What are the clinical uses of Sodium Thiopental?

A
  • Induction of anesthesia
  • Treatment of increased ICP
  • Anti-convulsant
  • Cerebral protection

Oldest IV anesthetic drug still in use
Rapid onset due to high-lipid solubility and low degree of ionization at physiologic pH

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10
Q

Sodium Thiopental and its Mixture

A

Dissolved in an Alkaline solution of 2Na+CO3-2

Comes in a yellowish powder which needs to be reconstituted
Used within 24hrs of mixing

Racemic mixture of two enantiomers
S (-) > clinical effects due to being more potent at the GABAA

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11
Q

Sodium Thiopental Structure

A

R group substitutions at C5 – add anticonvulsive properties

At C2 replacing the O with a Sulfur increases lipid solubility – rapid induction

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12
Q

Clinical Uses of Sodium Thiopental

A

Induction of anesthesia
Treatment of increased ICP
Anti-convulsant
Cerebral protection
↓ EEG
Executions

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13
Q

What is the pharmacokinetic profile of Sodium Thiopental?

A
  • Extensively binds to albumin (80%)
  • Rapid onset due to high blood flow to brain
    Crosses BBB rapidly
  • Return to alertness afterwards is due to redistribution rather then metabolism (KEY CONCEPT)
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14
Q

Sodium Thiopental Metabolism/Elimination

A

Return of awareness afterwards is due to redistribution rather then metabolism

Completely metabolized in liver via CYP 450
Oxidation

High doses can saturate liver enzymes and lead to a build up of the drug
Unsuitable for maintenance of anesthesia due to cumulative properties

Renal elimination… not a good choice for an infusion

*** return to consciousness happens before metabolism, happens after the redistribution

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15
Q

Sodium Thiopental Clinical Considerations

A

Cardio: ↓BP due to↓SVR; ↑HR
Exaggerated in pts w/ prior CV dysfunction

Resp: ↓MV due to ↓TV and ↓RR modest reduction in laryngeal reflexes (Compared to Volatile Agents = MV stays same because increased RR with decreased TV)

CNS: ↓ICP due to ↓CBF and ↓CMRO2
Depresses EEG (Compared to Volatile Agents = decreases CMRO2, but CBF and ICP goes up)

Hepatic: mild ↓HBF

Renal: mild ↓RBF and ↓GFR

Slight pain on injection

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16
Q

What is the dosing range for Sodium Thiopental?

A

3 – 5 mg/kg
2nd dose 25% of original dose
Reduced in elderly, neonates, renal failure

Equation
Dose (mg) = 350 + kg – (2 x y/o) – 50 (female)

Onset ~ 1 – 2 min

DOA ~ 5 – 15 min

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17
Q

Sodium Thiopental Preparation

A

Alkaline solution
pH 10.5
Bacteriostatic
Tissue damage if injected intra arterial or outside of vein

No preservatives

Commercial preparation
2.5% sodium thiopental

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18
Q

What is Methohexital designed for?

A

To be a short-acting, rapidly eliminated barbiturate.

High lipid-solubility

Alkaline solution
Bacteriostatic
Tissue damage

Extensively bound 80%

IS USED CLINICALY

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19
Q

Structure of Methohexital

A

Methylbarbiturate with a methyl group at N1 and oxygen at C2

β enantiomer is more potent and 4 – 5 times more active
Also associated with extensive motor activity

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20
Q

Clinical Uses of Methohexital

A

Induction of anesthesia

Pro-convulsant
Activates epileptic foci
Seizure mapping
LOWERS SEIZURE THRESHOLD

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21
Q

Pharmacokinetics of Methohexital

A

Extensively bound to serum albumin

Metabolized in liver by CYP 450

Clearance is higher and thus elimination half-time is shorter then pentothal
Suitable for maintenance

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22
Q

Clinical Considerations of Methohexital

A

Cardio: ↓BP & CO; ↑HR reducing baroreflex sensitivity

Resp: ↓MV due to ↓TV and ↓RR

CNS: excitatory movements

Slight pain on injection

Avoid in patients with high risk of psychomotor seizures or history of epilepsy

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23
Q

Preparation and Dose of Methohexital

A

Alkaline 1% solution
Must be reconstituted

Dose: 1.5 – 2.5 mg/kg

Infusion rate: 100 – 150 mcg/kg/min

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24
Q

What are the contraindications for all Barbiturates?

A
  • Proven allergy or hypersensitivity
  • Acute intermittent porphyria
    Disorder of enzyme in heme bio-synthetic pathway leading to build up of aminolaevulinic acid
    AIP – Overproduction and accumulation
    Abd pain, vomiting, neuropathy, weakness, cardiac arrhythmias, anxiety/depression, constipation/diarrhea
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25
What is Propofol's mechanism of action?
Potentiation of GABA A receptor by enhancing the inhibitory effects of GABA.
26
Propofol General Facts
Most commonly used IV induction agent Highly lipid soluble Nonionized Neutral pH 7.4 Extensively bound (96%) Antiemetic properties *** As close to an ideal induction agent we have
27
Structure of Propofol
Propofol or 2,6 – diisopropylphenol developed in 1975 In 1983 Diprivan – lipid emulsion of 1% Propofol, soybean oil, egg phospholipid (lecithin), with glycerol and sodium hydroxide Opaque white fluid Initially no preservatives Now EDTA is added Prevent bacterial growth
28
Mechanism of Action of Propofol
Potentiation of GABAA receptor by enhancing the inhibitory effects of GABA It binds to GABA receptor and keeps it open/activated longer
29
PK-Distribution of Propofol
Bound to both erythrocytes and serum albumin After bolus dose, concentrations decrease rapidly due to extensive redistribution to peripheral tissues Potential for accumulation Return to central compartment is slower then rate of elimination Persistence of clinical effects
30
PK - Metabolism/Elimination of Propofol
Rapidly metabolized in liver by hydroxylation and conjugation via CYP 450 Extrahepatic metabolism via kidney & GI Metabolites are eliminated via renally Context-sensitive ½ time ~ 20 min Even after 8 hours of infusion ## Footnote In anesthesia, CSHT helps predict how quickly a patient will wake up after stopping an infusion of a sedative or anesthetic. A short CSHT means the drug wears off quickly regardless of how long it was infused. A long CSHT means the drug lingers in the system longer, especially after prolonged infusions.
31
What are the clinical uses of Propofol?
* Induction of anesthesia Smooth * IV conscious sedation * ICU sedation * Maintenance of anesthesia * Anticonvulsant
32
Clinical Considerations of Propofol
Cardio: ↓SVR, ↓CO, ↓BP Blunts normal baroreceptor response to ↓BP Resp: ↓TV, ↓RR, apnea, suppresses airway reflexes (THIS IS BIG TO KNOW) CNS: ↓CMRO2, ↓CBF will ↓ICP,↓EEG, suppresses REM sleep, ~20% patients report dreaming, no analgesic properties, does not enhance NM blockade (NO ANALGESIA and NO ENHANCE OF NM BLOCKADE is big compared to Volatile Agents that does enhance NM Blockade) Hepatic & Renal: minimal Other: Combination of opioids/BDZ – reduce dose requirements Dose reduction in elderly and CV compromised Spontaneous excitatory movements (i.e. “shakes”)
33
Preparation and Dosing of Propofol
Commercial preparation 1% Propofol Soybean oil and egg lecithin EDTA as preservative Dosing: 1.5 – 2.5 mg/kg Infusion: 25 – 250 mcg/kg/min IVP Dose – 30 to 50 mg Onset ~ 30 – 45 sec DOA ~ 3 – 7 min
34
What are contraindications of Propofol?
Pain on injection (gluconate, the preservative) Can be a good growth medium for bacteria Used within ~12hrs Metabolic acidosis Propofol infusion syndrome (PIS) Lactic acidosis s/p prolonged high-dose infusions Hypersensitivity to propofol Disorders of fat metabolism
35
What is the dosing range for Propofol?
1.5 – 2.5 mg/kg.
36
Fospropofol
Only propofol analog approved by FDA A prodrug of propofol Rapid cleavage by alkaline phosphatase to Propofol + Formaldehyde + Phosphate 1 mg gives you 0.54 mg of propofol Onset is slower and longer DOA Used for sedation No reported pain on injection
37
What is the structure of Etomidate?
Structure is carboxylated imidazole ring Water-soluble at acidic pH and lipid-soluble at physiological pH Two enantiomers R > anesthetic properties Non-ionized base Bound to serum proteins
38
Pharmacokinetics of Etomidate
Pharmacokinetics Rapid onset with recovery dependent on redistribution to inactive sites Depresses RAS and enhances the inhibitory effects of GABA Metabolized in the liver hydrolysis and in plasma by esterase Elimination in urine Highly protein bound
39
What is the mechanism of action of Etomidate?
Depresses RAS and mimics inhibitory effects of GABA A for its receptors.
40
What are the clinical considerations for Etomidate?
Cardio: mild to no change in SVR (KNOW THIS IS DRUG OF CHOICE FOR THOSE CARDIAC ISSUES) Resp: ↓TV, ↑RR (KNOW HOW IT INCREASES RR) CNS: ↓CMRO2, ↓CBF, ↓ICP, no analgesic property Hepatic & Renal: no changes Other: Pain on injection - propylene glycol Involuntary myoclonic movements (MUCH MORE COMMON/NOTICABLE WITH ETOMIDATE THAN PROPOFOL) Adrenocortical function depression – inhibits adrenal steroidgenesis which leads to↓cortisol and lasts 4-8 hours... causes Hypotension
41
Preparation and Dosing of Etomidate
Formulated as 0.2% Dosing: 0.2 – 0.4 mg/kg pH 8.1 Onset ~ 3 – 5 min DOA ~ 5 – 7 min
42
Ketamine Basics
Analogue of phencyclindine Commonly initialized as PCP Racemic mixture of 2 enantiomers S (+) is 3 – 4 times higher potency Stable, clear, colorless Liver metabolism via CYP 450 Water soluble Minimally bound Has an active metabolite Only 20% of activity (leads to its longer DOA)
43
Ketamine Use
NMDA receptor antagonist Can be given IV, IM, intranasal, rectal or oral High BA with IV, IM, and nasal Often given IM to uncooperative adults Impairs memory Analgesia Used in combination with other drug Combined with BDZ due to hallucinogenic effects Used for severe asthmatics
44
Pharmacokinetics of Ketamine
High lipid solubility (when in physiological state) Single bolus effect terminated by redistribution Metabolism occurs in liver N-demethylation by CYP-450 Norketamine- less potent active metabolite Only intravenous anesthetic with low protein binding
45
Mechanism of Action
Inhibits reflexes in the spinal cord as well as excitatory neurotransmitter effect in brain ‘Dissociates’ the thalamus = eyes open, swallowing, muscle contracture but unable to process sensory input (nystagmic gaze) Ketamine binds non-competitively to the phencyclidine site on N-methyl-D-aspartate (NMDA) receptors
46
Clinical Uses of Ketamine
Induction of anesthesia IM induction uses in pediatrics and MR Hypovolemia Asthma Analgesia Burn patient dressing changes Severe asthmatics
47
Clinical Considerations of Ketamine
Cardio: ↑HR, ↑SVR, ↑CO & contractility Indirect effects: increased catecholamine release (Due to the increased cerebral demand, heart will have to work harder, not a great choice with those with a past heart MI, etc.) Resp: mild ↓RR, bronchodilation, ↑PVR CNS: ↑CMRO2, ↑CBF, ↑ICP Analgesia centrally and peripherally Treatment for Depression (Not good for those with intracranial pathology) Hepatic & Renal: no changes Other: Increase in cortisol & glucose Emergence delirium Prosialogogue Nystagmus *** Typically given with glycopyrrolate and a benzo/versed (keep secretions down and avoid the ketamine delirium potential)... have to be careful because the glyco will increase HR too...
48
What is the dosing range for Ketamine?
Induction of anesthesia Intravenous: 1 – 2.5 mg/kg Intramuscular: 4 – 8 mg/kg Intranasal: titrate to effect (~50mg push) Mixed in a Propofol drip 50 – 100 mg in 400 – 600 mg of Propofol Max does is around 100 mg usually Due to emergence delirium
49
Preparation of Ketamine
Can come in 1%, 5%, 10% solutions Onset depends on ROA IV – Rapid ~ 1 – 3 min IM – 5 min DOA ~ 15 – 30 min pH 3.5 – 5.5
50
Ketamine Contraindications
True allergy Head injury (all those results of the increased cerebral oxygen demand) Psychotic disorder Pheochromocytoma
51
What is Dexmedetomidine?
A highly selective alpha2-adrenergic agonist. PK Rapid hepatic metabolism Metabolites excreted in the urine Significant context-sensitive halftime 250 minutes after an 8-hour infusion | Takes longer to "wear off" ## Footnote Context-sensitive half-time (CSHT) is a pharmacokinetic concept that describes how long it takes for a drug’s plasma concentration to decrease by 50% after stopping a continuous infusion, and how that time depends on the duration ("context") of the infusion.
52
Pharmacodynamics of Dexmedetomidine
CNS – hypnosis from alpha2-recetptors in locus ceruleus Analgesic effects at level of spinal cord More resembles physiologic EEG sleep patterns CV Decrease in HR and SVR, bolus can see a pronounced decrease in HR RS Modest decrease in TV and ~change in RR Ventilatory response to carbon dioxide maintained (BIG TO KNOW) Used to facilitate fiber optic intubation
53
Dosing of Dexmedetomidine
200 mcg/2ml vial Preparation: mix 2 ml (200 mcg) in 48 cc 0.9% NaCL leads to 50 CC syringe Procedural Sedation Loading dose 1 mcg/kg IV over ten minutes 0.1-1 mcg/kg/hr
54
What are the effects of Dexmedetomidine on the cardiovascular system?
Decrease in HR and SVR.
55
Clinical Scenario #1
38 yr old 185# women for Lap Appy Came to ER with RLQ pain, N/V PMHx: Anxiety, Asthma Meds: Albuterol inhaler, Xanax PRN Vital Signs: 121/67, 67, 97%, 14/min What would you use to induce and maintain anesthesia? Want to use RSI due to N/V Due to Asthma want induction agent to be bronchodilator - Propofol or Ketamine Maintain with Propofol
56
Clinical Scenario #2
33 y/o male s/p MVA, pt presents with abdominal swelling, tachycardia hypotension and SOB Suspected spleen laceration PMHx: Smoker and mild HTN Vital signs: 88/45, 118, 95%, 23/min Induction agent and VA? RSI to secure airway quickly Etomidate due to all CV issues that are going on and potential to have intracranial pathology due to MVA Would not want to use VA due to potential due to intracranial pathology, would want an infusion. Would probably have to give propofol with a pressor due to the hypotension
57
Clinical Scenario #3
76 y/o male presents for hemicolectomy PMHx: HTN, CAD, PVD, aortic stenosis, AVA 0.5 cm2 PSHx: CABG x 2, Appy Induction agent for this patient? Primary concern is the aortic stenosis... thus etomidate
58
Fill in the blank: The ideal IV induction agent should have a _______ onset.
Rapid
59
True or False: Ketamine is a NMDA receptor antagonist.
True
60
What effect does increased SVR have on heart rate (HR)?
Pronounced decrease in HR ## Footnote SVR stands for systemic vascular resistance.
61
What is maintained during the ventilatory response to carbon dioxide with Precedex?
Ventilatory response to carbon dioxide maintained
62
What drug is used to facilitate fiber optic intubation?
Precedex

NSU AA Denver: Summer 2025 (2nd Semester) (19 decks)

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