Pharmacology

▪Minimal Alveolar Concentration (MAC)

Effects of Common Anesthetics on MAC

		Halothane	Isoflurane	Enflurane	Sevoflurane	Desflurane	Nitrous Oxide
	Odor	−	+	−	−	++	−
	MAC	0.75	1.17	1.63	1.80	6.6	104
	MAC w N₂0	0.29	0.5	0.6	0.66	2.83	—
Potency	O:G	224	91	97	55	19	1.4
Solubility Pp in blood	B:G	2.54	1.46	1.9	0.69	0.42	0.46
Vapor pr Gas volatility	VP In mm Hg	244	240	172	170	669	—
	Metab %	20	0.2	2-3	2-5	0.02	0.004
VP / 760	Vol %	32	31	23	21	87	0.004
incr oil solubility = incr potency = slow indxn		Most potent, most lipid soluble; hepatitis, heart arrhythmias	Great neuro pts; coronary steal	No neuro, seizure, renal	No renal → Comp A (Olefin) ped seizures ≥ 2 L flow canister fire	Quick on & off, expensive, renal toxic	Insoluble; faster induction; teratogenic, inhibits methionine, needed for DNA synthesis
Volatile Agents Metabolized: most: oxidative within liver via cytochrome P-450; some: kidneys, lungs, Gl.

MAC 95%: 1.3

MAC awake: 0.3-0.5

MAC BAR (Block Autonomic Response): 1.5

Insoluble agents (i.e., N₂0) are taken up by blood less avidly than soluble agents (such as H). Thus, the alveolar concentration of N₂O rises faster than halothane and induction is faster. The relative solubilities of anesthetic in air, blood, and tissues are expressed as partition coefficients. The greater the B:G coefficient, the greater the anesthetic solubility that goes to blood (pulm circ); alveolar PP rises more slowly and induction is prolonged.

Theories: Volatile agents work on a specific GABA receptor by a neuroinhibitory neurotransmitter; or according to the Meyer-Overton rule, increased volume at cell membranes reaches critical size causing anesthesia.

What increases the speed of induction? Increased concentration of volatile agent, high flows, and increased minute ventilation. An increased cardiac output slows induction.

Factors that Affect MAC

Increase MAC	Decrease MAC
Hyperthermia	Hypothermia
Hypernatremia	Hyponatremia
Incr levels of CNS excitatory transmitters (cocaine)	Pregnancy/increased age
Incr levels of CNS excitatory transmitters (cocaine)	Acute alcohol
Chronic alcohol	Alpha₂ agonists (Clonidine)
CNS depressants

Highest MAC need: infant at term to six months; MAC decreases with increasing age.

MAC decreases 7% for each degree decrease in Celsius temperature.

▪Volatile Agents and Physiologic Response

Volatile Response

	Halothane	Isoflurane	Enflurane	Sevoflurane	Desflurane	Nitrous
Myocardial depression		Primary effect of all volatile anesthetics is myocardial depression				mild
Contractility by decr intracell Ca⁺⁺	decr	decr (I = S)	decr greatest	decr (S = I) least effect	decr	decr
HR	– decr	– incr	– incr	incr (> 1.5 MAC)	no Δ < 1 MAC incr > 1 MAC	decr or incr
SV	decr	dec r	decr greatest	decr	decr	—
CO All myoc depression	decr	decr	decr	decr	decr	decr or incr
BP	decr	decr (> H)	decr (> H)	decr least effect	decr	– incr
RAP All increase x S	incr	incr	incr	no effect	incr	incr
SVR	decr	decr (> E) greatest	decr (< 1)	decr	decr potent venodilator	incr alpha/beta stim
PVR	—	—	—	—	—	incr
CA blood flow	incr	incr greatest	incr	mildly incr	—	—
Dysrhythmias	incr esp with epi	—	>1 < H esp with epi	—	—	—
Cerebral BF H>E>I = S>D	incr greatest	incr (= S) (< all others except D)	incr	incr (= 1)	incr least	incr
SNS	decr					offsets depression
Analgesia						mild

▪Sedatives

Midazolam

BZD

Amnestic

0.3-15+ mg/kg, 1 mg/cc or 5 mg/cc vials.

Methohexital (Brevital)

USDOA barbiturate

Amnestic

5-10 mg in incremental doses to effect.

Induction: 50-120 mg to start, 20-40 mg q 4-7 min.

Powder for reconstitution: 500 mg, 2.5 g, 5 g; 73% protein bound.

Onset immed; duration 10-20 min.

2-3 times more potent and faster onset and recovery time as pentothal.

Can cause hypotension, periph vascular collapse, seizures, H/As.

Used for ECT, dentistry (see excitatory phenomenon).

No!! AIP (porphyria), caution in pts w/liver impairment, asthma, and CV instability.

Lorazepam

BZD

Amnestic

Pre-tx: 0.04 mg/kg; 15-20 mg pre-surg IV, amnesia: 1-4 mg.

2-4 mg/mL

Onset 5-20 min for sedation, 20-30 min hypnosis, 5 min anticonv; duration 6-8 hr.

Diazepam

BZD

Amnestic

5 mg/cc 2 cc vial; 1 mg/cc 5 mg vial.

Onset immed; duration 20-30 min; 98% protein bind.

2 active metabolites: oxazepam and desmethyldiazepam, both with LDOA.

Droperidol

Dopamine antagonist

NO amnesia

Nausea: 0.625-2.5 mg.

Sedation: up to 10+ mg. 0.625 mg = 0.25 cc

No!! Parkinsonism, pheochromocytoma, head injury.

SE: QT prolongation. Pt wakes fearful and catatonic and can recount everything!!!

Used as: sedative, neuroleptic agent, antiemetic.

BZD produces effects by stimulating receptors in CNS, enhancing inhibitory effects of GABA. GABA activates chloride channel, Cl- enters neuron causing hyperpolarization which inhibits neuron.

BZDs decr CBF/ICP/O₂ consumption; are a potent antegrade amnestic, anxiolytic, ↑ the seizure threshold, and cause minimal circulatory depression.

BZDs are highly lipid soluble and highly protein bound.

▪Induction Drugs

Ketamine (Ketolar)

Induction 1 mg/kg IV or IM;maint 1/3-1/2.

Onset 1-2 min; duration 5-15 min.

+ analgesia / – amnesia / – histamine

Metab: demethylation CYP450.

10, 50, 100 mg/cc vials.

No!! Heart dz, incr ICP, HTN, aneurysms, no neuro surgery.

Extremely lipid soluble; acts like epinephrine.

Propofol (Diprivan)

Induction 2 mg/kg; sedation 25-75 mcg/kg/min; maint 100-200 mcg/kg/min.

Onset 30 sec; duration 3-10 min.

– analgesia / + amnesia / – histamine

Metab: glucuronide conjugates—ua

10 mg/cc; 20 and 50 cc vials.

No!! HTN/shock.

Generic form contains sulfites and should be used with caution in asthmatics and patients allergic to sulfites.

Etomidate (Amidate)

Bolus only induction 0.3 mg/kg (0.1-0.2 mg/kg for sick heart); great for hemodynamic stability).

Onset 30-60 sec; peak 1 min; duration 3-5 min.

– analgesia / – amnesia / – histamine

Metab: microsomal enzymes in liver and plasma esterases.

2 mg/cc; 10 and 20 cc vials

No!! Seizures; accelerates seizure focus.

Sodium Pentothal (Thiopental)

Induction 4 mg/kg; sedation 25-75 mg.

Onset 30 secs; awaken 20 mins.

– analgesia / + amnesia / + histamine

Exert action on reticular activating system → unconsciousness.

Metab: redistributed.

2.5% is 25 mg/cc.

No!! AI Porphyria, asthma, shock, COPD, severe CVD.

No Stage 2 anesthesia.

Extremely lipid soluble.

All induction drugs work by modulating GABAergic neuronal transmission, interfering with transmembrane electrical activity.

▪Narcotics/Opioids

Fentanyl (Sublimaze)

Sedation 1-2 mcg/kg; gen 5-15+ mcg/kg; cardiac surg 50-150 mcg/kg.

Onset immediate; duration 0.5-2 hr; peak 3-5 min.

SDOA analgesia.

50 mcg/cc; 100x more potent than MSO₄.

Very high index of safety; causes N/V, muscle rigidity, bradycardia in large dose.

– histamine

Sufentanil

MOST POTENT OPIOID

Sedation 0.25-10 mcg/kg; gen 1-30 mcg/kg.

Onset 1-3 min; duration r/t dose.

SDOA analgesia.

50 mcg/cc, but 5x more potent than Fentanyl, dilute!

1, 2, 5 cc vials.

Muscle rigidity, brady, hotn.

Alfentanil

Loading IV 8-100 mcg/kg, maint 0.5-3 mcg/kg/min.

SDOA analgesia.

500 mcg/cc, usu infusion only.

Profound brady, ↑ N/V, a lot of muscle rigidity.

Remifentanyl

Infusion only 0.25-1 mcg/kg; mix 1 mg in 20 cc in 60 cc syringe.

Onse: 1-3 min; T1/2 = 10 min.

Extremely SDOA.

Elim by ester hydrolysis.

Morphine

Intraop IV 0.1-1 mg/kg; postop IV 0.03-0.15 mg/kg.

Onset 5-10 min; duration for pain relief ˜ 4 hr.

LDOA analgesia.

10 and 15 cc vials

+ histamine

No!! Asthma or HOTN

Meperidine (Demerol)

0.5-1 mg/kg IM, intraop IV 2.5-5 mg/kg.

+ histamine

Negative inotrope

Can increase the amount of serotonin; avoid giving with tricyclic antidepressants/SSRIs.

Stimulates kappa receptors, decreasing shivering threshold; meperidine metabolizes to normeperidine. Opioids are cardio stable drugs but may show dosedependent bradycardia, except meperidine which can cause tachycardia because meperidine has a similar structure to atropine.

Can cause chest wall rigidity with rapid administration—treat with NDMR.

Potency (Most to Least Potent)

Sufentanil > Remifentanyl > Fentanyl > Alfentanil > Morphine > Meperidine

Effects of Agonists and Antagonists on Opioid Receptors

Receptor	Effects	Agonist	Antagonist
Mu-1	Analgesia: supraspinal/spinal Euphoria Low abuse potential Miosis, bradycardia, hypothermia, ua retention	Endorphins Morphine Synthetic opioid (fentanyl, etc.)	Naloxone Nalbuphine Buprenorphine
Mu-2	Analgesia: spinal Depression of ventilation Physical dependence Marked constipation	Endorphins Morphine Synthetic opioids	Naloxone
Kappa	Analgesia: supraspinal/spinal Dysphoria, sedation Low abuse potential Miosis	Dynorphins Nalbuphine Butorphanol Pentazocine	Naloxone
Delta	Analgesia: supraspinal/spinal Depression of ventilation Physical dependence Constipation minimal	Enkephalins Butorphanol Pentazocine Dezocine	Naloxone
Sigma	Mediates dysphoria		Ketamine