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ANESTHETICS

GENERAL PRINCIPLES CNS drugs must be EITHER: 1. Lipid soluble to cross BBB 2. Actively transported to cross BBB Drug solubility: 1. Blood solubility determines drug induction AND recovery times Speed of onset (induction) = speed of recovery Blood solubility = blood-gas partial coefficient = (1 / drug partial pressure) Blood-gas partial coefficient measures drugs active form: 1. Drug BOUND to proteins will increase blood solubility o BOUND drug does NOT exert partial pressure o More drug needs to absorbed into blood before partial pressure starts to rise and impedes onset of action of the drug Similar to hemoglobin binding oxygen allowing for partial pressure to remain low for more oxygen to diffuse into blood 2. free gas form will decrease blood solubility o Free gas form = drug partial pressure Drug partial pressure is inversely related to blood-gas partial coefficient Brain equilibration = drug partial pressure drug partial pressure = speed of onset and brain equilibration blood solubility = speed of induction and speed of recovery solubility free gas form free gas form concentration to enter BBB ( induction) and amount of drug that stays in body due to lack of metabolism ( recovery) blood solubility = speed of induction and speed of recovery blood solubility free gas form free gas form concentration to enter BBB ( induction) and amount of drug that stays in body due to increased metabolism ( recovery) 2. Lipid solubility determines potency and MAC POTENCY = (1 / MAC) MAC = minimal alveolar concentration at which 50% of the population is anesthetized 1. Prevent movement in response to a surgical stimulus when no other drugs are administered 2. Varies with age (usually lower MAC/increased potency in the elderly) 3. Inversely related to potency Less potent drug will need more alveolar concentration of the drug to anesthetize patient 4. ADDITIVE with other drugs MAC lipid solubility = potency due to increased diffusion across BBB potency = MAC lipid solubility = potency due to increased diffusion across BBB potency = MAC Organ effects on drug: Organ Mechanism of action Lungs rate + depth of ventilation = gas tension blood solubility = blood/gas partial coefficient = drug staying in blood = gas required to produce effects

Blood

Vessel-rich organs (brain, liver, kidney)

Rapid to take up and release drug

Vessel-poor organs (adipose tissue)

Slow to take up and release drug drug sink due to slow absorption early in procedure (lowers drug levels) but then slow release later in procedure (prolongs elimination)

ANESTHETICS

INHALED ANESTHETICS Drugs including: 1. Halogenated agents -flurane: 1. Halothane 2. Isoflurane 3. Enflurane 4. Sevoflurane 5. Methoxyflurane 6. Desflurane 2. Non-halogenated agents: 1. Nitrous oxide (N2O) Dont confuse with nitric oxide (also available in inhaled form) MOA: 1. Unknown o Most likely activate -aminobutyric acid A (GABAA receptor) Clinical use: 1. Anesthesia 2. Severe refractory status asthmaticus (rare indication) due to bronchodilation effects Drugs properties: 1. Halogenated compounds: 1. lipid solubility = potency = MAC 2. blood solubility = SLOW onset and SLOW recovery 3. Agents from fastest to slowest (lowest to highest blood solubility): (slowest) desflurane < sevoflurane < isoflurane < halothane (fastest) 2. Non-halogenated compounds: 1. blood solubility = FAST onset and FAST recovery 2. lipid solubility = potency = MAC Nitrous oxides MAC = 104% 1. CANNOT be given as a solo anesthetic Used adjunctively with gaseous anesthetics and narcotics 2. Useful for INDUCTION of anesthesia due to FAST recovery and FAST recovery Excretion: 1. Exhalation is main route of excretion for inhaled anesthetics Side effects include: 1. Hypotension may occur due to: 1. Myocardial depression increasing the risk for cardiac arrhythmias Less likely to occur with nitrous oxide 2. Vasodilation due to relaxation of vascular smooth muscle 2. Bronchodilation due to relaxation of vascular smooth muscle 3. Respiratory depression due to decreased central respiratory drive response to blood CO2 levels rising o Tidal volume is reduced but respiratory rate is INCREASED Vs. opioids increased tidal volume but decrease respiratory rate 4. Nausea and emesis 5. Increased cerebral blood flow due to decreased central respiratory drive response to blood CO2 levels rising o Contraindicated in head trauma/surgery! Toxicity includes: 1. Malignant hyperthermia o Treat with dantrolene 2. Hepatotoxicity due to Halothane o HAVAc 3. Nephrotoxicity due to methoxyflurane and sevoflurane 4. Proconvulsant due to enflurane o Seizures induced by enflurane are usually self-limited and not believed to have any permanent neurologic effects o Commonly seen as sporadic repetitive muscle jerking WITHOUT rigidity or fever Absent rigidity and fever differentiates from malignant hyperthermia o Enflurane Excites the brain 5. Expansion of trapped gas due to nitrous oxide o Results in diffusional hypoxia ( 02 in alveoli) and induce spontaneous abortions Can be used as analgesic DURING labor though

ANESTHETICS

INTRAVENOUS ANESTHETICS Intravenous anesthetics are also known as general anesthetics or sedative-hypnotics Drugs including: 1. Barbiturate class GABA mimetic (potentiates GABAA) o Drug properties: lipid solubility = potency = MAC blood solubility = FAST onset and FAST recovery o Useful for INDUCTION of anesthesia and short procedures Similar to nitrous oxide but has higher potency and thus can be used as a solo anesthetic Used adjunctively with gaseous anesthetics and narcotics o Due to barbiturates LACK of ANALGESIC properties (nothing for pain!) o Drugs include: 1. Thiopental 2. Propofol characteristics include: 1. Propofol is lipophilic and does not dissolve in water and therefore must be mixed with lipidcontaining, milk-colored emulsion for admiration looks like administration of milk Water soluble form is called fospropofol 2. Anti-emetic properties cause less postoperative nausea Starting to replace thiopental due to less nausea Propofol Prevents Puking 3. Side effects include: 1. Stings veins upon injection Often mixed with lidocaine to reduce stinging 2. Etomidate characteristics include: 1. MINIMAL cardiovascular depressant o Side effects include: 1. Cardiovascular depressant is a characteristic of GABA mimetics 2. Respiratory depression is a characteristic of GABA mimetics 3. cerebral blood flow is a characteristic of GABA mimetics o Useful for head trauma/surgery 2. Midazolam characteristics include: 1. Benzodiazepine class 2. Most common drug used for endoscopy 3. Used adjunctively with gaseous anesthetics and narcotics Due to benzodiazepines LACK of ANALGESIC properties (nothing for pain!) 4. Lower ICP and cerebral blood flow is a characteristic of GABA mimetics 5. Side effects include: 1. Cardiovascular depressant is a characteristic of GABA mimetics 2. Respiratory depression is a characteristic of GABA mimetics 3. cerebral blood flow is a characteristic of GABA mimetics o Useful for head trauma/surgery 4. Amnesia 6. Treat overdose with flumazenil 3. Ketamine aka arylcyclohexylamines aka PCP analogs (phencyclidine) characteristics include: 1. NMDA receptor antagonist NMDA receptor is a ligand gated (glutamate) AND voltage gated (Mg2+ ion plugs gate) channel o Permeable to Ca2+ and Na+ Dextromethorphan also has NMDA antagonism MSG (monosodium glutamate) is used to enhance flavor and may increase neuronal activation via glutamate stimulation and induce seizures 2. Dissociative anesthetic causing brain to no longer associated pain as negative (dissociates pain) NO CNS depression, NO amnesia, and NO analgesia (still FEEL pain but dont care) Useful in children with fractures and need to perform bone manipulation o No need to intubate for procedure but is very painful 3. Cardiovascular stimulant is a UNIQUE characteristic of ketamine Useful in patients with cardiovascular failure Think about the guys on PCP who are jacked up running around (couldnt do that if they were cardiac depressed!) 4. cerebral blood flow due to increased cardiovascular function! Contraindicated in head trauma/surgery! 5. Side effects include: 1. Hallucinations 2. Disorientation 3. Nightmares 4. Opiates characteristics include: o Morphine and fentanyl commonly used in combination other CNS depressants during general anesthesia 1. Most anesthesia agents LACK analgesic properties which opiates can provide o Side effects:

ANESTHETICS
1. Respiratory depression LOCAL ANESTHETICS Basic principles: 1. Penetration of tissues membrane due to M-gate located intracellularly: 1. Local anesthetics are weak bases and infected tissues are acidic Results in decreased penetration of anesthetics o Increased dose is needed or combined with carbonate solution to alkalinize tissue 2. Tertiary amine local anesthetics penetrate membrane in uncharged form Bind to ion channels in charged form 2. Order of nerve blockade: 1. Small diameter fibers > large diameter fibers Size predominates over myelination due to ability to concentrate anesthetic rapidly 2. Myelinated fibers > unmyelinated fibers Myelin impedes entry of drug into the cell 3. Order includes: Small myelinated fibers > small unmyelinated fibers > large myelinated fibers > small myelinated fibers Free nerve endings > (Meissners corpuscle and Merkels disc) > Pacinian corpuscle (first lost) pain > temperature > touch > pressure (lost last) 4. Last nerve blocked = first to recover Motor neurons are large and myelinated (therefore hard to block and first to recover) 3. Administered with vasoconstrictors (except cocaine due to intrinsic properties of blocking reuptake of norepinephrine) o Epinephrine is most commonly given o Enhances local actions by: 1. Decreasing bleeding 2. Increasing anesthesia 3. Decreasing systemic concentration to prolong effects and decrease toxicity o Concentrates anesthetic locally at site of injection 4. Metabolism: 1. Ester local anesthetics are predominately metabolized via ester hydrolysis by pseudocholinesterase Shorter duration of action 2. Amide local anesthetics are metabolized by microsomal P-450 enzymes in the liver Longer duration of action Drugs include: 1. Esters -caine with 1 I in name (caine = 1 I) 1. Cocaine 2. Procaine 3. Tetracaine 4. Benzocaine 5. Chloroprocaine 2. Amides -caine with 2 Is in name (amide + caine = 2 Is) 1. Lidocaine 2. Lignocaine 3. Mepivacaine 4. Bupivacaine 5. Ropivacaine 6. Prilocaine MAO: 1. Block Na+ channels by binding to M gate of inactivate Na+ channels to prevent reopening (and activation) o use dependant and therefore most effective in rapidly firing neurons Clinical use: 1. Minor surgical procedures 2. Spinal anesthesia Side effects include: (most commonly when toxic dose given or accidently injection into a blood vessel) 1. CNS excitation 2. Arrhythmias due to cocaine 3. Cardiovascular toxicity due to bupivacaine 4. Hypertension 5. Hypotension 6. Methemoglobinemia may occur with benzocaine or prilocaine Contraindications include: 1. Sulfonamide allergies with ester local anesthetics o Esters local anesthetics contain PABA (paraaminobenzoic acid) analog which is an ester of sulfonamide o Use amide local anesthetics instead in these patients