IV drugs

INTRAVENEOUS ANESTHETIC AGENTS SIRILUK CHUMNANVEJ MD. ANESTHESIOLOGIST

Degree Institution YearMD. (Second honor) 1997 Faculty of Medicine, 1999Cert. Of Clin. Sci. Thammasat University(Anesthesiology) 2001 Faculty of Medicine, 2003Thai Board of Pramongkutklao 2006Anesthesiology Hospital, Mahidol UniversityThai Board of FamilyMedicine Pramongkutklao Hospital, MahidolClinical Research UniversityFellow in CardiacAnesthesia The Royal College of Family Physicians of Thailand Anesthesiology and Critical Care Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

INTRAVENEOUS ANESTHETIC AGENTS• IV anesthetics lack analgesic properties; except ketamine• dose-dependent CNS depression; • Low doses  sedation • high doses  hypnosis (or unconsciousness)• IV anesthetics in combination with potent opioidanalgesics and/or local anesthetics  TIVA• Etomidate produces less cardiovascular depression thanthe barbiturates and propofol• Propofol possesses unique antiemetic property• Ketamine possesses analgesic and psychomimeticproperties

INTRAVENEOUS ANESTHETIC AGENTS 1. Intravenous Nonopioid Anesthetics 2. Intravenous Opioid Anesthetics 3. Depolarizing Neuromuscular Blockers 4. Non-Depolarizing Neuromuscular Blockers

1. Intravenous Nonopioid Anesthetics • PROPOFOL • BARBITURATES • BENZODIAZEPINES • FLUMAZENIL (ANEXATE, ROMAZICON) • KETAMINE (HENCYCLIDINES) • ETOMIDATE

PROPOFOL• Alkylphenol group  2,6-diisopropylphenol• 1% (weight/volume) propofol; consists of 10% soybean oil,2.25% glycerol, and 1.2% purified egg phosphatide• highly lipid soluble, pH 7• milky white substance or oil-in-water emulsion• hypnotic effects largely through action onthe GABA receptor• metabisulfite or ethylenediaminetetraaceticacid as the antimicrobial• compatible with 5% dextrose in water• rapidly metabolized in ttoheprliovdeurcbeywcaotnejru-sgoaltuibonletcoompounds,glucuronide and sulfatewhich are excreted by the kidneys.Less than 1% of propofolis excreted unchanged in urine, and only 2% is excreted infeces• extrahepatic metabolism  Lung ~ 30%

Blood levels required for anesthesia during surgery are 2 to 5 µg/mL,with awakening usually occurring at a blood level lower than 1.5 µg/mL.

Pharmacokinetic variables of intravenous anesthetics Drug Elimination Clearance Vd (L/kg) Half-Life (mL/kg/min)DiazepamEtomidate (hr) 0.2–0.5 0.7–1.7Flumazenil 20–50 18–25 2.5–4.5Ketamine 5–20 0.6–1.6Midazolam 2.9–5.3 12–17Propofol 6.4–11 3.1Thiopental 0.7–1.3 20–30 1.1–1.7 2–10 2.5–2.8 3–4 1.5–3 1.7–2.6 4–7 7–17

-The context-sensitive half-time is the time for the plasmalevel of the drug to drop 50% after cessation of infusion- etomidate, propofol, ketamine  shorter half-times

Uses and doses of propofolInduction of general 1–2.5 mg/kg IV;anesthesia dose reduced with increasing ageMaintenance of general 50–150 µg/kg/min IV combined with N2 O or an opiateanesthesiaSedation 25–75 µg/kg/min IVAntiemetic 10–20 mg IV; can repeat q5-10min or start infusion of 10 µg/kg/min• rapid onset (unconsciousness in 30-60 secs) and offsetwith context-sensitive decrement times of • ~ 10 minutes when infused < 3 hours • under 40 minutes when infused ≥ 8 hours

Side Effects and Contraindications• side effects; pain on injection, myoclonus, apnea,decrease arterial blood pressure, thrombophlebitis(rarely) – pain on injection  reduced by using a large vein, avoiding veins in the dorsum of the hand, and adding lidocaine• Propofol infusion syndrome – rare, but lethal syndrome, as a result of failure of free fatty acid metabolism – associated with infusion of propofol ≥ 5 mg/kg/hr for ≥ 48 hours – Clinical features; cardiomyopathy with acute cardiac failure, metabolic acidosis, skeletal myopathy, hyperkalemia, hepatomegaly, and lipemia

BARBITURATES• 2 major divisions - Thiobarbiturates ; Rapid acting,usually smooth onset of sleep, fairly prompt recovery,stable for 1 week if refrigerated after reconstitution - Oxybarbiturates ; Delay in onset of action,Prolonged action, Excitatory side effects,available for use for up to 6 weeks after reconstitution• hypnotic effects largely through action on GABA receptor• not to be coadministered or mixed in pancuronium,vecuronium, atracurium, alfentanil, sufentanil, midazolam• metabolized in the liver and excreted by the kidneys inactive metabolized• dose-related depression in CMRO2

• Thiopental ; affinity for fat, relatively large volume ofdistribution  low rate of hepatic clearance• not possess analgesic properties• Recommended doses  Thiopental Induction Dose 3–4 (mg/kg),Onset 10–30 (sec) IV Maintenance Infusion 50–100 mg q10-12min

Hypnotically active barbiturates listed according to duration of action Ultrashort Short Acting Intermediate Long Acting Acting Acting Pentobarbital PhenobarbitalThiopental Secobarbital Amobarbital Mephobarbital Butalbital BarbitalMethohexital Hexobarbital Aprobarbital Metharbital PrimidoneThiamylal Butabarbital

Side Effects and Contraindications• Side effects;- Cardiovascular depression  peripheral vasodilation, decrease incontractility- Dose-related central respiratory depression  apnea- Excitatory symptoms; cough, hiccough, tremors, twitching- urticarial rash (lasts a few minutes ; head, neck, trunk)• Complications ; garlic or onion taste, allergic reactions, localtissue irritation, tissue necrosis (rarely)- severe reactions (facial edema, bronchospasm, anaphylaxis)  Rx:1-mL increments of 1:10,000 epinephrine, Brnchodilators• Accidental intra-arterial injection  degree of injury is relatedto the drug concentrationRx: (1) dilution by the administration of saline into the artery, (2)heparinization to prevent thrombosis, (3) brachial plexus block• Contraindications ; respiratory obstruction or an inadequateairway, severe cardiovascular instability or shock, statusasthmaticus, porphyria

BENZODIAZEPINES• high lipophilicity• act through the GABA receptor• hypnotic, sedative, anxiolytic, amnesic, anticonvulsant,centrally produced muscle relaxant properties• reduce CMRO2 and CBF in a dose-related• increase the seizure initiation threshold of local anesthetics• dose-related central respiratory system depression  apnea• Slightly hemodynamic change  decreased ABP• receptor affinity lorazepam > midazolam > diazepam

• Midazolam & Diazepam have a more rapid onset ofaction (within 30-60 seconds) than lorazepam (60-120seconds)• lack analgesic properties• metabolized in the liver and excreted by the kidneys active metabolized ;- Diazepam  oxazepam and desmethyldiazepam- Midazolam  hydroxymidazolams

Uses and doses of Benzodiazepines• Intravenous Sedation ; dose of midazolam for anxiolysis and mildsedation is 0.015 - 0.03 mg/kg• Oral Sedation ; midazolam 0.5 mg/kg• Induction and Maintenance of Anesthesia ; midazolam Midazolam DiazepamInduction 0.05–0.15 mg/kg 0.3–0.5 mg/kgMaintenance 0.05 mg/kg prn 0.1 mg/kg prn 1.0 µg/kg/minSedation 0.5–1.0 mg repeated 2 mg repeated 0.07 mg/kg IM

Side Effects and Contraindications• remarkably safe drugs• free of allergenic effects• not suppress the adrenal gland• Side effect  respiratory depression - lorazepam & diazepam  venous irritation,thrombophlebitis• reversed with flumazenil

Flumazenil (Anexate, Romazicon)• benzodiazepine antagonist• short-lived compound  plasma half-life about 1hour• metabolized in the liver and excreted by the kidneys active metabolized• remarkably free of cardiovascular effects• safe drugs• free of allergenic effects

Uses and doses of FlumazenilReversal of benzodiazepines 0.1–0.2 mg repeated everyDiagnosis in coma 30-60 secs up to 3-5 mg 0.5 mg repeated up to 1.0 mg infusion rate of 30- 60 µg/min (0.5-1 µg/kg/min)

KETAMINE (HENCYCLIDINES)• high lipid solubility• antagonism at NMDA receptor• metabolized in the liver and excretedby the kidneys  active metabolized• dose-related unconsciousness and analgesia• “dissociative anesthesia “  cataleptic state• Corneal, cough, and swallow reflexes may all be present butshould not be assumed to be protective• amnesia is not prominent as benzodiazepines• provides important postoperative analgesia• increases cerebral metabolism, CBF, ICP, IOP• undesirable psychological reactions during awakening• bronchial smooth muscle relaxant• sympathomimetic action; increases in BP, HR, CO

Uses and doses of ketamineInduction of General 0.5–2 mg/kg IVAnesthesiaMaintenance of General 4–6 mg/kg IMAnesthesia 0.5–1 mg/kg IV prn with 50% N2 O in O2 15–45 µg/kg/min IV with 50%–70% N2 O in O2Sedation and Analgesia 30–90 µg/kg/min IV without N2 O 0.2–0.8 mg/kg IV over 2–3 minPreemptive/PreventiveAnalgesia 2–4 mg/kg IM 0.15–0.25 mg/kg IV- IVunconsciousness in 30-60 seconds- IMCNS effects onset 5 min, peak ~15 min- Elimination half-life = 2 - 3 hrs

• Routes of Administration  intravenous,intramuscular, oral, nasal, rectal, epidural(preservative-free)- IV administration  peak action occurs in 30-60seconds- IM administration  onset occurs in 5 minutes,peak action occurs 20 minutes- oral dose of 3 to 10 mg/kg generates a sedativeeffect in 20 to 45 minutes- suited for the sedation of pediatric patientsundergoing procedures outside OR

Side Effects and Contraindications• Side effect  psychological emergence reactions, potentiation of NDMR blockade, neurotoxicity of ketamine's preservative (chlorobutanol), Oral secretions• Contraindications ; - increased ICP - intracranial mass lesions - open eye injury - ischemic heart disease - vascular aneurysms - psychiatric disease - possibility of postoperative delirium from other causes (e.g., delirium tremens, possibility of head trauma)

ETOMIDATE (Amidate, Hypnomidate)• imidazole derivative• water insoluble• metabolized in the liver primarily byester hydrolysis(inactive), excretedas metabolites by kidney 85% and in bile 18%• 0.2-0.3 mg/kg  reduces CBF(34%) and CMRO2(45%)• decrease in ICP, IOP• not induce histamine release• hemodynamic stability• minimal respiratory depression• Rapid onset (one arm-brain circulation)• Duration of anesthesia  each 0.1 mg/kg administeredprovides about 100 seconds of loss of consciousness• rectal administration 6.5 mg/kg Hypnosis occurs in 4minutes

Uses and doses of etomidateInduction of general 0.2–0.6 mg/kg IVanesthesia 10 µg/kg/min IV with N2 OMaintenance of general and an opiateanesthesia 5–10 µg/kg/min IV.Sedation• most appropriate in patients with cardiovascular disease,reactive airway disease, intracranial hypertension• Regimens for infusion to achieve plasma level of - 300 to 500 ng/mL  maintenance of anesthesia - 150 to 300 ng/mL  sedation - 150 to 250 ng/mL  awakening• Prolonged periods of sedation are contraindicated becauseof inhibition of corticosteroid synthesis

Minor site Minor site Major site

• Infusion regimens consist of - initial rapid infusion of 100 µg/kg/min for 10 minutesfollowed by 10 µg/kg/min thereafter or - 100 µg/kg/min for 3 minutes, 20 µg/kg/min for 27 minutes,and 10 µg/kg/min thereafterLoss of consciousness with these techniques occurs after100-120 seconds• The infusion is usually terminated 10 minutes before thedesired awakening time

Side Effects and Contraindications• Side effect  - adverse effects when used for induction; nauseaand vomiting, pain on injection, myoclonic movement,hiccups - high-dose prolonged infusion has been reported toresult in propylene glycol toxicity• Contraindications ; - Prolonged sedation for patients in the ICU

2. Intravenous Opioid Anesthetics• Opioids• Classification of opioid compounds• Effects of Opioids• OPIATE TOLERANCE AND ADDICTION• Factors Affecting Pharmacokinetics andPharmacodynamics of Opioids• ANESTHETIC TECHNIQUES USINGOPIOIDS• OTHER OPIOID AGONISTS• Naloxone• DRUG INTERACTIONS WITH OPIOIDS

Intravenous Opioid Anesthetics• Endogenous Opioid Peptides; Enkephalin, β-endorphin,dynorphin• Mechanism of Analgesia  bind at specific receptors in brain,spinal cord, peripheral neurons - opioid receptors ; μ receptor, κ-receptor• decreases in CMR and ICP• increase muscle tone and may cause muscle rigidity• “opioid-induced neuroexcitatory phenomena “ Fentanyl can causeneuroexcitation ranging from delirium to grand mal seizure-like activity• constriction of the pupil by an excitatory action on theparasympathetic•ofremdeupceersidthineerm, torraemgualdaotlo(r0y.5thmrge/skhgo) lds ; antishivering effect• Pruritus ; Rx: Nalbuphine, Butorphanol, Ondansetron,Tenoxicam, Naloxone

Potential problems associated with opioid-induced rigidity System ProblemHemodynamicRespiratory ↑ CVP, ↑ PAP, ↑ PVRMiscellaneous ↓ Compliance, ↓ FRC, ↓ ventilation Hypercarbia Hypoxemia ↑ Oxygen consumption ↑ Intracranial pressure ↑ Fentanyl plasma levels

Chemical structures

Classification of opioid compoundsNaturally occurring Morphine Codeine Papaverine ThebaineSemisynthetic Heroin Dihydromorphone/morphinoneSynthetic Thebaine derivatives (e.g., etorphine, buprenorphine) Morphinan series (e.g., levorphanol, butorphanol) Diphenylpropylamine series (e.g., methadone) Benzomorphan series (e.g., pentazocine) Phenylapiperidine series (e.g., meperidine, fentanyl, sufentanil, alfentanil, remifentanil)

• NEUROPHYSIOLOGIC EFFECTS OF OPIOIDS•Analgesic Action of Opioids - nociceptive pain usually responsive to opioid analgesics - alteration of the emotional reaction to painful stimuli• Opioids as Anesthetics - opioids reduce the MAC of volatile anesthetics

• RESPIRATORY EFFECTS OF OPIOIDS - respiratory depression; incidence ~ 0.1-1% , Rx: Naloxone - peak onset; MO = 30±15 mins, fentanyl = 5-10 mins - MO  depressant effect on mucociliary flow - depressed upper airway, tracheal, lower respiratory tractreflexes - antitussive actions - decrease hypoxic ventilatory drive - Factors Affecting Opioid-Induced Respiratory Depression - High dose - Sleep - Old age - CNS depressant; Volatiles, alcohol, barbiturates, benzodiazepines - Renal insufficiency - Hyperventilation , hypocapnia - Respiratory acidosis - Decreased clearance; Reduction of hepatic blood flow - Secondary peaks in plasma opioid levels; Reuptake of opioids frommuscle, lung, fat and intestine - Pain

• CARDIOVASCULAR EFFECTS OF OPIOIDS - large doses of opioids  hemodynamic stability by - Neurologic Mechanisms - Cardiac Mechanisms - Hormonal Mechanisms - Vascular Mechanisms

• ENDOCRINOLOGIC EFFECTS OF OPIOIDS - reduced the stress response• RENAL AND URODYNAMIC EFFECTS OF OPIOIDS - μ-Receptor activation  antidiuresis, decreases electrolyteexcretion - κ-receptor stimulation predominantly produces diuresis - disturbances of micturition  urinary retention

• GASTROINTESTINAL EFFECTS OF OPIOIDS - decrease gastrointestinal motility - Fentanyl increases intestinal blood flow - Biliary and Hepatic Effects - increase biliary duct pressure and sphincter of Oddi Rx: reversible with naloxone, except meperidine - Nausea and Vomiting - stimulate the chemoreceptor trigger zone through δ-receptors - Rx: anticholinergic, butyrophenones, dopamineantagonists, serotonin antagonists and acupressure

• OTHER OPIOID EFFECTS- Obstetrics - Fentanyl (50–100 µg IV every hour), compared withmeperidine (25–50 mg IV every 2 to 3 hours), results in lessnausea, vomiting, and sedation in mother and in lower naloxonerequirements in newborns - Morphine, meperidine, fentanyl found in breast milk- Allergic Reactions - local reactions caused by preservatives or histamine; wheal and flare- Ocular Effects - fentanyl, sufentanil, alfentanil prevent increasesIOP- Immune Effects - immunosuppressive effects

Context-Sensitive Half-Time

• OPIATE TOLERANCE AND ADDICTION - development of acute opioid tolerance in humans remainscontroversial• Management of the Opioid-Dependent Patient - Problem lists; – cardiopulmonary problems – restrictive lung disease – increased alveolar-arterial O2 gradients – renal disease – anemia – adrenal hypertrophy and impairs corticosteroid secretion – viral and nonviral hepatitis – acquired immunodeficiency syndrome – osteomyelitis, – muscle weakness – neurologic complications

• OPIATE TOLERANCE AND ADDICTION- Anesthetic management; - adequate premedication with opioids - acute opioid overdose  reversed withincrements of naloxone (40–80 µg every 1-2 mins IV,total dose of 12.4 mg) - adequate IV fluids - monitoring; ABG and pulmonary function

Factors Affecting Pharmacokinetics and Pharmacodynamics of Opioids• Age• Body Weight - lean body mass is a better predictor ofmetabolic capacity than total body weight

• Renal Failure - Morphine  active metabolites (M3G and M6G) dependent on renal clearance mechanisms for elimination - meperidine  active metabolites  analgesic and CNSexcitatory effects - Fentanyl clearance is not altered by renal failureNormal Renal Failure

• Hepatic Failure - does not have a major impact on the pharmacokineticsof most opioids  extrahepatic metabolism (morphine) - Meperidine, Alfentanil metabolism altered by liverfailure  prolonged terminal half-times - Remifentanil pharmacokinetics  unchanged• Cardiopulmonary Bypass - significant alterations in pharmacokinetics - CPB-induced modifications in distribution volumes(secondary to priming), changes in acid-base balance, organblood flow, plasma protein concentrations, body temperature Overall prolonged elimination, decreased clearance• Acid-Base Changes - respiration alkalosis and respiratory acidosis  prolongand exacerbate opioid-induced respiratory depression• Hemorrhagic Shock - prolonged opioid effect

Morphine• low lipid solubility• little transient first-pass uptake by the lung• slower penetration of MO into and out of the brain• 20-40% of MO is bound to plasma proteins, mostly albumin• metabolized by conjugation in liver, but kidney plays a keyrole in the extrahepatic metabolism• Morphine 3-glucuronide (M3G) is the major metabolite, notbind to opioid receptors, little or no analgesic activity• Morphine 6-glucuronide (M6G) nearly 10% metabolites , morepotent μ-receptor agonist than morphine, with similar duration

Meperidine• first-pass uptake by the lungs is ~ 65%• highly bound to plasma proteins than morphine is, principally(70%) to α1 -acid glycoprotein• relatively high hepatic extraction ratio• major metabolite normeperidine has analgesic activity• elimination half-life of normeperidine is longer thanmeperidine• normeperidine  potentially producing seizures(•mMilokr-ptoh-ipnleas&mMa erapteiroisdionfe2hatvoe3b:1e)e, nnefwoubnodrninnatrhceobsirseaisst milkinsignificant• dual effect on the biliary tract – Low concentrations  produce an inhibitory effect on the response of the common bile duct to electrical stimulation – Higher concentrations  produce an excitatory effect and increase spontaneous contractions

Fentanyl• highly lipophilic• lungs exert a significant first-pass effect ~ 75%• 80% of fentanyl is bound to plasma proteins – 40% are taken up by red blood cells• relatively long half-life, because of widespread distribution(i.e., large volume of distribution) in body tissues• primarily metabolized in the liver by N-dealkylation andhydroxylation• Metabolites begin to appear in plasma 1.5 minutes afterinjection• norfentanyl, the primary metabolite, is detectable in theurine for up to 48 hours after intravenous administration• 2.5 mcg/Kg prevent increases in IOP