1. Review the process of drug development.

2. Describe novel clinical agents.

3. Review avenues of investigation for new drugs.

4. Examine the potential causes of transient neurologic symptoms in spinal anesthesia.

5. Discuss the advantages and disadvantages of lidocaine, tetracaine, bupivacaine, mepivacaine, procaine, and 2-chloroprocaine in outpatient spinal anesthesia.

Nouveau Pharmacology in 2009
Joseph R. Tobin, MD, Professor and Chair, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC

New drug development: expensive; ≈80% of drugs discovered and put through preclinical testing never get approved; those approved have restricted uses; discovery screening occurs when chemist makes large number of compounds and then determines, in vitro, whether any specific activity exists; after drug determined to have some potential activity, must then be synthesized and purified; next, preclinical testing involves ≥2 animal species; necessary to determine short-term efficacy and toxicity, and potential accumulation or hypersensitivity after repeat exposure; average 8 to 10 yr of preclinical trials before starting phase I trials in humans; after obtaining animal data, sponsor of drug files investigational new drug (IND) application with Food and Drug Administration (FDA); if FDA does not respond within 30 days, sponsor can begin phase I clinical trials (5-100 participants) to look at safety; phase II studies focus on efficacy (100-300 participants); phase III trials look at proposed safety and efficacy in larger base (200-10,000 participants); at this point, FDA reviews new drug application (NDA) to determine whether drug can be released for specific use; on-label use defined as using drug exactly as label indicates; once approved for specific use, practitioners use drug for other indications (off-label); phase IV studies involve after-marketing surveillance and adverse reaction reporting (eg, MedWatch web site)

Food and Drug Administration: under much criticism in public press in past 24 mo; won new government initiative award in late 1980s for retooling process to evaluate and release drugs to treat HIV; drugs come to market 10 to 18 mo after FDA receives NDA, instead of previous 24 to 36 mo; mission of FDA to enhance safety and improve public health, not support or deny commercial sponsor of drug; does not respond favorably to large pharmaceutical companies just because portion of budget comes from those companies

Off-label uses of drugs: neither immoral nor illegal; defined as uses not directly addressed in product label; includes, eg, nasal fentanyl, intravenous (IV) hydroxyzine, IV promethazine (Phenergan), methotrexate (for rheumatoid arthritis); most drugs not approved for use in children

Newer drugs: compounds released—include Organon 25969 (ie, sugammadex); dexmedetomidine; fenoldopam (selective dopamine agonist used to treat malignant hypertension; useful after cardiac bypass); almitrine (negative side-effect profile; improves V/Q matching in patients with severe chronic obstructive pulmonary disease [COPD]); vardenafil (longer-acting type of sildenafil; active along guanylate cyclase axis to increase nitric oxide [NO] and cause vasodilatation); methyl salicylate (Salonpas; nonsteroidal anti-inflammatory drug [NSAID] used topically); pentazocine (Talwin NX; mixed opioid agonist/antagonist); Glaxo Wellcome (GW) 280430A, bosentan (endothelin antagonist; used for long- term pulmonary hypertension); E-TRANS (delivers fentanyl transcutaneously using patient-controlled analgesia [PCA]- type delivery); and remodulin (prostaglandin); drugs in phase I, II, III trials—include nicotinic agonists; adenosine agonists; mixed opioid agonists/antagonists; alosetron (Lotronex) and tegaserod (Zelnorm); statins; and cyclooxygenase-2 (COX-2) antagonists; novel ideas—transdermal electrophoresis PCA; combinatorial chemistry; development of host- guest compounds; novel uses—vasopressin first-line therapy for advanced cardiac life support (ACLS); amiodarone first-line therapy for ventricular arrhythmia; botulinum toxin used in cosmetic surgery and for spasticity in orthopedic patients (systemic absorption may cause vocal cord paresis and potential airway obstruction); minoxidil used for hair loss; novel delivery—lidocaine (Lidoderm 5%) topical application; E-TRANS (fentanyl)

Neuromuscular blockade: succinylcholine—rarely used but always available for life-threatening airway crisis; shortest onset and shortest offset of all neuromuscular blockers; rocuronium—onset in 60 to 75 sec, but longer offset; rapacuronium—approved by FDA but withdrawn after 7 mo; ultrafast-onset and offset, nondepolarizing muscle relaxer; caused intense bronchospasm, leading to hypoxic cardiac arrest; bis- and mixed-tetrahydroisoquinolinium chlorofumarates (GW 280430A)—nondepolarizing muscle relaxants that may come to market over next few years; some of chemical bridges are ester-based and therefore can be broken down by plasma esterases

Cyclodextrin: novel reversal agent meant to surround rocuronium and “pull it off” neuromuscular receptor; if nontoxic, will allow quick offset of rocuronium and possibly vecuronium; avoids need for nonspecific anticholinesterase (eg, neostigmine, edrophonium) and for specific antimuscarinic agent; could rapidly reverse effect of rocuronium and return patient with myasthenia to full strength; could make succinylcholine obsolete

Sugammadex: cyclodextrin designed to bind rocuronium; phase I to III trials completed; FDA held public meeting with advisory committee in April 2008; received preliminary approval; later in 2008, FDA expressed concern about hypersensitivity (eg, serious bronchospasm that occurred with rapacuronium); FDA informed manufacturer of “nonapprovable” status in August 2008; near same time, sugammadex approved in Europe; provides effective reversal of rocuronium block

Dexmedetomidine: sedative (induces tranquility and cooperation); mild stimulation awakens patient; opioid or other anxiolytic required in combination; do not rely on it for deep sedation or general anesthesia; side effects include mild hypotension, cardiac arrest, and bradycardia; paradoxical effect (eg, severe hypertension) in unintended large dose; limited to ≤24 hr use due to possible adrenal suppression; neither hyponatremia nor hypoglycemia noted in speaker’s experience of using it to wean patients from high doses of opioids and benzodiazepines

Fenoldopam: dopamine-1 receptor agonist (DA); effective only on DA1A and DA1B receptors and possibly on DA2 subclasses; elicits vasodilatation; indicated for malignant hypertension and used to promote natriuresis, kaliuresis, and diuresis in pediatric heart room and intensive care unit; pediatric optimal dose (1.0 to 1.5 µg/kg per min) 4 times maximal dose approved in adults (0.05 to 0.3 µg/kg per min); doses recommended on label and approved by FDA only for adults

Phentolamine: used only in unusual circumstances because now have better control over systemic vascular resistance; important in dental anesthesia for oral injection to vasodilate and promote absorption of peripheral local anesthetics into systemic circulation; www.lipidrescue.org

Pulmonary hypertension: better drugs needed to either change pulmonary vasculature and improve ability to remodulate or to enhance function of right ventricle; treatment options—inhaled NO; bosentan (endothelin antagonist); treprostinil (Remodulin; subcutaneous or IV, both short-term and long-term); inhaled prostaglandin I(2) [PGI2 ] and prostaglandin E(1) [PGE1 ]; drugs active in guanylate cyclase and NO classes (eg, iloprost, vardenafil)

Nitric oxide axis: sodium nitroprusside and nitroglycerin release NO upon entry into circulation; increased NO concentrations lead to systemic and pulmonary vasorelaxation; however, inhaled NO selectively delivered vasodilator to pulmonary vasculature; does not have systemic vascular relaxation effects because it becomes attached to hemoglobin in pulmonary capillaries, and therefore unavailable to systemic circulation; in acute respiratory distress syndrome (ARDS) and sepsis, goal to achieve balance between relaxing pulmonary vasculature and improving oxygenation and also not relaxing systemic vasculature to improve systemic blood pressure (BP); using inhaled NO will improve pulmonary vasorelaxation, systemic oxygenation, and ability to excrete CO2 ; important to support systemic circulation when using higher doses; NO synthase antagonists being investigated to support BP; inhaled NO and sildenafil or vardenafil coming into use

Agents active in coagulation cascade: argatroban and ancrod (useful for heparin-induced thrombocytopenia or true anaphylaxis to heparin; not in widespread use); factor VIIa (eg, NovoSeven; use with caution); aprotinin (discontinued in United States; concern about increased risk for renal failure following primary or secondary use for treatment of heparin- or bypass-induced bleeding)

Chiral chemistry: new drugs designed to use biologically active enantiomer; most compounds racemic mixtures; biologically active selectivity desired to reduce side effects

New biologics: proteins or other live biologic entities used in clinical medicine; tumor necrosis factor (TNF)-α antagonists used to “knock down” immune response; risk for anaphylaxis; patients coming to OR on these drugs may be refractory to resuscitation attempts; be prepared for major resuscitation

New analgesics: tramadol—µ-opioid receptor agonist; also has other active properties that raise catecholaminergic levels of monoamine transmitters in brain; secondary effect may be to improve depression associated with chronic pain

E-TRANS (fentanyl) electrotransport system: placed on shoulder or chest; deactivated after 24 hr; patient pushes button to deliver 25- or 50-µg dose of fentanyl over 10 min; lock-out time included; challenges include premature failure; originally evaluated for inpatient use only, but eventually will probably be available for outpatient use

Gender-specific medicine: when neostigmine used on neuraxial axis as adjuvant analgesic, women have better maximum possible effect (improvement of analgesia to standard stimulus); nicotinic component of neuraxial analgesia may be dependent on estrogen; possible new analgesic strategies may be sex-specific

Concerns about prolonged QT syndrome: concerns about combination of macrolide antibiotic and statin with drug that may be associated with prolonged QT syndrome (eg, antiemetic)

Statins: associated with rhabdomyolysis; confusion with malignant hyperthermia

Herbal supplements: biologically active compounds; patients often do not disclose use (either do not want to disclose or believe herbal supplements not drugs); may have some implications for anesthetic

Anesthetic Agents for Outpatient Spinal Anesthesia
Julia E. Pollock, MD, Attending Anesthesiologist, Virginia Mason Medical Center, Seattle, WA

Advantages of spinal anesthesia: fast onset; easy to perform; provides excellent surgical conditions; if timed appropriately, results in rapid recovery; minimal equipment necessary; least expensive form of anesthesia available

Drug selection: no problem selecting drugs for inpatients; bupivacaine (in hyperbaric and isobaric formulations) “fantastic spinal anesthetic” for inpatient surgery; for outpatient procedure, gold standard has been hyperbaric 5% lidocaine; provides reliable anesthesia for 1.5 hr and good surgical conditions; concerns with lidocaine include transient neurologic symptoms (TNS) and permanent sequelae; incidence of profoundly negative outcomes “extremely low” (≈11 in 5 million patients studied); higher incidence of TNS (ie, pain or dysesthesia occurring within 24 hr of spinal anesthesia; usually gone within 4 days; may be masked by postoperative narcotics or NSAIDs])

Transient neurologic symptoms: increased awareness of TNS beginning in early 1990s; incidence dependent on type of surgery; patient in lithotomy or gynecologic position at highest risk (≈40%); next highest group appears to be knee arthroscopy (due to positioning and manipulation); group with lowest incidence (4%-8%) are those having spinal anesthesia and placed in supine position (eg, inguinal hernia repair, umbilical hernia repair)

Potential causes of TNS: local anesthetic toxicity (all local anesthetics toxic); neural ischemia related to stretching (particularly of sciatic nerve); needle trauma, maldistribution, patient positioning, muscle spasm, and early ambulation have all been discounted as causes

Recommendation: lidocaine can be used in patients in supine, but not lithotomy position; also avoid in knee arthroscopy; speaker uses less lidocaine than in past (rarely uses >60 mg); no difference in incidence based on needle type; dilution probably not helpful

Longer-acting agents: tetracaine—most research indicates tetracaine, 3 mg, unsuccessful (“just too long-acting”); bupivacaine—low-dose bupivacaine, 2.5 mg, mixed with narcotic (eg, fentanyl 25 µg) does not provide good motor blockade (surgeon unable to get to lateral and medial compartments, particularly for knee arthroscopy; pruritus common); also large variability in duration of motor and sensory blockade, compared to other drugs; mepivacaine—excellent spinal anesthetic; not approved by FDA for spinal use (isobaric bupivacaine, chloroprocaine, and isobaric lidocaine also labeled “not for spinal use”); 4% solution available in Europe for spinal anesthesia, but longer duration than lidocaine; reliable drug; incidence of TNS less than with lidocaine, but “there is an incidence”; procaine—provides less-reliable anesthesia; higher incidence of nausea and vomiting, compared to lidocaine; incidence of TNS; high dose required for good block, so patient remains in recovery as long as with lidocaine

2-chloroprocaine: not approved by FDA for spinal anesthesia (approved for epidural); first introduced in 1952; formally produced in 1956; bisulfite and methylparaben added to be both antioxidant and preservative (chemical formulation unstable; undergoes photodegradation); used for first 25 to 30 yr predominantly for epidural anesthesia in laboring women and for epidural and caudal anesthesia for abdominal surgery; before 1980, ≥3 cases in literature of unintended large intrathecal doses with no postoperative neurologic sequelae; in 1990, 3 separate reports included 9 cases of patients who received unintentional intrathecal injections of epidural doses of 2-chloroprocaine and had permanent neurologic sequelae; patients who received total intrathecal dose <400 mg had no permanent neurologic sequelae; patients with long-term complications received >400 mg of 2-chloroprocaine; study data—found low pH of 2-chloroprocaine in combination with bisulfite caused neurotoxicity; in 1987, bisulfite removed from 2-chloroprocaine and ethylenediaminetetraacetate (EDTA) added; led to back pain in association with epidural anesthesia; in 1996, EDTA removed; 2 formulations contain no additives (brown bottle), 1 contains preservatives (clear bottle; not recommended for spinal anesthetics); Kopacz studies—looking at 2 mL of 2% lidocaine vs 2 mL of 2% chloroprocaine found lidocaine provides predictable (1.25 to 1.5 hr) surgical anesthesia, whereas chloroprocaine provides 15 min less surgical anesthesia “almost every time”; Kopacz performed other studies, adding fentanyl, epinephrine, dextrose, and clonidine; compared it to lidocaine, bupivacaine, and procaine in various dosing regimens; Casati dose-ranging study—looked at duration and was unsuccessful using chloroprocaine, 30 mg (speaker suggests minimum dose of ≈40 mg); found low incidence of TNS when compared with lidocaine (32% incidence); unanswered questions—true incidence of TNS in very large patient population unknown; addition of epinephrine to 2-chlorprocaine in Kopacz study resulted in 7 of 8 volunteers with flu-like symptoms; etiology difficult to determine; speaker does not add epinephrine to outpatient spinal anesthetics because of increased incidence of urinary retention; conclusion—in speaker’s experience, median dose 40 mg, and average time to ambulation 155 min