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December 2, 2014 Mr. John D. Hadden Assistant Attorney General Litigation Division Office of the Attorney General 313 North East 21st Street Oklahoma City, OK 73105 Re: Charles F. Warner, et al, v. Gross, et al, No CIV-14-665F Dear Mr. Hadden: I have been requested to address the pharmacological effects of the drugs used in the execution protocol for the State of Oklahoma. The following outlines the classification of the drugs in the protocol, their mechanisms of action, dosing in therapeutic use and the consequences of toxic doses as outlined in AttachmentAttachment D1, Charts A-D. 1) Midazolam Midazolam is a short acting benzodiazepine which is use as a pre-anesthetic agent for routine medical procedures to allay patient apprehension, create amnesia, and anesthesia induction. It produces different levels of central nervous system (CNS) depression through binding to gamma-aminobutyric acid (GABA) receptors. It is available in an injectable dosage form. Once the drug is administered the onset of action is 1.5-5 minutes. It is widely distributed after administration and crosses the blood brain barrier. Maximum effects are seen in 20-60 minutes with recovery occurring in 2-6 hours. Serious adverse events include cardiac arrest, agitation, apnea and respiratory depression/arrest. The drug can result in depression of the spinal reflexes and reticular activating system leading to coma and respiratory arrest. The drug will potentiate the effect of other central nervous system depressants, such as ethanol, opioids and sedative hypnotics. When given together with opioids, the dose of both drugs can be reduced. The therapeutic dose as a pre-anesthetic for adults is 1.5 – 3.5 mg for a 70kg adult less than sixty years old with a maximum recommended dose of 5mg intravenously. The maximum daily dose should not exceed 10mg. When the drug is used for induction of anesthesia no more the 40 mg. should be used. Fatalities have occurred from midazolam in doses ranging from 0.04 to 0.07mg/kg. (2.8 – 4.9mg/70Kg adult) The dose indicated in Charts C & D of Attachment D of the State of Oklahoma’s execution protocol is 500 mg IV. This dose is at least 100 times the normal therapeutic dose. When the drug is administered rapidly in this large dose it will lead to toxicity resulting in CNS depression, respiratory and cardiac arrest. Midazolam is not an analgesic however the dose administered per Chart B will render the person unconscious and ”insensate” during the remainder of the procedure. The lowest dose resulting in human deaths according the manufacturer’s “material Safety Data Sheet” is .071 mg/kg, intravenously. Over 80 deaths from the use of midazolam had occurred as of 2009. 1 Attachment D in this report refers generally to the attachment to the Oklahoma Department of Corrections execution protocol identified as OP-040301 with an effective date of 9/30/2014 that identifies specifics regarding the preparation and administration of chemicals for use in the execution of offenders sentenced to death. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPSU 2) Pentobarbital Chart A of Attachment D calls for the use of pentobarbital. This drug is a short-acting oral or parenteral barbiturate having sedative-hypnotic and anticonvulsant properties. In general, the drug has a nonselective depressant effect throughout the central nervous system due to a decrease in both pre- and postsynaptic excitability. The sedative-hypnotic effects of pentobarbital are related to its inhibition of ascending conduction in the reticular formation, which controls central nervous system arousal. The inhibition depresses the sensory cortex: decreases motor activity; alters cerebral function; and increases the threshold for electrical stimulation, which contributes to its anticonvulsant properties. It has been suggested that the sedative-hypnotic and anticonvulsant effects of barbiturates may be due to their ability to mimic the inhibitory synaptic action of gamma-aminobutyric acid. Historically, the drug was used to induce a coma characterized by absent brainstem reflexes and suppression of the EEG for patients with status epilepticus, acute eclampsia or poisoning. In order to use the drug this way, patients had to be mechanically ventilated first and a loading dose of 10-15 mg/kg IV for 1 hour with the maximum loading dose of 30mg/kg would be used. The onset of action of pentobarbital is about 1 minute following intravenous dosage. Therapeutically the drug should not be administered at rate higher than 50 mg/minute with at total dose 200-500mg. Chart A calls for 5,000 mg to be administered in an IV bolus (as rapidly as possible). Adverse Drug Reactions (selected): Apnea, respiratory depression, hypoventilation, bronchospasm, hypotension, sinus tachycardia, syncope and vasodilatation leading to cardio-pulmonary collapse may occur with rapid intravenous (IV) administration of pentobarbital. When the drug is administered in accordance with Chart A it will lead to toxicity resulting in cardio- pulmonary collapse. 3) Sodium Thiopental (Pentothal®) Chart B of Attachment D of the State of Oklahoma’s execution protocol calls for the use of sodium thiopental. Thiopental is used to induce general anesthesia prior to administration of other anesthetic agents or as the sole anesthetic agent for short surgical procedures. It is a barbiturate which had dose related hypnotic effects ranging from light sleep to unconsciousness and anterograde amnesia but no analgesia. Thiopental works by enhancing GABA activity by altering inhibitory synaptic transmissions mediated by GABAa. Onset of activity occurs in 10-40 seconds with maximal effects occurring in about one minute. The duration of action is 5-8 minutes after a single dose. This can be extended with continuous IV administration. Doses required to induce and maintain anesthesia are 50-75mg (2-3 m Lof a 2.5% solution) administered every 20-40 seconds with additional drug administered should the patient’s anesthesia lighten. Alternatively, anesthesia could be rapidly inducted with a bolus dose of 210-280 mg (3-4 mg/kg) given in 2-4 divided doses in an average 70 kg adult. Thiopental could induce respiratory depression leading to decreased ventilator response to carbon dioxide. Myocardial depression could occur resulting in arrhythmias, increased heart rate, circulatory depression and death. Oklahoma’s execution protocol Attachment D Chart B calls for 5 grams to be injected all at once which is over 20 times the dose for rapid induction which is given in divided doses. At this dose and rate of injection cardio-pulmonary arrest will occur. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPSV 4) Hydromorphone Chart C of Oklahoma’s execution protocol calls for the use of Hydromorphone Hydrochloride (Dilaudid®). The drug is an opioid agonist. It is a semisynthetic analog of morphine used to relieve severe pain in in cancer, surgery, trauma, burn, and cardiac patients. Fatal cases of respiratory arrest have occurred even when the drug was used as recommended and not misused or abused. The FDA has required a “black box warning” concerning the dangers of the drug regarding fatalities secondary to the drug’s use to be included in the manufacturer’s package insert. It is a potent mu (OP3) receptor agonist. Mu receptors couple with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Analgesia is mediated through changes in the perception of pain at the spinal cord and in the central nervous system. Opioids close N-type voltage-operated calcium channels and open calcium dependent inwardly rectifying potassium channels resulting in hyperpolarization and reducing neuronal excitability. Opiates do not alter afferent nerve stimulation secondary to noxious stimuli. They do however blunt the emotional response to pain. Clinically, stimulation of mu receptors produces analgesia, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Respiratory depression is caused by direct action on the respiratory centers of in the brain stem. A reduction in the responsiveness of the brain stem to carbon dioxide and electrical stimulation occurs. Since the respiratory center is severely depressed at high doses of hydromorphone, it does not respond to increasing levels of carbon dioxide and therefore, there is no urge to breathe (no “air hunger”). In clinical use, 0.2 to 1 mg IV may be administered over at least 2-3 minutes every 2-3 hours as needed for pain. In the opiate naïve patient, the dose is initiated at the lowest possible amount and titrated upwards to obtain pain control. With appropriate titration there is no maximum dose. Duration of action is 4-5 hours. Intravenous administration drug distribution has two half-lives with the initial half-life being 1.27 minutes followed by 14.7 minutes. The first half-life is the time to reach equilibrium in the plasma and the second half represents the distribution to other tissues. Drug elimination is through hepatic and renal mechanism; therefore the dose would be reduced for patients with diminished hepatic or kidney function. The primary metabolite of hydromorphone is hydromorphone-3-glucuronide which has 35-40 times greater exposure than parent compound. The time it takes to eliminate half of an administered dose is 2.3 hours. These properties indicate that the drug has a very quick onset of action with its peak pharmacological effect occurring within 15 minutes. The majority of the drugs effect is seen quickly after administration via the intravenous route. At therapeutic doses, cardiovascular adverse effects include: sinus bradycardia (<2%), sinus tachycardia (<2%), palpitations (<2%), hypertension, hypotension, orthostatic hypotension, faintness, flushing, extrasystoles (<2%), and syncope. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur. t^okboLOMNQJNOJMOLaÉÑëD=bñéÉêí=oÉéçêíLSPTM An overdose causes respiratory depression, extreme somnolence, stupor or coma, skeletal muscle flaccidity, cold and clammy skin, bradycardia, hypotension apnea, circulatory collapse, cardiac arrest and death.

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