Barbituates instructor

INTRODUCTION TO BARBITURATES (BTS)

  • Barbiturates (BTS) are a class of drugs that were initially used for various medical purposes.

INITIAL USES OF BARBITURATES

  • BTS emerged for four distinct applications:

    • Surgical Anesthetics:

    • Example: Sodium thiopental

    • Note: Not analgesics (pain relievers).

    • Anxiolytics:

    • Example: Phenobarbital

    • Hypnotics:

    • Examples: Amytal, Seconal

    • Antiepileptics:

    • Example: Phenobarbital

  • Important Question: Is sedation synonymous with targeted treatment for the specific condition being addressed?

PHARMACOKINETICS OF BARBITURATES

  • BTS are grouped based on structural similarities but have different pharmacokinetics.

  • Absorption and Distribution:

    • Rapidly absorbed and effectively distributed via bloodstream.

    • Classified into Ultrashort Acting and Normal Classes.

    • Blood-Brain Barrier (BBB):

    • Lipid-soluble ultra-short-acting barbiturates quickly cross BBB, inducing immediate effects (e.g., sodium pentothal induces total sedation 20 seconds post-injection).

    • Water-soluble forms cross BBB more slowly, leading to delayed effects.

    • Global Action: Barbiturates impact overall bodily functions; for example, one cannot experience anxiety reduction without sedation.

  • Clearance and Metabolism:

    • Primarily cleared by the liver; metabolic tolerance can develop.

    • Pharmacodynamic Tolerance:

    • Emerges quickly in higher brain regions (sedation effects) and slower in brainstem (respiration drive).

    • Results in a diminishing therapeutic index.

MECHANISMS OF ACTION FOR BARBITURATES

  • Barbiturates, akin to ethanol, function through at least two primary actions:

    • Action #1: Reduce the conductance (ionic movement) of Na+ ions.

    • Consequence: Prevents excitatory postsynaptic potentials (EPSPs) at the axon hillock, effectively inhibiting the “on” signal.

    • Action #2: Reduce Ca++ inflow at presynaptic membranes, which decreases neurotransmitter release.

    • Primary Action:

    • Barbiturates mimic GABA (γ-aminobutyric acid), acting as agonists:

      • Promote Cl- influx, hyperpolarizing neurons (inducing inhibitory postsynaptic potentials or IPSPs), making it harder to reach action potential thresholds at the axon hillock.

      • Specific examples, such as pentobarbital, effectively open Cl- channels independently, resulting in potent sedation (potentially toxic).

EFFECTS OF BARBITURATES

  • Induce global inhibition similar to the effects of ethanol:

    • May result in disinhibition, leading to transient euphoria and potential for abuse.

  • Pharmacodynamic Tolerance:

    • Can escalate the effective dose (ED50) by as much as 600%, indicating a higher risk of dependence and abstinence syndrome.

  • Mortality Data:

    • In the 1970s, estimates indicated 10 billion doses of BTS produced in the U.S.; not all were used medically.

    • Associated with approximately 1,500 deaths and 10,000 non-lethal overdoses annually during the '70s to '90s.

    • Cause of death often rooted in respiratory drive suppression, analogous to opiate overdoses (Telling comparison: 80,000 opiate deaths in 2023 and 178,000 ethanol deaths in 2021).

CONTRIBUTION OF PHARMACOKINETICS TO DEPENDENCE

  • It is commonly asserted that drugs with rapid onset and offset are typically more addictive:

    • Barbiturates, with variable onset speeds, serve as a test for this claim.

    • Pentobarbital: Ultrashort-acting, with a very brief half-life.

    • Barbital: Long-acting, longer half-life.

  • Experimental Result: Upon reversing their half-lives:

    • Pentobarbital: Changed from 5 hours to 27 hours.

    • Barbital: Changed from 30 hours to 7 hours.

  • Observations: Changes in withdrawal severity were noted, reinforcing the role of the half-life in addictive potential predictions.

QUIZ QUESTIONS ON BARBITURATES

  • Quiz Question 1: Barbiturate (BTS) abuse appears most associated with:

    • a. ultrafast acting BTS

    • b. more potent BTS

    • c. BTS with longer half-lives

    • d. BTS that operate on the GABA receptor

  • Quiz Question 2: Shortening the half-life of barbital results in:

    • a. reduced ED50

    • b. reduced LD50

    • c. reduced therapeutic margin

    • d. increased severity of withdrawal

NON-BARBITURATE SEDATIVES

  • Non-BT sedatives are seldom used today due to their replacement with safer drugs that have superior dose-response functions.

  • Example: Meprobamate (Miltown)

    • From 1955 to 1960, it gained popularity as an accessible sedative (nicknamed "mother’s little helper").

  • Historical Reference: Meprobamate was widely discussed in the following publication:

    • Ramchandani, D., López-Muñoz, F., & Alamo, C. (2006).

HISTORY OF METHAQUALONE

  • Methaqualone was discovered as an antimalarial drug with sedative and anxiolytic properties, approved initially as Schedule 5 (low potential for abuse) in 1965.

  • It was sold as Quaalude.

  • Evolving regulations: Moved to Schedule 2 in 1980 due to abuse potential, and ultimately to Schedule 1 in 1983.

  • Current status: Most Quaaludes available today are either foreign or contain alternative ingredients.

GENERAL ANESTHETICS

  • Example: Propofol (Diprovan)

    • Used for rapid onset general anesthesia and provides amnesiac effects via GABA site occupancy, inducing global inhibition and sedation.

  • Case Study: Michael Jackson's cause of death was attributed to propofol overdose in June 2009.

  • Administration caution: Administering 20 mg IV every 10 seconds until onset (1-1.5 mg/kg) is recommended, avoiding rapid bolus to mitigate risks of cardiorespiratory depression, hypotension, and airway obstruction.

    • Example Calculation: For a 110 kg patient:

    • Total dose: 165 mg

    • Timing: Administering 165 mg at a rate of 20 mg every 10 seconds takes approximately 82.5 seconds.

PHARMACOKINETIC PROPERTY OF PROPOFOL

  • Notes the timeline of effects:

    • Infusion → drug enters heart → circulation goes to lungs → back to the heart → to the brain → sedation begins.

KETAMINE AS A RECENT ANTIDEPRESSANT

  • November 2023 case: Matthew Perry's death during ketamine treatment for resistant anxiety and depression, with overdose exceeding his recognized effective dose (ED).

  • Mechanism of Action: Works as a noncompetitive antagonist at NMDA receptor complex, blocking Na+ channels and blocking voltage-sensitive K+ and Ca++ channels.

    • Reference: Schnoebel et al. (2005).

  • Recent Findings: Ketamine can effectively mitigate treatment-resistant depression (various studies presented).

    • Notably contradictory: Ketamine acts as a depressant yet increases AMPA receptor activity after NMDA blockade, yielding an arousal effect that alleviates depression.

  • Reference studies showing antidepressant effects:

    • Zarate et al. (2006), Berman et al. (2000), Liebrenz et al. (2007).

QUIZ QUESTION ON KETAMINE

  • Question 3: Ketamine’s antidepressant effect is due to:

    • a. blocked serotonin reuptake

    • b. excess release of GABA

    • c. pharmacodynamic changes in glutamate receptors

    • d. improved sleeping

ANTIEPILEPTIC MEDICATIONS

  • Epilepsy: Referring to a spectrum of neurological disorders, including absence and grand mal seizures.

  • Localized epilepsy involves two phases:

    • 1. Large synchronous depolarization, potentially “kindling” a seizure.

    • 2. Rebound hyperpolarization, rendering focal neurons unresponsive.

  • Mechanism suggested: GABA may hyperpolarize neurons, minimizing excitation and preventing massive depolarization.

    • Introduction of GABA deficit theory.

GABA DEFICIT THEORY EVIDENCE

  • Supporting data for the GABA deficit theory includes:

    • 1. Blocking GABA receptors increases seizure likelihood.

    • 2. Inhibiting GABA metabolism corresponds to seizure reduction.

    • 3. Enhancing GABA actions using various agents (BTS, BDZs, ethanol) mitigates seizures.

    • 4. Common antiepileptic medications like phenobarbital function as GABA agonists.

  • Other medications such as Valproic acid (Depakote) have speech variations in actions including:

    • Augmenting GABA synthesis.

    • Blocking sodium channels (phenytoin and carbamazepine).

    • Lamictal (Lamotrigine) performs similarly.

NEUROMODULATORS IN TREATMENT

  • Many antiepileptic medications fall under a newly recognized category called "neuromodulators," potentially employed for treating bipolar disorder as well.

QUIZ QUESTION ON EPILEPSY

  • Question 4: One major theory suggests seizures are due to:

    • a. excessive serotonin

    • b. excessive GABA

    • c. lack of glutamate

    • d. lack of GABA

ANTIEPILEPTIC MEDICATIONS AND TERATOGENICITY

  • Teratogenesis: Defined as birth defects induced by an external factor during pregnancy.

    • Common examples include ethanol, smoking (CO), and malnutrition.

  • Antiepileptic medications present a unique challenge.

    • Increased risk of birth defects in mothers using AEDs: approximately double compared to the general population.

    • Research indicates a two- to threefold risk of major malformations associated with AEDs, influenced by dosage and polytherapy.

  • Notable findings:

    • Lamotrigine emerged as a preferred AED during pregnancy, though it has been associated with an increased risk for cleft palate.

RESEARCH ON AEDs AND PREGNANCY OUTCOMES

  • Study (Mawer, G. et al., 2010):

    • Included 277 women with epilepsy (WWE) vs. 315 control women.

    • Results indicated:

    • 45% of WWE faced obstetric complications compared to 33% in controls (p = 0.01).

    • Normal vaginal delivery rates were comparable (63% WWE vs. 61% control).

    • Major congenital malformations (MCM) occurred more often in WWE (6.6%) versus controls (2.1%) (p = 0.02).

    • Fetal/infant deaths: WWE (2.2%) vs. controls (0.3%) (p = 0.09).

    • MCM prevalence highest with Valproate (11.3%).

    • Lamotrigine (5.4%) and Carbamazepine (3.0%) did not significantly differ from controls.

SPECIFIC FINDINGS ON LAMOTRIGINE

  • A subset of the study involving lamotrigine showed five cases of isolated cleft lip/palate arising from 564 women treated with lamotrigine alone, resulting in a prevalence of 8.9 per 1000 cases.

    • This prevalence is significantly higher than the controls but remains below 1%.

  • Important Note: Women on lamotrigine are advised to consult healthcare providers upon pregnancy considerations, weighing risks

    • Manufacturer’s statement: "Lamictal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."