GABA

Inhibition

GABA RECEPTOR DISTRIBUTION IN HUMAN BRAIN

Chloride ion flow inward is usually responsible for the generation of an IPSP

17.7 Dose-dependent effects of GABA on levels of consciousness

Increasing action of GABA at its receptor

Inhibitory transmission in the brain is largely mediated by the GABA-A receptor subtype

“anxiolytics” increase GABA-A receptor activity in the CNS

This potentiation of GABA produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects.

Picrotoxin

BenzodiazepinesGABA

SteroidsBarbiturates

Ethanol

BARBITURATES. 

1912 PHENOBARBITAL (LUMINAL) :FIRST USEFUL, NON‑TOXIC SEDATIVE AND ANTI CONVULSANT. THESE ACTIONS APPEARED TO BE BY INDEPENDENT ACTIONS.

DURATION WAS TOO LONG FOR SOME USES; PERFECT FOR OTHERS. E.G. THERAPY FOR EPILEPSY. STILL IN USE TODAY. 

Brand name for butabarbital.

"Mabel is unstable...it's 'that time' in her life. To see her through the menopause, there's gentle 'daytime sedation' in Butisol Sodium."

When little patients balk at scary, disquieting examinations...When they need prompt sedation (and the oral route isn't feasible)...try Nembutal sodium suppositories...There is little tendency toward morning-after hangover."

PENTOBARBITAL (NEMBUTAL) AND SECOBARBITAL (SECONAL) HAD SHORTER DURATION AND SHORTER LATENCY OF ACTION.

THIOPENTAL (PENTOTHAL). ANESTHESIA IN SECONDS. LATENCY: ULTRA‑SHORT; DURATION: SHORT. 5 MIN.

ONSET AND DURATION ARE DETERMINED BY LIPID SOLUBILITY, RATES OF IONIZATION, PLASMA PROTEIN BINDING, METABOLISM AND EXCRETION RATES. 

MOST IMPORTANT FOR THESE IS LIPID SOLUBILITY. 

17.8 Chemical structure of the barbiturates (Part 2)

AUGMENTS CL- ION FLOW BY KEEPING GABA CHANNELS OPEN LONGER.

EFFECTS OF BARBS DIFFER IN DIFFERENT BRAIN REGIONS.

RESULT: EXCITATORY SYNAPTIC EVENTS ARE SUPPRESSED; INHIBITORY EVENTS ARE ENHANCED.

RETICULAR ACTIVATING SYSTEM FUNCTIONS PRIMARILY BY EXCITATION; THEREFORE, IT IS AFFECTED FIRST AND MOST COMPLETELY, ALONG WITH THE THALAMUS.

EFFECTS ON BEHAVIOR. FOR MOST BEHAVIORS: INVERTED DOSE‑RESPONSE CURVE. LOW DOSES INCREASE ACTIVITY; HIGH DOSES DECREASE BEHAVIORAL ACITIVITY. SIMILAR TO ALCOHOL.

LAW OF INITIAL VALUE APPLIES HERE. IF YOU EXPECT TO SLEEP, YOU SLEEP; IF YOU EXPECT TO BE AWAKE AND ALERT AND HAVE A GOOD TIME - YOU WILL.

ACUTE ADMINISTRATION: ATAXIA, DYSARTHRIA (DIFFICULTY IN SPEAKING), DROWSINESS, LATERAL NYSTAGMUS, HYPOREFLEXIA, PUPILARY CONSTRICTION, EMOTIONAL LABILITY ‑ GARRULOUS, COMBATIVE.

PHYSIOLOGICAL EFFECTS: BLOOD SUGAR LEVELS DECREASE, METABOLIC RATE DOES NOT CHANGE.

METABOLISM BY LIVER, EXCRETED BY KIDNEYS

TOLERANCE AND WITHDRAWAL.TOLERANCE DEVELOPS GRADUALLY.PHYSICAL AND PSYCHOLOGICAL TOLERANCE.

WITHDRAWAL AFTER PROLONGED USED IS SERIOUS MEDICAL PROBLEM.

SIMILAR TO ALCOHOL WITHDRAWAL.

ANXIETY, WEAKNESS, NAUSEA, DISORIENTATION, HALLUCINATIONS, CONVULSIONS, OCCASIONALLY DEATH (5%), INSOMNIA, MYOCLONUS (CLONIC CONSTRICTION OF MUSCLES), TACHYCARDIA, NIGTHMARES, SWEATING.ALCOHOL CAN PREVENT WITHDRAWAL EFFECTS OF BARBITURATES. SHOWS COMMONALITY OF ACTIONS.

Cortical desynchonization increases with the progression from Stage 1 to 4. Progressive REM stages become longer

as SWS becomes lighter.

Enhancement of Stage 2; loss of deeper stages

Drug-induced sleep is abnormal

DRUGS INTERACTIONSORAL ANTICOAGULANTS; CORTICOSTEROIDS; ESTRADIOL; ORAL CONTRACEPTIVES (LEADS TO REDUCED ACTIVITY OF OCS); DIGITOXIN. BARBATURATES INCREASE METABOLISM OF THESE AGENTS BY ACTIVATING THE P450 SYSTEMS IN LIVER.

BENEFICIAL EFFECTS.FEWER CALORIES THAN ALCOHOL. SLEEPING PILLS. 100 ‑ 200 MG BEFORE BED. BARBITURATE HANGOVER.

THE DRUG OF CHOICE FOR THOSE COMMITTING SUICIDE. 5000/YR.

ABUSE:EVERYONE ABUSES THEM, NO GENERATION GAP.

OVERDOSE DEPRESSION, COMA, RESPIRATORY ARREST, PYREXIA, HYPOTENSION

TREATMENT OF OVERDOSEADEQUATE OXYGEN AND CARBON DIOXIDEIF AWAKE ‑ GIVE IPECAC (FROM PSYCHOTRIA IPECACUANHA)

NO STIMULANTS!!! - THEY WOULD OVERTAX THE RESPIRATORY SYSTEM AND HEART.

REPLACED BY…METHAQUALONE. 

FIRST SYNTHESIZED AND TESTED IN INDIA. FOUND TO BE IN EFFECTIVE AS ANTIMALARIA DRUG.  GOOD SEDATIVE.INTRODUCED INTO GREAT BRITAIN IN 1959. THALIDOMIDE DISASTER INCREASED NEED FOR SAFE NON‑BARBITURATE. ANSWER:...MANDRAX: 250 MG OF METHAQUALONE AND 25 MG OF ANTI‑HISTAMINE.1965 ‑ MASSIVE SALES CAMPAIGN BEGAN. 2 MILLION PRESCRIPTIONS. 1971.BECAME MAJOR DRUG OF ABUSE IN 1968‑71, ESPECIALLY BY HERION USERS. IN 1965 QUAALUDE AND SOPORS INTRODUCED AS PRESCRIPTION DRUG: PACKAGE INSERT STATED "ADDICTION POTENTIAL NOT ESTABLISHED."NO ONE PAID ATTENTION TO FACT THAT 44% OF DRUG OVERDOSES IN THESE YEARS WERE RELATED TO METHAQUALONE!FINALLY, 8 YRS AFTER BEING INTRODUCED INTO US; 4 YRS AFTER AMERICAN SCIENTISTS SAID IT WAS DANGEROUS AND ADDICTING;

ADDICTION CAN DEVELOP AS FAST FOR METHAQUALONE AS FOR BARBITURATE.

SAME SYMPTOMS: ONE DIFFERENCE, LOSS OF MOTOR COORDINATION, ESPECIALLY WALKING.  SLANG TERM FOR IT WAS "WALLBANGER.“

ACUTE ADMINISTRATION: "SENSUAL" EUPHORIA; RELAXATION; DISHINHIBITION; DROWSINESS; ATAXIA; DYSARTHRIA; PERIPHERAL ANESTHESIA; PARESTHESIAS.

OVERDOSE: DEPRESSION OF CONSCIOUSNESS ‑‑‑ COMAANTI‑CHOLINERGIC SIDE‑EFFECTSINTERACTS WITH ALCOHOLPARKINSON‑LIKE TREMORSTOLERANCE: PHYSICAL AND PYSCHOLOGICAL

Picrotoxin

Benzodiazepines

GABA

SteroidsBarbiturates

Ethanol

BENZODIAZEPINESANOTHER CLASS OF ANTIANXIETY AGENTS

ONCE CALLED MINOR TRANQUILIZERS.

THE FIRST BDZ WAS CHLORDIAZEPOXIDE. SYNTHESIZED IN 1947; USE DISCOVERED IN 1957 DURING LAB CLEANING; SOLD COMMERCIALLY IN 1960.

DR. LEO STERNBACH ‑ POLISH IMMIGRANT, INVENTOR, USING MICE AND CATS. DIED - 2005LIBRIUM (EQUILIBRIUM). 

DIAZEPAM (VALIUM: LATIN FOR "BE STRONG AND WELL"), WAS THE MOST PRESCRIBED DRUG IN THE WESTERN WORLD. (1975) 88 MILLION PRESCRIPTIONS WERE WRITTEN THAT YEAR.NOW USED BY 8 TO 9 MILLION AMERICANS. (61 MILLION PRESCRIPTIONS) THE FOURTH MOST PRESCRIBED DRUG.

Molecular structure of several benzodiazepines

Benzodiazepine metabolism

THERAPEUTIC USES:

INSOMNIA (VIA ACTIONS AS MUSCLE RELAXANT); ANTI‑CONVULSANTS (VIA ACTIONS ON CORTEX, HIPPO, AMYGDALA); MUSCLE RELAXANTS (VIA ACTIONS ON RAS); APPETITE STIMULATORS (VIA ACTIONS ON VENTRAL HYPOTHALAMUS)

DEATHS RELATED TO PSYCHOTROPIC DRUGS: BDZ ACCOUNT FOR 68% OF PSYCHO PHARMACOLOGICAL THERAPIES, YET ONLY 19% DRUG RELATED DEATHS.

RISK OF TAKING DRUG MUST BE COMPARED WITH RISK OF NOT TAKING THE DRUG.MINIMAL SIDE EFFECTS IN COMPARISON TO OTHER DRUGS.

PLACEBOS CAN BE GIVEN AFTER BDZ HAVE HAD SOME EFFECT. 

IF PATIENT DOESN'T SHOW POSITIVE EFFECTS IN 2 WEEKS, LONGER TREATMENT WILL NOT HELP. 

ANOTHER CRITICISM OF THEIR USE: (BRITISH SCIENTIST) "IF MAN TAKES TRANQUILLIZERS IN ORDER TO WITHDRAW FROM UNIVERSAL DIFFICULTIES WHICH MAN IS BORN TO COPE WITH, THIS UNDERMINES SOCIAL CHARACTER."

WITHDRAWAL. ABRUPT WITHDRAWAL MAY RESULT IN SEIZURES (UP TO 12 DAYS LATER) EVEN WITH TAPERING DOSE, PATIENT MAY EXPERIENCE CONSIDERABLE DISCOMFORT. LASTING 2 ‑ 3 WKS. E.G., GI DISTRESS, TREMORS, LETHARGY, DIZZINESS, RESTLESSNESS, TINNITUS, ODD SMELLS.

REBOUND EFFECTS ARE INSOMNIA AND ANXIETY!

SIDE EFFECTS. 1) MAJOR: DROWSINESS.2) IMPAIRMENT OF TRACKING EYE-MOVEMENTS. (SIMILAR TO ALCOHOL)WITH NORMAL DOSE, FOR 3.5 HRS AFTER TAKING DRUG, LARGE CHANGES IN LANE-TRACKING ABILITY AND SMALLER CHANGES IN LANE-CHANGING AND STOPPING ABILITY. THERE IS 45% INCREASE IN DRIVING ACCIDENT RISK WHEN ELDERLY TAKE THIS DRUG.

OVERDOSE: DECREASING LEVEL OF CONSCIOUSNESS, DEPRESSED RESPIRATION, ATAXIA, VERTIGO, DYSARTHRIA, DELIRIUM, HYPOREFLEXIA (I.E. DEPRESSED CNS).

THE BDZS ARE THE NO 1 REASON THAT PEOPLE GO TO EMERGENCY ROOMS IN THE U.S. FOR DRUG ABUSE PROBLEMS.

THIS IS AHEAD OF COCAINE AND HEROIN!

MECHANISM OF ACTION

SIGNIFICANT EFFECTS ON LIMBIC STRUCTURES ASSOCIATED WITH EMOTION AND AGGRESSION.  EEG EFFECTS ON CORTEX SIMILAR TO STIMULATION OF RAS.

BDZS EXERT THEIR EFFECTS ONLY IN PRESENCE OF GABA DURING ACTIVITY OF GABAERGIC NEURONS.

BDZ HIGH AFFINITY RECEPTOR SITES IN CNS.  HIGHEST CONC. IN CORTEX, HIPPO, AND CEREBELLUM AND THROUGHOUT THE LIMBIC SYSTEM (WHICH IS OF COURSE INVOLVED IN EMOTIONAL RESPONSES).

PRESENT PRIOR TO BIRTH OR APPEAR SOON AFTER BIRTH.

ALL SITES ARE IN CNS. ABSENT PERIPHERALLY. E.G. AMYGDALA IS RICH IN GABA AND BDZ SITES.

BDZS ARE NEUROMODULATORS ONLY ON GABA RECEPTORS

ENHANCEMENT OF GABA‑MEDIATED PRE‑ AND POST‑SYNAPTIC INHIBITION IN SPINAL CORD, CEREBELLUM, CAUDATE, AND NEOCORTEX.

BDZ ARE NOT AGONISTS AT RECEPTOR SITE, RATHER THEY ENHANCE BINDING OF GABA TO THE GABA-A RECEPTOR SITE. BDZ INCREASES THE FREQUENCY OF Cl- CHANNEL OPENING IN RESPONSE TO GABA.

TOLERANCE ASSOCIATED WITH INCREASED NUMBER OF BDZ RECEPTORS.THERE IS A SIMILAR INCREASE IN BDZ RECEPTORS IN FETUS OF MOTHER WHO USES BDZ.

TOLERANCE DEVELOPS TO SOME EFFECTS, BUT NOT TO ANXIOLYTIC EFFECTS IN MOST PATIENTS.

CROSS-TOLERANCE TO ALCOHOL AND BARBITURATES.

BDZS CAN BE USED IN MANAGEMENT OF ALCOHOL WITHDRAWAL.

16‑18% EUROPEANS AND 13% OF AMERICANS HAVE USED BDZ IN PAST YR.6% USED 1 YR OR MORE.1/3 OF ALL THOSE THAT TAKE THEM ARE CHRONIC USERS.USE OF TRANQUILIZERS INCREASE WITH AGE. 12 PRESCRIPTIONS PER 1000 MALES AGED 10 - 19 YR. 18 " " 1000 FEMALES, " " 358 " " 1000 MALES AGED 60 AND OLDER. 672 " " 1000 FEMALES 60 AND OLDER.

PRIMARY USER: OLD PEOPLEMAJORITY OF USERS ARE WOMEN, PRESCRIBED TO TWICE AS OFTEN! BUT...

MOST LONG TERM USERS ARE MALES!55% ARE COLLEGE EDUCATED.87% HAVE FAMILY MEMBERS WITH PSYCHOLOGICAL PROBLEMS.

IN HIPPOCAMPUS:

BDZ ACT AS AMNESICS. MAY BE RELATED TO SLEEP‑INDUCED AMNESIA AND NOT A DIRECT ACTION OF THE DRUGS.BDZ ACTION ON GABA SITES ALSO INHIBITS CA++ CHANNELS.

PRESENCE OF RECEPTORS SUGGEST THAT THERE IS AN ENDOGENOUS AGENT THAT INTERACTS WITH THESE RECEPTORS

BETA-CARBOLINES

SOME BETA-CARBOLINES ANTAGONIZE GABA FUNCTION, OTHERS ENHANCE IT.

RECENT EVIDENCE INDICATES THAT THE CARBOLINES ACT AT THE GABA SITE; NOT AT THE BDZ SITE.

BDZ FUNCTION: IN HIPPOCAMPUS, BDZ RECEPTORS MAINTAIN ANTI‑CONVULSANT STATE, THAT BDZ ANTAGONISTS DISTURB TO CAUSE SEIZURES.

IT IS NOW THOUGHT THAT ANXIETY MAY BE RELATED TO A DISORDER OF GABA RECEPTOR SITES.

17.19 PET scans of a control subject (left panel) and a patient with panic disorder (right panel)

Benzodiazepines (next generation) and Barbs are used to treating insomnia

Picrotoxin

BenzodiazepinesGABA

SteroidsBarbiturates

Ethanol