Transcript Psychopharmacology - Ohio State University

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.
Barbiturates
Steroids
GABA
Benzodiazepines
Ethanol
Picrotoxin
BARBITURATES.
1912 PHENOBARBITAL (LUMINAL) :FIRST USEFUL, NON-TOXIC
SEDATIVE AND ANTICONVULSANT. 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 INTERACTIONS
ORAL 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 OVERDOSE
ADEQUATE OXYGEN AND CARBON DIOXIDE
IF 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 INEFFECTIVE 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 --- COMA
ANTI-CHOLINERGIC SIDE-EFFECTS
INTERACTS WITH ALCOHOL
PARKINSON-LIKE TREMORS
TOLERANCE:
PHYSICAL AND PYSCHOLOGICAL
Barbiturates
Steroids
GABA
Benzodiazepines
Ethanol
Picrotoxin
BENZODIAZEPINES
ANOTHER 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 - 2005
LIBRIUM (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 PSYCHOPHARMACOLOGICAL
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 PEOPLE
MAJORITY 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
Barbiturates
Steroids
GABA
Benzodiazepines
Ethanol
Picrotoxin