Download 4 Depressants

ALCOHOL #1 DRUG
CH3CH2OH ethanol
Average BC use is 8.8L of pure (100%) alcohol per
person per year in 2007!!
(equiv to 0.5L per day of beer)
Alcohol is absorbed quickly:
58% in 30 min; 93% in 90 min
BUT LIVER CAN ONLY
OXIDIZE ALCOHOL
at ~ 15g (½ ounce) per hour
1 Beer = 360 mL x 5% (EtOH) = 18 mL ~ ½ oz.
(1 shot of spirits ~ same)
so drinking faster than 1 beer or 1 shot per hour leads to
accumulation of alcohol in blood.
“0.08" = 80 mg alcohol per 100 mL blood
A 70kg person reaches ‘.08’ with 3 beers and then
eliminates about 1 beer per hour
i.e. 5 beers over 2 h will keep you at .08
BUT it depend on weight, metabolism, amount of fat, etc.
Alcohol dissipates throughout all tissues so heavier
people can drink more but remain under limit
NOTE THIS SAYS NOTHING ABOUT WHETHER
YOU ARE IMPAIRED OR NOT!!!!
Alcohol has a double action: between 0.01 and 0.05%
inhibitions are removed, makes us happy but
above this it is a CNS depressant
0.05% start to get clumsy, slow reaction times, risk taking
0.1% most are visibly drunk
>0.2% most blackout
>0.3% for most is coma (5-10h), then maybe death
Tolerance develops so levels rise in experienced drinkers
The lethal dose is about 700g for most
( i.e. about 1.5L of scotch straight down)
ACTION
1
Stimulates acid production
2
Causes dilation of periphery blood vessels of
skin - warm feeling, hot flushes, red face
not good to give to hypothermia/drowning
victims
3
Diuretic - stimulates urine production
4
Depresses sexual ‘performance’ in males
ALCOHOL, THE BRAIN, DOPAMINE AND GABA
GABA (g-aminobutyric acid): INHIBITORY neurotransmitter
Dopamine: the main EXCITORY neurotransmitter
When GABA is high, dopamine levels are low (balanced)
Release of dopamine causes powerful excitation of the brain.
Amphetamines, cocaine, nicotine and heroin all increase dopamine
levels (not all by the same mechanism, for example cocaine
inhibits the re-uptake that normally occurs after the message has
been sent).
Vigabatrin (see Section 3) inhibits the enzyme that breaks
GABA down, increasing GABA levels, which forces down
dopamine levels
ALCOHOL also appears to enhance the effect of GABA:
‘makes things sluggish’
ALCOHOL appears to weaken the effects of glutamine,
another excitory neurotransmitter, presumably by
occupying the receptors
ORDER of ALCOHOL affects are:
Cerebral Cortex (processes thoughts)
Alcohol depresses the behavioural inhibitory centers:
become more talkative, self confident, less socially inhibited
Slows information processing: see, think, hear less clearly
Limbic System (controls emotions)
get angry, quiet, aggressive, withdrawn...
Cerebellum (co-ordinates muscles)
get less control, eg. touching finger to nose, balance...
Other Effects of Alcohol:
Hypothalmus (controls secretions of some hormones)
increase sexual arousa
inhibits secretion of the anti-diuretic hormone,
which increases urination.
Medulla (controls body functions like breathing)
body temp falls, blood pressure falls, stop breathing!
Stomach
irritates lining, so vomiting; increases stomach acid
Skin
increases blood flow to skin (flushing)
Muscles
reduces blood flow (aches)
Abuse: increases liver enzymes
must drink more to feel the same effect
nerve activity increases to compensate, but when not drinking
causes irritability and delirium
Get liver cell death, hardening of tissues: cirrhosis
Get stomach ulcers
Get higher blood pressure
heart compensates for initial lowering
GETTING RID OF ALCOHOL
Kidneys eliminate ~5% in urine
Lungs eliminate ~5% in breath (BREATHALYSER)
Liver oxidizes most:
1
CH3CH2OH
2
CH3CHO
CH3CO2Excreted, fat build-up
1
Alcohol dehydrogenase (cytochrome P450 type)
NAD co-enzyme (forms NADH)
2
Aldehyde dehydrogenase (oxidation)
Heavy drinkers build up more P-450 type enzymes:
greater tolerance BUT ALSO get more fat deposition
and scarring of the liver (CIRRHOSIS)
Apr 2001 study reports men increase alcohol
dehydrogenase 2x faster than women: greater liver
damage
Building up too much NADH also starts non-normal
biochemical pathways:
CH2OH
HO
abnormal HO
NH
NADH
COOH
CHO
normal
NH
HO
NAD
serotonin aldehyde
nerve cell ends
CH3CHO can react with many amines;
possibly responsible for hangovers
NH
DISULFURAM [Antabuse] inhibits aldehyde dehydrogenase
leads to acetaldehyde buildup; if you drink you vomit,
get headaches, chest pains....(effective but not a lot of fun!)
Oral naltrexone [Revia, 1994]: reduce drink cravings
Vivitrol is naltrexone embedded in polymer microspheres
for once monthly injections
Nalmefene is approved in US (mainly for heroin addicts)
HO
HO
Et
S
N
Et
Et
S S
O
N
S
O
OH
N
Et
OH
N
O
Disulfuram
Naltrexone
Nalmefene
FETAL ALCOHOL SYNDROME
1972- U. Washington
Alcohol crosses placenta, but baby lacks liver enzymes,
so levels in baby stay ~ 2x those in mother
ALCOHOL is a TERATOGEN
-affects development of fetus
-DAYS 18-50 CRITICAL
small heads
joint-limb abnormalities
heart-genital defects
Symptoms:
upper lip vertical groove
absent
upper lip thin
nose short flattened
brief attention spans
mental retardation
hyperactivity
~4000 children born per year with FAS
in Canada (ca. 1 per 1000 live births)
Depressants (downers)
Sleeping Pills - Barbiturates
Bayer first made barbituric acid in Germany in 1864 from
urea and malonic acid (apples)
O
HOOC
NH2
+
O
NH2
Urea
HOOC
R1
R2
- 2H2O
NH
R1
NH
R2
O
O
R1 = R2 = H
Barbituric acid
Malonic acid
no acid group!
Barbituric acid itself is not active, but use of substituted
malonic acids does give active ones
Divided by length of action:
LONG ACTING
activation: 30-60 min duration: 6-12 h
Phenobarbital (LUMINAL)
R1, R2 = Et, Ph
[1912 anti convulsant for epileptics]
INTERMEDIATE activation: 30 min
duration: 3-6 h
Amobarbital (AMYTAL)
R1, R2 = Et, i-pentyl
Butabarbital
R1, R2 = Et, sec-butyl
Talbutal
R1, R2 = allyl, sec-butyl
Barbital (VERONAL)
R1, R2 = Et, Et
[used to put euthanize dogs since 1903]
2001: Kodiak, Alaska
Eagles stagger ‘drunk’: had eaten cats from
local dump – vets had euthanized cats with
barbiturates but had not cremated or buried!
‘Blue Birds’
SHORT ACTING
activation: 15 min duration: < 3 h
Pentobarbital (Nembutal)
[Yellow Jackets, Goof Balls]
R1, R2 = Et, sec-pentyl
Secobarbital (Seconal)
[Red Devils, Red Birds]
R1, R2 = allyl, sec-pentyl
ULTRA-SHORT activation: < 10 sec
duration: < 30 min
Thiopental (PENTOTHAL)
Na+ salt increases solubility
Used as a quick knockout before an operation in tandem
with a longer lasting anaesthetic
O
ONa
N
N
Et
NaO
S
s-Pentyl
NH
N
O
O
Thiopental
Methohexital
Methohexital (BREVITAL):
<7 secs
~ 7 mins
recovery more rapid than pentothal, dose 1mg/kg
ACTION (next slide)
Barbiturates (and valium) ENHANCE the action of GABA
(g-aminobutyric acid) in suppressing dopamine (the brain
activator)
All excitable nervous tissue is depressed, BUT CNS is
especially affected
THUS respiratory depression (controlled by brain) is the
OVERDOSE mechanism
NO blood-brain barrier, so short acting are the most
dangerous.
About 1000 accidental + 3000 suicides per year in US
The diazepams bind close to the GABA receptor and
increase the affinity of GABA for its receptors,
which diminishes the excitation of nerves;
it also alters rate of peptide formation in neurons,
which induces amnesia. This is potentiated by alcohol.
ANTIDOTES: need a stimulant
eg. ephedrine
Remain in blood stream for > 24 h (driving)
Body develops tolerance - same enzymes as alcohol
Doses > 400mg per day cause severe withdrawal:
irritability, insomnia, convulsions, delirium
ANESTHETICS
Act on brain to produce unconsciousness
and insensitivity to pain
Pre-1860 Alcohol
1846 Diethyl Ether (CH3CH2)2O
Morton, a Boston dentist, safe because of large gap between
effective and toxic dose, BUT EXPLOSIVE with air, flammable and
causes nausea
1847 Chloroform CHCl3
Non-flammable, but much smaller safety gap - hard on liver; Queen
Victoria used it in childbirth
1869 Chloral hydrate (Mickey Finn’s) CCl3CH(OH)2
from Cl2 and alcohol; movie knock out drops 1896-1903, Whisky row
in Chicago: ‘Lone Star house girls’ gave to their customers to sedate
them to remove cash!
1880 Laughing gas N2O
(use 1:1 with O2;
brain damage with air!)
Still in wide use, non-toxic, no odor
(food aerosol cans – fat soluble)
- some giddiness/exhilaration
1934 Cyclopropane
very potent, but very flammable, not
used now (1964 explosion killed 6)
MODERN ONES: many halogenated ethers
Desflurane
HCF2-O-CF2CF2H
Isoflurane
HCF2-O-CHClCF3
Enflurane
HCF2-O-CF2CHFCl
Sevoflurane
CF3-CH(OCH2F)-CF3
Methoxyflurane
CH3-O-CF2CHCl2
Halothane
CF3-CHBrCl
irritating but short acting, BP up
easy to inhale
easy to inhale, BP down
They have different MAC
Minimum Alveolar Concentrations: conc. at which 50%
of humans cease to feel pain
eg. Desflurane (Suprane) = 6% in 100% O2
Typical anesthetic sequence:
Prior to injection: muscle relaxant like succinylcholine to
partially block the acetylcholine sites - allows less
anesthetic to be used and no muscle spasms
CH2COOCH2CH2NMe3+
CH2NMe3+ -OH
2Cl-
CH2COOCH2CH2NMe3+
succinylcholine
CH2OCOCH3
acetylcholine
sometimes also a tranquilizer (valium)
and an injection of atropine to dry up secretions
Anesthetic administered:
Quick knockout: pentothal (sometimes fentanyl)
Keep patient out: 3% isoflurane in 50-70% N2O - rest O2
ACTION
stops acetylcholine from working: saturates nerve
endings, maybe involving a shape change
RECOVERY
slow by diffusion of the agent out via breathing
usually sick for several hours; take two days to fully
eject
LOCAL ANESTHETICS
1860 Cocaine ( but name applies to family)
PABA esters
H2N
CO2Et
H2N
benzocaine
para-aminobenzoic acid (ethyl ester)
CO2CH2CH2NHEt2+ -Cl
procaine
paba-(choline ester)
Topical: Benzocaine: sunburn creams, sprays,
throat lozenges, insect bites
Dental: Procaine (Novocaine) 350-600 mg (injection)
needs a vasoconstrictor (e.g. epinephrine ~ 1 in 105)
otherwise too quickly absorbed away from injection site
Since 1948 the more powerful amides have been used
N
NHCONHEt+ -Cl
lidocaine
NHCO
mepivacaine
Lidocaine [Abbott]; Xylocaine [Astra] (120-200 mg)
amides hydrolyze more slowly than esters: don’t need
vasoconstrictor
Mepivacaine (Carbocaine, Isocaine) 400mg (once only)
can block whole jaw for 20-40 mins
Speciality:
BuNH
CO2CH2CH2NHMe2+ -Cl
tetracaine
PrO
H2N
CO2CH2CH2NHEt2+ -Cl
proparacaine
Tetracaine (Pontocaine)
5-20mg as spinal anesthetic, lasts 2-3 h
Proparacaine (Opthaine) for ophthalmic use
These all appear to alter the membranes of the nerve cells,
stopping Na+ passage, stopping the impulses.
TRANQUILIZERS
BENZODIAZEPINES (Valium types)
R
N
O
Y
Z
N
A
B
Name
R
Z
Y
A
B
Diazepam (Valium)
CH3
Cl
H
H
H
Lorazepam
H
Cl
OH
Cl
H
Flurazepam
-CH2CH2NEt2
Cl
H
H
F
Flunitrazepam
CH3
NO2
H
F
H
VALIUM = diazepam: oral dose 2-30mg
5mg valium = ‘0.08’ blood alcohol in terms of driving
Injection for minor surgery: no feeling or memory
Generic lorazepam (ATIVAN) most popular (2, 5, 10 mg)
Flunitrazepam = ROHYPNOL ‘ the date rape drug’
available in Europe, Mexico, S. America for insomnia
- now made BLUE
With alcohol: unconscious in ~30 mins, lasts ~ 12h, no
memory of incident
NOTE: GHB g-hydroxybutyric acid HOCH2CH2CH2COOH
also known as date rape drug recently
Ketamine (an approved Canadian anesthetic + vet) has
has appeared on streets (controlled substance!)
Cl
O
Known as Special K,.....
get ‘spaced out’, hallucinations
like ‘near death experiences’
NH
liquid (iv, smoked,...) crystals (.HCl salt) inj, snorted,...
Benzodiazapine receptors directly located in brain and
do not affect other tissues (see slide 20 of this section
for mechanism: Half-lives in body of 1-3 days!
Withdrawal symptoms can persist for 3-4 weeks(!):
anxiety, restlessness, bizarre dreams
Side effect: some patients get orgasms
- prompts complaints of fondling, etc.
Safer than the barbiturates: more difficult to overdose
CARBAMATES H2N-CO-OR
R=
-CH2
CH2OCONH2
mepbromate
-CH2
CH2OCONH-iPr
soma
Mepbromate (Equanil, Miltown) 400mg
Soma 350 mg
Both are also used as muscle relaxants, eg. in back pills
act more like barbiturates as sleeping pills, but depress
respiratory center less, so suicide or overdose less likely
ROBAXIN (methocarbamol)
500/750 mg most common
back-ache medication
CH3O
(skeletal muscle relaxant)
O
O
O
NH2
OH
Often sold in combination, egs.
Robaxacet = methocarbamol + acetaminophen
Robaxisal = methocarbamol + ASA
Robaxisal-C = methocarbamol + ASA + codeine
Seem particularly safe: adults have been known to
consume 30-50 g/day (!!) with no serious effects.