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 (-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

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

ORDER of ALCOHOL affects are:

Limbic System (controls emotions) get angry, quiet, aggressive, withdrawn...

Cerebellum (co-ordinates muscles)get less control, eg. touching finger to nose, balance...

Hypothalmus (controls secretions of some hormones) increase sexual arousainhibits secretion of the anti-diuretic hormone, which increases urination.

Medulla (controls body functions like breathing) body temp falls, blood pressure falls, stop breathing!

Stomachirritates lining, so vomiting; increases stomach acid

Skinincreases blood flow to skin (flushing)

Musclesreduces blood flow (aches)

Other Effects of Alcohol:

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:

CH3CH2OH CH3CHO CH3CO2-

1 2

1

2

Alcohol dehydrogenase (cytochrome P450 type)NAD co-enzyme (forms NADH)

Aldehyde dehydrogenase (oxidation)

Excreted, fat build-up

Heavy drinkers build up more P-450 type enzymes:greater tolerance BUT ALSO get more fat depositionand 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:

NH

CHOHO

NH

CH2OHHO

NH

COOHHO

normalabnormal

NADNADH

serotonin aldehyde

nerve cell ends

CH3CHO can react with many amines; possibly responsible for hangovers

DISULFURAM [Antabuse] inhibits aldehyde dehydrogenaseleads 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 microspheresfor once monthly injections

Nalmefene is approved in US (mainly for heroin addicts)

O

N

HO

OH

O

O

N

HO

OHSS

NS

NS

Et

Et

Et

Et

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 FASin 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)

ONH2

NH2

+HOOC

HOOC

R1

R2

NH

NHO

O

O

R1

R2

Urea 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

- 2H2O

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 ‘Blue Birds’

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!

SHORT ACTING activation: 15 min duration: < 3 h

Pentobarbital (Nembutal) R1, R2 = Et, sec-pentyl

[Yellow Jackets, Goof Balls]

Secobarbital (Seconal) R1, R2 = allyl, sec-pentyl

[Red Devils, Red Birds]

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

N

NHS

ONa

O

Et

s-Pentyl

N

N

O

O

NaO

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 (-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

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)

1869 Chloral hydrate (Mickey Finn’s) CCl3CH(OH)2

from Cl2 and alcohol; movie knock out drops 1896-1903, Whisky rowin Chicago: ‘Lone Star house girls’ gave to their customers to sedatethem to remove cash!

MODERN ONES: many halogenated ethers

Desflurane HCF2-O-CF2CF2H irritating but short acting, BP up

Isoflurane HCF2-O-CHClCF3

Enflurane HCF2-O-CF2CHFCl

Sevoflurane CF3-CH(OCH2F)-CF3 easy to inhale

Methoxyflurane CH3-O-CF2CHCl2

Halothane CF3-CHBrCl 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

CH2OCOCH3

CH2NMe3+ -OH

CH2COOCH2CH2NMe3+

CH2COOCH2CH2NMe3+ 2Cl-

succinylcholine 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 CO2CH2CH2NHEt2+ -Cl

benzocaine procaine

Topical: Benzocaine: sunburn creams, sprays, throat lozenges, insect bites

para-aminobenzoic acid (ethyl ester) paba-(choline ester)

Since 1948 the more powerful amides have been used

Dental: Procaine (Novocaine) 350-600 mg (injection)

needs a vasoconstrictor (e.g. epinephrine ~ 1 in 105) otherwise too quickly absorbed away from injection site

NHCONHEt+ -Cl NHCON

lidocaine 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 PrO CO2CH2CH2NHEt2+ -Cl

H2Ntetracaine 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)

N

N

RO

Z

A

B

Y

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 -hydroxybutyric acid HOCH2CH2CH2COOH

also known as date rape drug recently

Ketamine (an approved Canadian anesthetic + vet) hashas appeared on streets (controlled substance!)

O

Cl

NH

Known as Special K,.....get ‘spaced out’, hallucinationslike ‘near death experiences’

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 -CH2 CH2OCONH-iPr

mepbromate 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 commonback-ache medication (skeletal muscle relaxant)

O

OH

O NH2

O

CH3O

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.