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1

Statistics of Alcohol

17 million people DEPENDENT

Alcohol is responsible for 100,000 deaths a year!

2

Alcohol Content and Proof

14 g ethanol = 1 drink

Percentage of beverage that is that 14 grams = alcohol content

4-6% = beers
10-15% = wine
> 40% = liquor

PROOF is twice this number

8-12 = beer, 20-30 = wine, 80+ proof

3

BAC

Determined with breathalyzer - analyzes the percentage of ethanol in the blood

Alcohol in the alveolar capillary blood will equilibrate with the alcohol in the air of the alveolar sac

Assuming a constant blood:breath ratio (partition coefficient) of 2000:1, where every 2000 ml of blood contains the same alcohol in 1 mL of breath, ethanol will react with the machine contents

It then extrapolates the content in the blood based on the content of the expired air

Legal limit is 0.08 g/dL or 17 mM

BUT, everybody has slightly different partition coefficients

4

Gender and Alcohol

Women who weights 70 kg drinks exact same amount as a man who weighs 70 kg, but will have a HIGHER BAC than the man!

Why?

There is less gastric metabolism in women than in men --> lower concentration of alcohol dehydrogenase!!

Lower total body water content - same amount of alcohol in a woman will be at a higher concentration than in men because it is dissolved in a smaller pool!!!!

5

Metabolism of Alcohol

Readily absorbed from the SMALL INTESTINE, though some is absorbed in the gastric mucosa

On an EMPTY STOMACH, peak absorption takes place 30 minutes AFTER ingestion (food slows gastric emptying and gives alcohol slower release into the duodenum, so it is more GRADUALLY ABSORBED IN THE BLOODSTREAM

As alcohol is absorbed, it experience FIRST PASS METABOLISM by ALCOHOL DEHYDROGENASE which slowly (RATE LIMITING) turns alcohol to ALDEHYDE

Aldehyde is therm RAPIDLY METABOLIZED to acetate by aldehyde dehydrogenase and goes into the circulation as such

1 drink (14 g ethanol) will be completely metabolized in 1 hour (1 drink out of system in an hour)

Number of things like ASPIRIN will affect alcohol dehydrogenase

6

Alcohol displays ZERO ORDER KINETICS

Metabolism requires the reduction of NAD+ to NADH, limiting the amount of NAD+ in hepatocytes

Limited NAD+ allows the alcohol dehydrogenase mediated metabolism to be QUICKLY SATURATED and this usually occurs at concentrations lower than what the BAC will be even on 1 drink!!!

So, alcohol metabolism is completely dependent on BAC and holds constant with time --> 8 g/hr in a 70 kg person and thus alcohol displays ZERO ORDER KINETICS

7

Effects of Alcohol

It is obviously a DEPRESSANT and acts in a similar fashion to BENZOS!

Anti-anxiety properties at low concentrations with sedation and even DEATH at very high concentrations --> do not mix with barbiturates/benzos or other sedatives!

Immediate disinhibition effects are because the FRONTAL LOBES ARE VERY SENSITIVE TO ALCOHOL --> in chronic alcoholics, there is a decrease in brain glucose metabolism, and an overall SHRINKAGE of gray and white matter with compensatory ventricular enlargement!!!!

Several effects based on the amount of alcohol ingested (normal ingestion; chronic alcoholics will have enzyme systems induced and will be able to metabolize more than the average person)

Primary activity is GABAergic enhancement --> sleepiness, muscle relaxation and other symptoms similar to benzos

Alcohol can ENHANCE and INHIBIT nicotinic cholinergic receptors, and INHIBIT excitatory glutamate receptors! NMDA (glut) receptors INCREASE during chronic alcohol use to attempt to further sensitize the cells to glutamate

8

Positive Effects of alcohol?

CARDIOPROTECTIVE!

Protects for coronary heart disease (20-30g/day)

Good at low amounts, but when things get crazy there are BAD CV effects!!! Arrhythmias, cardiomyopathies, hemorrhagic stroke!

Alcohol seems to INCREASE HDL CHOLESTEROL --> reduces atherosclerosis and risk for MI!

Alcohol ALSO REDUCES THE AMOUNT OF BLOOD CLOTTING by increasing tPA, decreasing fibrinogen and inhibiting platelet aggregation (again reduces risk for MI)

FLAVINOIDS in red wine are best (darker the better) --> have an ADDITIONAL anti-atherogenic role! Prevent the oxidation of LDLs and their uptake into macrophages!!! This is critical to forming unstable plaques (foam cells) so this is PREVENTED with FLAVINOIDS

Also inhibits endothelin-1 synthesis, which is a vasoconstrictor!

9

NEGATIVE CV EFFECTS

Heavy use increases BP --> HTN

Alcohol can cause ARRHYTHMIAS because it is associated with prolongation of the QT interval (Torsades!!)

Alcohol can also STIMULATE THE SNS and should be considered as a cause of arrhythmias resistant to cardioversion, digitalis or calcium channel blockers

Can DEPRESS CONTRACTILITY just by direct tissue toxicity and thus cause cardiomyopathy! --> 50% of cardiomyopathy patients are alcohol dependent!!!!! They better stop or they die within a few years!

People who drink 40-60 g per day (3+ drinks) will have a higher incidence of hemorrhagic and ischemic stroke! Usually due to HTN or the arrhythmia risk

Low Mg2+ predisposes to stroke, and alcoholics have less Mg2+

Also HEAD TRAUMA from being drunk and falling!!!

10

Negative blood vessel effects

Decreased hematopoiesis, anemia (secondary to folic acid depletion), reversible thrombocytopenia, suppression of lymphocytes/granulocytosis

11

Other Negative effects 1 -- musculoskeletal, body temp, renal

Musculoskeletal!!! Heavy alcohol consumption can lead to IRREVERSIBLE muscle damage; also, with liver damage seen in alcoholics, vitamin D hydroxylation is INTERRUPTED and can result in WEAKER Ca2+ regulation and osteoporosis

Temperature --> increases cutaneous and gastric blood flow that results in a LOSS OF BODY HEAT --> long term use can compromise the hypothalamic regulating mechanism and cause hypothermic death!

RENAL -- alcohol decreases the release of ADH so drinkers have increased urine production (less water retained) --> over time alcoholics develop a TOLERANCE TO THIS --> if they go through withdrawal there is a large compensatory increase in ADH release!!! Lots of retention --> DANGEROUS HTN!

12

Other Negative effects 2 -- GI

GI --> causes ESOPHAGEAL dysfunction because it decreases peristalsis and lower esophageal sphincter pressure --> causes eophageal REFLUX and potential BARRET'S ESOPHAGUS which predisposes to esophageal cancer!

Also, forceful vomiting with prolonged alcohol use could cause MALLORY-WEISS TEARS and traumatic RUPTURE of the esophagus

Also increases gastric secretions --> disrupts the mucosal barrier --> acute and chronic gastritis

WIth malabsorption in the small intestine it can lead to chronic diarrhea!

Direct effect on PANCREATIC ACINAR CELLS and is directly responsible for the MAJORITY OF ACUTE AND CHRONIC PANCREATITIS CASES IN THE COUNTRY

13

Other Negative effects 3 -- Hepatic

Metabolism of alcohol through ADH and ALDH causes a buildup of EXCESS NADH (and depletion of NAD+)

Excess NADH acts as a NEGATIVE FEEDBACK SIGNAL onto the Kreb's cycle and beta oxidation of fatty acids --> PREVENTS BREAKDOWN OF FAT and causes FATTY INFILTRATION OF THE LIVER (fatty liver!) or HEPATITIS

As the alcohol DIRECTLY DAMAGES the liver, it will REPLACE normal tissue with FIBROUS TISSUE and lead to CIRRHOSIS (Mallory Bodies in cirrhotic hepatocytes)

Cirrhosis and direct liver damage can be expedited through ACETAMINOPHEN INGESTION --> as it is metabolized, it has a reactive intermediate NAPQI, which is DIRECTLY HEPATOTOXIC

Normally NAPQI is rapidly conjugated to glutathione and excreted, but EXCESS ALDEHYDE from alcohol breakdown STEALS THE GLUTHIANONE --> NAPQI has more time to hang out and damage hepatocytes

14

Other Negative Effects 4 -- CNS and Sexual

CNS --> alcoholics have prolonged NUTRIENT DEFICIENCIES particularly with B complex vitamins!

Thiamine (vit B1) causes an acute neuropsyche reaction called WERNICKE'S ENCEPHALOPATHY --> mental disturbance, eye movement paralysis, ataxia --> can go on to develop KORSAKOFF'S PSYCHOSIS --> retrograde and anterograde amnesia with confabulation (invention of memories that occurred during blackout episodes)


Sexual --> disruption of normal sexual function!

Disinhibition --> more likely to want or attempt sex --> but had low function!

Reproductive/sexual health problems (cycle abnormalities, testicular atrophy, decreased arousal, latency on ejaculation, loss of libido, etc)

Chronic alcoholism can lead to IMPOTENCE

FAS!!! CNS dysfunction, growth retardation, learning deficits, craniofacial abnormalities

15

Dealing with ETHANOL intoxication

1 drink is completely metabolized within 90 minutes

Acute intoxication --> comatose and respiratory depressed patients should be INTUBATED, given STOMACH LAVAGE, and HEMODIALYZED

Non-comatose --> observe for 4-6 hours!

16

METHANOL INTOXICATION

More dangerous --> converted by ADH to FORMALDEHYDE and then by ALDH to FORMIC ACID which is degraded to CO2

Formic acid causes CLASSIC TOXICITY OF: blurry vision, optic disk hyperemia, abdominal pain, vertigo, vomiting, headache, back pain, cold extremities, motor restlessness, metabolic acidosis

Normal BP, causes less inebriation than alcohol

USUALLY CAUSES BLINDNESS AND DEATH BY RESPIRATORY FAILURE IN DOSES AS SMALL AS 15 ML!!!!!!!!

17

Treating Methanol Intoxication

Prevent the formation of formaldehyde/formic acid to avoid these toxicities

Used to use ETHANOL to outcompete methanol for ADH

Worked because ethanol has a higher affinity, but could cause dangerous alcohol intoxication

*****FOMEPIZOLE***** is what we use now

It is an inhibitor of Alcohol dehydrogenase!

Then we DIRECTLY REMOVE THE METHANOL WITH DIALYSIS

Also give RESPIRATORY SUPPORT for the resp. depression

Metabolic acidosis -->treat with BICARB and FOLIC ACID to increase oxidation of formic acid to CO2 to lower all intermediates as much as possible

18

ETHYLENE GLYCOL

Found in ANTIFREEZE

Ethylene glycol is converted to glycoaldehyde by ADH then to glycolic acid by ALDH

Eventually metabolized to oxalic acid

Toxicities include ANION GAP ACIDOSIS, OSMOLAR GAP, and EXCRETION OF CALCIUM OXALATE CRYSTALS IN THE URINE

Treat with FOMEPIZOLE

19

What is Alcoholism?

It is actually a SPECTRUM OF DISEASES that are associated with negative social and medical outcomes

Genetics and environment
Characterized by TOLERANCE and DEPENDENCE

Tolerance --> the gradual reduction in the behavioral or physical response to alcohol

Dependence --> physical (causes withdrawal) and pyschological (cravings)

These features, along with alteration of receptors (GABA, NMDA) contribute to alcohol addiction

20

Why does alcohol become addictive?

Increase in DA release --> euphoria, reward

With chronic use, the cells from the VTA projecting to the nucleus accumbens will INCREASE IN NUMBER or in SYNAPTIC STRENGTH due to long-term potentiation of the DA neurons

Synaptic "memory" that is formed is also what gives the strong practical memory of the drug EXPERIENCE and is a major reason why relapse is such a huge issue --> patient remembers the physical DA reward and can't get enough!

21

Withdrawal

Observed after COMPLETE CESSATION OF ALCOHOL USE or during a period where alcohol use is reduced

Early withdrawal --> within 48 hours; Coarse action tremor, irritability, restlessness, anxiety, agitation, etc

Late withdrawal --> 1-6 days later; DELIRIUM TREMENS (often fatal), extreme agitation, appears frightened, confused, hallucinations, etc

22

DISULFURAM

Used to PREVENT RELAPSE

Directly inhibits aldehyde dehydrogenase --> allows acetaldehyde to build up, which causes UNCOMFORTABLE SIDE EFFECTS IF ALCOHOL IS INGESTED AFTER (vasodilation, pulsating headache, respiratory distress, N/V, sweating, thirst, chest pain, blurry vision, confusion -- all caused by acetaldehyde buildup! This drug allows it to stay as acetaldehyde and not be broken down!)

This will help people not go back to drinking!!!

23

NALTREXONE

Blocks the OPIATE REWARD PATHWAY to reduce the FREQUENCY and SEVERITY of drinking (helps maintain abstinence); reduces cravings!

When an alcoholic drinks, it indirectly causes DA release --> mediated through endogeous endorphins (endogenous opioids) that bind and activate DA neurons projecting to the nucleus accumbens --> if we INTERRUPT THIS PATHWAY, we can help the addiction

If there is poor compliance --> there is poor effectiveness --> works BEST in psychosocial therapy combo!

24

ACAMPROSATE

Analog of GABA

Can also block the NMDA receptor to REDUCE CRAVINGS during withdrawal and thus help maintain abstinence

Best used after a patient has ALREADY DETOXED and has even better effectiveness when used in COMBINATION WITH DISULFURAM

25

FOMEPAZOLE

For Methanol and Ethylene Glycol intoxication!!!!! Inhibits alcohol dehydrogenase

26

ACETAMINOPHEN

NAPQI is the metabolite; directly hepatotoxic; chronic alcohol will prevent its degradation

27

Other drugs not on the need to know list

ONDANSETRON --> 5HT3 receptor antagonist (anti-emetic) and is used to REDUCE ALCOHOL CONSUMPTION --> believed that 5HT causes cravings --> works best in YOUNG early onset alcoholics with a polymorphism at the 5HT receptor; reduces cravings


TOPIRAMATE --> also an anti-epileptic; potentiates GABA transmission while inhibiting glutamitergic transmission to decrease DA release in the reward pathway; used to both LESSEN WITHDRAWAL and DECREASE THE FREQUENCY OF DRINKING; can be used WHILE A PATIENT IS DRINKING HEAVILY; can cause METABOLIC ACIDOSIS

Quetiapine --> atypical antipsychotic that antagonizes 5HT, DA, histamine and adrenergic receptors

GHB and IBOGAINE --> both SCHEDULE 1 in the US --> but can be used to treat addiction in other countries