PHRM845-FINAL EXAM Flashcards by Meghan Collins

Today’s use for alcohol

-Fuel
-Chemical processes
-Disinfectant
-Vehicle (ex: almond extract)
-Recreation/social drinking
~Anxiolytic, euphoria, disinhibition
~Alcoholism (10% of the population)

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Absorption of alcohol

-10% from stomach; 90% from small intestine
-Peak 30-90 minutes
-Limited by gastric emptying
~Slowed by food (eat before drinking; decreases the amount of alcohol that gets to brain)
-Alcohol increases acid release–>GERD/induce ulcers

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Distribution of alcohol

-Distributed in total body water
~58% in men; 48% in women
~Men dilute alcohol more

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Elimination of alcohol
-What kinetic is the elimination?
-Elimination rate is ____
-What is the rate-limiting step?

-Follows a zero-order kinetic
-Elimination is at or above 10-20 mg/dL (metabolizing 1-1.5 drinks/hour)
-ADH is the rate-limiting step

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Metabolism of alcohol
**2 important steps

-90% in the liver
-ADH
-Microsomal ethanol oxidizing system (MEOS)
~Only at high alcohol concentration
~LOW affinity for alcohol
-Aldehyde dehydrogenase (ALDH)–> toxin (makes people sick)

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Glucuronidation of alcohol
-What test is used?
-Who is it best suited for?

0.5%-EtG test
-Test used to monitor alcohol consumption for days after–too sensitive
-Ethyl glucuronide has a very long half-life
-Not used for drunk driving
-Mainly for high school athletes

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Alcohol is metabolized by ____
-Where is that enzyme found?
-Do men or women express higher levels?

-ADH
-Found in liver, brain, and stomach
-Men express higher levels of gastric ADH which is why they can drink more than women

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Fomepizole (Antizole)

-ADH inhibitor
-ONLY used for alcohol poisoning
-Alcohol can be used as well to slow toxin metabolites
~Giving more substrate
-Fomepizole slows metabolism of the toxin so the body has more time to deal with it
-Slow formation of formaldehyde and toxic metabolites
-Liver has more time to further metabolize toxic metabolites

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Acetaldehyde is metabolized by ____
-Importance of ALDH2 and the possible mutations

-Aldehyde dehydrogenase
-ALDH1B1 and ALDH2 are isoenzymes important for alcohol metabolism (50% of Asians only have ALDH2)
-SNP in ALDH2 reduces activity (ALDH22)
-Heterozygous ALDH22 reduces metabolic activity, causes flushing and increased skin temp, but pts can STILL CONSUME ETHANOL Build up more acetaldehyde
-Homozygous ALDH2*2 causes a deficiency int he ability to metabolize acetaldehyde
~Neurotoxic (Pt CANNOT CONSUME ETHANOL)
~Strong “hangover” from acetaldehyde build up
~Also alcoholic neuropathy

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Disulfiram (Antabuse)

-Irreversible inhibitor of ADH
-Effects persist up to 14 days
-Must avoid meds with alcohol, such as Nyquil

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Is tx with disulfiram effective?

NO; pts generally are not adherent because it makes them sick

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Alcohol MOA

-Really “dirty” drug
-Potentiates opioid receptors
-Possibly works on GABA receptor to control DA release
-Possible works on nucleus accumbens

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Ligand-gated ion channels that alcohol targets

-GABA-A receptors (allosteric activator of inhibitory neurotransmitters–cells become more negative and hyperpolarize)
-NMDA receptor inhibitor
-Alpha7 nicotinic receptors

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Neurotransmitter release from alcohol consumption

-Opioids (enkephalin–endogenous opioid peptides)
~DA
-Serotonin and NE
-ACh
-Increases CNS and blood ACTH levels

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Alcohol has a concentration that is (small/large) at different targets.

SMALL; mM unit

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Blood alcohol level can be depicted in different ways

0.10% is equal to 100 mg/dL or 22 mmol/L of blood alcohol

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What is mg%

-Milligrams of ethyl alcohol in 100 millilitres (1 dL) or blood
>0.1% = 100 mg/dL = 100 mg%
>USA 80mg% is the legal driving limit
-Independent of behavior tolerance (even if pt drinks all the time and no longer has a change in behavior from drinking, if they blow over 0.8mg%, they will be arrested.

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Pharmacological actions of low alcohol levels

-Euphoria (warm feeling)
-Disinhibition (30-60 mg/dl)
-Talkative
-Analgesia (60-90 mg/dl)

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Pharmacological actions of intermediate levels of alcohol

-CNS stimulation (80-120 mg/dL)
~Mood swings (lose volume control: yelling) & aggression
-CNS depression (100-200 mg/dl)
~Slurred speech, ataxia, sedation, loss of motor control, irrational behavior

Pharmacological actions of high/fatal levels of alcohol

-Coma/death (300-500 mg/dl)
~Respiratory paralysis
~People have survived 1000-1500 mg/dl

Acute CV effects induced by alcohol

-Vasodilation
~Warm, flush
~Reduced BP
~Increased HR (decreased at high doses)

Moderate use CV effects

-Reduced risk of coronary disease (increases HDL)
**primarily red wine

CV effects from heavy/chronic alcohol use

-Affects heart
~Cardiomyopathy
~Arrhythmias (binge drinking)
~HTN (5% of all cases)
~Homeostasis (change in platelets)

Physiological effects of alcohol consumptions

-Thermoregulation
~Hypothermia (with higher doses)
>Moderate in man
>Possible lethal with cold temp and large dose
-Gastrointestinal
~Alcohol is a secretagogue
>Increases HCl (acid) secretion
>Chronic gastritis in alcoholics
~Appetite stimulant (low dose)
~Appetite depressant (high dose–lots of carbs&cal)

Long-term impact of alcohol consumption on liver

-Increases fat metabolism (promotes triglyceride synthesis from FFA) -Fatty liver leading to cirrhosis is common in abusers -Vitamin deficiencies; glutathione reduced (small intestine damage-->diarrhea) -Can cause ascites, edema, and effusions

Long-term impact of alcohol consumption on blood

-Mild anemia -Gastritis-->chance of blood loss -Alcohol related folic acid defiency

Long-term impact of alcohol consumption on cancer

-Liver -Along route of ingestion (mouth, larynx, esophagus, stomach) -Interacts with a lot of other carcinogens (ex: tobacco)

CNS depressants that interact with alcohol

Opioids Antipsychotics Anti-histamine Sedative hypnotics (Z-hypnotics and benzodiazepines)

ALDH inhibitors that interact with alcohol

Disulfiram Antimicrobials (metronidazole, cephalosporin) Sulfonylureas hypoglycemics (Tolbutamide)

What is the issue with acetaminophen (Tylenol) and alcohol?

-Increases metabolite (NAPQI) -Alcohol upregulates CYP2E1 -Tx with n-acetylcysteine to detoxify NAPQI

Issue with ASA and alcohol consumption

Increases ulcers and GI bleeding

Alcohol is toxic and ____

Teratogenic

Acute intoxication management

-Prevent respiratory depression -Prevent aspiration of vomit

Teratology of alcohol

Fetal alcohol syndrome (FAS) -Facial dysmorphology -Low birth weight -Decreased brain size -Mental retardation *Lower testosterone and sperm quality

Alcohol abuse and dependence is widespread

-1 in 8 US adults meet alcohol use disorder criteria (12.7%) -Less than 8% got treatment -88,000 people die from alcohol-related deaths each year which is a BIG problem

Sx of alcohol withdrawal

-Anxiety -Insomnia -Seizures/tonic clonic convulsions -N/V -Tactile hallucinations/delirium tremens

Tx for alcohol withdrawal

-Benzodiazepines -Phenytoin for seizures (excitatory is more active because GABA is no longer stimulated) -Electrolytes -Alpha-2 adrenergic partial agonists ~Clonidine, guanfacine ~Alcohol desensitizes alpha-2 adrengeric receptors ~Withdrawal increases NE response

Relapse from alcohol cessation

-Cue triggered ~Seeing a glass of alcohol ~Favorite bar ~Mood (stress, anxiety, depression)

Disulfiram (Antabuse)

-FDA-approved tx for alcoholism -ALDH inhibitor -Causes flushing, throbbing, HA, N/V, sweating, hypotension, and confusion -Pts should be alcohol-free for 24 h before use (Some OTC contain alcohol) -Aversive tx (build up acetaldehyde and get sick)

Acamprosate (Campral)

-FDA-approved tx for alcoholism -NMDA receptor antagonist/GABA agonist -Reduced relapse and prolong abstinence -Some of the same activity as alcohol -Replacement tx

Naltrexone (Revia)

-FDA-approved tx for alcoholism -Opioid receptor antagonist -Prevents relapse and ppl who do relapse are in better control -Blocks enkephalin binding (drinking does not feel as rewarding)

____ is more effective in patients with a SNP in the mu opioid receptor gene

Naltrexone -Alanine118glycine mutation (allows enkephalins to bind more tightly; decreases rewarding effect if their binding is blocked) ~N-terminal tail of mu opioid receptor ~Changes asparagine amino acid-->aspartate (N40D) ~3x higher potency for beta-endorphins -118G patients respond better to naltrexone -Highest prevalence in Asians -Clear indication for precision/personalized medicine

Topiramate (Topamax)

-Off-label tx for alcoholism -Inhibits glutamate signaling; enhances GABA signaling -Similar in MOA to Acamprosate -Approved for epilepsy and migraine -Encouraging results in 2 trials for alcoholism

Baclofen

-Off-label tx for alcoholism -Stimulates GABA-B receptors -Approved for tx spasticity -Reduces anxiety and craving -High doses reduced drinking in several small trials for alcoholism -Not better than placebo in double blind trial

Varenicline (Chantix)

-Nicotinic acetylcholine receptor partial agonist -Approved for smoking cessation (rewarding behavior) -Human tests for alcoholism are underway--based on mechanism that alcohol can hit nicotinic receptors

Alcoholics anonymous

-Originated in 1935 -12-step program -Spiritual -Sponser-sponsee -around 2 million members -1 yr retention rate is about 33% -Meds and psychotx

PHRM845-FINAL EXAM Flashcards

Pharmacology and pharmacotherapy of alcohol use/abuse