PHRM845-FINAL EXAM Flashcards
Pharmacology and pharmacotherapy of alcohol use/abuse
Today’s use for alcohol
-Fuel
-Chemical processes
-Disinfectant
-Vehicle (ex: almond extract)
-Recreation/social drinking
~Anxiolytic, euphoria, disinhibition
~Alcoholism (10% of the population)
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
Distribution of alcohol
-Distributed in total body water
~58% in men; 48% in women
~Men dilute alcohol more
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
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)
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
- 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
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
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
Disulfiram (Antabuse)
-Irreversible inhibitor of ADH
-Effects persist up to 14 days
-Must avoid meds with alcohol, such as Nyquil
Is tx with disulfiram effective?
NO; pts generally are not adherent because it makes them sick
Alcohol MOA
-Really “dirty” drug
-Potentiates opioid receptors
-Possibly works on GABA receptor to control DA release
-Possible works on nucleus accumbens
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
Neurotransmitter release from alcohol consumption
-Opioids (enkephalin–endogenous opioid peptides)
~DA
-Serotonin and NE
-ACh
-Increases CNS and blood ACTH levels
Alcohol has a concentration that is (small/large) at different targets.
SMALL; mM unit
Blood alcohol level can be depicted in different ways
0.10% is equal to 100 mg/dL or 22 mmol/L of blood alcohol
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.
Pharmacological actions of low alcohol levels
-Euphoria (warm feeling)
-Disinhibition (30-60 mg/dl)
-Talkative
-Analgesia (60-90 mg/dl)
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
