Please enable JavaScript.
Coggle requires JavaScript to display documents.
The Alcohols (■ BASIC PHARMACOLOGY OF ETHANOL (Consequences of Chronic…
The Alcohols
■ BASIC PHARMACOLOGY OF ETHANOL
Pharmacodynamics of Acute Ethanol Consumption
B. Heart
Significant depression of myocardial contractility
Impaired myocardial function
Acetaldehyde--> releasing myocardial stores of catecholamines--> arrhythmia
Incr in HR (muscles activity incr bc cortex off, reflex)
acute use & toxicity (
depression of vasomotor system
)
Hypothermia
(
vasodilatation due to effect (direct and indirect) on CNS (vasomotor)
)
(surface temp high bc of activity, but internal temp low)
Effect on HDL & LDL
Hyperlipidemia (sympathic activity (incr in fat release from stores) & decr in lipoprotein lipase (acute alcohol consumption reduces liver Es but chronic use induces it))
C. Smooth Muscle
Vasodilator (CNS & direct effect on smooth muscles)
-
Hypothermia (vasodilation)
Uterine relaxants
A. Central Nervous System Alcohol:
No specific R identified
;
Neurotransmission
interacts w/ GABA-A R--> facilitates GABA transmission
--> activation of DA neurons in mesolimbic system; involved in
sedative
& anxiolytic effects & rebound hyperexcitability seen during withdrawal.
inhibits NMDA R
, not by direct interaction w/
Glu
binding site, but rather by modifying way Glu binds to its site on R complex (allosteric effect)--> sedative/hypnotic effects, as well as neuroadaptation; also important in withdrawal.
was believed that ethanol’s primary effect:
disruption of biologic membranes
through reduction in lipid viscosity.
Respiration, moderate amount,
depressed respiration
Charac responses:
euphoria, impaired thought processes and decr mechanical efficiency
a
CNS depressant--> depression of inhibitory control mechs (cortex depression)--> apparent stimulatory effects
Consequences of Chronic Alcohol Consumption
H.
Incr Risk of Cancer
: cancer of the mouth, pharynx, larynx,
esophagus
, and liver
A. Liver and Gastrointestinal Tract
Fatty liver
Incr in gastric & pancreatic secretion (
gastritis & pancreatitis
,
release of histamine
in GI)
Hemorrhage in GI (anemia)
Pr malnutrition
Damage to intestine (diarrhea, weight loss, Vit deficiency)
Thiamine deficiency
(
Korsakoff’s psychosis
)
Blood (anemia due to folic acid deficiency & bone marrow depression)
B. Nervous System
Neurotoxicity:
brain damage, memory loss, sleep disturbances, psychosis
Tolerance and dependence
When tolerance occurs within time course of a single exposure to drug: acute tolerance, while chronic tolerance occurs over repeated uses
Tolerance mechs:
induction of Es (in chronic use)
cellular mechs
Tolerance to alcohol also makes individual
cross-tolerant to other CNS depressant drugs
ex barbiturates and benzodiazepines
genetic determinants
of tolerance
reinforcer
:
In most cases reward is
positive
(euphoric effects of drugs, or altered consciousness following the drug, or to conform to behavior of peers)
If pharmacological effect
reverses an aversive state: negative
reinforcement (relief of stress and negative emotions or the relief of withdrawal)
dopamine (DA) system originates in ventral tegmental area (VTA) and connects to nucleus accumbens, prefrontal cortex
as well as hippocampus: mesocorticolimbic system;
Activation of VTA-->
release of DA in nucleus accumbens
& limbic system &
prefrontal cortex
--> rewarding/reinforcing effects, not only for alcohol but for almost all abused drugs
C. Cardiovascular System
Hypertension
Coronary heart disease
Arrhythmias
Cardiomyopathy
and heart failure
D. Blood
E. Endocrine System and Electrolyte Balance
gynecomastia, testicular atrophy due to steroid imbalance
Kidney: Diuresis due to excess of water intake & inhibition of ADH; Alternation of whole body K+ due to vomiting & diarrhea
F. Fetal Alcohol Syndrome
Teratogenic effects: mental retardation, congenital malformation
Retatrded body growth, microcephaly, poor coordination, underdevelopment of midfacial region, minor joint anomalies.
G. Immune System
Pharmacokinetics
Absorption:
oral--> absorbed almost completely from duodenum, rapidly by diffusion; rate
extremely variable
, depends on:
volume, type and
alcohol [ ]
of beverage - less concentrated--> absorbed more slowly, however very concentrated--> can inhibit gastric emptying; carbonation can incr absorption
rate
of drinking:
faster--> faster absorption
food: major effect: amount, timing and type: high-fat foods can significantly delay absorption; effect of food primarily due to
delay in gastric emptying seen after meal consumption
;
absorption faster when gaster empty
;
Griseofulvin can inhibit ADH
gastric metabolism & hepatic first-pass metabolism
can significantly decr bioavailability of alcohol
Distribution: Volume of distribution: total body water
Metabolism: primarily in
liver
alcohol--> acetaldehyde
A. Alcohol Dehydrogenase Pathway (ADH):
saturates at fairly low blood alcohol [ ]s (has a low Km and follows Michaelis-Menten kinetics)--> at moderate blood alcohol [ ]s, it follows apparent zero-order kinetics (rate of metabolism is at max capacity & has a constant rate of ~7-10 g/hr, equivalent to 1-drink/hr); rate extremely variable betw individuals & even within individuals from day-to-day
Genetic variation
5 functional classes of ADH arising from 7 human genes; Polymorphism occurs at ADH2 & ADH3 loci--> different sub-units w/ different catalytic properties: 3 sub-units from ADH2 & 2 sub-units from ADH3, each w/ a different P in different ethnic population;
ex:
ADH2-1 predominates in whites and blacks
ADH2-2 predominates in Asians,
ADH2-3
in 15% of
black Americans
: corresponding isozyme has a 25%
higher metabolic rate
compared to more common ADH2-1 allele--> may have a
protective effect against alcohol-related birth defects in pregnant black-American women who drink while pregnant
B. Microsomal Ethanol-Oxidizing System (MEOS)
C. Acetaldehyde Metabolism
Aldehyde dehydrogenase
u. not rate-limiting
Accumulation of acetaldehyde a. w/ headache, gastritis, nausea, dizziness (hangover)
Aldehyde dehydrogenase inhibition (disulfiram, chloramphenicol, sulfonamides, some antibiotics,...)
Genetic Variation
variant allele - ALDH2*2: possessed by 50% of Asian populations--> isozyme w/ decr elimination of acetaldehyde and consequently a charac flushing response to alcohol, along w/ nausea, headache and other unpleasant experiences--> alcohol very aversive to these individuals and may protect them from becoming alcoholic
gender difference
in gastric ADH activity--> differences in
absorption and bioavailability
in body composition and total body water--> Differences in
distribution
(women:
lower proportion of total body water--> achieve higher blood alcohol levels
)
in
metabolism
--> women having higher alcohol elimination rates/ kg body weight or lean body mass possibly related to higher liver volumes per unit lean body mass seen in women, or due to gender differences in alcohol dehydrogenase activity
effect of menstrual cycle: not appear to be any effect, although response to alcohol may be different in women during different phases of the cycle. Also, studies on effect of OCPs on alcohol pharmacokinetics are conflicting
Alcohol-Drug Interactions
■ CLINICAL PHARMACOLOGY OF ETHANOL
MANAGEMENT OF ALCOHOL WITHDRAWAL SYNDROME
Agitation, anxiety, insomnia, reduction of seizure threshold.
Thiamine administration, electrolyte balance, long-acting sedative-hypnotics (diazepam, chlordizepoxide)
Clonidine
& propranolol
TREATMENT OF ALCOHOLISM
Naltrexone
Acamprosate
Disulfiram: Inhibitor for aldehydedehydrogenase --> acetaldehyde accumulation--> extreme discomfort
: flushing, headache, nausea, vomiting sweating, hypotension & confusion
Other Drugs:
BDZ (best choice to use this for a long period, then decr gradually (addicting px to another drug))
;
SSRI
MANAGEMENT OF ACUTE ALCOHOL INTOXICATION
■ PHARMACOLOGY OF OTHER ALCOHOLS
METHANOL
Methanol (not very toxic)--> formaldehyde-->formic acid--> acidosis & visual disturbance
Treatment: IV ethanol administration (copetitive substra for ADH)
ETHYLENE GLYCOL
ethylene glycol--> oxalic acid
Treatment: ethanol administration,
dialysis
,
fompizol (an ADH inhibitor)