Module 7 Pharm

Front 1

What is BAC?

Back 1

Blood alcohol concentration

Index of consumption and reflects absorption, distribution and metaboliism

Front 2

How is BAC measured?

Back 2

measured directly from blood via
-- gas chromatograph analysis OR
-- enzyme analysis

Front 3

BAC depends on...?

Back 3

1. quantity of ethanol ingested and consumption rate

2. speed of absorption

3. body weight and percentage of total body water

4. rate of metabolism

Front 4

Alcohol absorption?

Back 4

1. simple diffusion largely in PROXIMAL INTESTINE, but also through stomach mucosa (20-30%)

2. delays in gastric emptying slows absorption rate from proximal intestine

3. rate of ethanol absorption is concentration-dependent (20-30% solutions absorbed faster than more dilute solutions)

4. concentrated ethanol can produce gastric irritation and pylorospasm which slows absorption

5. drugs can also decrease gastric absorption

Front 5

Alcohol distribution?

Back 5

1. enters systemic circulation to be distributed first to the liver

2. distributes to entire body water

3. typical peak BAC occurs 30-90min after ingestion

Front 6

Oxidation of alcohol?

Back 6

Over 90% completely oxidized to CO2 and H2O (98% at lower conc)

Rate of oxidation follows zero-order kinetics
-- independent of time and concentration of ethanol
-- 7-10g of ethanol oxidized per hour

Front 7

Steps of alcohol metabolism -- general?

Back 7

1. GASTRIC mucosal alcohol dehydrogenase

2. HEPATIC enzymatic mechanisms

Front 8

Describe the primary hepatic enzyme mechanism.

Back 8

Alcohol dehydrogenase (ADH)






-- Availability of nicotinamide adenine dinucleotide (NAD+) is the rate-limiting factor
-- conversion of NAD+ to NADH increases cellular reducing equivalents (H+)
-- acetaldehyde (CH3CHO) is oxidized in the liver via ALDEHYDE DEHYDROGENASE (AIDH)to acetate and subsequently to CO2 and H2O

Front 9

Describe the secondary hepatic enzyme mechanism.

Back 9

Microsomal enzyme oxidizing system (MEOS)

-- microsomal ethanol oxidizing system has a high Km for ethanol (>100 mg/dL)
-- does NOT depend on NAD+
-- can be induced by chronic, high levels of ethanol (increased metabolism of other substrates for MEOS)

Front 10

What is the tertiary enzyme mechanism for alcohol metabolism?

Back 10

catalase

Front 11

What are the mbrn effects of alcohol?

Back 11

1. By virtue of its lipid solubility, ALL tissues and cells can be affected by ethanol, however, organ systems differ in sensitivity

2. Generalized perturbation of MBRN PROTEINS that participate in neuronal signaling
-- enzymes --> Na/K ATPase, adenyl cyclase, protein kinase C
-- voltage-gated ion channels --> Ca++ and K+ voltage-dependent ion channel function

Front 12

Neurotransmitter effects of alcohol at lower concentrations?

Back 12

Increased neuronal signaling (stimulant effects) through ethanol-induced:

1. decreased actons of GABA to reduce inhibitory neuron strength (disinhibition)

2. increased release of DOPA in the nucleus accumbens appears to mediate pleasureable effects of EtOH

Front 13

Neurotransmitter effects of alcohol at higher concentrations?

Back 13

Decreased neuronal signaling (depressant effects) occurs at higher concentrations through ethanol induced:

1. enhancement of inhibitory signaling via facilitation of effects of GABA

2. inhibition of glutamate effects at the NMDA receptor

Front 14

CNS acute effects with alcohol use?

Back 14

1. low concentrations produce disihibition of cortical inhibitory control mechanisms producing impairment of the reticular activating system

2. higher concentrations produce impairment of the reticular activating system leading to generalized depression of neuronal function

Front 15

CNS chronic effects with alcohol use?

Back 15

1. directly associated with serious neurologic and mental disorders such as
-- memory loss
-- sleep disturbances
-- psychoses

2. associated deficiency in B vitamins leads to peripheral neuropathies

Front 16

Acute EtOH effects on cardiovascular and respiratory systems?

Back 16

1. SMALL doses initially cause cutaneous vasodilation
-- direct smooth muscle relaxant effects

2. TOXIC doses can produce myocardial depression, and central vasomotor and respiratory depression

Front 17

Chronic EtOH effects on cardiovascular and respiratory systems?

Back 17

1. HTN, worsening of existing HTN

2. abuse can produce irreversible cardiomyopathy

Front 18

Acute hepatic system effects of EtOH?

Back 18

1. excess reducing equivalents (H+) formed from the ADH and AIDH-dependent metabolism increases hepatic NADS/NAD ratio

2. increase in avb H+ leads to number of metabolic consequences, including:
-- transient hyperglycemia or hypoglycemia w/ decreased gluconeogenesis
-- hyperlacticacidemia
-- hyperurucemia
-- hyperlipidemia and ketoacidosis

Front 19

Chronic hepatic system effects of EtOH?

Back 19

1. NADH-induced inhibition of glycerophosphate dehydrogenase leads to increased glycerophosphate and esterification of fatty acids (triglycerides)

2. decreased oxidation of fatty acids

3. hepatic accumulation of "neurtral" fat (fatty liver)

Front 20

Acute effects of EtOH on the GI system?

Back 20

1. low concentrations increase gastric acid secretion

2. higher concentrations (greater than 40%) produces gastric irritation and possibly pylorospasm (direct effects)

Front 21

Chronic effects of EtOH on the GI system?

Back 21

1. erosive gastritis and esophageal and duodenal abnormalities

2. pancreatitis may also occur due to increased pancreatic secretion

Front 22

Acute effects of EtOH on the endocrine-reproductive system?

Back 22

1. Pituitary ADH secretion is inhibited causing diuresis of variable intensity and duration

2. inhibition of oxytocin secretion and impaired secretion of LH as well as decreased serum testosterone levels

Front 23

Chronic effects of EtOH on the endocrine-reproductive system?

Back 23

1. inhibition of hormone secretion has been assoc w/ testicular atrophy, impotence, sterility, and gynecomastia in males

2. excessive maternal EtOH abuse during pregnancy can produce birth defects and has been characterized as "Fetal Alcohol Syndrome"

Front 24

Acute alcohol toxicity?

Back 24

1. effects quantitatively related to blood-ethanol concentration leading to CNS and CV system depression

2. treatment is largely supportive (especially respiratory depression) w/ prevention of aspiration

Front 25

Chronic alcohol toxicity?

Back 25

1. assoc w/ increased mortality

2. LIVER DISEASE -- alcoholic fatty liver (reversible) progressing to alcoholic hepatitis and, finally, cirrhosis

3. CNS abnormalities including symmetrical peripheral neuropathies

4. increased risk of development of certain cancers

Front 26

Types of alcohol tolerance?

Back 26

1. metabolic

2. pharmacodynamic

Front 27

Metabolic alcoholic tolerance?

Back 27

1. occurs as evidenced by increased capacity to metabolize ethanol

2. mechanism involves induction of hepatic cytochrome p450 2E-1 (amt can increse 2-fold)

Front 28

Pharmacodynamic alcohol tolerance?

Back 28

1. chronic abuse results in cellular or pharmacodynamic tolerance to ethanol

2. response of mbrn systems affected by ethanol is reduced (mbrn adaptation)

3. behavioral adaptation as well as a significant increas in toxicity threshold

Front 29

Types of dependence?

Back 29

1. psychological dependence

2. physical dependence

Front 30

Describe physical dependence.

Back 30

Due to chronic abuse and is characterized by adaptive changes in neurotransmitter systems.
1. downregulation of inhibitory GABA receptors
2. upregulation of excitatory glutamate (NMDA) receptors
3. increased central norepi activity

Front 31

Acute EtOH effects on cardiovascular and respiratory systems?

Back 31

1. SMALL doses initially cause cutaneous vasodilation
-- direct smooth muscle relaxant effects

2. TOXIC doses can produce myocardial depression, and central vasomotor and respiratory depression

Front 32

Chronic EtOH effects on cardiovascular and respiratory systems?

Back 32

1. HTN, worsening of existing HTN

2. abuse can produce irreversible cardiomyopathy

Front 33

Acute hepatic system effects of EtOH?

Back 33

1. excess reducing equivalents (H+) formed from the ADH and AIDH-dependent metabolism increases hepatic NADS/NAD ratio

2. increase in avb H+ leads to number of metabolic consequences, including:
-- transient hyperglycemia or hypoglycemia w/ decreased gluconeogenesis
-- hyperlacticacidemia
-- hyperurucemia
-- hyperlipidemia and ketoacidosis

Front 34

Chronic hepatic system effects of EtOH?

Back 34

1. NADH-induced inhibition of glycerophosphate dehydrogenase leads to increased glycerophosphate and esterification of fatty acids (triglycerides)

2. decreased oxidation of fatty acids

3. hepatic accumulation of "neurtral" fat (fatty liver)

Front 35

Acute effects of EtOH on the GI system?

Back 35

1. low concentrations increase gastric acid secretion

2. higher concentrations (greater than 40%) produces gastric irritation and possibly pylorospasm (direct effects)

Front 36

Chronic effects of EtOH on the GI system?

Back 36

1. erosive gastritis and esophageal and duodenal abnormalities

2. pancreatitis may also occur due to increased pancreatic secretion

Front 37

Acute effects of EtOH on the endocrine-reproductive system?

Back 37

1. Pituitary ADH secretion is inhibited causing diuresis of variable intensity and duration

2. inhibition of oxytocin secretion and impaired secretion of LH as well as decreased serum testosterone levels

Front 38

Chronic effects of EtOH on the endocrine-reproductive system?

Back 38

1. inhibition of hormone secretion has been assoc w/ testicular atrophy, impotence, sterility, and gynecomastia in males

2. excessive maternal EtOH abuse during pregnancy can produce birth defects and has been characterized as "Fetal Alcohol Syndrome"

Front 39

Acute alcohol toxicity?

Back 39

1. effects quantitatively related to blood-ethanol concentration leading to CNS and CV system depression

2. treatment is largely supportive (especially respiratory depression) w/ prevention of aspiration

Front 40

Chronic alcohol toxicity?

Back 40

1. assoc w/ increased mortality

2. LIVER DISEASE -- alcoholic fatty liver (reversible) progressing to alcoholic hepatitis and, finally, cirrhosis

3. CNS abnormalities including symmetrical peripheral neuropathies

4. increased risk of development of certain cancers

Front 41

Types of alcohol tolerance?

Back 41

1. metabolic

2. pharmacodynamic

Front 42

Metabolic alcoholic tolerance?

Back 42

1. occurs as evidenced by increased capacity to metabolize ethanol

2. mechanism involves induction of hepatic cytochrome p450 2E-1 (amt can increse 2-fold)

Front 43

Pharmacodynamic alcohol tolerance?

Back 43

1. chronic abuse results in cellular or pharmacodynamic tolerance to ethanol

2. response of mbrn systems affected by ethanol is reduced (mbrn adaptation)

3. behavioral adaptation as well as a significant increas in toxicity threshold

Front 44

Types of dependence?

Back 44

1. psychological dependence

2. physical dependence

Front 45

Describe physical dependence.

Back 45

Due to chronic abuse and is characterized by adaptive changes in neurotransmitter systems.
1. downregulation of inhibitory GABA receptors
2. upregulation of excitatory glutamate (NMDA) receptors
3. increased central norepi activity

Front 46

Forced reduction or discontinuation of ethanol consumption from physiologic dependence results in…?

Back 46

Withdrawal symptom
-- hallucinations
-- seizures
-- possible delirium tremors

Front 47

EtOH addiction treatment?

Back 47

1. counseling and other behavioral intervention

2. CLONIDINE – alpha2 adrenergic agonist used to decrease W/D symptoms

3. NALREXONE or NALMAFENE – long acting narcotic antagonists help reduce craving

4. DISULFIRAM (Antabuse) – used as aversive deterrent to alcohol ingestion (see further)

5. ACOMPRASE – NMDA receptor antagonist
-- one of number of new agents used in alcoholic treatment programs which have been determined to decreased the relapse rate in alcoholics

6. TIAPRIDE – dopa receptor antagonist that blocks pleasurable effects of alcohol

Front 48

Ethanol and disease states?

Back 48

1. precautions in various disease states extend from the properties of ethanol which affect specific organ fxns

2. should be avoided in hepatic and severe renal disease, skeletal or cardiac myopathies, peptic ulcer, pancreatitis and gout

3. disinhibition properties of ethanol on CNS inhibitory pathways predict potential interaction in pts w/ epilepsy or other seizure disorders

Front 49

How does EtOH affect drug bioavailability?

Back 49

1. Solubility of diazepam and aminoglycoside antibiotics are increased by low concentrations of ethanol thus increasing bioavailability

2. High concentrations of ethanol can induce pylorospasm and decrease levels and/or delay onset of any drug absorbed preferentially in proximal intestine

Front 50

How does EtOH affect drug metabolism?

Back 50

1. DECREASED – acutely high conc of ethanol can interfere w/ hepatic metabolism of drugs such as:
-- pentobarbital
-- phenoparbital
-- phenytoin

2. INCREASED – chronic ethanol can induce hepatic cytochrome P450 microsomal enzyme system to enhance drug metabolism
-- phenytoin
-- morphine
-- benzodiazepines
-- meprobamate

3. ALTERED – disulfiram, metronidazol and the hypoglycemic sulfonylureas inhibit hepatic aldehyde dehydrogenase leading to a buildup of acetaldehyde in the body
-- subsequent “aldehyde syndrome” is assoc w/ cutaneous vasodilation, throbbing headache, respiratory difficulties, nausea, copious vomiting, sweating, chest pain, blurred vision, hypotension, orthostatic syncope and confusion

Front 51

What kind of potentiation of effects can occur when mixing alcohol with drugs?

Back 51

1. CNS – enhanced sedation may occur w/ ALL agents which have CNS depressant properties

2. GI – potentiation of gastric irritation due to salicylates

3. ENDOCRINE – potentiation of hypoglycemic response w/ oral sulfonylureas and biguinides

4. CV – potentiation of hypotensive response w nitrates

Front 52

What is methanol?

Back 52

“wood alcohol”
-- frequently found in the home as canned heat or in windshield washing solutions
-- used as an adulterant for tax-free ethanol and as an industrial solvent

Front 53

Pharmacokinetics of methanol?

Back 53

1. rapidly absorbed from the stomach and distributed to the total body water

2. substrate for alcohol dehydrogenase resulting in formation of formaldehyde which is then converted via aldehyde dehydrogenase to formic acid

Front 54

Methanol toxicity?

Back 54

1. Headache, vertigo, vomiting, dyspnea, and blurring vision can be delayed in appearance 8-36 hours following ingestion

2. Profound alterations in respiration and acid-base balance, especially metabolic acidosis

3. formic acid productes destructive inflammation of retinal ganglion cells and can produce bilateral blindness

Front 55

Treatment of methanol toxicity?

Back 55

1. largely supportive

2. correction of acidosis is most important step in treatment

3. both ethanol and 4-methylpyrazole can be administered which are substrates for ADH thus blocking metabolism of methanol to its toxic metabolites

Front 56

What is isopropyl alcohol?

Back 56

1. described as “rubbing” alcohol

2. used as surface disinfectant (70%) and also in lotions

Front 57

Isopropyl alcohol pharmacokinetics?

Back 57

1. initial substrate for alcohol dehydrogenase

2. ultimately oxidized to acetone

Front 58

Isopropyl alcohol toxicity?

Back 58

1. fatal dose is 4-8oz, thus more toxic than ethanol

2. signs and symptoms similar to ethanol, though more prominent gastritis, pain, and vomiting (and potential aspiration)

3. intox lasts longer due to slower oxidation to acetone

4. CNS depression proceeds to coma

5. evidence of ketoacidosis and ketones in urine confirms intoxication

Front 59

What is ethylene glycol?

Back 59

Polyhedric alcohol

1. ethylene glycol is used primarily in antifreeze

2. may also be used as industrial solvent

Front 60

Ethylene glycol pharmacokinetics?

Back 60

Ethylene glycol is converted first via ALCOHOL DEHYDROGENASE to GLYCOALDEHYDE and subsequently by ALDEHYDE DEHYDROGENASE to GLYCOLIC ACID

GLYCOLIC ACID is then metabolized to GLYOXYLIC ACID and subsequently to OXALIC ACID

Front 61

Ethylene glycol toxicity?

Back 61

1. Initial sign is CNS depression followed by metabolic acidosis

2. nephrotoxicity can result due to deposition of oxalic acid crystals in the renal tubules
-- crystals of calcium oxalate may be found in the urine

Front 62

Ethylene glycol treatment?

Back 62

1. supportive w/ correction of metabolic acidosis

2. formation of toxic metabolites can be reduced by admin of ethanol or 4-methylpyrazole which favorable competes for alcohol dehydrogenase and hence blocks oxalic acid formation