drug interactions in mice

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drug interactions in mice
Clinical Pharmacology I

• W.M. Tom
• Department of Pharmacology
• University of Hong Kong

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(No Transcript)
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H
O II
CH2-CH3
O
5
CH2-CH3
Barbitone the first sleeping drug
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O II
H
H
O
H
Barbituric acid
5
O II
H
H
O
H
Barbituric acid devoid of sedative, hypnotic or
antiseizure effects
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O II
H
O
5
C-5 substitution with alkyl or aryl groups
essential for hypnotic activity
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phenyl ring (an aryl group)
O II
H
O
5
CH2-CH3
Phenobarbitone a long-acting barbiturate
ethyl side-chain (an alkyl group)
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O II
H
CH3 I
CH-CH2-CH2-CH3
O
5
CH2-CH3
Pentobarbitone an intermediate-acting barbiturate
5-carbon side-chain
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O II
substitute oxygen atom with sulphur
H
CH3 I
CH-CH2-CH2-CH3
S
5
2
CH2-CH3
Thiopentone an ultra-short-acting barbiturate
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Structure-activity relationships (SARs) of
barbiturates

• barbituric acid itself lacks central depressant
  activity
• presence of alkyl or aryl groups at C-5 position
  confers sedative-hypnotic effects
• the oxygen atom at C-2 position replaced by
  sulphur increases the lipid solubility of the
  drug, decreases duration of action,
  decreases latency to onset of activity,
  accelerates metabolic degradation and
  often increases hypnotic potency

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Pharmacokinetics of thiopentone

• used for induction of anesthesia
• highly lipid-soluble and penetrate the brain very
  rapidly ? rapid onset of action
• quickly redistributed to other parts of the body
  ? short duration of action
• duration of action depends more on redistribution
  rate than metabolic rate in liver

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Brain, heart, liver kidney
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Factors affecting the duration of action of some
representative barbiturates

• thiopentone pentobarbitone
  phenobarbitone
• duration of action 10 min 5
  hours 10 hours
• lipid solubility
• redistribution
• metabolism
• excretion unchanged () 0 10 25
• excretion as metabolites () 100 90 75
• clinical use anaesthetic
  hypnotic anticonvulsant
• route of administration intravenous
  oral oral
  

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Time course of action of a single i.p. dose
Time of onset T1 T0Time to peak effect
T2 T0Duration of action T3 T1MEC
minimum effective concentration
peak
Plasma drug concentration
MEC
T0
T1
T2
T3

Time
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Drug interactions

• -- occurs whenever the pharmacologic action of a
  drug is altered by another drug
• Pharmacokinetic interactions
• -- change is related to differences in the plasma
  levels of a drug, achieved with a given dose of
  that drug
• Pharmacodynamic interactions
• -- change is related to differences in effects
  produced by a given plasma level of a drug

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Pharmacokinetic interactions

• -- change is related to differences in the plasma
  levels of a drug, achieved with a given dose
  of that drug
• e.g. alterations in absorption, distribution,
  metabolism and/or excretion of one drug by
  another drug

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Metabolism of phenobarbitone by liver cytochrome
P450 enzymes
P450 enzymes oxidizes drug molecule
O II
H
O
5
CH2-CH3
Phenobarbitone
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Metabolism of phenobarbitone by liver cytochrome
P450 enzymes
OH
O II
H
O
5
CH2-CH3
Repeated exposure induces more P450 enzymes to
inactivate the drug much more efficiently ?
shorter duration of action
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Metabolism of pentobarbitone by liver cytochrome
P450 enzymes
P450 enzyme
O II
H
CH3 I
CH-CH2-CH2-CH3
O
5
CH2-CH3
Pentobarbitone
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Metabolism of pentobarbitone by liver cytochrome
P450 enzymes
O II
H
CH3 I
OH I
CH-CH2-CH-CH3
O
5
CH2-CH3
Inactivation of pentobarbitone is also faster in
phenobarbitone-induced animals ? shorter duration
of sleeping time
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Enzyme induction

• chronic administration of barbiturates not only
  stimulates its own metabolism, but also the
  metabolism of other drugs
• discontinuation of the barbiturates may result
  an exaggerated clinical response of other drugs

P450
P450
P450
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Mechanisms of barbiturate action

• Barbiturates depress the activity of all brain
  cells, however they selectively depress the
  reticular activating system (RAS) in the brain
  stem
• Low doses of the drugs enhance the effects of
  GABA (an inhibitory neurotransmitter) which
  allows chloride ions to enter nerve cells,
  making them less likely to fire

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Barbiturate Site
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Mechanisms of barbiturate action

• In anesthetic doses, the barbiturates may lead to
  reduced sensitivity of the postsynaptic
  membranes to excitatory neurotransmitters
• In toxic overdoses, the barbiturates may cause
  death due to depression of respiratory center
  in the brain stem

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Therapeutic and toxic effects
Sleep
Death
Responding
LD50
ED50
Log dose of phenobarbitone
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CNS depressant effects

• small amounts can produce calmness and relaxed
  muscles
• larger doses can cause slurred speech,
  staggering gait and altered perception
• very large doses can cause respiratory
  depression, coma and death
• the combination of depressants and alcohol can
  multiply the effects of the drugs, increasing
  the risks

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Alcohol effect

• Alcohol or other CNS depressants may enhance
  the action of the barbiturates
• Respiratory depression occurs at lower than
  expected dose of barbiturates, death results

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Combo of alcohol and barbiturate
With alcohol
Without alcohol
Dead
LD50
Log dose of phenobarbitone
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Pharmacodynamic interactions

• -- change is related to differences in effects
  produced by a given plasma level of a drug
• e.g. the action of one drug may be enhanced or
  suppressed by another drug
• additive e.g. 1 1 2
• synergistic e.g. 1 1 5
• potentiate e.g. 0 1 5
• antagonistic e.g. -1 1 0

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Medical uses of barbiturates

• were used in the treatment of anxiety, insomnia,
  and epilepsy
• most uses replaced by benzodiazepines except
  epilepsy
• phenobarbitone most commonly prescribed
  anticonvulsant
• cheap, low in toxicity, effective dose well below
  hypnotic level
• used today for general anesthesia

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Drug abuse problems !phenobarbitone (purple
hearts)pentobarbitone (yellow
jackets)secobarbitone (red devils)amobarbitone
(blue angels)
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The End

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