The Development of Drug Tolerance and Physical Dependence

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The Development of Drug Tolerance and Physical
Dependence

• C.H. Cho
• Department of Pharmacology

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Tolerance Body adaptation to drugs larger
doses are required to produce the original
effects Physical dependence Appearance of
objective signs when drug is deprived
abruptly Psychological dependence Strong desire
to experience the effects of the drug repeatedly
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Hypothesis Common mechanisms between opiates
sedatives in tolerance dependence. Evidences
1. Morphine endorphines release, alcohol
does the same 2. Naloxone inhibits
development of alcohol dependence, the
central depressive effects of alcohol
benzodiazepines 3. Naloxone- ppt withdrawal
in morphinized rats can been suppressed by
alcohol 4. Morphine convulsion due to
alcohol withdrawal
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• Pharmacological basis of dependence tolerance
• Alteration of metabolic pathways Stimulation of
  hepatic
• enzymes responsible for its metabolism
• 2. Cellular adaptation Secondary to protein
  synthesis
• 3. Activation of parallel biochemical systems
  Stimulation of
• the 2nd compensatory pathway
• 4. Denervation of supersensitivity Depression of
  presynaptic
• release of neurotransmitters
  supersensitivity of
• postsynaptic receptors

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• Alternation of in neuroregulatory function
  Noradrenergic
• mechanism opiates firing of neurons and
  release of
• norepinephrine, abrupt withdrawal
  rebound
• secretion of norepinephrine
• Cholinergic
• mechanism morphine Ach release, increase
  dose is
• needed to achieve this, discontinuing results in
  outpouring
• of Ach
• Changes in receptor number Chronic morphine
  m?
• receptor density opiate gene expression
  tolerance
• Depression of c-AMP release Morphine
  administration
• basal PG-mediated in cAMP level. Continued
  
• administration back to normal adenylate
  cyclase activity

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• Evidences A. phosphodiesterase inhibitors
  produce effects
• similar to opiate withdrawal
• B. Effects of morphine on cAMP
  can be
• blocked by naloxone
• C. withdrawal markedly
  increases cAMP
• Role of Ca Ca is involved in the neuronal
  function
• of opiates, i.e. lowering neuronal Ca
• Evidences A. Ca and its ionophores
  opiate action
• B. Ca antagonist enhance
  opiate action
• C. Abstinence syndrome can be
  attenuated by
• reducing neuronal Ca
• D. Acute opiate lowers
  neuronal Ca

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• E. Chronic opiate elevates neuronal Ca
• F. Ca lowering analgesia, Ca
  elevating
• hyperalgesia
• G. Loss of sequestered Ca with abrupt
• discontinuation
• Severity of Withdrawal Symptoms
• Individual susceptibility
• Pattern of drug use interval and duration

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• Intensity of drug effects is governed by
• The concentration of the drug at the site of
  action
• dose pharmacokinetics
• 2. The sensitivity of the target cells
• Tolerance

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• Tolerance
• Mechanisms differ with drugs
• Pharmacokinetics absorption, metabolism,
• distribution excretion
• 3. Pharmacodynamics adaptive changes
• neurotransmitters release receptors

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• Cross Tolerance
• Development of tolerance to one drug confers
• tolerance to another drug, e.g. barbiturates,
  alcohol
• other sedatives/hypnotics
• Similarities in mechanisms of action
• Common in sedative-hypnotics, psychostimulants,
• alcohol-inhaled general
  anesthetics

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Cross tolerance metabolic Two drugs
metabolized by the same enzymes, therefore one
drug would enhance the metabolism of
other Cross tolerance CNS Drugs produce
similar psychological effects with the same
adaptive mechanisms
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• Dependence
• It is an adaptive state and has the following
  properties
• Need to continue to take a drug
• pleasure prevent withdrawal
• Appearance of symptoms when abruptly suspended
• Need to increase the dose to sustain the initial
  effects

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• Facts about Dependence
• Dependence requires a period of continued
  exposure
• Dependence is accompanied by tolerance to the
• acute effects of opiate
• Withdrawal syndrome can be suppressed by
• retreatment with opiate
• Withdrawal disturbance can be ppt with
  antagonist

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• Induction of dependence requires the activation
  of a
• specific opiate receptor
• Clonidine inhibits the opiate withdrawal
  disturbance

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• Drug Dependence
• Physical dependence
• The body has adjusted to the presence of a
• drug to avoid withdrawal symptoms
• Symptoms of drug withdrawal tend to be opposite
• of the effects produced by the presence of the
• drug in the body
• Long-acting drugs produce less withdrawal
• symptoms

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• Psychological Dependence
• Craving for a drug is the most common withdrawal
  
• symptom leading to continued self-administration
• compulsive drug taking
• Desire to experience the effects of the drug
• Psychological physical dependences are not
• mutually exclusive

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• Management of Withdrawal
• Non-pharmacological approach
• reassurance, personal attention general
  nursing
• care
• 2. Pharmacological means
• Administration of a drug with cross tolerance
  but
• with milder withdrawal reactions
• Clonidine for withdrawal symptoms

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• Methods of detoxifying the patient who is
• physically dependent on abused drug
• Gradual withdrawal of the addicting agent
• Substitution of the addicted drug gradual
• withdrawal of the substitute agent
• Principle use longer acting agent