DRUG DEPENDENCE AND DRUG ABUSE

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DRUG DEPENDENCE AND DRUG ABUSE
Leo Fuksa, MSc. Martin terba, PharmD.,
Ph.D. Department of Pharmacology Faculty of
Medicine in Hradec Kralove
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DEFINITIONS

• DRUG DEPENDENCE - state when drug-taking becomes
  compulsive, taking precedence over other needs.
  Syn. substance dependence
• DRUG ADDICTION - is not clearly defined but
  implies a physical dependence, however, sometimes
  it is used as a syn. to drug (substance)
  dependence
• DRUG ABUSE - more general term, includes
  recurrent use of any illegal/harmful substance,
  e.g., in sport
• TOLERANCE - the decrease in a pharmacological
  effect on repeated administration of the drug
• imply the need to increase the dose to reach the
  pharmacological effect of the same intensity on
  repeated administration of the drug
• often accompanies the state of dependence
• WITHDRAWAL (syn. ABSTINENCE) SYNDROME - adverse
  effects, both psychological and physical, of
  stopping taking a drug. Distinguish commonly
  observed rebound phenomenon from the true
  dependence.
• REWARDING EFFECT important and common feature
  of psychoactive addictive substances.

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Tolerance induction

• Two major mechanisms
• Pharmacokinetic (auto-induction of enzymes
  responsible for drug metabolism, e.g., in
  barbiturates)
• Pharmacodynamic (tissue type)
• changes in receptor density (downregulation in
  most of drugs in this topic the agonists)
• changes in receptor sensitivity
  (desensitisation, adaptation at the level of
  second messengers)

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• process of habituation, or adaptation, is coupled
  with the direct rewarding effect of the drug when
  the drug is given repeatedly or continuously
• cessation of the drug leads to the aversive
  effect (negative reinforcement) from which the
  subject will attempt to escape by
  self-administration of the drug
• Dependence types and conditions
• psychological dependence result of
  positive/negative reinforcement associated with
  drug aadministration.
• Drug withdrawal ? craving
• physical dependence (tolerance and withdrawal
  syndrome)
• conditioning - significant especially in
  sustaining psychological dependence-effect of
  environment, perception of stimuli associated
  with pleasurable experiences

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REWARD PATHWAYS

• virtually all dependence-inducing drugs so far
  tested, including opioids, nicotine, amphetamine,
  ethanol and cocaine, activate the REWARD PATHWAY
  - mesolimbic dopaminergic pathway, which runs via
  the medial forebrain bundle, from the ventral
  tegmental area (VTA) of the midbrain to the
  nucleus accumbens and limbic region
• ? positive reinforcing effect
• addictive drugs increase the release of dopamine
  in the nucleus accumbens even though primary
  sites of action are generally elsewhere in the
  brain
• the hedonic effect of dependence-producing drugs
  results from activation of this pathway, rather
  than from a subjective appreciation of the
  diverse other effects (e.g. alertness or
  stimulation)
• Importance for drug-seeking behaviour

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Classification of drugs (substances) of abuse

• nicotine (tobacco)
• ethanol
• cannabis
• psychotomimetic drugs (hallucinogens)
• psychomotor stimulants
• opiates
• CNS depressants (sedatives/hypnotics)
• solvents

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NICOTINE AND TOBACCO

• Originally, Nicotiana plant growing, tobacco
  chewing and smoking was common only on American
  subcontinent
• It was brought to Europe during 16th century
• currently, estimation is that 18 of world
  population are smokers, the number rapidly
  increases in the third-world countries, while it
  has been slowly declining in developed countries
• the only pharmacologically active agent in
  cigarette smoke is nicotine, apart from the toxic
  carcinogenic tars and carbon monooxide
• An average cigarette provides about 0.8-1.5 mg of
  nicotine

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• MECHANISM OF ACTION
• Nicotine is an agonist on nicotinic acetylcholine
  receptor, ligand-gated cation channels type,
  widely expressed in brain, in cortex and
  hippocampus, supposed to play a role in cognitive
  function
• ? neuronal excitation and enhanced
  transmitter release
• EFFECTS
• central mixture of inhibitory and excitatory
  effects increased alertness, reduction of
  anxiety and tension, decreased appetite (? lower
  average body weight in smokers ? 4 kg)
• peripheral NN-receptors in autonomic ganglia
  tachycardia, ?blood pressure, ?cardiac output,
  ?GIT motility,, first dose vomiting (stimulation
  of sensory receptors in the stomach)
  NM-receptors tremor, skeletal muscle relaxation

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• Pharmacokinetic aspects
• during smoking cca. 10 of nicotine contained in
  a cigarette is absorbed
• Absorption rapid from the lungs (when smoking a
  cigarette) or more slowly from the mouth and
  nasopharynx (when smoking a cigar or a pipe)
• following drop in nicotine plasma concentration
  is due to distribution from blood to other
  tissues and later slow decrease caused by
  nicotine liver metabolism in to inactive cotinine
• nicotine patch applied for 24 hours causes plasma
  concentration to rise to 75-150 mmol/l over 6
  hours and to remain mainly constant for about 20
  hours
• In smokers there is an induction of liver and
  intestine CYP450s ? decreased effects of some
  drugs (e.g., theophyline)

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Tolerance and dependence

• very quick tolerance to peripheral (not central)
  ganglionic stimulation, perhaps due to
  desensitization of receptors
• addictiveness of smoking is solely caused by
  nicotine
• withdrawal syndrome craving ! increased
  irritability, anxiety, impaired performance of
  psychomotor tasks, aggressiveness and sleep
  disturbances, headache increased appetite lasts
  for 2-3 weeks
• highly addictive with the very strong
  psychological component (craving most commonly
  hampers efforts to give up)

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Harmful effects of smoking

• smoking - greatest preventable cause of death it
  is responsible for 10 adult deaths worldwide
  (estimation is 17 in 2030)
• CANCER - lung (the upper respiratory tract,
  oesophagus)
• 20 cigarettes/day is estimated to increase the
  risk about 10fold 90 of lung cancer is due to
  smoking tar is responsible !
• Low tar cigarettes smokers puff harder
• CORONARY HEART DISEASE AND OTHER FORMS OF
  PERIPHERAL VASCULAR DISEASE nicotine and carbon
  monoxide
• CHRONIC BRONCHITIS - smoking remains the main
  cause of this disease in developed countries
• HARMFUL EFFECTS IN PREGNANCY -significant
  reduction in birth weight, increased perinatal
  mortality, retardation in mental and physical
  development
• Acute Intoxication after swallowing
  cigarettes/butts risk in children (1-2 peaces)
  ? salivation, vomiting, arrhythmias and/or
  convulsions (fatality is mostly reduced by
  vomiting)

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Treatment of nicotine dependence

• Most smokers would like to quite but few succeed
• Combination of psychological and pharmacological
  treatment achieve success rate about 25 (after 1
  year)
• Nicotine replacement therapy
• Nicotine in patches (controlled release), chewing
  gums, nasal sprays several times daily (short
  effect)
• Adjunct therapy
• Bupropion (NDRI, even in non-depressed patients!
  Mechanism an increase in dopamine activity in
  nucleus accumebens?)
• Clonidine rarely used due to the side-effects
  (hypotension, drowsiness)
• Are there any positives of nicotine and
  smoking?
• Decreased incidence of both Parkinsons and
  Alzheimers disease?

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ETHANOL

• most commonly taken substance leading to physical
  dependence (it is legal for adults!)
• content in beverages varies from 3.5 (weak beer)
  to 40-50 (spirits)
• single drink usually contains 8-12g of ethanol
• intake expressed in units (1 unit 8g)
• ? current official recommendation is a maximum
  of 3 drinks/day for MEN, 2 drinks/day for WOMEN
• alcohol dependence (alcoholism) occurs in 4-5
  of European population

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Pharmacokinetics of ethanol

• rapid absorption after oral administration
  (measurable concentration after 5 min),
  immediately from the stomach
• Wide distribution to the whole body fluids
• More than 90 of ethanol is metabolised, less
  than 5-10 excreted unchanged in expired air and
  in urine (but this fraction is not significant
  from PK point of view, however, it is used for
  plasma conc. estimation)
• Saturation character of metabolism ? linear fall
  of plasma concentration
• Significant first pass effect (drinking on empty
  stomach ? higher effects)
• Main metabolism via 2 subsequent oxidations
• a) cytoplasmic alcoholdehydrogenase
  (?acetaldehyde)
• b) aldehydedehydrogenase (?acetic acid)
• this enzyme can be inhibited by various
  substances ?disulfiram effect (disulfiram but
  also chlorpropamide, nitrofurantoin etc.)
• Symptoms nauzea, flushing, tachycardia,
  hyperventilation, panic.
• Alternative metabolic pathway MEOS - microsomal
  ethanol oxidizing system - minor alcohol ?
  acetaldehyde pathway, inducible in alcoholics.

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Limiting factor for ethanol metabolism is a NAD
availability
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Genetic factors in ethanol metabolism

• 50 Asians have the inactive isoform of
  aldehydedehydrogenase experiencing
  disulfiram-like reaction after alcohol intake
• Another group of Asian population has an isoform
  of alcoholdehydrogenase with lower activity
  increased effects and excessive drinking
  behaviour
• American indians?

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Pharmacological effects of ethanol

• 1. CNS EFFECTS
• - mainly depressant action at the cellular level
• - three main theories
• enhancement of GABA-mediated inhibition, similar
  to that of benzodiazepines (different binding
  site)
• inhibition of Ca2 entry through voltage-gated
  calcium channels
• inhibition of NMDA-receptor function
• relationship btw plasma concentration / effect
  is highly variable
• symptoms of acute intake
• - slurred speech, euphoria, motor incoordination,
  increased self-confidence, decreased
  concentration and learning ability.
• - higher plasma levels lead to mood lability,
  later ataxia, stupor and coma, death from
  respiratory failure
• - Rather excitatory effects in low doses are
  attributed to neuronal desinhibition

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Ethanol plasma concentrations vs. CNS effects
!!!! alcohol potentiate the effects of other
drugs with central depressant effects
barbiturates, benzodiazepines, H1-anithistamines.
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Pharmacological effects of ethanol

• 2. effect on peripheral systems
• - cutaneous vasodilatation warm feeling,
  sweating ? heat loss
• - ?diuresis (due to ?ADH secretion)
• - heart rate ?blood pressure
• - ?salivatory and gastric secretion
• - ?concentrations of hydrocortisone
• - ? oxytocin secretion (delay in parturition at
  the term)

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Tolerance and dependence

• The major component is tissue tolerance it
  develops over 1-3 weeks of continuing
  administration 2-fold decrease in alcohol
  potency. There is a cross-tolerance with many
  anaesthetics (e.g. halothan, problems with
  alcoholics)
• Mechanism not well explained, changes in CNS
  neurons down-regulation of GABAA-receptors,
  up-regulation of voltage-gated Ca channels and
  NMDA receptors?
• Minor tolerance component - increased metabolism
• Physical abstinence syndrome develops, in severe
  forms, after cca 8 h (culminating in 24-36h)
  tremor, nausea, sweating, fever, occasionally
  hallucinations and epilepsy-like seizures!
• delirium tremens over few following days
  confusion, agitation, aggression, unpleasant
  hallucinations
• Anorexia, tremor, nausea, vomiting and anxiety
  might be present even 2 weeks later

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Harmful effects of chronic alcohol abuse

• Behavioural defects loss of self-control,
  reliability and productivity, disrupted social
  and family network
• Neurological disorders CNS damage associated
  with dementia, peripheral neuropathies (thiamine
  deficiency).
• GIT disturbances gastritis, peptic ulcers and
  GIT bleeding, hematemesis.
• Liver damage fatty liver, progression to
  hepatitis and eventually to irreversible hepatic
  necrosis and fibrosis
• Mechanisms (rather complex)
• Cummulation of NAD dependent substrates
  lactate, hydroxybutarate, a-glycerofosfate ? ?
  gluconeogenesis ? hypoglycaemia ? ? triglyceride
  synthesis
• ? release of fatty acids from adipose tissue
• impaired fatty acid oxidation due to metabolic
  load of ethanol itself
• Diverted portal blood flow ? oesophageal varices
  and bleeding
• Biochemistry Gamma glutamoyl traspeptidase (ALT,
  AST, bilirubin.)
• Pancreatitis ?secretin production, ?pancreatic
  enzyme, Oddi sphincter oedema ? partial pancreas
  autodigestion (other factors like ROS)

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• Ethanol fetal development
• FAS (fetal alcohol syndrome)
• typical of anatomical, mental and behavioural
  abnormalities
• - facial development, reduced cranium size
• - retarded growth
• - mental retardation and behavioural
  abnormalities
• ARND (alcohol-related neurodevelopmental
  disorder)
• - less serious than FAS (3x more common),
• - behavioural, cognitive and motor deficits

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Treatment of alcoholism

• Disulfiram blockade of aldehydedehydrogenase ?
  cummulation of acetaldehyde - nausea, flushing,
  tachycardia, hyperventilation, panic
• Aim to make alcohol consumption unpleasant and
  intolerable
• Naloxone reduces alcohol-induced reward
  (unclear mechanism)
• Acamprosate anti-craving effects (also
  naltrexon)
• The drugs used to alleviate the acute abstinence
  syndrome benzodiazepines, clonidine (inhibits
  exaggerated neurotransmitter release) and
  propranolol (blocks excessive sympathetic
  activity).

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CANNABIS and Cannabinoids

• extracts of the hemp plant (Cannabis
  sativa,Canabis indica) originally from Himalaya
  and Kashmir
• Marijuana - dried leaves and flower heads
• Hashish - extracted resin
• active substances cannabinoids (lipophilic
  non-alkaloid natural compounds)
• THC (?9-tetrahydrocannabinol) most abundant and
  active cannabinoid
• THC constitutes 0.5-10 of marijuana and hashish
  preparations
• routes of administration mainly inhaled in
  cigarette smoke (joint) or orally as an
  ingredient in various meals or beverages

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• Pharmacological effects
• On CNS combination of psychotomimetic,
  depressant and centrally mediated peripheral
  effects
• central effects
• a feeling of relaxation, well-being and euphoria
  - without accompanying aggression
• Uncontrolled laughing without reason
• a feeling sharpened sensory awareness, with
  tastes, sounds and sights more intense and
  fantastic
• impairment of motor coordination (driving),
  short-term memory and judgement. Feeling of time
  passing slowly, depersonalisation increased
  appetite and
• Analgesia, antiemetic action
• In high doses hallucination, paranoia, anxiety
• peripheral effects
• vasodilatation (obvious on conjunctive vessels)
• tachycardia
• Bronchodilation (but opposite may appear during
  smoking)
• reduction of intraocular pressure

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Mechanism of action

• Through cannabinoid receptors (GPCR type)
• CB1- brain highly abundant in hippocampus
  (memory), cerebellum (loss of coordination), and
  substantia nigra (motor disturbances),
  hypothalamus (appetite) and mesolimbic
  dopaminergic pathway (reward) and cortex.
• Mostly localised presynaptically their
  activation inhibits neurotransmitter release
• Their paucity in the brain stem ? lack of
  serious respiratory and cardiovascular toxicity.
• Endogenous agonist anandamide
• CB2- periphery - immune system
  (immunosuppressive effects?!)

Pharmacokinetics - lipophilic
compound - well absorbed, highly bound to
plasma proteins, widely distributed and partially
sequestrated in body fat ? excretion lasts
for days (can still be detected in urine)
- liver metabolism to mostly inactive metabolites
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Tolerance and drug dependence

• Tolerance and physical dependence occur only to a
  minor degree in heavy users
• Withdrawal syndrome weak and usually mild
• irritability, restlessness, confusion, sweating
  tremor and sleep disturbances

Harmful effects - Relatively safe from the
viewpoint of acute drug overdose - Problems are
rather with chronic use Somatic effects
decreased testosterone and sperm count
Long-term psychological changes apathy, impaired
memory and decision ability, may promote
schizophrenia in pre-disposed patients -
Gateway drug???
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Therapeutic use of cannabinoids?

• Synthetic analogues
• Nabilone and dronabilone
• Potential indications
• Antiemetic therapy in cancer chemotherapy
• Analgesia
• Glaucoma
• Multiple sclerosis
• Therapeutic values and utility?
• Legal limitations

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Psychotomimetic drugs (hallucinogens,
psychedelics)

• affect thought, perception and mood without
  causing psychomotor stimulation or depression
• Effects thoughts and perceptions tend to become
  distorted and dream-like, colours and sounds are
  more sharp. Induction of euphoria and happiness.
• Different kind of hallucination (visual,
  auditory, tactile and olfactory appear). Thought
  process tend to be illogical and disconnected
  but subject mostly retain insight that these
  effects are drug-induced. Increased sense of
  empathy.
• Major groups/drugs (different classification in
  literature)
• LSD and related compounds (psilocybin, mescaline)
• MDMA and related compounds
• Phencyclidine and ketamine

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• LSD (Lysergic acid diethylamide, LSD-25)
• Originally produced as a drug candidate in Sandoz
  Labs in 1938 by Albert Hoffman today no medical
  use!
• It is among the most potent drugs known so far
  (dose 1 ?g/kg)
• Abused in the form of papers- trips (low
  amounts of LSD)!
• Good trips vs bad trips
• flash backs may appear even months later
• Mechanism of action acting on different 5-HT
  receptors in CNS
• mainly as agonist on 5-HT2A autoreceptors in CNS
  ? ? firing of 5-HT neurons in Raphe nuclei (even
  in spiders bizarre/erratic webs)
• Somatic effects sympathomimetic (?blood
  pressurere and HR)
• neurological
  (tremor, ataxia)
• Mescaline (from Mexican cactus Lophophora)
• Psilocybin (from fungus Psilocybe e.g.
  Bohemica)
• Tolerance develops quickly (on CNS effects)
• Adverse effects and dangers persistent mental
  disorder, schizophrenia, injury due to violent
  behaviour

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Other hallucinogens

• MDMA (MethylenDioxyMethAmphetaminem, ecstasy)
• Dance-floor drug
• Stimulant and hallucinogenic effects (related to
  amphetamines)
• Danger in acute overdose exhaustions,
  dehydratation, hyperpyrexia, arrhythmias
• Phencycline (angel dust, PCP)
• Chemically related to ketamine (anaesthetic drug)
  and originally also developed as a drug with this
  indication
• Not so frequent among abusers, unpleasant
  vegetative effects
• Some delusions and/or hallucination may turned
  into the violent behaviour

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PSYCHOMOTOR STIMULANTS

• 1)AMPHETAMINES AND RELATED DRUGS
• 2)COCAINE
• 3)METHYLXANTINES (CAFFEINE CO.)

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Amphetamines and related compounds

• substances amphetamine (speed), methamphetamine
  (pervitine) and other drugs like ephedrine,
  phentermine, methylphenidate and MDMA.
• Routes of administration oral, nasal, inhalation
  and parenteral
• Mechanism of action indirect CNS
  sympathomimetic effect release of monoamines
  (noradrenaline, dopamine, or 5-HT) from nerve
  terminals in the brain
• Main effects on CNS locomotor stimulation,
• euphoria and excitement, increased
  self-confidence, stereotyped behaviour,
  resistance to fatigue, decreased appetite,
  anorexia
• Peripheral effects tachycardia and palpitations,
  ?blood pressure, ?GIT motility
• Morning after intoxication fatigue,
  depressions, anxiety

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Amphetamines and related stimulants

• Tolerance develops rapidly to the peripheral
  sympathomimetic and anorexic effects, but more
  slowly to the central effects
• no clear-cut physical withdrawal syndrome ?
  dependence seems to be a consequence of the
  unpleasant after-effects (i.e. fatigue, lethargy,
  anxiety, depression, hunger) and the effort to
  avoid them
• full-blown dependence occurs in 5 of users
  characterized by strong craving, increased doses,
  and common uncontrolled runs)
• Amphetamine psychosis closely resembles the
  Schizophrenic attack incoherent thought,
  hallucinations, paranoia, aggression.
• Therapeutic use minimal e.g., narcolepsia,
• phentermine (rather obsolete use in the
  treatment obesity)

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COCAINE

• alkaloid of South American shrub Erythroxylon
  coca
• the most expensive drug illegally sold
• Routes of administration salt - nasal or i.v.
  (rush effect), free base smoking-inhalation
  (crack, flush effect)
• MECHANISM OF ACTION
• inhibition of catecholamine Re-uptake ? increase
  noradrenaline and dopamine transmission
• indirect sympathomimetic agent
• Pharmacological effects very similar to those
  of amphetamines yet less prone to cause
  stereotyped behaviour, paranoia, delusions
• Duration of effect is much more shorter (30 min,
  i.v.) than in amphetamines, rapid metabolism
  liver and plasma esterase (hair deposit of
  metabolites).
• no clear-cut physical dependence syndrome but
  depression, tiredness and dysphoria coupled with
  very intensive craving for the drug (strong
  psychological dependence)

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Cocaine

• Tolerance in most abusers is on rush/euphoria
• Intoxication (overdose) tremor, hypertension,
  tachycardia, arhythmias, cardiac pain,
  hyperpyrexia, convulsions and shock even with
  fatal consequences
• Long term abuse
• Characteristic behavioural changes paranoia,
  anxiety, aggression, loss of social contacts
• Increased risk of coronary and cerebral
  thrombosis
• slowly developing damage to myocardium leading to
  heart failure may appear
• Cocaine used in pregnancy impairs fetal
  development and produces fetal malformations
• Therapeutic use rarely as a local anaesthetic
  drug in ophthalmology (event. nose/throat surgery)

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METHYLXANTHINES

• natural alkaloids occurring in various beverages,
  namely tea, coffee, cocoa and cola-flavored
  drinks
• substances caffeine, theophylline, theobromine
• a cup of coffee or strong tea contains 50-100 mg
  of caffeine
• Pharmacological effects
• CNS stimulation
• diuresis (vasodilatation of the afferent
  glomerular arteriole)
• stimulation of cardiac muscle
• relaxation of smooth muscle, especially
  bronchial.
• MECHANISMS
• inhibition of phosphodiesterase, responsible for
  intracellular metabolism of cAMP
• antagonism on both A1 and A2 adenosine receptors
• tolerance and habituation develop to a small
  extent and withdrawal effects are very slight
  (headache, fatigue)

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OPIOIDS

• Abused drugs heroin, morphine, codeine but also
  other drugs from this group (historically also
  opium, occasionally today)
• Psychotropic effects are route of administration
  dependent
• i.v. - rush and flush effect (orgasm and
  warm feeling)
• Oral euphoria and happiness, well-being
• Other routes nasal, inhalation (smoking) other
  parenteral (s.c.)
• Mechanism
• Opioid receptors for abuse dependence mainly
• ? -receptor subtype!
• Tolerance
• On most effects develops quite quickly (including
  euphoria and toxicity respiratory depression,
  chronic abusers tolerate doses which might induce
  respiratory failure in a normal subject)
• Exceptions miosis and constipation
• Mechanism unclear, it seems to be neither of PK
  origin nor due to the receptor down-regulation

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Opioids

• Dependence strong both physical and
  psychological
• Clear-cut withdrawal syndrome
• - early symptoms (8-12 after last dose of
  heroin)
• profuse nasal and ocular secretion, sweating and
  yawning, piloerection cold turkey
  (influenza-like symptoms)
• - later symptoms (maximum in 2-3 days, disappear
  in 7-10 days)
• mydriasis, tremor, hyperalgesia, nausea,
  diarrhoea, insomnia and typical abdominal cramps
  and colic pain
• Some residual symptoms and physiological
  abnormalities persist for several weeks
• - can be suddenly induced by the administration
  of antagonist (naloxone, possible complication
  in treatment of the acute overdose)
• Psychological dependence intensive craving

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• Treatment
• Methadone - similar to morphine
• duration of action is considerably longer (t0.5
  24 h)
• the physical abstinence syndrome is less acute
  than with
• morphine
• main use is treatment of morphine and heroin
  addiction
• in a patient taking methadone, the injection of
  morphine does
• not cause expected euphoria
• AIM to get the addicts away from morphine and
  heroin by
• treating them with regular oral dose of
  methadone
• best treated by specialized addiction clinics
  and centres
• Heroin lung case report!!!!

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Sedative/hypnotic drugs

• Barbituretes and benzodiazepines
• Mechanism of action barbiturate and
  benzodiazepine receptors on GABA-A receptor
  complex (coupled with chloride channels)
  increase response to the endogenous ligand -GABA
• Tolerance (among major drawbacks)
• In both groups - but in barbiturates it is more
  pronounced (PK type)
• In barbiturates - lack of tolerance on toxicity!
  Danger!
• Both groups may induce psychological and physical
  type of dependence (markedly more likely, sever
  and earlier onset in barbiturates!!!) Do not
  suddenly stop chronic treatment (t1/2)!
• Withdrawal syndrome nervousness, restlessness,
  tremor, anxiety, confusion, dizziness, delirium,
  convulsions! See the case report!!!!
• Risk of acute intoxication and respiratory
  depression is much greater with barbiturates! BZD
  are safer but severe cases often appear when they
  are combined with alcohol!!!

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Solvents

• Different lipophilic organic solvents act as
  unspecific narcotics (e.g., toulene, acetone)
• Route of administration inhalations (plastic
  bags)
• Lower doses desinhibition and euphoria,
  pseudohallucinations, pleasant dreams
• High doses? profound CNS depressant effect, coma
  and respiratory failure
• Extremely dangerous and highly likely acute
  overdose with potentially fatal consequences
• Chronic abuse neurodegenaration behavioural
  and mental disturbances
• Other toxicities according to the specific
  chemical - e.g., hepatotoxicity, pulmonary
  hypertension