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									UNWANTED DRUG EFFECTS




        J. Mojžiš
  SIDE EFFECTS OF DRUGS
   WHO deffinition of drug side effects:

      any response to drug which is:
              • unexpected
          • damaging organism
• appearing in dosing used in prophylaxis,
  diagnosis or modification of physiological
             functions (therapy)
         Out of definition
• mistakes in dosing

• drug abuse

• accidental or suicidal intoxications

• inadequate dosing

• changes in bioavailability
  Occasionally

     - impurities
      - vehicle

- degradation products
          Type A
    (Augmented) reactions
• pharmacologically predictable
• usually cause low mortality
• occur at normal doses and tend to
  resolve on dose reduction
• the most common type of ADR (80% of
  all ADRs)
                 Type A

• reaction appears in whole population

• it is dose-dependent

• symptoms are similar to pharmacological
  properties of drug

• reaction can appear during first contact
  with drug
      Type A - mechanism

• the mechanism of action can vary:
a primary therapeutic action of the
 drug at its primary site
 (bradycardia with -blockers, haemorrhage with
 anticoagulants)
a primary action at a different site
 (GI bleeding with NSAID)
   They may be avoided by
• assessing predisposing factors e.g.
  genetics - slow acetylators may
  experience peripheral neuropathy with
  INH
• using low doses and adjusting to
  therapeutic end points e.g.
  antihypertensives and blood pressure.
• adjusting for renal or hepatic function
  e.g. avoid prolonged sedation with
  benzodiazepines in hepatic failure
                    Type B
              (Bizarre) reactions
• not predictably related to the pharmacology of the
  drug
• idiosyncratic and will occur only in some individuals
• not usually dose related  may have high mortality
• they include allergic reactions  reactions due to
  inherited abnormalities (haemolysis in G6PD deficiency)
• rarer (20% of all ADRs) (their occurrence will be
  minimised by taking drug history and family history and by
  avoiding certain drugs in certain disease states (NSAID in
  asthmatics)
• if an ADR of this type occurs, the drug must be
  stopped
       Type C
(Continuous) reactions

 due to long term use e.g. tardive
 dyskinesias with antipsychotics


       Type D
 (Delayed) reactions
    teratogenesis, carcinogenesis
               Type E
       (End of use) reactions

• this type of reaction may also be
  seen as the appearance of a
  symptom that did not exist before
  initiation of the therapy

 rebound convulsions on withdrawal of
  carbamazepine in non-epileptic patients
Severity of drug side effects
•   Mild: no interruption of treatment
    (antihistaminics  sedative effect)

•   Middle: change of regimen is needed
    (iron  nausea)

•   Severe: interruption of treatment is
    mandatory
    (PNC  anaphylactic reaction)
             1. Allergy
    Differs from toxicity in:
•    reaction appears only in part of
     population
•    it is not dose-dependent
•    symptoms differ from pharmacological
     effect
•    reaction is a result of previous
     sensitisation
•    allergene  protein or hapten 
     circulating antibodies are present
        Allergic reactions

• acute-anaphylaxis (circulating
  antibodies)
• delayed-tuberculine
  hypersensitivity (sensitised cells)
      Hypersenzitivity induction:
               • antigenes
                • haptens
      Hypersensitive reactions
           classification

• systemic (anaphylaxis, fever, vasculitis)
• skin (urticaria, erythema, photosensitivity)
• lung (asthma, pneumonia)
• hepatal (cholestatic, hepatocellular)
• renal (glomerulonephritis, interstitial nephritis)
• bone marrow (myelosuppresion)
Examples:
• anaphylaxis (hormones, enzymes,
  ATB, LA)
• fever (ATB, sulfonamides)
• skin (majority of drugs)
• lung (ASA, ATB)
• liver (imipramine, INH)
• kidneys (allopurinol, captopril)
• bone marrow (majority of drugs)
         2. Teratogenity
• 1. week of pregnancy (embryo is killed if harmful
  drug acts)

• 1. trimester-organogenesis (most dangerous
  stage for malformation development)

• rest of pregnancy – growth 
  development of some organ systems (CNS,
  endocrine, musculoskeletal)

• labour (application of drug to mother  direct or
  indirect effect in child-morphine)
    Physician responsability

• eliminate inadequate drug use

• the best risk / benefit ratio drug choice

• information of pregnant patients

• exact diagnosis and evidence of
  malformations
  Examples:
• antineoplastics (high risk teratogenity)
• antiepileptics (applied with the risk of
  malformations)
• lithium (right heart damage)
• coumarines (nasal hypoplasia, growth
  retardation)
• antithyroidal drugs (fetal hypothyroidism)
• TTC (interference with calcification)
            GENDER- pregnancy
     C o n f i r m e d teratogens (in h u m a n s):
thalidomide (phocomelia), cytostatics-antimetabolites,
lithium (cardiac defects), warfarin (chondrodysplasia
punctata), sex hormones (cardiac defects, multiple
abnormalities)

     S u s p e c t e d teratogens (evidence is inconclusive,
the impact of diseases?): antiepileptics (phenytoin,
carbamazepine- craniofacial defects),

    P o t e n t i a l teratogens (in a n i m a l s):
 chemotherapeutics (metronidazole), sulphonamides-
trimethoprim
 Gross malformations
thalidomide - phocomelia
      3. Carcinogenity
Examples:

• antineoplastics (secondary
  malignities)

• diethylstilbestrol (vaginal ca)
    How to minimize drug side
             effects
•   individualisation of therapy
•   information about interactions
•   relatively frequent in newborns or
    elderly
•   more frequent in prolonged therapy
•   identify initial symptoms of side
    effects (patients)
•   optimalisation of pharmacotherapy
DRUG DEPENDENCE
  DRUG ABUSE
   CANNABIS
Cannabis sativa L.
         • MAIN PSYCHOACTIVE
           SUBSTANCE

         • (-)-trans-delta-9-
           tetrahydrocannabinol

         • TETRAHYDROCANNABIN
           OL CONTENT (%)

         • Herbal cannabis 0.5 - 5
         • Cannabis resin 2 - 10
         • Cannabis oil    10 - 30
                CANNABIS
  Common illicit forms-        Common illicit forms-
            plant                        resin
• loose herbal material,   •   fine powder
  blocks of compressed     •   fine powder
  herbal material              compressed
• vegetable fibre herbal   •   compressed resin
  material                     pressed or rolled
                                   Abuse pattern
     Abuse pattern         •   Smoked (alone, or
• Usually smoked (0.5 to       mixed with tobacco
  1g of plant material)    •   Orally ingested (food,
                               tea)
                     CANNABIS

    Common illicit forms-oil   Certain common street
• dark viscous oil                      names
         Abuse pattern
• Smoked (1 - 2 drops put on
                                    • marihuana
  tobacco or wiped on paper)
                                      • khif
• Orally ingested

                                     • hashish

                                    • honey oil
                                       red oil
                              CANNABIS
             PHARMACOLOGICAL EFFECTS
•   Sought-after effects
•   sense of well being, euphoria, pleasurable state of relaxation
•   enhancement of sensory experiences (sight, smell, taste and hearing)
•   Short-term effects
•    increased appetite
•    increased pulse rate
•    reddening of the eyes
•    impaired intellectual and physical performance
•    with larger doses sensations may be sharpened
•    thinking becomes slow and confused
•    in very large doses, the effects of cannabis are similar to those of a hallucinogen
•    may cause anxiety and panic, or precipitate a psychotic episode
•    Long-term effects
•    development of moderate tolerance
•    possible psychological dependence
•    loss of interest in sustained activity
•    Cannabis smoke contains 50% more tar than smoke from cigarette; with regular
    use, risk
     of lung cancer, chronic bronchitis, and other lung diseases increases
                      CANNABIS
                       MEDICAL USE
          THC (manufactured synthetically, dronabinol)

• anti-emetic substance in cancer chemotherapy
• to stimulate appetite, especially in AIDS patients

     Possible therapeutic uses of cannabis (plant material)

•   to ease nausea and vomiting from cancer chemotherapy
•   to stimulate appetite, especially in AIDS patients
•   to lower intraocular pressure associated with glaucoma
•   to decrease muscle spasms, for instance, associated with
    generalized epilepsy
        COCA
Coca Bush (Erythroxylon)
            • MAIN
              PSYCHOACTIVE
              SUBSTANCE

            • Cocaine

            • COCAINE CONTENT
              (%)

            • Coca leaves 0.5 - 2.5
            • Coca paste 30 - 80
            • Crack up to 90
                            COCA
        Coca leaf                       Coca paste
• green to yellow-greenish    • can vary from a brown gummy
        elliptical leaves       material to an off-white creamy
                                   or beige coloured coarse
 Pattern of use/abuse                       powder

        • chewed
    •   brewed as tea             Pattern of use/abuse
                              • smoked / inhaled (alone, or
                                mixed with tobacco)
                              • orally ingested
                           COCA
 Cocaine, crack, free base         Certain common street
• white or off-white crystalline            names
  powder with a characteristic
  odour
• crack: hard white rocks                • bazuco (paste)
    Pattern of use/abuse
• Cocaine: sniffed/snorted                •   crack
  smoked
• Crack/Free base: injected              • star dust
                                COCA
           PHARMACOLOGICAL EFFECTS
• Sought-after effects
•   feelings of physical and mental well being, euphoria
•   increased alertness and energy
•   postponement of hunger and fatigue

• Short-term effects
•   loss of appetite
•   faster breathing, increased heart rate and blood pressure
•   increased body temperature, sweating, dilation of pupils
•    bizarre, erratic, sometimes violent behaviour
•   larger doses: hallucinations, sense of power and superiority, restlessness,
    hyperexcitability, irritability which can lead to panic and paranoid
    psychosis (disappears if discontinued)
•   excessive doses may lead to convulsions, seizures, stroke, cerebral
    hemorrhage or heart failure
                             COCA
          PHARMACOLOGICAL EFFECTS

• Long-term effects
• destruction of tissues in nose if sniffed
• respiratory problems if smoked
• infectious diseases, abscesses, if injected
• malnutrition, weight loss
• disorientation, apathy, confused exhaustion due to lack of sleep
• development of tolerance
• strong psychological dependence
• with continued use a state similar to paranoid psychosis may develop
• after stopping, there usually follows a long period of sleep and then
  depression
• during the crash, death from respiratory failure may occur
                 COCA
             MEDICAL USE




Cocaine as a local anaesthetic, in particular:

  • in surgery of the ear, nose and throat
             • never inject !
     OPIUM
     Opium Poppy
(Papaver Somniferum L.)
            • MAIN
              PSYCHOACTIVE
              SUBSTANCES
            • Morphine
            • Codeine

            • ALKALOID CONTENT
              (%)
            •   Morphine      4 - 21
            •   Codeine      0.7 - 3
            •   Thebaine      0.2 - 1
            •   Papaverine    0.5 - 1.3
            •   Noscapine    2-8
                        OPIUM
         Raw opium                  Medicinal opium
• sticky or hard, dark brown   • fine brown powder
  material in any form         • pastilles
       Abuse pattern           • syrup
• smoked
• chewed
                                         Production
• eaten
                                  • pulverizing of raw opium
                                  • drying at 60°C
                                  • adjusting morphine
                                    content (10%)
                         OPIUM
      Crude morphine             Certain common street
• finely ground powder                    names
• compressed blocks
• in many cases with "999"
  trade mark tablets
                             •      ah-pen-yen
                             •      noir(e)
       Abuse pattern         •      hop
            • injected       •      O
                             •      chandu
       Average dose          •      sukhteh

       • 10-20 mg
                             HEROIN
             HEROIN                         Certain common street names
•   Heroin is a semi-synthetic opiate
    synthesized from morphine           •    boy
                                        •    H
         Abuse pattern                  •    harry
•   injected                            •    horse
•   inhaled ("chasing the dragon")      •    joy powder
•   sniffed/snorted                     •    junk
•   Smoked                              •    smack
                                        •    white lady
          Average dose
                                        •    white stuff
• 5-15 mg, up to 250 mg a day
    OPIUM, MORPHINE, HEROIN
           PHARMACOLOGICAL EFFECTS
•   Sought-after effects
•   sense of well being by reducing tension, anxiety and depression
•   euphoria
•   in large doses warmth, contentment, relaxed detachment from
    emotional as well as physical distress
•   relief from pain (analgesia)
•   Short-term effects
•   sometimes nausea and vomiting
•   constricted pupils
•   drowsiness, inability to concentrate, apathy, lessened physical activity
•   acute overdose can result in death due to respiratory depression
  OPIUM, MORPHINE, HEROIN
          PHARMACOLOGICAL EFFECTS
• Long-term effects
• rapid development of tolerance and physical and psychological
  dependence
• constipation
• menstrual irregularity
• infectious diseases, abscesses, if injected
• damage of structures in nose, if sniffed/snorted
• respiratory problems, if smoked
• decreased appetite leading to malnutrition, weight loss chronic
  sedation
• apathy leading to self-neglect
• abrupt withdrawal results in moderate to severe withdrawal syndrome
  which is generally comparable to a bout of influenza (cramps, diarrhea,
  running nose, tremors, panic, chills and sweating)
    OPIUM, MORPHINE, HEROIN
                      MEDICAL USE


    Opium and opiates are still widely used in medicine


•   as analgesic (pain killer; e.g., morphine)
•   as cough suppressant (e.g., codeine)
•   against diarrhoea in some countries
•   heroin is under investigation for the maintenance therapy
    for heroin addicts
                         OPIOIDS
• Opioid is a generic term             Potency compared to
  applied to opiates and their               morphine
  synthetic analogues, with
  actions similar to those of
  morphine, in particular the
  capacity to relieve pain.
                                   •   fentanyl           80- 200
                                   •   -methylfentanyl   200-1000
         FENTANYLS                 •   carfentanil        3000
• are short-acting highly potent   •   Lofentanil         6000
  narcotic analgesics (pain
                                   •   3-methylfentanyl   7000
   killers).
                           OPIOIDS
       Common forms                   PHARMACOLOGICAL
• liquid pharmaceutical                    EFFECTS
  preparations for injection white   • Sought-after, short-term and
  / off-white to brown powders         long-term effects of the
                                       fentanyls are indistinguishable
        Abuse pattern                  from those of heroin, but they
                                       are up to hundreds of times
• injected intravenously
                                       more potent.
• smoked
• snorted
                                      Certain common street names
                                     • China white
         Average dose                • synthetic heroin
             1-50 µg
        OPIOIDS
       MEDICAL USE




 Fentanyls are mainly used:


       • as pain killers
• as anaesthetic during surgery
             CNS DEPRESSANTS
                    BENZODIAZEPINES
       Common forms                 Duration of action
• tablets and capsules
• liquids (gel) in capsules   • Alprazolam            short
• for injection               • Temazepam            short

                              • Flunitrazepam intermediate
        Abuse pattern
• orally ingested
                              • Diazepam         long
• injected
                              • Chlordiazepoxide long

         Average dose                       Half-life
                                        short: < 10 hours
                                   intermediate: 10-24 hours
    • 0.25 - 30 (100) mg
                                       long: > 24 hours
          BENZODIAZEPINES
          PHARMACOLOGICAL EFFECTS

• Sought-after effects

• relief of tension, mental stress and anxiety
• positive feelings of calmness, relaxation and well
  being in anxious individuals
• improved coping with situational pressures or
  psychological problems
• enhancement of the "high" induced by other drugs,
  or relief of side effects associated with over-
  stimulation or withdrawal of other drugs (i.e., as
  part of a pattern of multiple drug use)
                BENZODIAZEPINES
               PHARMACOLOGICAL EFFECTS

• Short-term Effects

• diminished emotional responses to external stimuli, e.g. pain

• reduced inhibition, mental activity and alertness; drowsiness, lethargy
  and impairment of clarity of thought and impaired judgement may
  occur

• initial increase of risk of accidental injury due to depressant effects

• with larger doses, possible impairment of muscle coordination,
  dizziness, low blood pressure, and/or fainting

• unlike barbiturates, large doses of benzodiazepines are rarely fatal
  unless combined with other drugs or alcohol
                 BENZODIAZEPINES
                PHARMACOLOGICAL EFFECTS

•    Long-term effects
•    headache, irritability, confusion, memory impairment, depression,
     insomnia and tremor as a result of chronic high dose use

•    development of tolerance:
1.   after two weeks - ineffective as sleeping pills
2.   after a few months - ineffective against anxiety

•    development of psychological and physical dependence

•    abrupt cessation after prolonged use leads to withdrawal syndrome
     (insomnia, anxiety, perceptual hypersensitivity, tremor, irritability,
     nausea and vomiting, and even mental confusion and life-threatening
     convulsions)
           BENZODIAZEPINES
                  MEDICAL USE


 Various benzodiazepines are used in medicine:

• as anxiolytic (treatment of anxiety and stress)
• as sedative-hypnotic in the premedication and
  induction of general anaesthesia
• as anti-epileptic and muscle relaxant
              CNS DEPRESSANTS
                          BARBITURATES
        Common forms                 Duration of action
•   white powders
•   capsules or tablets         • Secobarbital 3 hours
•   liquid preparations
•   Suppositories               • Pentobarbital 3 hours

         Abuse pattern          • Amobarbital    3 - 6 hours
• orally ingested
• Injected                      • Phenobarbital 6 -12 hours

        Average dose
     • 75-200mg
                    BARBITURATES
               PHARMACOLOGICAL EFFECTS

• Sought-after effects
• relief of tension, mental stress and anxiety
• positive feelings of pleasure, calmness, relaxation and sociability

•   Short-term effects
•   loss of motor coordination, decreased self-control
•   increased risk of accidental injury due to depressant effects
•   slurred speech, poor control of speech, impaired judgement
•   extreme, unpredictable emotional reactions and mental confusion,
    disorientation
•   respiratory depression, suppression of cough reflex
•   dilated pupils, weak and rapid pulse
•   in higher doses there can be "drunken" behavior, drowsiness, stupor,
    unconsciousness, coma
•   acute overdose can be fatal due to respiratory failure
                   BARBITURATES
              PHARMACOLOGICAL EFFECTS

• Long-term effects
• development of tolerance, strong physical and psychological
  dependence

• severe depression and amnesia after chronic use

• bronchitis, pneumonia (due to depressed cough reflex)

• infectious diseases and skin abscesses, if injected

• abrupt cessation of use leads to withdrawal syndrome which can
  include irritability, nervousness, progressive restlessness, sleep
  disturbances, nausea, anxiety, tremors, delirium and convulsions
              BARBITURATES
                  MEDICAL USE

  While barbiturates were formerly widely used as
   hypnotics (to induce sleep) and sedatives (for
    daytime sedation), their medical use is today
                  limited to the use:

• as anti-epileptics (long-acting substances)
• as adjuncts to anaesthesia (ultrashort-acting
  substances)
            AMPHETAMINE-TYPE
               STIMULANTS

     Common substances                    Abuse pattern
                                 •   injected
•   Amphetamine (Benzedrine)     •   orally ingested
•   Pemoline                     •   sniffed / snorted
•   Methamphetamine (Pervitin)   •   smoked
•   Fenetylline
•   Methcathinone                          Average dose
•   Methylphenidate (Ritalin)    • amphetamine,
                                   methamphetamine: 5-15 mg, up
                                   to 200 mg per day in frequent
                                   users
                    AMPHETAMINES
                PHARMACOLOGICAL EFFECTS

• Sought-after effects
•   similar to cocaine:
•   feelings of physical and mental well being, exhilaration, euphoria
•   increased alertness and energy
•   postponement of hunger and fatigue
•   improved performance at manual or intellectual tasks
• Short-term effects
•   loss of appetite
•   faster breathing, increased heart rate and blood pressure, increased body
    temperature, sweating
•   dilation of pupils
•   bizarre, erratic, sometimes violent behaviour
•   with larger doses: hallucinations, sense of power, restlessness,
    hyperexcitability, irritability - can lead to panic and paranoid psychosis
•   excessive doses may lead to convulsions, seizures and death from respiratory
    failure, stroke, cerebral hemorrhage or heart failure
                  AMPHETAMINES
               PHARMACOLOGICAL EFFECTS

• Long-term effects
•   destruction of tissues in nose, if sniffed
•   respiratory problems, if smoked
•   infectious diseases, abscesses, if injected
•   malnutrition, weight loss
•   disorientation, apathy, confused exhaustion due to lack of sleep
•   development of tolerance
•   strong psychological dependence
•   with continued use, a state similar to paranoid psychosis may develop
•   after stopping, there usually follows a long period of sleep and then
    depression
              AMPHETAMINES
                    MEDICAL USE

  Formerly widely used in medicine, the therapeutic use of
   certain amphetamine-type stimulants is today limited to:


• the treatment of attention deficit disorder (ADD)
• the treatment of narcolepsy (sudden uncontrolled
  fits of sleep)
• the use as appetite suppressant ('slimming pills')
• the treatment of nasal congestion
            ECSTASY' GROUP
   Common substances                   Abuse pattern
• Tenamfetamine (MDA)
• 3,4methylenedioxymethamphet   • orally ingested
  amine (MDMA)                  • sometimes snorted
• N-ethyl-3,4-tenamfetamine     • rarely injected
  (MDE)

                                        Average dose


                                       • 75-100mg
               ECSTASY' GROUP
             PHARMACOLOGICAL EFFECTS

• Sought-after effects
• feelings of emotional closeness to others (empathy), facilitation of
  communication and increased sociability
• increased physical and emotional energy
• Short-term effects
• fatigue and perhaps depression after the drug is stopped
• restlessness, anxiety and pronounced visual and auditory hallucinations
  at larger doses
• nausea and vomiting
• a rise in blood pressure and heart rate, death from heatstroke
• Long-term effects
• prolonged regular use can lead to the same long-term effects as with
  synthetic stimulants, including a potential for neurotoxicity and brain
  damage as well as liver damage
            HALLUCINOGENES
     D-LYSERGIC ACID                   Common illicit forms
    DIETHYLAMIDE (LSD)
• LSD is a semi-synthetic drug
  derived from lysergic acid, an   • impregnated on paper (blotter
  alkaloid found in Claviceps        papers)
  purpurea                         • mini tablets ('microdots')
                                   • capsules gelatine sheets
           Abuse pattern
•   orally ingested
                                     Certain common street
                                              names
           Average dose
                                   • hippie
                                   • acid
           • 25-200µg
                              LSD
         PHARMACOLOGICAL EFFECTS

  The effects of LSD are extremely variable and strongly
            depend on the mental state of the user

• Sought-after effects
• alterations in thought, mood and sensory perception, "mind
  expansion", as a key to quasi-religious transcendental experiences
• similar to 'ecstasy‘ - type substances: feelings of empathy,
  facilitation of communication and increased sociability
                                 LSD
          PHARMACOLOGICAL EFFECTS
• Short-term effects
• distorted perception of depth and time, size and shape of objects;
  movements of stationary objects; intensified colours, sound and touch;
  generally the user knows these effects to be unreal; true hallucinations
  are relatively rare

• increased risk of injuries due to perceptual and emotional effects,
  especially when driving

• unpleasant reactions may include anxiety, depression, dizziness,
  disorientation and paranoia

• physical effects are very slight compared with psychological or
  emotional effects; they may include dilated pupils, lowered body
  temperature, nausea and vomiting, profuse sweating, and rapid heart
  rate; occasionally convulsions occur
                                LSD
          PHARMACOLOGICAL EFFECTS

• Long-term effects
• physical dangers attributable to long-term LSD use are not known

• rapid development of tolerance which disappears rapidly after
  cessation of use; no physical dependence

• "flashbacks" (i.e., short-lived, vivid re-experiences of part of a
  previous trip) can occur days or even months after taking the last dose

• occasionally prolonged anxiety and depression follow use of LSD

								
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