CHEMICAL TRANSMITTERS IN THE CNS Drugs acting on CNS SEDATIVE by liaoqinmei

VIEWS: 39 PAGES: 47

									                                                                                   C.N.S

                CHEMICAL TRANSMITTERS IN THE CNS
   1- Amino-acids:
        a- Excitatory      Glutamate & Aspartate
                            acting on NMDA & AMPA receptors
         b- Inhibitory     GABA ( in brain) & Glycin ( in spinal cord)
  2- Opioids
  3- Others:
             a- Acetyl choline
             b- Noradrenaline & Dopamine
             c- Histamine & Serotonin
             d- Peptides ( eg.: Purines – Melatonin – Nitric oxide)

                               Drugs acting on CNS

                Depressants                            Stimulants
   1.   Sedative, Hypnotic & Anxiolytics          1. Cerebral stimulant
   2.   Analgesics                                2. Brain stem stimulant
   3.   Anticonvulsants                           3. Spinal cord stimulant
   4.   Antiparkinsonians
   5.   Antipsychotics                            4. Antidepressants
   6.   General anaesthesia                       5. Hallucinogens



                  SEDATIVE, HYPNOTIC & ANXIOLYTICS

Classification:
 1) Benzodiazepines:
              The most important
 2) Bz1 receptor agonist ( Zolpidem) & Bz2 receptor agonist ( Zopiclone & Eszopiclone)
 3) Buspirone (5-HT1A partial agonist):
              Anxiolytic but not sedative or hypnotic
 4) Barbiturates: obsolete now, used only in anaesthesia & epilepsy
 5) B blockers ( Propranolol):
              Used to treat some forms of anxiety by blocking peripheral sympathetic
              responses rather than central effects
 6) Ramelteon (Rozerim): a new hypnotic drug acting as a melatonin receptor agonist
 7) Others (Older):
              Chloralhydrate – Paraldehyde – Ethyl alcohol –
              Thalidomide – Glutethemide - Meprobamate




                                           215
                                                                                            C.N.S

                                  Benzodiazepines
                         Classification according to t1/2

 Ultrashort (<6h)        Short (12-18h)             Medium (24h)              Long (24-48h)

-Triazolam            - Lorazepam*(ativan)      - Alprazolam (xanax)       - Diazepam (valium)
- Midazolam           - Oxazepam*               - Nitrazepam*              - Clonazepam*
                      - Temazepam*                                         - Chlorzepate
                                                                           - Chlordiazepoxide
                                                                           - Flurazepam

                                 Pharmacokinetics
1) Absorption:
      - Oral:       - Well absorbed orally          Gastric
                    - Chlorzepate (prodrug)                   Nordazepam
                                                    HCl       (active & rapidly absorbed)

      - IV:         - Diazepam & Midazolam   as IV anesthesia & Anticonvulsants
      - IM:         - Slow absorption
                    - Midazolam & Lorazepam may be used in status epilepticus when IV
                      is difficult
2) Distribution:
      1. All over the body – passes BBB & placental barrier
      2. Redistributed & gradually accumulate in body fat
      3. Highly bound to plasma protein
3) Metabolism:
      1. Most of them    oxidation producing active metabolites followed by
                     conjugation with glucuronic a.
      2. Some of them     conjugation directly with glucuronic a. producing inactive
                      Metabolites (as: LOT / Nitrazepam / Clonazepam)
4) Excretion:
      Excreted in urine after conjugation with glucuronic acid

N.B: Classification of Bz. according to activation & inactivation in body:
1) Bz. Inactivated in body:
      LOT / Nitrazepam / Clonazepam
2) Bz. Activated in body:
      1. Activated by gastric Ph: Chlorzepate
      2. Activated by liver: others




                                              216
                                                                                      C.N.S

                                  Mechanism of action

Through binding with Bz. Receptors [Bz1, Bz2 & Bz3] which
facilitate GABAA transmition    frequency of Cl- channel
                 -
opening       Cl conductance   hyperpolarization &
 post-synaptic inhibition
NB: Inverse agonist: -carbolines bind with Bz. Receptors & act as inverse agonist
                       ( anxiety & convulsions)

                                     Actions & uses
1) Sedation & Taming effect in animals
2) Hypnotic in cases of insomnia:
       - Short acting is used to initiate sleep & long acting to maintain it
       - Advantages over Barbiturate:
           a. less of REM sleep          less hang over (Headache – Drowsiness – Depression)
           b. less Tolerance as it is not HME inducer
           c. wide safety margin
           d. specific antidote is available (Flumazenil)
3) Anxiolytic
4) Panic disorders
5) Preanaesthetic medication (sedation – hypnosis – amnesia)
6) IV Anaesthesia (Diazepam – Midazolam)
7) Muscle relaxant (Diazepam – Clonazepam)
8) Anticonvulsant (Diazepam – Clonazepam – Lorazepam)
9) Antidepressant ( Alprazolam only)
10) Control ethanol withdrawal symptoms
11) Diagnostic in psychiatry
12) Respiration & CVS:
       - No effect in healthy persons
       - Respiratory & cardiovascular depression in patients with respiratory or
              cardiovascular disease

                                       Side effects
 1- Day time sedation after long acting & Anxiety after short acting
 2- Depress bone marrow & Depress respiration & heart specially in diseased patient
 3- Allergy
 4- Appetite increase & GIT disturbances
 5- Alcohol intolerance (supersensitivity)
 6- Aged patient Confusion & Hypotension
 7- Amenorrhea in females
 8- Accumulate in fetus & neonates & Teratogenic
 9- Anterograde amnesia (Amnesia during drug intake)
 10- Aggravate Schizophrenia & Sexual dysfunction

                                             217
                                                                                     C.N.S

 11- Chronic use       Dependence, Tolerance & Addiction:
                     - After long use > 1 week
                     - Cross tolerance with other hypnotics
                     - Withdrawal should be gradual
 12- Acute toxicity:       CNS – CVS – Respiration
      ttt: IV Flumazenil :         - Competitive antagonist at Bz. Receptors
                                     - Extensive hepatic metabolism      use IV
                                     - Short t1/2  use repeatedly or infusion

                                Zolpidem &Zopiclone




- Zolpidem:
   1- Non-benzodiazepine acting as selective Bz1 receptor agonist facilitate GABAA
      transmition & antagonized also, by Flumazenil
   2- Metabolised into inactive metabolite
   3- Used as Hypnotic & short term anxiolytic
   4- Unlike Benzodiazepines : - Weak anticonvulsant & muscle relaxant
                                  - Minimal Dependence & Tolerance
- Zopiclone: selective Bz2 receptor agonist – as Zolpidem but has bitter taste

                                        Buspirone
Kinetic:
   1- Rapidly absorbed orally
   2- Extensively metabolized in the liver into several active metabolites which may
      have 2-blocking effect
Mechanism of action: Partial agonist at 5-HT1A receptors in brain
Actions:
    1- Anxiolytic with no sedation, hypnosis, CNS depression or drug dependence
    2- The effect appears after 1- 2 weeks
Uses:
        Chronic generalized anxiety especially in eldery
Side effect:
 1. Nervousness
 2. Dose dependant pupillary constriction
 2. GIT disturbances
 3. Tachycardia
 4. Hypertension & serotonin syndrome with MOA.I

NB.: Ipsapirone & Gepirone: as Buspirone
                                             218
                                                                                       C.N.S

                                        Barbiturates
                                        Classification
 Ultrashort (20-30 min)          Short (2-4h)       Medium (4-6h)             Long (6-8h)

- Thiopentone                 - Pentobarbitone      Amobarbitone         - Barbitone
- Hexobarbitone               - Secobarbitone                            - Phenobarbitone

                                     Chemical structure
  - They are derived from Barbituric acid
  - Barbituric acid is a condensation of urea + malonic acid (malonyl urea)
  - Barbituric acid itself is not sedative or hypnotic

                                        Kinetic
1- Absorption: well absorbed orally & from injection sites
2- Distribution:
          - All over the body, passes BBB & placental barrier
          - Ultrashort is rapidly redistributed into fat
          - Bound to plasma protein (30% long – 50% short – 70% ultrashort)
3- Metabolism:
          - Metabolised in liver by oxidation then conjugation
            except Phenobarbitone & Thiopentone
          - Phenobarbitone depends mainly on renal excretion             Pheno
                                                                         .
          - Thiopentone depends on tissue & fat redistribution           Thio.
4- Excretion in urine:
          - After conjugation, BUT Phenobarbitone is excreted mainly unchanged
          - Alkalinization of urine   their excretion

                                    Mechanism of action
  As Bz.: they facilitate GABAA transmition      duration of Cl- channel opening      Cl-
  cnductance     hyperpolarization & post-synaptic inhibition

                                            Actions
  1- CNS:
     a- Sedative – Hypnotic – Anxiolytic
     b- Amnesia     Automatism
     c- Anaesthesia
     d- Analgesia: potentiate analgesics but not analgesic alone even it may cause
        hyperalgesia if used alone
     e- Anticonvulsant
     f- Large dose       RC – VMC – HRC
  2- CVS:           Large dose     Hypotension
  3- Respiration: Large dose          RC
  4- GIT:      - tone & motility
               - HME inducer        metabolism of other drugs & their own metabolism
                                              219
                                                                                             C.N.S

 5- Urinary bladder:        Urine retention due to:            -   wall -   Bl.pr -   ADH
 6- Uterus:    contractility
 7- Sk. m.: Curare like
 8- Hormones:         ACTH - ADH

                                                   Uses
  They are obsolete as sedative & hypnotic & they are used for:
1- Thiopentone: IV anesthesia
2- Phenobarbitrone:           - Anticonvulsant
                              - Hyperbilirubinaemia as it HME

                                      Side effects & Toxicity
1- Allergy
2- Abnormal sleep : REM Hang over (Headache – Drowsiness – Depression)
3- Acute porphyria in patients with Acute intermittent porphyria as barbiturate ALA
   synthase      level of ALA (which is responsible for the acute attack)

                                                      ALA Strong enz.
                                    ALA synthase
      Succinyl Co-A + glycine                                           Protoporphyrin       Haem

      NB.: In Acute intermittent porphyria there is     of the strong enzyme    accumulation of ALA

4- Inducer of HME       tolerance – cross tolerance & drug dependence
5- Idiosyncrasy: excitation instead of sedation especially in eldery
6- Acute poisoning: [narrow safety margin]:
      - Manifestation: hypothermia – hypotension – hypoventilation – hypoxia – coma &
         death [ RC]
      - Management:
         • Promote drug elimination:
             - Gastric lavage, but may cause aspiration pneumonia
             - Promote excretion: - Alkalinization of urine by NaHCO3
                                      - Diuretics
                                      - Haemodialysis
         • Respiratory care: - Artificial respiration
                                  - Analeptics e.g.: Bemegride
                                  - Antibiotics to guard against Pneumonia
         • CVS care: Correct hypotension by IV fluids
7- Chronic poisoning : [Addiction]
      - Sudden stop        withdrawal symptoms & status epilepticus
      - So, the drug should be gradually withdrawn

                                          Drug interaction
 1-   HME: - Tolerance & cross tolerance
               - metabolism of other drugs as oral anticoagulants – digitalis ……
 2- Potentiate other CNS depressants as aspirin – ethyl alcohol – anesthesia
 3- Physiological antagonism with caffeine

                                                   220
                                                                                         C.N.S

                                    Contraindication
1- Acute intermittent porphyria
2- Allergy
3- Alone in pain
4- Aged patients & neonates
5- Head injury
6- Respiratory or cardiovascular disease
7- Liver or Kidney disease
8- During pregnancy or Labour

                                   Chloral hydrate

Kinetics:
 1- Well absorbed orally & rectally
 2- Distributed all over the body & passes BBB
 3- Metabolized in liver & RBCs into more active metabolite "Trichloroethanol" then
    inactivated by oxidation or conjugation with glucuronic acid
 4- Excreted in urine
Dynamics:
 1- Hypnotic:        - Onset 1/2 h - Duration 6-8 h
                     - Does not RC or VMC in therapeutic dose
                     - Bad taste
 2- HME inducer
Uses:
 1- Hypnotic esp in eldery & children
 2- Prenaesthetic medication
Contraindication:
 1- Liver disease – Kidney disease – Peptic ulcer
 2- With ethanol     synergism RC & coma
Toxicity:
   1- Acute: Vomiting – pin point pupil (P.P.P) – respiratory failure – cardiovascular
             failure
   2- Chronic: Tolerance – Dependence – Addiction

                                     Paraldehyde
Actions & Uses:
   Route of administration change the action
 1- Orally    Hypnotic
 2- IM     Anticonvulsant
 3- Rectally    Basal anesthesia
Contraindication:
        1- Liver disease
        2- Lung disease


                                            221
                                                                                          C.N.S

                                       ANALGESICS
  CNS depressants that relieve pain centrally without loss of consciousness or other sensations
                           *Classification of analgesics
  A) Central (Proper analgesics):
         1- Narcotic (Opioid) analgesics
         2- Antipyretic analgesics
  B) Peripheral (Non-proper analgesics):
         1- Causal: eg.:     a- Anticolics eg.: Atropine
                             b- Antianginal drugs eg.: Nitroglycerine
         2- Non-causal: eg.:        a- Local anesthetics
                                    b- Astringents
                                    c- Physical protectives as demulcents
                                    d- Counter-irritants
                                    e- Obtundants in tooth cavity
                                 Narcotic (Opioid)                         Antipyretic
1- Example            Morphine                                 Aspirin
2- Potency & type     Potent, effective in all types of pain   Less potent, effective in superficial
   of pain relieved   esp. deep visceral pain but not          pain
                      itching
3- Site of action     Central on spinal & supraspinal level    - Central on thalamus
                                                               - Peripheral as anti-inflammatory
4- With analgesia     Narcosis [Stupor & Drowsiness]             elevated body temp. to normal
5- Long use           Tolerance, dependence & addiction        No Tolerance, dependence or
                                                               addiction

                             Narcotic (Opioid) analgesics
        CNS depressant drugs that relieve pain centrally, but in large dose they produce
  Narcosis [Stupor & Drowsiness]. On long use they may cause Dependence.

                                        Classification:
  1) Opioid agonist:
                1- Phenantherene group of opium alkaloids: Morphine & Codeine
                2- Semisynthetic Morphine derivatives:
                             a. Diacetylmorphine (Heroin)
                             b. Dihydromorphinone                 c. Oxymorphone
                             d. Dihydrocodeinone                  e. Oxycodone
                3- Synthetic Morphine substitutes:
                             a. Meperidine                  b. Methadone
                             c. Fentanyl                    d. Dextropropoxyphene
  2) Mixed agonist-antagonist:
                a. Pentazocine                            b. Nalbuphine
                c. Butorphanol                            d. Buprenorphine

                                               222
                                                                                      C.N.S

                                  Opium Alkaloids
Opium is the dried milky juice of incised unripe fruit of papaver somniferum
                              Classification of Opium Alkaloids
                    A) Phenantherene group:           B) Benzyl-isoquinoline group:
 1- Members         - Morphine (the main)              - Papaverine
                    - Codeine                          - Narcotine
                    - Thebaine (convulsing)            - Narceine (convulsing)
 2- Actions:
    - CNS           Narcotic – analgesic               Not narcotic – Not analgesic
    - Smooth m.     spasmogenic                        spasmolytic
 3- Long use        Addiction                          No addiction

                                       Morphine
Natural main alkaloid (10%) of phenantherine group of opium.
                                    Pharmacokinetic
1. Absorption:
      a. Absorbed orally, but low bioavailability (25-30%)
      b. Better absorbed S.C & I.M
      c. In case of shock, it is given diluted & slowly I.V
2. Distribution:
      All over the body. Passes BBB & placental barrier    neonatal asphyxia during
      labour (treated by Naloxone IV to mother or IU to neonate)
3. Metabolism:
      a. Extensively metabolized in the liver by conjugation with glucuronic acid
      b. Morphine-6-conjugate is more active than morphine but morphine-3-
    conjugate is inactive
4. Excretion:
      a. Saliva: used to test racing horses
      b. Stomach: stomach wash in every case of poisoning even parentral poisoning
      c. Bile: enterohepatic circulation. & Some are excreted in stool
      d. Milk: may affect suckling baby
      e. Renal: the major excretory route

                                 Mechanism of action
      Morphine is a direct opioid receptor agonist:
*Opioid receptors:
      -Site: CNS & periphery esp. smooth m. & GIT
      -Structure: G-proteine coupled receptor either:
                -     Adenylate cyclase enz.       c.AMP
                - Opening of K+ Channels hyperpolarization
                - Close Ca++ Channels         Ca++ influx release of mediators
                                            223
                                                                                                  C.N.S

    -Types: mu ( 1&2), kappa ( 1&2), delta ( 1&2), sigma ( ), epsilon ( ):
    -Agonists: - Exogenous opioid agonist (e.g: Morphine)
                  - Endogenous opiopeptides : - Enkephalins[short duration]
                                                      - Endorphins[long duration]
                                                      - Dynorphins)
    -Relation to other mediators:         substance P
                                          Serotonin & Dopamine

                                                Actions
  1) C.N.S: mixed &
               Depressant actions:                                     Stimulant actions:

1. Analgesia:                                              1. Euphoria
   a. All types of pain esp. deep visceral pain            2. Excitement & convulsions in some
   b. not effective in itching as it releases histamine       human & animals (eg: horse & mice)
   c. Mechanism:                                              esp in I.V large dose due to of GABA
     - Spinal: release of substance P                      3. Edinger Westiphal nucleus (III rd
     - Supraspinal:                                           cranial nerve)    pin point pupil (PPP)
            - pain threshold in sensory cortex
           - Alter psychological reaction to pain on
             frontal area
           - Narcosis is an adding factor
2. Narcosis: stupor & drowsiness
3. R.C:
4. Cough center
5. V.M.C VD & hypotension                                  4. CIC       Bradycardia
                                                           5. CTZ       Vomiting esp. in small dose
6. Heat regulating center     Hypothermia
7. Hormones: ACTH – FSH – LH                               6. Hormones: ADH – Growth - Prolactin
8. Polysynaptic spinal reflexes    withdrawal              7. Monosynaptic spinal reflexes
  reflex                                                        stretch (patellar)
                                                              reflex in man &
                                                              Straub reaction
                                                             in mouse

                                                           8. Trunkal rigidity due to of
                                                              hippocumbal pyramidal cells
  -------------------------------------------------------------------------------------------------------
  2) A.N.S:         parasympathetic & sympathetic
  -------------------------------------------------------------------------------------------------------

  3) Eye: Miosis & PPP due to of Edinger Westiphal nucleus
  -------------------------------------------------------------------------------------------------------
  4) Skin:       Histamine release        Itching & triple response

                                                   224
                                                                                                C.N.S

5) CVS:
       a. Therapeutic dose   no effect
       b. Large dose    Hypotension                V.M.C
                                                 Direct veinodilator
                                                 Histamine release
                           Bradycardia         CIC
-------------------------------------------------------------------------------------------------------
6) Respiration:
       a. Central:     -RC
                       -Cough center
       b. Peripheral: Bronchoconstriction due to: histamine release & spasmogenic effect
-------------------------------------------------------------------------------------------------------
7) Spasmogenic on smooth muscle:
       a- GIT: spasmogenic & constipation
               1) Central: Defecation reflex
               2) Peripheral: 1. All secretion (except salivary)
                              2. Propulsive movement
                              3. Segmental contraction
                              4. Spasm of sphincters
          N.B: Loperamide (no CNS action) & Diphenoxylate (mild CNS) are
            selective opiate agonist on GIT      useful in ttt of diarrhea
       b. Biliary tract:
               a. Spasm of biliary duct & sphincter of Oddi
             intrabiliary pressure (Avoid after Cholecystectomy)
       c. Urinary tract:                                                         ++
               a. Central: - ADH           Oliguria
                             - Micturition reflex
         b. Peripheral: Spasm of ureters & sphincters        urine retention
       d. Uterus:
               Does not affect contractility but passes placenta       neonatal asphyxia
       e. Bronchi: Bronchospasm
-------------------------------------------------------------------------------------------------------
8) Metabolism: BMR

N.B.: Tolerance to Morphine:
       1. It occurs to the depressant action of morphine after 10-14 days of
             continued use due to depletion of endogenous opiopeptides
       2. No tolerance to excitatory, miosis or constipation
       3. Cross tolerance with other CNS depressants




                                                 225
                                                                                       C.N.S

                                    Uses of Morphine
1) Pain: Analgesic in severe visceral pains eg.:
       a. Cardiac pain: myocardial infarction & cardiogenic shock
       b. Cancer pain: terminal cancer pain
       c. Colicy pain: biliary & renal (add atropine)
       d. Bone fractures (not in head injury)
       e. Post-operative pains (not after eye or gall bladder operations)
2) Pre-anaesthetic medication: to provide analgesia & sedation
       *Disadvantage:
     a. Miosis – Vomiting – Bronchoconstriction
     b. Delay awaking from anaesthesia
     c. Post operative constipation & urine retention
3) Pulmonary edema: due to
       a. Sedate the patient      sympathetic      VD       Afterload
       b. Venodilator        venous return       Preload
4) Neurogenic shock

                             Contraindication of Morphine
1- Extremities of age
2- History of allergy or addiction
3- Head injury:      a. Miosis masks lateralization
                     b.VD         synthesis of CSF   ICP      RC
4- Increased intracranial pressure
5- Epilepsy
6- Myxoedema ( BMR, liver & CNS actions)
7- Respiratory diseases
8- Acute abdomen eg.: acute appendicitis as morphine mask diagnosis
9- Liver disease & alcoholism
10- Alone in biliary or renal colic
11- Pregnancy & labour: Pregnancy (addict fetus) & labour (neonatal asphyxia)

                          Side effects & Toxicity of Morphine
1. Dysphoria                     2. PPP          3. Itching             4. Vomiting
5. Bronchoconstriction           6. RC           7. Constipation        8. Urine retention
9. Mask diagnosis of serious infections eg.: acute abdomen
10. Tolerance & cross tolerance with other CNS depressants
11. Acute morphine poisoning:
       - Coma + Triad (PPP / Respiratory failure / Circulatory failure)    Death
       - Treatment:
              a. Artificial respiration
              b. Stomach wash with K+ permenganate even after injection
              c. Purgative with MgSO4
              d. Specific antagonist: Naloxone 0.4 mg IV or Naltrexone orally


                                             226
                                                                                         C.N.S

12. Chronic poisoning (Addiction):
       a. Occurs after 10-14 days of continued use  Tolerance + Psychic &
    Physical dependence
 b. Due to depletion of endogenous opiopeptides
 c. Sudden stop      Withdrawal or Abstinance syndrome (reversal of morphine
    actions yawning – mydriasis – excitation – diarrhea – urination –
    sweating – hyperventilation – hypertension
     – tachycardia - convulsions)
                                                                  Morphine

                                                                                       Methadone
                                                           Dose
 d. Management:
     1. Hospitalization & Psychotherapy
     2. Gradual withdrawal of morphine
        till stabilizing dose                                                              Days
     3. Gradual substitution with long
          acting opiates as Methadone or Levomethadyl acetate (LAAM)
     4. Gradual withdrawal of methadone       less withdrawal symptoms
     5. Oral Naltrexone (opioid antagonist) as maintenance to maintain opioid
          free state

                                Codeine ( Methylmorphine)
Like morphine but:
        - Better oral bioavailability - Shorter duration     - Weaker (1/5 morphine)
Actions:
 a. Narcotic analgesic - Antitussive
 b. Less constipating - Less addicting - Less        RC
Uses:
 a. Antitussive
 b. Analgesic, used alone or with Aspirin & Paracetamol (APC mixture)

                                          Papaverine
Actions:
 1. No CNS actions
 2. Smooth m.: Direct spasmolytic esp. on GIT, uterus & blood vessels
 3. Heart: quinidine like action
Uses:
 1. Antispasmodic in colics eg.: intestinal
 2. Vasodilator eg.: in pulmonary embolism

                                           Narcotine
Non narcotic, non-addicting, central antitussive


                                               227
                                                                                  C.N.S

                         Synthetic Morphine substitutes
                              1) Meperidine ( Pethedine)
Nature: Synthetic phenylpiperidine
Pharmacokinetics:
   1. 50% oral bioavailability
   2. Rapid onset & short duration
   3. Metabolized in liver into
         a. Meperidinic acid      conjugation with glucuronic acid      urine
         b. Normeperidine       active   excitation & convulsions
Pharmacodynamics:           Atropine like + 4 less + 4 no + 2L
   1. Atropine like
   2. Less analgesic 3. Less addictive 4. Less emetic      5. Less RC
   6. No PPP        7. No constipation      8. No narcosis 9. No antitussive
   10. Local irritant then local anesthetic
   11. Large dose excitation & convulsions (Normeperidine + Atropine like)
   12. ADH secretion
       ** ttt of toxicity by IV Naloxone
Uses:
   1- Analgesic as morphine esp.
         a. Alone in renal or biliary colic ( atropine like)
         b. Obestatric analgesia (less RC)
   2- Preanaesthetic medication (better than morphine as it is atropine like)
NB.: Meptazinol: as meperidine used mainly in obstetric analgesia

                                      2) Methadone
As potent as morphine but:
   1. Better oral bioavailability (50%)
   2. Less addiction & withdrawal symptoms
Uses ( orally)
     a. Analgesic as morphine
     b. Help withdrawal of morphine
NB.: Levomethadyl acetate (LAAM): as Methadone

                                       3) Fentanyl
1. Derivative of meperidine
2. Strong analgesic (80 times > morphine) & mainly agonist
Uses: as IV anaesthesia:
    a. Alone
    b. Fentanyl + Droperidol "major tranquilizer" = Neurolept analgesia (Thalamonal)
Side effect: Vomiting – Marked RC – Muscle rigidity
N.B: Alfentanil is more potent & Sulfentanil is short acting
                                            228
                                                                                        C.N.S

                4) Loperamide ( Imodium) & Diphenoxylate (Lomotil)
1. Derivatives of Meperidine
2. Selective opiate agonist on GIT      constipation    Antidiarrheal
3. Loperamide does not pass BBB         no CNS action, while Diphenoxylate & its active
  metabolite Difenoxine has some lipid solubility      narcosis
4. Side effects:      - Paralytic ileus
                      - LD of Lomotil [Diphenoxylate + Atropine] esp. in children
                        Narcosis & Atropine like toxicity

                                 5) Dextropropoxyphene
1. Derivatives of methadone
2. Analgesic (1/6 morphine). Used in pain resistant to aspirin
3. Large dose     Convulsions & RC

NB.: Tramadol:
          -    It is a metabolite of antidepressant Trazadone & has an analgesic effect as
               effective as morphine or meperidine
          -    Mechanism of analgesia: is a weak agonist & uptake of serotonin &
               noradrenaline

                                  Opioid Antagonists

               Pure antagonist                                   Partial agonist

     Naloxone               Naltrexone &                 Nalorphine & Levalorphan
       (IV)                  Nalmefene
                              (Orally)
1- Naloxone:
       Uses:
               1. Treatment of: - Acute morphine poisoning: 0.4 mg IV
                                - Neonatal asphyxia: either IM to mother before labor or IU
                            to neonate
               3. Diagnosis of morphine addicts SC Naloxone        withdrawal symptoms
2- Naltrexone & Nalmefene:
       a. As Naloxone but: effective Orally - Stronger – Longer
       b. Uses: to maintain the opioid free state in treated addicts
3. Nalorphine & Levalorphan:
       Actions & uses:
        1. In absence of morphine    morphine like    analgesia but cause
           Dysphoria & Hallucinations
        2- In presence of morphine    antagonist   used to treat acute morphine
            poisoning
        3. In morphine addicts    withdrawal symptoms. Used to diagnose addicts
                                             229
                                                                                   C.N.S

                         Mixed Agonist ( )-Antagonist( )

- Examples:         a. Pentazocine (Talwin) ……. (Parentally & orally)
               b. Nalbuphine………………. (Parentally)
                    c. Butorphanol………………(Parentally)
               d. Buprenorphine ………….(Parentally)
- Actions:
       1- In absence of morphine , they act as Agonist     strong analgesic
               - Pentazocine &Nalbuphine are less potent while
                Butorphanol & Buprenorphine as potent as morphine
             - Used in ttt of severe pain
       2- In presence of morphine they act as antagonist      withdrawal symptoms in
           addicts
       3- Partial agonist on respiratory depression
          Ceiling effect with low doses (increasing the dose will lead to more
          analgesia but no more depression of RC)
       4- Weak addiction        weak withdrawal symptoms




             Analgesia                                       Analgesia


                          RC
                                                                     RC


                                                                   Dose
                 Dose


       Morphine                                      Mixed agonist antagonist




                                           230
                                                                                          C.N.S

                          Antipyretic Analgesics ( NSAIDs)
1- CNS depressants that relieve pain centrally with decreasing elevated body temperature
   to normal but without narcosis
2- Most of them (except Acetaminophin [Paracetamol]) have anti-inflammatory effects
      Non-steroidal anti-inflammatory drugs (NSAIDs)

Mechanism of action:
       - They inhibit COX      synthesis of prostanoids (PGs – PGI2 – ThXA2)
       - Types of COX enz.:
              a. COX-1 (Constitutive) esp in    Stomach       HCl (prevent Peptic Ulcer)
                                               Kidney      Renal VD
              b. COX-2 (Inducible) by inflammation at inflammatory sites
              c. COX-3 has been recently identified present mainly in CNS

Clasification:
       a. Non-selective COX inhibitors:
              1. Aspirin (Salicylates)
              2. Pyrazolone derivatives eg.: Phenylbutazone
              3. Propionic acid derivatives eg.: Ibuprofen
              4. Enolic acid derivatives (Oxicams) eg.: Piroxicam
              5. Diclofenac
              6. Acetic acid derivatives eg.: Indomethacin
              7. Fenamates
   b. Selective COX-2 inhibitors:
              Celecoxib – Rofecoxib – Etoricoxib –Valdecoxib
     They have little side effect on gastric acidity & kidney, but they may cause fatal
           arrhytmia
 c. Selective COX-3 inhibitors:
         eg.: Aniline derivatives ( eg.: Paracetamol)
          They have no anti-inflammatory or peripheral action



                                         I-Salicylates
- They are salicylic acid derivatives. Salicylic a. itself is very irritant
- They include:
       1. Acetylsalicylic acid (ASA, Aspirin)
       2. Sodium salicylate
       3. Diflunisal (potent anti-inflammatory – no antipyretic action)




                                               231
                                                                                                C.N.S

                                        Pharmacokinetic
1- Absorption:
        Orally from upper GIT
        (better from stomach but more from upper intestine)
2- Distribution:
        a. All over the body. Passes BBB & placental barrier
        b. Highly bound to plasma protein
3- Metabolism:
        a. Mainly conjucated with glucuronic a. & glycine           salcyluric acid (inactive)
        b. 1% is oxidized   gentesic acid (active)
4- Excretion:
        Mainly in urine & Alkalinization of urine           excretion
5- t 1/2:
        a. At low conc.      1st order kinetic
        b. At high conc.      zero order kinetic

                                      Pharmacodynamics
Aspirin      irreversibly (by acetylation) COX enzyme (1, 2&3)
1) CNS:
        A) Analgesic:
                PGs :         a. Centrally    pain threshold esp. in thalamus
                              b. Peripherally   anti-inflammatory effect
        B) Antipyretic:
               a. synthesis of PGs induced by IL1, IL6 & TNF- that released by
                  bacterial toxins   resetting of HRC         heat loss by :
                - Mobilization of fluids from tissues to plasma              O2
                - Peripheral VD        heat loss by radiation                 CHO
                - Sweating         heat loss by evaporation
               b. Toxic dose     hyperthermia due to uncoupling of oxidative    E
   VD             phosphorylation     rate of heat production > heat loss         ATP
-------------------------------------------------------------------------------------------------------
2) Anti-inflammatory & anti-rheumatic:
        1.   PGs synthesis (directly & indirectly):
            - Directly: COX-2 induced by inflammation              PGs synthesis
            - Indirectly: large dose of aspirin      ACTH         Cortisol     Phospholipase A2
                           Arachidonic acid synthesis        PGs synthesis
        2. Kallekrein enz         synthesis of Bradykinin        pain & VD
        3. Hyaluronidaze enz.           capillary permeability       swelling & edema
        4. Fibrinolysin & tissue damaging enzymes
        5. Migration of polymorphs & macrophages to inflammatory sites
        6. Stabilization of Lysosomes        release of proteolytic enzymes
-------------------------------------------------------------------------------------------------------
3) CVS:
        a. Therapeutic dose no effect.
        b. Toxic dose VD & hypotension
                                                 232
                                                                                                C.N.S

4) Respiration & Acid/Base balance:
      a. Small dose: no effect
      b. Large dose:
             1. In adults: RC (Central direct effect & Peripheral through CO2
 HCO3   -       production from uncoupling oxidative phosphorylation)
                hyperventilation      CO2 wash       Respiratory alkalosis  excretion
                of excess alkali by kidney      Compensated respiratory alkalosis
             2. In children: Metabolic acidosis due to:
     H +       a- Dissociation of salicylate ,in blood, into salicylic a.
               b- Impaired CHO metabolism with accumulation of pyruvic a. & lactic a.
               c- Impaired renal function with retention of acids
      c. Toxic dose: RC        Respiratory acidosis
NB.: Aspirin may precipitate bronchial asthma in susceptible patients??
-------------------------------------------------------------------------------------------------------
5) GIT & Liver:
        A- GIT: a. Hyperacidity, Ulceration & Bleeding: due to:
                    - Local irritation due to release of salicylic a.
                    - Systemic due to synthesis of PGE2 & I
                  b. Nausea & Vomiting:
                   - Local irritation due to release of salicylic a.
                   - Central due to CTZ.
       B- Liver:                                                         Glycogenolysis
              a. Hydrochloretic ( water in bile     volume)                           H2O
              b. Glycogenolysis due to release of adrenaline
-------------------------------------------------------------------------------------------------------
6) Kidney & Uric acid excretion:
        A- Kidney:
      a. synthesis of PGs    renal VD             renal VC         renal blood flow         edema
      b. LD of aspirin  Nephrotoxic

       B- Uric acid excretion:                                             LD                       SD
      a. Small dose (1-2 gm /day): uric acid secretion in proximal
         convoluted tubules hyperuricemia worsens the gout (Contraindicated)
      b. Large dose (5 gm /day): uric acid reabsorption in proximal convoluted
         tubules uricosuric     treat the gout.
-------------------------------------------------------------------------------------------------------
7) Uterus:          - Delay onset of labour due to of PGE2 & PGF2
-------------------------------------------------------------------------------------------------------
8) Endocrine:
       a.   ACTH due to of hypothalamus & ant. Pituitary           cortisol
       b.   Adrenaline due to of adrenal medulla
       c.   Free form of T3 & T4 due to displacement from plasma proteins                   TSH
              thyroid gland functions eg.: radioactive iodine uptake.
-------------------------------------------------------------------------------------------------------
9) Immunological:              antigen/antibody reaction trough release of cortisol
                                                 233
                                                                                                C.N.S

10) Blood:
       1. Elevated erythrocytic sedimentation rate
       2. Lecocytosis to normal
       3. Platelet aggregation in SD (75-100 mg/day)
          as in SD it selectively thromboxane A2 (ThXA2)         bleeding time
       4. Hypoprothrombinemia in LD
          As it competes with vit K (coumarine like effect)     synthesis of
          prothrombin & factors VII, IX & X        coagulation (prothrombin) time
       5. Haemolysis (idiosyncrasy) in patients with G-6-PD deficiency (Favism)
-------------------------------------------------------------------------------------------------------
11) Metabolism:
       1. CHO: LD produces hyperglycemia due to adrenaline & cortisol
       2. Protein: LD produces
         - - ve nitrogen balance due to amino acid loss in urine
         - Glutamate / GABA ratio       Convulsions
       3. BMR & hyperpyrexia due to uncoupling oxidative phosphorylation

                                                Uses
1- Local:
     a. Salicylic acid as : Keratolytic
     b. Methylsalicylate as counterirritant
2- Systemic:
     1. Analgesic & Antipyretic in:
        a- Mild superficial pain eg.: Headache, Toothach, Myalgia, Arthralgia, Neuralgia
            & Dysmenorrhea
        b- Common cold: to treat fever, headache, myalgia & arthralgia
        c- Rheumatic fever: (10 g/d)
        d- Rheumatoid arthritis: (8 g/d)
     2. Uricosuric: in large dose> 5g/d in ttt of Gout
     3. Antiplatelet: (SD = 75-100 mg/d) in Prophylaxis of thromboembolic disease
     4. Chronic use of aspirin may decrease Cancer colon & Cataract

                                   Drug & Food interactions
   1- Displace other drugs from plasma protein eg.: oral hypoglycemic & anticoagulants
           their effect & toxicity
   2- Antagonize :         - Other uricosurics eg.: Probenicid
                           - Antihypertensive effect of Thiazide
                           - The anti-inflammatory effect of : Indomethacin –
                             Fenamates – Propionic acid – Pyrazolone derivatives
   3- The ulcerogenic effect is by: Alcohol – Cortisone – Phenylbutazone
   4- Salicylism is by: carbonic anhydrase inhibitors
   5- The toxicity is by:
                    - NH4Cl
                    - Food containing salicylate (Curry powder - Paprika – Prunes
                      Raisins – Tea – Licorice)
                                                 234
                                                                                        C.N.S

                                  Side effects & Toxicity
1- Acute poisoning:
      - Manifistation:
             1- Hyperpyrexia              2- Hyperhydrosis     dehydration
             3- Hyperventillation         4- Hyperacidity, nausea & vomiting
             5- Hyperglycemia             6- Hyperreflexia, convulsions & coma

              7- Hypotension              8- Hypoprothrombenemia & Bleeding

              9- Acid / base disturbances      It is the prominent manifestation (see before..)
       - Treatment:      no specific antidote
              1- Eliminate the drug by: - Stomach wash by NaHCO3
                                         - Alkalinization of urine by IV NaHCO3
                                         - Haemodialysis
              2 - Symptomatic ttt:         - Cold fomentations for fever
                                           - IV fluids for dehydration
                                           - Vit. K for hypoprothrombenemia
                                           - Correction of Acid / base disturbances
2- Allergy : urticaria – rash & bronchial asthma
       NB.: Bronchial asthma may be due to allergy or PGs           LTs
3- Salicylism: long use of LD     headache & irritability
              – Vertigo - Tinnitus – Blurring of vision –
              nausea & vomiting – Hyperventillation
4- Hypoprothrombenaemia & bleeding
5- Gastric irritation: nausea – vomiting – hyperacidity – ulceration & bleeding
       Prostaglandins (eg.: Misoprostol) is useful in ttt of NSAID-induced peptic ulcer

6- Reye syndrome:       fatal hepatic injury & encephalopathy in children with viral
                       infections (eg.: influenza & chicken pox)
7- Teratogenicity: cardiac septal defect - bleeding risk at birth – delay labour
8- Idiosyncrasy: haemolysis in patients with G-6-PD deficiency
9- Nephrotoxicity

                                    Contraindications
1- Allergy
2- Idiosyncrasy: patients with G-6-PD deficiency
3- Bronchial asthma
4- Bleeding tendency: eg.: hemophilia
5- Peptic ulcer
6- Pregnancy (but it is the safest anti-inflammatory among NSAIDs if needed)
7- In gout: (a. small dose < 5 g/d b. combination with other uricosurics)
8- Infants & children < 6 years:
              (a. Reye syndrome with viral infections b. More susceptible for toxicity)


                                             235
                                                                                    C.N.S

                                  II- Pyrazolone derivatives
   1.   Antipyrine
   2.   Dipyrone (Novalgine): rarely used due to bone marrow depression
   3.   Phenylbutazone
   4.   Oxyphenylbutazone

Pharmacokinetic:
             1. Well absorbed from GIT (orally& rectally) & parentrally
             2. Disributed all over the body
             3. Highly bound to plasma protein
             4. Metabolized in liver:
                 a. Phenylbutazone (active)    2 active metabolites:
                         - Oxyphenbutazone (potent anti-inflammatory & anti-rheumatic)
                         - -hydroxyphenylbutazone (uricosuric)
                 b. Conjugation with glucuronic acid
             5. Excreted in urine
                                                                              CNS
Pharmacodynamics:
             1. Potent anti-inflammatory & antirheumatic
             2. Weak analgesic antipyretic
             3. Uricosuric

Uses: Anti-inflammatory in: Acute gout – Rheumatoid arthritis

Side effects & Toxicity:
        1.   CNS: Headache, nervousness & vertigo
        2.   Allergy & skin rash
        3.   GIT upsets & ulceration
        4.   Liver & kidney damage
        5.   Teratogenic
        6.   Bone marrow depression
        7.   Salt & water retention : edema & hypertension

Drug interactions:
        1. Displaces other drugs from plasma protein         their activity
           eg.: oral hypoglycemic, oral anticoagulants
        2. HME inducer


NB.: Uricosuric NSAIDs:
   1. Salicylates
   2. Pyrazolone derivatives




                                             236
                                                                                   C.N.S

                             III- Acetic acid derivatives
  1- Indomethacin                2- Sulindac (Prodrug)             3- Etodolac
Indomehacin:
     *Kinetics:
           Absorbed orally – bound to plasma protein – metabolized in liver – excreted
           in urine & bile (enterohepatic circulation)
                                                                             CNS
     *Actions:
        1. Potent analgesic, antipyretic & anti-inflammatory
        2. Not uricosuric
     *Uses:
        1. Anti-inflammatory in: Acute gout-
                                   osteoarthritis – pericarditis
        2. Patent Ductus Arteriosus
     *Side effects:
        1. CNS: headache – vertigo – psychosis
        2. Corneal opacities
        3. Allergy & skin rash
        4. GIT upsets & ulceration
        5. Liver & kidney damage
        6. Teratogenic
        7. Bone marrow depression

                            IV-Propionic acid derivative
           1) Naproxen (Naprosyn): long t ½ (14 hours)
           2) Tiaprofenic acid (Surgam)
           3) Ibuprofen           4) Fenoprofen     5) Ketoprofen       6) Flurbiprofen
Actions:
  1. Potent analgesic, antipyretic, anti-inflammatory
  2. Not uricosuric

                                      V- Fenamates
  Mefenamic acid (Ponstan) & Flufenamic acid       As propionic a. derivatives

                         VI- Diclofenac (Voltaren & Cataflam)
  As propionic acid & concentrated in synovial fluids

                                      VII- Oxicams
  Piroxicam – Pivoxicam – Ampiroxicam – Meloxicam
  As propionic a. & Piroxicam has long t 1/2 (45 h)

                                   VIII- Nabumetone
  Prodrug given orally
                                          237
                                                                                     C.N.S

                               IX- Aniline Derivatives
                    Phenacetin & Paracetamol (Acetaminophen)
Parmacokinetics:
   1. Well absorbed orally
   2. Distributed all over the body
   3. Hepatic metabolism:
      Phenacetin (active)     Paracetamol (active)                Toxic metabolite (NAPQI)
                                                                  detoxified by Glutathione
                                                                  Conjugation with glucuronic
   4. Excreted in urine                                           acid & sulfuric acid

Pharmacodynamic:
   1. They inhibit selectively COX-3 enz. Present mainly central (not peripheral)
   2. Antipyretic Analgesic as potent as aspirin
   3. No anti-inflammatory – no respiratory – no CVS - no gastric acidity – no
      uricosuric – no platelet aggregation
Uses:
   Antipyretic analgesic in patients who cannot tolerate aspirin as:
      Children – Bronchial asthma – Peptic ulcer (Paracetamol may be beneficial?) – Gout
      – Allergy
Side effect & Toxicity:
   1. Hepatotoxicity: (Paracetamol) LD [ 10g in adult & 5g in child]
           excess toxic metabolite    depletion of S-H of glutathione in liver
     ttt: Oral N-acetylcysteine (converted to glutathione in liver )
        + Methionine within 8-16 hours

   NB.: Alcohol & Phenobarbital are HME inducer
            hepatotoxicity of paracetamol which may occure at smaller
           doses

   2. Nephrotoxicity (Phenacetin): Fatal chronic interstitial nephritis


   3. Met Hb & Haemolytic anaemia in patients with G.6.P.D deficiency with Phenacetin
   4. Allergy to Paracetamol & Phenacetin

NB:Propacetamol: is an injectable prodrug of Paracetamol converted to Paracetamol
                 by plasma esterase enzyme
NB: Benorylate: Ester of Aspirin + Paracetamol


                                             238
                                                                                     C.N.S

                      Common side effects of NSAIDs
1- Allergy & skin rash
2- Idiosyncrasy: Aspirin & Phenacetin           haemolysis in patients with G-6-PD
    deficiency
3- CNS:
            a. Phenylbutazone       Nervousness & vertigo
            b. Indomethacin       Psychosis
            c. Aspirin LD      Convulsions due to Glutamate / GABA ratio
            d. Convulsions when given with Quinolone antibiotics
4- CVS:
            a. Aspirin LD      Hypotension
            b. Phenylbutazone       fluid retention, edema & Hypertension
5- Blood:
            a. Aspirin Hypoprothrombinaemia & bleeding
            b. Phenylbutazone       bone marrow depression
6- Respiration: Bronchial asthma due to
            a. Allergy
            b. Block of COX pathway & shift to LOX pathway             LTs
7- GIT: Gastric irritation      Hyperchlorhydria, ulcer & bleeding
8- Hepatotoxicity: with Paracetamol
9- Nephrotoxicity: due to
            a. PGs       renal VC       analgesic nephropathy
            b. Direct toxicity as with Phenacetin
    NB.: Selective COX-2 has little effect on GIT ulceration & kidney
10- Uterus: Teratogenicity (if needed Aspirin is the safest anti-inflammatory &
     Paracetamol is the safest analgesic antipyretic)
11- Specific to Aspirin:
            a. Acute toxicity (see before)
            b. Salicylism (see before)
            c. Reye syndrome (see before)
12- Drug interaction:
    - Most of them are highly bound to plasma protein        displace other drugs     their
    activity
    - Phenylbutazone is HME inducer

                           Common uses of NSAIDs
1- Analgesic, antipyretic & anti-inflammatory (except Paracetamol has no anti-
   inflammatory)
2- Dysmenorrhea & as Tocolytic in premature labour
3- Patent Ductus Arteriosus
4- Antagonize hypotension induced by PGs in Systemic mastocytosis
5- Antagonize the flush induced by PGs associated with Niacin



                                          239
                                                                                                       C.N.S

                           Treatment of Rheumatoid arthritis
                              (Anti-inflammatory drugs)
1- Steroidal Anti-inflammatory drugs: Cortisol
2- Non-steroidal Anti-inflammatory drugs (NSAIDs): except Paracetamol
3- Disease modifying (Slow acting) anti-rheumatoid drugs (DMARDs):
   They alter the course & improve the prognosis of Rheumatoid arthritis. They include:
                1. Gold salts:
                       - Preparations: Gold aurothiomalate IM & Auranofin orally
                       - Mechanism: phagocytosis & lysosomal enz.
                       - Side effects: Stomatitis – Dermatitis – Nephritis – Bone marrow
                2. Chloroquine & Hydroxychloroquine: anti-malarial drug                    T-lymphocytes
                3. D-penicillamine: oral chelating for copper
                4. Sulphasalazine (Sulphapyridine + 5-Aminosalicylic acid)
                5. Methotrexate – Azathioprine: Immunosuppressants
                6. Levamizole: Immunostimulants & Anti-helmenthic
                7. Leflunomide (Arava):
                               orally - DNA synthesis in lymphocytes
                8. Anticytokines:
                       A- Anti- TNF-
                          - Etanercept (Enbrel): SC – block TNF- receptor
                          - Infleximab (Remicade): IV infusion – monocolonal antibody
                             against TNF-
                          - Adalimumab (Humira): SC - monocolonal antibody against TNF-
                       B- Anti-interleukin-1:
                          -Anakinra (Kineret): SC - block interleukin-1 receptor

4- Counter-irritants: used topically as Methylsalicylate & Camphor
---------------------------------------------------------------------------------------------------------------
NB.: Colchicine is useful in gouty arthritis only
---------------------------------------------------------------------------------------------------------------
NB: Chondroitin & Glucosamine: Are natural products that can be used in ttt of
osteoartheritis




                                                     240
                                                                                                         C.N.S

                            Treatment of Hyperuricemia & Gout
Hyperuricemia results from:
   • overproduction of uric acid (20%) : from excessive cell destruction (e.g. lymphoproliferative
       disorders, especially during their treatment, inherited defects that increase purine synthesis & high
       alcohol intake
   • reduced renal excretion of uric acid (80%): renal failure and drugs (e.g. most diuretics, low-dose
       aspirin and lactate formed from alcohol) can reduce the tubular secretion of uric acid

               Joint                                                        Cell

                                               1- Colchicine              Nucleoprotein

                                                                             Purines
                                               -
                                       migration                         Hypoxanthines
          Phagocytosis     mono Na+                    Macrophages
                            urate                                               XO enz.
                                                                                                  1- Allopurinol
                                                                            Xanthines
Rupture                                                                                           & Febuxostat
                                                                                XO enz.
 Lactic a.                more                                               Uric a.               2- Rasburicase
                       precipitation

          Inflammatory                                                                 Urate oxidase     Soluble
                                                                          Uric a.
            acidity                                                                    (Not in human)    Allantoin
                                                                                                         .


                                                               #
                                                                      3- Uricosurics


      2- Anti-inflammatory


             ttt of Acute attack                                               Prophylaxis



A) Acute attack:                 Anti-inflammatory drugs
          1- Colchicine or Demicolcine are the drug of choice
          2- NSAIDs: as indomethacin – Phenylbutazone – Naproxen …..
          3- Steroidal anti-inflammatory drugs: as Prednisolone orally
                                                & ACTH IM

B) Prophylaxis:                   Drugs that       uric a. in blood
          1- Uric acid excretion (Uricosurics):
               a. Large doses of: Aspirin (> 5g/d) - Probenicid - Sulphinpyrazone
               b. Benzbromarone
          2- Uric acid oxidation: (Rasburicase)
          2- Uric acid synthesis: (Allopurinol & Febuxostat)
                                                      241
                                                                                           C.N.S

                                          Colchicine
Kinetics:
        Well absorbed orally – Excreted in urine & bile

Dynamics:
        1) Anti-Gout effect:      Drug of 1st choice
               a. It binds to microtubular protein (Tubulin) of Granulocytes      migration
                   of leucocytes (PNLs) to joints    No phagocytosis of urate crystals    No
                   rupture of leucocytes & no release of lactic acid   break the
                   inflammatory cycle
               b. release of Chemotactic factors as Glycoprotein & IL-1that causes
                   pain & inflammation
        2) Anti-Mitotic effect:      cell division

Uses:
        1- Gout:
               a. Acute: it is the drug of choice (orally 1 mg then 0.5 mg /2 h till
                 disappearance of symptoms or appearance of toxicity . May be used IV
               b. Prophylaxis: 1-2 mg orally / week
        2- Prophylaxis of Familial Mediterranean fever (familial paroxysmal serositis)
        3- Psoriasis
        4- Improve liver functions in liver cirrhosis

Side effects & Toxicity:
        1- Alopecia
        2- CNS depression
        2- GIT: Nausea – Vomiting – Bloody Diarrhea
        3- Liver damage
        4- Kidney damage: Haematuria
        5- Myopathy
        6- Bone marrow depression

NB.: Demecolcine: as Colchicin e. Both are Plant alkaloid



                                      Uricosuric Drugs
Common side effects:
        1- Formation of renal urate stones, prevented by:
           Alkalinization of urine & plenty of fluids
          NB.: In patients secreting large amount of uric a. in urine, avoid uricosurics
        2- Aspirin antagonize uricosurics
        3- Allergy
        4- GIT disturbances


                                              242
                                                                                         C.N.S

Actions
      1- Probenicid:
             1- Small dose ( < 1g/d): uric a. secretion worsens gout
             2- Large dose (> 1g/d): uric a. reabsorption uricosuric ttt gout
             NB.: Probenicid tubular secretion of some drugs:
                      a. Penicillin & PAS        their duration of action
                      b. Thiazide & Loop diuretics        their effect
      2- Sulphinpyrazone
             1. Potent uricosuric used in prophylaxis of gout
             2. Platelet aggregation used in prophylaxis of thrombo-embolic disease
             3. It is a derivative of Phenylbutazone but not analgesic , nor antipyretic
      3- Benzbromarone: Potent uricosuric
      4- Aspirin LD (> 5 g/d)        see before, but not commonly used nowadays

                           Inhibitors of uric acid synthesis
                                Allopurinol (Zyloric)
Actions:    Xanthine oxidase (XO)enz.       uric acid synthesis (It is not uricosuric)
Uses:
      1- Hyperuricemia in: - Chronic gout esp. in:    a. Renal complications
                                                       b. Patients resistant to uricosurics
                            - associated with malignancy or not controlled by uricosurics
      2- Recurrent renal urate stones
Side effects:
      1- Acute gouty attacks during initial stage of treatment (add colchicine)
      2- CNS: headache & vertigo
      3- Allergy & skin rash
      4- GIT disturbances
      5- Hepatomegally & peripheral neuritis
      6- Bone marrow depression & Leucopenia
Drug interaction:
      a. toxicity of Azathioprine & mercaptopurine ( as they are metabolised by XO enz)
      b. It is HME        effect of warfarin

                                       Rasburicase
Mechanism: it is a recombinant urate oxidase enzyme, which oxidize uric a.     allantoin
(more soluble metabolite) (NB.: This enzyme is present in mammals other than human)
Uses: Prophylaxis of hyperuricaemia associated with malignancies
Side effects: anaphylaxis – rash – GIT disturbances

N.B: Drugs contraindicated in Gout:
      1- Small doses of: Aspirin – Probenicid – Sulphinpyrazone
      2- Diuretics: Thiazide – Loop – Acetazolamide
      3- Clofibrate: hypocholestremic agent
      4- Ethambutol & Pyrazinamide: anti-TB                 5- Anticancer drugs
                                            243
                                                                                    C.N.S

                     TREATMENT OF PARKINSONISM
1- Parkinsonism is a disease of basal ganglia characterized by:
    a- Static tremors     b- Muscle rigidity    flexion posture
    c- Akinesia mask face & shuffling gait d- Depression
2- It is due to: imbalance between dopamine & A.Ch
   ( Dopamine & A.Ch)
3- Aim of ttt is to restore this imbalance,
    so Antiparkinsonian include:
                        a. Dopaminergic drugs
                        b. Anticholinergic drugs

                                 A) Dopaminergic drugs
Dopaminergic drugs include: L-Dopa – Seligiline (Deprenyl) – Tolcapone – Amantadine –
Bromocriptine - Pramipexole & Ropinerol

                                    1- Levo-dopa (L –Dopa)
Kinetics:

        GIT                                   Blood               BBB        CNS
                                 1 % pass
                                                                              L-DOPA
       L-DOPA
                                          COMT 3-O-methyl dopa
                                                                  -               CDD
                              99 %                                            Dopamine
                             metabolism
                                            PDD                                   MAO-B
                                            Vit.B6    Dopamine    #               & COMT
                                                                              Metabolism



     1- Absorbed orally by active process & absorption is by food esp. proteins
     2- 99 % of the ingested L-dopa is metabolized by Peripheral dopa decarboxylase
        enz.(PDD) & COMT:
              - By PDD      Dopamine that cannot pass BBB
              - By COMT       3-O-methyl dopa that compete with L-dopa for active
                               uptake in CNS
     3- 1 % only of the ingested L-dopa passes BBB where it is metabolized by central
         dopa decarboxylase (CDD) into dopamine, then dopamine is metabolized by
         MAO-B enz.

NB.:    the brain level of L- dopa by:
       1- Add Peripheral decarboxylase inhibitor eg.: Carbidopa & Benserazide
             a. Carbidopa(25 mg) + L-dopa (250 mg) = "Sinemet"
             b. Benserazide (25 mg) + L-dopa = "Madopar"

       2- Add MAO-B inhibitor eg.: Selegiline (Deprenyl)
       3- Add COMT inhibitor eg.: Tolcapone & Entacapone
                                                244
                                                                                  C.N.S

Side effect: The 2 main Types are: Dyskinesia & On-Off phenomenon
      1- Fluctuation in response ("On-Off" phenomenon) due to fluctuations in dopamine
         level (avoided by using SR preparations)
      2- CNS: - Dyskinesia (excessive, abnormal movements) (ttt by decreasing the dose)
                - Psychological disturbances (euphoria - hallucinations)
                – Insomnia – Anxiety – Abnormal sexual activity
      3- Eye: Mydriasis - IOP
      4- CVS: Tachycardia – arrhythmia – postural hypotension
      5- GIT: Anorexia – nausea – vomiting – peptic ulceration
Contraindications:
      1- Psychological disturbances
      2- Glaucoma
      3- Cardiac disease
      4- Peptic ulcer
Drug interactions
      1- The effect is antagonized by:
            a. D2 receptor blockers as phenothiazine , butyrophenones ….
            b. Reserpine as it deplete dopamine
            c. Pyridoxine (vit.B6) as it PDD enz.
      2- The effect is potentiated by:
            a. Muscarinic antagonist
            b. PDD inhibitors
            c. MAO-B inhibitors
            d. COMT inhibitors
      3- With non-selective MAO inhibitors      severe hypertension

                               2- Selegiline (Deprenyl)
Selective MAO-B inhibitor potentiates the effect of L-dopa
NB.: Rasagiline: as selegiline but more potent

                            3- Tolcapone & Entacapone
Mechanism: COMT            formation of 3-O- methyl dopa, which compete with L-
              dopa for active uptake in CNS
Side effect: 1- L-dopa side effect
              2- Diarrhea                    L-doopa
              3- Hepatic necrosis              SE
 NB.: Entacapone:
      as Tolcapone but no Hepatotoxicity

                                4- Amantadine (Symmetrel)
Antiviral agent used in prophylaxis of influenza A2
Mechanism: Acts mainly by releasing dopamine & delaying its reuptake
Side effect:
       1- CNS: Insomnia – irritability – confusion - hallucination
       2- CVS: Hypotension – Ankle edema
       3- GIT disturbance
                                           245
                                                                                   C.N.S

                             5- Bromocriptine (Parlodel)
Derivative of ergot alkaloid
Kinetics: Absorbed orally – Metabolized in liver – Excreted in urine
Mechanism: Direct D2 agonist & D1 partial agonist
Uses:
       1- Parkinsonism
       2- To suppress lactation
       3- Hyperprolactinaemia & Galactorrhea-amenorrhea syndrome
Side effects:
       1- CNS: Dyskinesia – Psychological disturbance – Visual & auditory hallucination
       2- CVS: Arrhythmia – 1st dose hypotension – digital vasospasm –
                Erythromyalgia (red, tender, hot swollen feet)
       3- GIT: Anorexia – nausea – vomiting – peptic ulcer

NB.: Pergolide & Quinagolide: are direct agonist on D1 & D2


                             6- Pramipexole & Ropinerol
Non-ergot dopaminergic agonist

                              B) Anti-Cholinergic drugs
1-Belladonna alkaloids:
        a- Natural belladonna:
                        Atropine – Hyoscine
        b- Synthestic atropine substitutes:
                       Benztropine – Benzhexol (Trihexphenidyl) – Biperiden –
                       Procyclidine - Carmiphen
2- Anti-histaminics:
         Diphenhydramine – Orphenadrine


NB.: Drugs contraindicated in Parkinsonism:
          1- Anti-Dopaminergics:
             - D2-receptor blockers: Phenothiazine – Butyrophenone – Metoclopromide
             - Depletion of dopamine: Reserpine
             - Dopaminergic synthesis: -methyldopa

          2- Cholinomemitics passing BBB: Pilocarpine – Physostigmine




                                           246
                                                                                           C.N.S

                               TRETMENT OF EPILEPSY

Types of epilepsy:
        1- Generalized seizures:       loss of consciousness
               a. Grand-Mal epilepsy (tonic-clonic)
               b. Petit-Mal (Absence) epilepsy: momentary clouding of consciousness
               c. Myoclonic: shock like contraction of muscle
               d. Atonic: sudden loss of muscle tone
        2- Partial (Focal) Seizures:
               a. Simple: no loss of consciousness (sensory, motor, or autonomic symptoms)
               b. Complex: loss of consciousness (abnormal behavior or sensations + amnesia)
        3- Status epilepticus: severe sustained attack lasting more than 30 min.

Aim of treatment:
        1- epileptic focus & prevent its spread
        2- Treatment should be continued for 2-3 years after the last fit
        3- Withdraw anti-epileptic drugs gradually to avoid status epilepticus

Mechanism of action antiepileptic drugs:
        1- Potentiation of GABA activity: Barbiturates – Benzodiazepines
                                           Vigabatrin – Na Valproate
                                           Topiramate – Tiagapine - Gabapentine
        2- Inhibition of Glutamate activity:   Block AMPA Topiramate
                                                Block NMDA       Felbamate
        3- Block of Na+ channel: Phenytoin – Carbamazepine – Na Valproate –
                                 Lamotrigine – Topiramate - Zonisamide
        4- Block of Ca++ channel: Ethosuximide – Na Valproate

                          A)Grand-Mal & Partial seizures
                            1- Phenytoin (Diphenylhydantoin)
Kinetics:
    1- Well absorbed orally, IM & IV
    2- Distributed all over the body. Highly bound to plasma albumin
    3- Metabolized in liver:     a. small dose 1st order kinetic (constant t 1/2)
                                 b. Large dose zero-order kinetic (longer t1/2)
    4- Excreted in urine
Mechanism of action: Block of inactivated Na+ channels
Uses:
        1- Anti-epileptic:               all types except Petit-Mal
                a. Drug of choice in Grand-Mal & Partial seizures
                b. Effective in Status epilepticus
                c. Contraindicated in Petit-Mal epilepsy
        2- Anti-arrhythmic: Class I-B anti-arrhythmic. Drug of choice in ventricular
           arrhythmia with heart block eg.: Digitalis toxicity
        3- ttt of Trigeminal neuralgia
                                               247
                                                                                 C.N.S

Side effects & Toxicity:
      1- Allergy & SLE like syndrome
      2- Gastric irritation & Gum hyperplasia
      3- Hirsutism (due to androgen)
      4- Hepatotoxicity
      5- Hormonal: ADH & insulin secretion - androgen
      6- Ataxia, nystagmus & vertigo
      7- Agranulocytosis & Lymphadenopathy
      8- During Pregnancy:
             a. In 1st trimester Teratogenic (Cleft palate & Hare lip)
             b. Late months Hypoprothrombenemia in neoborn
                                & bleeding. Treated by vit. K
Drug interactions:
      a. Phenytoin is HME inducer:
             - its own metabolism        Tolerance
             - metabolism of other drugs          their effect as oral contaceptives,
                    Theophyllin, Digitalis, other anti-epileptics
             - metabolism of Folic a. Megaloplastic anemia                Methotrexate
                    toxicity
             - metabolism of vit.K Hypoprothrmbinemia & bleeding
             - metabolism of vit.D Osteomalecia & hypocalcemia
      b. HME inducers (eg.: Phenobarbitone – Carbamazepine – Glutethemide – Alcohol)
                 metabolism of phenytoin
      c. HME inhibitors (eg.: Cimetidine – Chloramphenicol – Valproate - isoniazide)
                 metabolism of phenytoin
      d. Phenytoin displaces Oral anticoagulants – Thyroxin – TCA
      e. Phenytoin is displaced by Aspirin - Na+ valproate

NB.: Mephenytoin & Ethotoin: as phenytoin
NB.: Fosphenytoin is a more soluble prodrug of phenytoin used parenterally, IV & IM

                            2- Carbamazepine (Tegretol)
Kinetics: Given orally
Mechanism of action: as Phenytoin
Actions & uses:
      1- Anti-epileptic:           all types except Petit-Mal
              a. Drug of choice in Grand-Mal & Partial seizures
              b. Contraindicated in Petit-Mal epilepsy
      2- ttt of Trigeminal neuralgia
      3- Antidiuretic, so useful in diabetes insipidus
Side effects:
     1- Allergy – Anorexia – Atropine like – Ataxia – Aplastic anemia
     2- Fluid retention – Hepatitis like & jaundice
     3- HME inducer
NB.: Oxcarbazepine: as Carbamazepine
                                           248
                                                                                    C.N.S

                                    3- Barbiturates
Include:
   1- Phenobarbital
   2- Mephobarbital & Metharbital
   3- Primidone: Active & metabolized in liver into another active metabolites as
                 Phenobarbitone

Mechanism of action:
      Facilitate GABAA transmition       Cl- channel opening       Cl- influx
      hyperpolarization & post-synaptic inhibition
Antiepileptic effects:             all types except Petit-Mal
      a. Effective in Grand-Mal & Partial seizures
      b. Contraindicated in Petit-Mal epilepsy
Side effects:
      1- Sedation
      2- Ataxia & Nystugmus
      3- HME inducer: (as Phenytoin…….)

                                 Petit-Mal epilepsy
                             1- Ethosuximide (Zarontin)
Mechanism: Blocks Ca++ channels
Action & Uses: Drug of choice in Petit-Mal epilepsy
Side effects: 1.Sedation
                2. Leucopenia
                3. Worsens Grand-Mal

                             2- Acetazolamide (Diamox)
- Carbonic anhydrase enz inhibitor       CO2 in CNS     Excitability
- Useful in resistant Petit-Mal epilepsy

                                3- Oxazolidinediones
                         (Trimethadione & Paramethadione)
- Used in Petit-Mal epilepsy but worsens Grand-Mal
Side effects:
       1- Alopecia
       2- Sedation & worsens Grand-Mal
       3- Glare effect (blurred vision in bright)
       4- Nephrotic syndrome
       5- Hepatotoxicity
       6- Bone marrow depression


                                           249
                                                                                         C.N.S

                         Broad spectrum anti-epileptics
                                   1- Benzodiazepines
Include: Diazepam (Valium) – Clonazepam - Lorazepam (Ativan)
Mechanism of action: As barbiturates facilitate GABAA transmition
Antiepileptic effects:       all types & they are drug of choice in Status epilepticus

                             2- Na+ Valproate (Depakene)
Mechanism of action:
      1- GABA transaminase         GABA level in brain
      2- Block Na+ & Ca++ channels
Actions & Uses:      Broad spectrum anti-epileptic effective all types
Side effects:
      1- Temporary alopecia
      2- Sedation
      3- GIT irritation
      4- Hepatotoxicity
      5- Thrombocytopenia
      6- Teratogenic (Spina bifida)
Drug- interactions:
      1- It is HME inhibitor (the only antiepileptic)    effect of Phenytoin &
          Phenobarbitone
      2- Displace Phenytoin from plasma protein

                                      3- Vigabatrin:
   • Vinyl GABA transaminase inhibitor          GABA level in brain
   • Broad spectrum useful in resistant epilepsy esp. Partial seizures
   • Vigabatrin may cause visual field defect

                 New anti-epileptics useful in Partial seizures
      - Drugs potentiating GABA:
            1- Gabapentin & Pregabalin: They are GABA analogs, Potentiate GABA
            release & replaced carbamazepine in ttt of neuropathic pain due to less side
            effects
            2- Tiagabin: GABA uptake
      - Drugs blocking NMDA receptors
            Felpamate: Block NMDA receptor of glutamate
      - Drugs modifying both GABA & Glutamate:
            - Levetiracetam: Modifies the release of GABA & Glutamate
      - Drugs blocking Na+ channels:
            1- Lamotrigine: As phenytoin, blocks Na+ channels but not teratogenic
            2- Topiramate: its spectrum like Phenytoin – High incidence of kidney stones
                          It also, affects both GABA & Glutamate
            3- Zonisamide:        - A sulfonamide derivative, Block Na+ channels
                                  - Broad spectrum, may cause kidney stones
                                            250
                                                                                                       C.N.S

                                         PSYCHOTROPIC DRUGS
- Psychotropics are drugs that affect psychology & behavior
- Classification:
          1- Tranquilizers (Psychotropics):                a. Minor tranquilizers (Anxiolytics)
                                                           b. Major tranquilizer (Anti-psychotics)
          2- Antidepressants & Lithium:         a. Mood elevating                   Antidepressants
                                                b. Mood stabilizing                  Lithium
          3- Psychomotor stimulants: Amphtamine
          4- Psychomemitics( Hallucinogenics): eg.: LSD

                                         Major Tranquilizer
                         (Anti-Psychotic – Anti-Schizophrinc – Neuroleptics)
Psychosis (Schizophrenia):
      - Characterized by: -ve symptoms (eg: flatting of emotions – society withdrawal)
                          +ve symptoms (eg: hallucinations – delusions)
      - Cause: may be Dopamine or Serotonin

Classification of Anti-Psychotics:
      1) Typical:
                1- Phenothiazine: Chlorpromazine – Thioridazine – Trifluperazine
                2- Thioxanthines: Chlorprothexine – Thiothexine
                3- Butyrophenones: Haloperidol – Droperidol
          2) Atypical:
               1- Clozapine           2- Olanzapine                3- Loxapine
               4- Resperidone         5- Pimozide                  6- Sulpiride
               7- Aripiprazole
NB.:         - Most of them block D2 receptors in hypothalamus & limbic system
             - Reserpine may be used (rarely) as it depletes catecholamines including Dopamine

                                          Chlorpromazine (Largactil)
Kinetics: Well absorbed orally – Metabolized in liver – Excreted in urine
---------------------------------------------------------------------------------------------------------------
Dynamics:
    1) CNS:
                1- Block D2 receptors in:
                         Limbic system       Anti-psychotic
                         Basal ganglia      Worsens Parkinsonism
                         Hypothalamus            Prolactin & Appetite
                                                 Temperature  Hypothermia
                          CTZ Antiemetic in all vomiting except motion sickness
                2- Sedation (due to antihistaminic effect)
                3- Seizures (as it seizure threshold)
* Psychotropic (Greek): affecting mind
                                                     251
                                                                                                       C.N.S

        2) Receptors:
             Potent: Antidopamine –            Antiserotonine        –       -blocker
             Weak: Antimuscarine (Atropine like) - Antihistamine – Ganglion blocker
        3) Endocrine:
             1- Prolactin Gynecomastia & Galactorrhea
             2- Growth h. – ACTH – FSH & LH                    infertility & amenorrhea
        4) Curare like on skeletal m.
        5) Quinidine like & Local anesthetic effect
        6) CVS:                                                                                      1

             1- Bl.V.: VD – Hypotension – Postural hypotension due to:
                         1. VMC                                                                2

                         2. Ganglion block                3. -block                                     3
                         4. Direct VD
                         5. Direct myocardial depressant                                     5
                                                                                                     4
             2- Heart: 1. Direct myocardial depressant
                           2. Tachycardia (Atropine like & Reflex from hypotension)
---------------------------------------------------------------------------------------------------------------
Uses:
        1- Psychosis & Schizophrenia
        2- Preanesthetic medication
        3- Antipruritic
        4- Antiemetic in SD in all vomiting except motion sickness
        5- Intractable hiccough
---------------------------------------------------------------------------------------------------------------
Side effects:
        1) Psychological:
              1- Pseudo-depression
              2- Toxic confusion
        2) Neurological:
               1- Extra-pyramidal manifestations:
                      (Acute dystonia – Akathesia [restlessness] – Parkinsonism)
               2- Tardive dyskinesia:
                      - Late onset, irreversible, abnormal movement (esp. of the jaw &
                         tongue), after long use & may persist after discontinuation
                         of the drug )
                      - It is due to upregulation of D2 receptors
                      - It is resistant to ttt & worsens if the drug is stopped
               3- Neurolept malignant syndrome (Idiosyncratic reaction similar to
                  malignant hyperthermia due to muscle rigidity & ttt by IV Dantrolene or
                  Bromocriptine)
               4- Sedation
               5- Seizures
        3) Autonomic nervous system:
               1- -block        Postural hypotension – Failure of ejaculation
               2- Muscarinic block         Dry mouth – Blurred vision

                                                     252
                                                                                                       C.N.S

        4) Endocrine:
               1- Gynecomastia – Galactorrhea
               2- Infertility – Amenorrhea
               3- Weight Gain
        5) Blood: Agranulocytosis
        6) Heart: Arrhythmia
        7) Liver: Allergic obstructive cholestatic jaundice

        8) Hypersensetivity
        9) Teratogenicity
        10) Photosensitivity & Corneal opacities
---------------------------------------------------------------------------------------------------------------
Drug interactions:
        1) Potentiate:      1. Sedatives (eg: Alcohol)
                            2. Hypotensives (eg: -blockers)
                            3. Anticholinergics (eg: Tricyclic antidepressants)
                            4. Muscle relaxants (eg: Curare)
        2) Antagonize: The hypotensive effect of Guanithedine as it its neuronal uptake
        3) Reverse the pressor effect of adrenaline


                                     Other major Tranquilizers

1) Thioridazine:
        As Chlorpromazine BUT it is Cardiotoxic , causes Ritinopathy & Not antiemetic
-------------------------------------------------------------------------------------------------------
2) Trifluperazine:
        More powerful anti-Psychotic & Extrapyramidal manifestation
-------------------------------------------------------------------------------------------------------
3) Thioxanthenes: (Chlorprothixene & Thiothexene) As Chlorpromazine
-------------------------------------------------------------------------------------------------------
4) Butyrophenones: (Haloperidol & Droperidol):
            • As Chlorpromazine but stronger
            • Droperidol + Fentanyl (Thalamonal):
                    a- Neurolept analgesia as IV anesthesia for short operations
                    b- The antiemetic effect of Droperidol antagonize the emetic
                       effect of Fentanyl
-------------------------------------------------------------------------------------------------------
5) Atypical:
            • As Clorpromazine BUT less Extrapyramidal manifestation & Not antiemetic
            • Clozapine    High affinity for D4 & High incidence of Agranulocytosis
            • Aripiprazole   Partial agonist at D2 & 5-HT1A




                                                     253
                                                                                           C.N.S

                        Antidepressant drugs (Psychoanaleptics)
- Types: Depression may be Unipolar or Bipolar (depression alternating with mania)
- Cause of depression: may be due to deficiency of monoamines (Noradrenaline & 5-HT), so the
  aim of ttt is to their level

Classification of antidepressant drugs:
          1- Tricyclic antidepressants (TCA)
          2- Mono-amine oxidase inhibitors (MAOI)
          3- Selective Serotonin Reuptake Inhibitors (SSRI)
          4- Serotonin /Norepinephrin reuptake inhibitors (SNRI)
          5- Atypical antidepressants

                   (1) TCA                                       (2) MAO.I
                                           Members:
1- Imipramine        2- Desipramine              1) Non-selective MAO-I
3- Clomipramine                                      (A) Hydrazine group:
                                                        1- Isocarboxazide
4- Amitriptyline    5- Nortriptyline                    2- Phenelizine
6- Amineptine       7- Doxipen                          3- Nialamide
                                                    (B) Non-Hydrazine group:
NB: In liver:                                           1- Tranylcypromine
- Imipramine (active)    Desipramine                    2- Pargyline
                         (active)                2- Selective MAO-B inhibitor:
- Amitriptyline (active)   Nortriptyline                Selegiline (Deprenyl)
                          (active)               3- Selective MAO-A inhibitor
                                                         - Clorgyline     Irreversible
                                                         - Moclobemide        Reversible
                                   Mechanism of action:
1-    Neuronal uptake-1 (cocaine like) of        1-     MAO enz.     monoamines (NA &
     monoamines (NA & 5HT)                            5HT) intrasynaptically in CNS &
      intersynaptically                                body but VMA & HIAA in urine
                                                                  M
                                                                  O
                                                                  A


2- Antidepressant effect appears after 2-3       2- Antidepressant effect appears after 2-3
   weeks & lasts for 2-3 weeks                      weeks & lasts for 2-3 weeks
                                             Actions:
1- Antidepressant                                1- Antidepressant
2- Atropine like (strong)                        2- Atropine like (weak)
3- Antihistamine (H1) & H2 block                 3- Pargyline     Antihypertensive &
4- Antiserotonin                                    antianginal as it Sympathetic
5- Alpha1 block                                  4- Selegiline    Antiparkinsonian
                                                    & in large dose    Antidepressant
                                               254
                                                                                          C.N.S

                                             Uses:
1- Psychic depression                            1- Psychic depression
2- Nocturnal enuresis                            2- Selegiline   in Parkinsonism
3- Prophylaxis of migraine                       3- Pargyline    in Hypertension &
                                                                 prophylaxis of angina
                                         Side effects:
                                 1- Delayed onset (after 2-3 weeks)
                                 2- Appetite stimulation & weight gain
3- Atropine like (Strong)                       3- Atropine like (Weak)
   Dry mouth – Blurring vision –
   Urine retention – Constipation
4- Cardiotoxic                                  4- Hypertensive crises
      Fatal arrhythmia                             - if patients eat food containing
                                                      tyramine (eg: cheese – broad beans –
                                                       yoghurt)
                                                     - ttt by - blockers
5- CNS Sedation                                 5- CNS Excitation
   (Excitation & Tremors may occur)                (Insomnia – Tremors – Convulsions)
6- Allergic obstructive jaundice                6- Hepatotoxic
                                                       Hepatocellular jaundice
                                      Drug interactions

1- Potentiate:                                   1- Potentiate:
   1. Sedatives                                      1. Sympathomimetics
   2. Anticholinergics                               2. Other drugs eg.: Barbiturate &
2- Antagonize:                                          Morphine because MAO.I are
    1. Hypotensive effect of Guanithidine               HME
       ( uptake)                                 2- Reverse hypotensive effect of
    2. Hypotensive effect of Clonidine &            Reserpine
        Methyldopa (down regulation of           3- With TCA Toxicity (Atropine like)
         2-receptors)                            4- With SSRI      Serotonin syndrome
3- With MAO.I Toxicity (Atropine like)               (Hyperthermia – Hypotention – Coma
                                                      & death)
                                                 5- With food containing tyramine
                                                     Hypertensive crisis (Cheese reaction)
NB.:
1) In TCA: Amineptine:
       1- mainly uptake of Dopamine with no effect on NA or 5HT
       2- Quick onset (7 days) & no anticholinergic effect
2) 2 Types of MAO enzyme:
                    1. MAO-A                                           2. MAO-B
- metabolizes NA & 5HT in intestine & neural tissues - metabolizes Dopamine in CNS.
- Inhibited selectively by Clorgyline & Moclobemide - Inhibited selectively by Selegiline (Deprenyl)

                                              255
                                                                                        C.N.S

                  3- Selective Serotonin Reuptake Inhibitors (SSRI)
Members:
    1- Fluoxetine (Prozac)                2- Fluvoxamine
    3- Paroxetine                         4- Sertraline
    5- Citalopram                         6- Escitalopram
Mechanism: SSRI       5-HT
Uses:
        1- Depression & obsessive compulsive disorders
        2- Prophylaxis of migraine
Advantages:
        1- No anticholinergic & Atropine like effect
        2- Little drug interaction
Side effects:
        1- Anorexia – Nausea –Diarrhea – Weight loss
        2- Anxiety – Headache
        3- Agitation & jitters
        3- Sleep disturbances & insomnia
        4- Suicidal attacks especially in children & teenagers
        5- Sexual dysfunction: as loss of libido & delayed ejaculation
        6- Drug interactions:- Fluoxetine + MAO.I Serotonin syndrome (Fatal)
                              - Fluoxetine is HME inhibitor    Potentiate other drugs

        4- Selective Serotonin/Norepinephrine Reuptake Inhibitors (SSNRI)
They are effective in ttt of depression associated with neuropathic pain
1- Venlafaxine:
      - Potent inhibitor of serotonin & at larger doses it norepinephrin reuptake
      - Side effects: GIT disturbances
2- Duloxetine:
      - Potent inhibitor of both serotonin & norepinephrin at all doses
      - Side effects: GIT disturbances – Sexual dysfunction

                               5- Atypical antidepressants
1- Maprotiline: as TCA but
      - Selectively blocks the uptake of NA
      - Few Atropine like - Little effect on CNS - Less interaction with Guanithedine
2- Mianserine:
      - Block presynaptic 2-receptors        release of NA
      - Not cardiotoxic but causes sedation
3- Mirtazepine:
      - Block presynaptic 2-receptors & 5HT2 receptors
      - No sexual dysfunction & no anticholinergic but may appetite         weight gain
4- Bupropion:
      - release of NA        - No sedation but may cause seizure at high doses
                                             256
                                                                                                       C.N.S

                              Antimanic – Mood stabilizing drugs

Mania characterized by: Excessive exuberance & self confidence – Impulsive actions –
Irritability – Aggression – Grandiose delusions

                                                  Lithium

Lithium is an endogenous monovalent cation with no known physiological role

Kinetic:
        1- Well absorbed orally
        2- No hepatic metabolism
        3- Excreted by kidneys
                     - excretion by: Osmotic diuretics & Na+ bicarbonate
                     - excretion by: Loop & Thiazide diuretics
-------------------------------------------------------------------------------------------------------
Mechanism of action:
        Not clear but may:
                 1- Affect release of NA, Dopamine, 5HT or,
                 2- Depletion Phosphatidyl inositol in neuronal membranes of CNS (Inhibit
                    recycling of inositol) or,
                 3- Affect nerve conduction
---------------------------------------------------------------------------------------------------------------
Uses:
        1- Acute Mania (but slow onset)
        2- Manic-Depressive disorders (Bipolar depression) (esp. in manic phase)
---------------------------------------------------------------------------------------------------------------
Side effects:
        1- CNS: Confusions - Convulsions
        2- Thyroid: Thyroid synthesis       Smooth benign enlargement
        3- GIT: Anorexia – Nausea –Vomiting – Diarrhea
        4- Kidney: Polyurea (Nephrogenic diabetes insipidus) – Excessive Thirst
        5- CVS: Arrhythmia – Hypotension
        6- Teratogenic in early pregnancy
        7- Acute toxicity: (extremely low safety margin)
                Manifistations: - < 2.5 meq/L     Confusions - Drowsiness -Tremors
                                 - > 2.5 meq/L    Convulsions

                  ttt: Osmotic diuretics - Na+ bicarbonate – Dialysis in severe cases

NB.: Antiepileptic drugs: Carbamazepine & Valproic acid can be used to alleviate some
     symptoms of Mania



                                                     257
                                                                                                C.N.S

                                   C.N.S STIMULANTS
1- Cerebral stimulants:
       1. Amphetamine
      2. Atropine
      3. Metyhlxanthines
      4. Methylphenidate: similar to Amphetamine without anorexigenic effect
      5. Cocaine
2- Brain stem stimulants: Analeptics
3- Spinal cord stimulants: Strychnine

                                     Methyl-xanthines
                         (Caffeine – Theophylline – Theobromine)
Kinetics:
        1- Well absorbed from GIT (orally, rectally) & parenterally
        2- Distributed all over the body, passes BBB & Placenta
        3- Metabolized in the liver into Methyl uric acid which is soluble & don't
           precipitate (so not contraindicated in Gout)
        4- Excreted in urine
-------------------------------------------------------------------------------------------------------
Mechanism of action:
        1- PDE enz. Type IV          c.AMP
        2- Block adenosine receptors
-------------------------------------------------------------------------------------------------------
Actions:
    NB.: Caffeine is more selective & potent on: CNS, Gastric acidity & Sk..m
.
        1- CNS:        Caffeine
               1.   Cortex: Alertness – Wakefulness – Antifatigue
               2.   Medulla: RC – VMC – CIC
               3.   Spinal Cord: Hyper-reflexia

        2- CVS:        Theophylline
                                     Heart                                 Blood vessel
Direct effect:       - +ve inotropic & chronotropic              VD but cerebral VC
                     - Work & Automaticity
Central effect:     -ve chronotropic ( CIC)                      VC
Net result:         - SD No effect                               - SD No effect
                    - LD Direct action takes the upper           - LD Direct action takes the
                    hand     Tachycardia - Arrhythmia            upper hand  Hypotension

        3- Respiration:
               - Direct: Bronchodilataion & Mast cell stabilization (Theophylline)
               - Central: RC (Caffeine)
                                                 258
                                                                                                       C.N.S

        4- GIT:
                Spasmolytic &        Acidity
        5- Kidney:         Theophylline
                 1. Spasmolytic
                 2. Diuretic: Extrarenal ( CO) & Renal ( NaCl reabsorption)
        6- Smooth m.: Theophylline Spasmolytic
        7- Skeletal m.: Caffeine                 Capacity for muscle work
---------------------------------------------------------------------------------------------------------------
Uses:
        1- Theophylline:
                 a- Aminophylline:
                         1. Anticolic
                         2. Bronchial asthma: acute attack – status – prophylaxis
                         3. Cardiac asthma (Acute pulmonary edema):
                                 +ve inotropic – Diuretic – Bronchodilatation
                         4. Diuretic
                 b- Pentoxifylline:
                         used in intermittent claudication ( flexibility of RBCs & platelet
                         aggregation)
        2- Caffeine:
                 1. Acute Migraine headache (+ Ergotamine)
                 2. Myasthenia gravis (+ Neostigmine)
                 3. Mental & physical fatigue
                 4. Toxicity with CNS depressant
---------------------------------------------------------------------------------------------------------------
Side effects
        1- Caffeine: [High therapeutic index]
                 - CNS: Headache – Insomnia – Irritability - Convulsions
                 - GIT: hyperacidity
        2- Aminophylline: [Low therapeutic index]
                 1. Irritant: IV      Thrombophlebitis - Rectal             Proctatitis
                 2. Rapid IV       Velocity reaction & syncope
                 3. CNS: Headache – Insomnia – Irritability – Convulsions
                 4. CVS: Arrhythmia – Arrest – Hypotension
                 5. GIT: Irritation
        3- Long use: Tolerance – Cross tolerance – Psychic dependence
---------------------------------------------------------------------------------------------------------------
Contraindications:
        1- Arrhythmia                     2- Angina                        3- Peptic ulcer
---------------------------------------------------------------------------------------------------------------
Drug interaction:
                1- Metabolism by:                         2- Metabolism by:
   1. Antimicrobials: Erythromycin & Quinolones 1. Anti-epileptics
   2. Cimitidine                                2. Rifampicin
   3. Heart & liver disease                     3. Smoking
                                                     259
                                                                                   C.N.S

                                          Cocaine
Natural from coca leaves

Mechanism of action:
      1- Local anesthetic: Block Na+ channels
      2- Catecholamines: Neuronal uptake & MAO inhibitor
Actions:
      1- L.A.: as surface anesthesia only
      2- CNS: stimulation but less than Caffeine
      3- CVS:       - Heart:      - SD    Bradycardia ( CIC)
                                  - LD    Tachycardia ( catecholamines)
                    - B.V:     VC
      4- Eye: Active Mydriasis + Decongestion + Loss of corneal reflex
Side effects:
      1- Excitation & Convulsions
      2- Arrhythmia
      3- Death from respiratory failure
      4- Dependence (No Tolerance)

                                      Analeptics
Character:
      1- Stimulate RC & VMC
      2- Awaken deeply anesthetized patient
      3- Toxic dose produces Clonic convulsions & with larger dose     Tonic
Classification:
      1- Direct:
             1. Bemegride: used in acute barbiturate poisoning
             2. Phnylenetetrazole (Leptazole – Cardiazole): used in diagnosis of
                epilepsy
             3. Picrotoxin: has narrow safety margin
      2- Indirect (Reflex): through stimulation of Chemoreceptors eg: Lobeline
      3- Dual:
             1. Coramine (Nikethamide)
             2. Carbogen (5 % CO2 + 95 % O2)
             3. Daptazole (Amiphenazole)
             4. Doxapram : the safest – IV infusion
             5. Ethamivan
NB.: Analeptics are OBSOLETE nowadays (Except carbogen & doxapram)

Other drugs having analeptic effects:
             1. Reflex through of nerve ending eg: Ammonia – Alcohol – Camphor
             2. Descending stimulation eg: Aminophylline
             3. Ascending stimulation eg: Strychnine
             4. Receptor blockers: as Naloxone & Flumazenil only if RC by opioid
                or benzodiazepine
                                            260
                                                                                   C.N.S

                                    Strychnine
Alkaloid from Nux-Vomica seeds

Dynamic:
      CNS: Stimulation
           - Compete with Glycine in spinal cord
           - Ascending: - Spinal cord         Polysynaptic
                        - Medulla        RC & VMC
                        - Cortex        Sensory area

Toxicity:
      1- Tonic convulsions
      2- Cause of death: Spasm of respiratory muscles
            ttt:   1. Dark room
                   2. Stomach wash by tannic acid or K+ permanganate
                   3. Anticonvulsants
                   4. Specific antidote: Mephenesine IV


                              Psychomemitic drugs

                     1- LSD (Lysergic acid               2- Cannabis (Hashish):
                         diethylamide)                   Tetrahydrocannabinol

- Mechanism:      5-HT1A agonist in CNS &            - Cannabinoid recept         c.AMP
                  5-HT2 antagonist in periphery      - Block Ca++ channels
- Actions:        Eye:                               Eye:
                  Mydriasis – Visual hallucination   Red conjunctiva - IOP
                  CNS:                               CNS:
                  - Elation – Mood changes           - Loss of sense of: time – sounds
                  - Bad trip of severe anxiety –       & distance
                    Depression & suicide             - Euphoria & uncontrolled
                                                       laughing
                                                     - Antiemetic (Tried in vomiting
                                                       due to cancer therapy)
- Long use:       - Tolerance but no physical        - Tolerance but no physical
                    dependence                         dependence

3- Mescaline

4- Adrenochrome




                                          261

								
To top