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1. CNS Pharmacology

2. Neurotransmitters in CNS
• Can be inhibitory or excitatory
Inhibitory: GABA, Glycine
Excitatory: Glutamate,
both Aspartate, Ach, NE, DA, 5-HT

3. Sedative-Hypnotic drugs cont…
• Sedative vs. Hypnotic
– Sedative - Tranquilizers
• Depress the CNS to sedate or relax, producing a calming effect
– Hypnotic
• Depress the CNS enough to cause sleep
• Sedative-Hypnotic
– Produce calming effect at lower dose and sleep at higher dose
– Barbiturates and Benzodiazepines

4. Sedative-Hypnotic drugs
Barbiturates
• Potentiate GABA action on chloride entry into the neuron by
prolonging the duration of the chloride channel openings
• Classified by duration of action
– Ultra short-acting (Thiopental Na) - Duration of 20 min or less
– Short-acting (Secobarbital, pentobarbital) - DOA - 3 - 4 hrs
– Intermediate-acting (Amobarbital, aprobarbital & butabarbital) -
6- 8 hrs
– Long-acting(Phenobarbital, mephobarbital) - 10 - 16 hrs

5. Sedative-Hypnotic drugs
Barbiturates cont…
• Depression of CNS
– At low doses - Produce sedation (calming effect, reducing excitement)
– At higher doses - Hypnosis, followed by anesthesia (loss of feeling or
sensation), and finally, coma and death
– No analgesic properties - May even exacerbate pain
– Chronic use leads to tolerance
• Respiratory depression
– Suppress hypoxic and chemoreceptor response to CO2
• Enzyme inducers - ↓ Action of other drugs

6. Sedative-Hypnotic drugs
Barbiturates cont…
• Therapeutic uses
– Anesthesia: Thiopental are used IV
– Anticonvulsant: Phenobarbital
• Tonic-clonic seizures, status epilepticus, and eclampsia
• Drug of choice for treatment of young children with recurrent
febrile seizures
• Can depress cognitive performance in children - Used cautiously
– Anxiety - Mild sedatives to for anxiety, nervous tension and insomnia
• As hypnotics, they suppress REM sleep
– Most have been replaced by the benzodiazepines

7. Sedative-Hypnotic drugs
Barbiturates cont…
• Adverse effects
– Drowsiness, impaired concentration, mental and physical
sluggishness
• Depressant effects synergize with ethanol
– Drug hangover, nausea, dizziness
– Physical dependence: Abrupt withdrawal cause tremors, anxiety,
weakness, restlessness, nausea and vomiting, seizures, delirium,
and cardiac arrest
• Withdrawal is much more severe than that associated with opiates
and can result in death

8. Sedative-Hypnotic drugs
Benzodiazepines
• Potentate effect of GABA by ↑ the frequency of Cl channel
opening
• Classifications
– Short acting agents - Triazolam
– Intermediate acting agents - Alprazolam, Lorazepam, Oxazepam,
Temazepam, Chlordiazepoxide
– Long acting agents - Diazepam, Flurazepam

9. Sedative-Hypnotic drugs
Benzodiazepines cont…
• Reduction of anxiety - At low doses
• Sedative and hypnotic actions: All have some sedative
properties and some produce hypnosis at higher doses
• Anterograde amnesia - Temporary impairment of memory
– Impairs a person's ability to learn and form new memories
• Anticonvulsant: Several of the benzodiazepines
– Some are used to treat status epilepticus and other seizure disorders
• Muscle relaxant: At high doses

10. Sedative-Hypnotic drugs
Benzodiazepines cont…
• Therapeutic uses
– Anxiety disorders
– Muscular disorders: Muscle spasms - Diazepam
– Amnesia – Short acting ones
– Seizures – Clonazepam, diazepam and lorazepam
– Sleep disorders – Flurazepam, temazepam, triazolam

11. Sedative-Hypnotic drugs
Benzodiazepines cont…
• Adverse effects
– Drowsiness, confusion, ataxia, cognitive impairment,
tolerance, dependence (Psychological and physical
dependence) and withdrawal symptoms
• Precautions – Avoid in pregnancy
– Liver disease, acute narrow-angle glaucoma.
– Alcohol and other CNS depressants
– Less dangerous than older anxiolytic and hypnotic drugs

12. Epilepsy
• Group of disorders characterized by excessive excitability
of neurons within the CNS
• Initiated by synchronous, high-frequency discharge from
group of hyperexcitable neurons (focus)
– Symptoms depend on location of focus

13. Epilepsy cont…
• Sudden, transient disturbance of brain function, manifested by
involuntary motor, sensory, autonomic, or psychic phenomena,
often accompanied by alteration or loss of consciousness
– May range from mild twitching to loss of consciousness and
uncontrollable convulsions
• A seizure may occur after a metabolic, traumatic, anoxic, or
infectious insult to the brain
– Idiopathic cause (>75%), drugs, brain tumor

14. Epilepsy cont…
• Pathogenesis
– Enhanced excitatory NT glutamate
– ↓ Inhibitory gamma amino butyric acid (GABA)
• Classification of seizures
– Based upon nature not the cause of seizures
• 1. Partial (local) seizure
• 2. Generalized seizure
• 3. Status epilepticus

15. Epilepsy cont…
• 1. Partial (local) seizures
– Are seizures localized to certain areas of the brain only
– Further classified as
• Simple partial - No loss of consciousness
• Complex partial - Simple partial seizure followed by loss of
consciousness
• Secondary generalized seizures - Partial onset which evolves to
generalized tonic-clonic seizures

16. Epilepsy cont…
• 2. Generalized seizures
– Affects wider areas of the brain & are associated with loss of
consciousness
– Involves both hemispheres of the brain
– Could be classified into different groups
• Absence seizures
• Myoclonic seizures
• Clonic seizures
• Tonic seizures
• Tonic-clonic seizures

17. Epilepsy cont…
• 3. Status epileptics
– Is any recurrent or continuous seizure activity lasting
longer than 30 minutes in which period the patient doesn’t
regain consciousness
– Is a medical emergency
• Because it can lead to brain damage & death

18. Anti-epileptic drugs
• Treatments for epilepsy
– No effective preventions or cures known
• Surgical methods
– To remove the epileptogenic part of the brain
• Seizure inhibiting drugs

19. Anti-epileptic drugs
• Class of drugs for epilepsy
– Type I antiepileptics - Inhibit Na+ channels
• Phenytoin, Carbamazepine, lamotrigine, felbamate, oxycarbazepine
– Type II antiepileptics – Multiple action
• Inhibit Ca++ or Na+ channels or promote GABA activity
• Valporic acid, benzodiazepines, primidone, Phenobarbital
– Type III antiepileptics - Ca++ channel inhibitors
• Ethosuximide, trimethadione
– Type IV - GABA promoters
• Vigabatrin, tiagabine, gabapentine

20. Anti-epileptic drugs
Phenytoin
• Is one of the Na+ channel inhibitor antiepileptic drugs
• Limited water solubility, slow, incomplete and variable
absorption
• Equal efficacy as phenobarbital but with lesser CNS
depressant effect
• It is highly plasma protein bound

21. Anti-epileptic drugs
Phenytoin cont…
• Adverse effects
– Acute toxicity - Results of over dosage
• Nystagmus, ataxia, vertigo, diplopia
– Chronic toxicity - Related to long term use
• Behavioral changes
• Gingival Hyperplasia (overgrowth of the gums)
• Enlargement of lips & nose
• Coarsening of facial features
• Hirsutism (excessive hairiness)

22. Anti-epileptic drugs
Carbamazepine
• Is highly efficacious & well tolerated, Na+ channel blocker
– Has fewer long term side effects than other anti-epileptics
• Metabolized in the liver by the CYP450 enzymes
– Enzyme inducer & can induce its own metabolizing enzyme as
well as enzymes of other drugs
• SEs:
– Drowsiness, headache, dizziness & incordination
– Allergic reactions, rare but sever aplastic anemia
– Most SEs occur at first therapy & tolerance develops
– Toxicity is low as compared to phenytoin

23. Anti-epileptic drugs
Ethosuximide
• Drug of choice for Absence seizure
– Not effective in other seizure types
• Blocks Ca++ currents (T-currents) in the thalamus
• SEs
– GI complaints - Most common
– CNS effects - Drowsiness & lethargy
– Potentially fatal bone marrow toxicity and skin reactions
(both rare)

24. Anti-epileptic drugs
GABA transmission enhancers
• 1. Phenobarbital
– Is the only barbiturate with selective anticonvulsant effect
– Bind at allosteric site on GABA receptor & ↑ duration of
opening of Cl channel
– Inducer of microsomal enzymes → Drug interactions
– Toxic effects
• Sedation (tolerance develops), nystagmus, ataxia at higher
dose, osteomalacia, folate and vitamin K deficiency

25. Anti-epileptic drugs
GABA transmission enhancers cont…
• 2. Benzodiazepines
– Clonazepam, lorazepam & clorazepate
– Bind to another site on GABA receptor & increase
frequency of opening of the Cl- channel
– Are well absorbed from the GIT
– Metabolized by CYP450 enzymes to active metabolites
– Toxicities
• Lethargy, drowsiness, CNS sedation

26. Anti-epileptic drugs
GABA transmission enhancers cont…
• 3. Gabapentin - Developed as GABA analogue
– ↑ release of GABA from gabanergic neurons by unknown
mechanism
• 4. Vigabatrin
– Irreversible inhibitor of GABA transaminase enzyme which
metabolizes GABA
• 5. Tiagabine
– ↓ GABA uptake by neuronal and extraneuronal tissues so
as to increase GABA at the synapse

27. Anti-epileptic drugs
GABA transmission enhancers cont…
• 6. Valporic Acid
– Effective in the treatment of multiple seizure types
– Works by multiple mechanisms
• Blocks both Na+ & Ca++ channels and ↑ GABA activity
– Drug interactions: Inhibits metabolism of phenobarbital,
Carbamazepine & phenytoin
– Side effects
• Fatal hepatic failure (most serious SE), reversible hair loss, ↑ in
body weight, transient GI disturbances

28. Anti-epileptic drugs
Magnesium sulphate
• CNS depressant
– Block transmission of neuromuscular signals by ↓ Ach
– Vasodilation
– ↓ Cerebral edema (Protect BBB)
• SE – Respiratory depression and loss of deep tendon
reflexes

29. Anti-psychotics
• Drugs that primarily affect psyche (mental process) &
useful in psychiatric disorders
• Also called
– Psychotropic drugs
– Neuroleptics
– Major tranquillizers

30. Anti-psychotics
Schizophrenia
• Is a group of heterogeneous, chronic psychiatric disorders
– It is one particular kind of psychosis
• It is characterized by two clinical symptoms
– Positive symptoms - Delusion hallucination & thought disorders
• Commonly occur in acute phase of the illness
• Usually respond to antipsychotic drug therapy
– Negative symptoms - Apathy, social withdrawal & lack of drive
& enthusiasm
• Occur in chronic phase of illness and is resistant to drug therapy

31. Anti-psychotics
Schizophrenia cont…
• Pathogenesis
– Genetic & environmental factors (Maternal virus infection)
– Neurochemical abnormalities - DA & glutamate
• Abnormality of DA activity in mesolimbic-mesocortical
pathway of DA
• 5-HT & other NTs might also be involved

32. Anti-psychotics cont…
• Classification based on chemical structure
– 1.Phenothiazine derivatives with
• Aliphatic side chain - Chlorpromazine (CPZ), triflupromaizne
• Piperidine side chain - Thioridazine, mesoridazine, piperacetazine
• Piperazine ring side chain - Fluphenazine, trifluoperazine
– 2. Butyrophenones - Haloperidol, trifluperidol, penfluperidol
– 3. Thioxanthenes - Chlorprothixene, flupenthixol
– 4. Atypical Neuroleptics - Clozapine, risperidone, olanzapine,
ziprasidone, aripiprazole
– 5. Miscellaneous - Reserpine

33. Anti-psychotics cont…
• Can also be grouped into two groups
– 1st generation ('typical') antipsychotics
– 2nd generation ('atypical') antipsychotics
– Grouping is based on
• Receptor profile
• Incidence of extrapyramidal side effects (less in atypical
group)
• Efficacy in 'treatment-resistant' patients (atypicals are more
efficacious)
• Efficacy against negative symptoms (atypicals are more
efficacious)

34. Anti-psychotics
Mechanism of action
• All effective antipsychotic drugs block D2 receptors
– Degree of blockade to other actions on different receptors
considerably varies
• Clozapine - 5-HT2A > α1 > D2 > D1
• Haloperidol - D2 > α1 > D4 > 5-HT2A> D1>H1
• Antipsychotic action has shown good correlation with the
capacity to bind to D2 receptor
– No clear correlation with D1, D3 & D4 binding
• Activities on other NT receptors - Determine their SE

35. Anti-psychotics
Pharmacological action
• ANS - Varying degree of α-blocking activity
– Weak anticholinergic & antihistamine property
• Local anesthetic – CPZ but causes irritation
• CVS - Postural hypotension, ↓ BP, ↑ HR
• Endocrine effects
– ↑ prolactin secretion by blocking inhibitory effect of DA
– Galactorrhea, gynacomasteia

36. Anti-psychotics
Uses of anti-psychotics
• Schizophrenia - the main use
• Anxiety
– Should not be used for simple anxiety b/c of autonomic &
extraipyramdal side effects
– Those not responding to BDZs or having psychiatric base
• As antiemetic - Control drug & disease induced vomiting
– At dose much lower than those needed for psychosis
– Ineffective in motion sickness
• Other uses - Potentiate hypnotics, analgesics & anesthetics

37. Anti-psychotics
Adverse effects of anti-psychotics
• CNS effects
– Drowsiness, lethargy, mental confusion
– Increased appetite & weight gain (not with haloperidol)
– Aggravation of seizures in epileptics
• High dose cause seizure - Clozapine & olanzapine
• CVS effects
– Postural hypotension (not with haloperidol)
– Palpitation

38. Anti-psychotics
Adverse effects of anti-psychotics
• Anticholinergic effects - Dry mouth, blurred vision,
constipation
• Endocrine effects – Hyperprolactinemia
– Galactorrhea, gynacomasteia
– Atypical - Free of such endocrine problems
• Extrapyramidal (EP) disturbances
– Pseudo parkinsonism, acute muscular dystonia, akathisia, tardive
dyskinesia

39. Parkinson’s disease (PD)
• Disorder of movement that occurs mainly in the elderly
individuals
• Occurs for a variety of possible reasons
– Exposure to certain toxins (manganese dust, carbon- disulfide)
– Drug induced parkinsonism - Reserpine, haloperidol,
chlorpromazine & other antipsychotics that block D2
– Post encephalitic parkinsonism - After viral infection
– Idiopathic parkinsonism - Unknown cause

40. Parkinson’s disease cont…
• The basal ganglia are responsible for controlling automatic
movements of body by action of DA
• DA level in brain’s substantia nigra normally fall with ageing
– Level has to fall to 1/5th of normal for signs of PD to emerge
• In PD, there is extensive destruction of dopaminergic neurons
of Substantia nigra
– Leads to DA deficiency

41. Parkinson’s disease cont…
• Shortage of DA & excess of Ach (imbalance)

42. Parkinson’s disease cont…
• Cardinal Features of PD
– Bradykinesia
• Is an extreme slowness of movement
• Is the most disabling feature b/c it affects all motor systems
– Muscular rigidity: increased muscle tone which leads to
movement resistance
– Resting tremor: involuntary movements of limbs at rest
– Impaired postural balance

43. Parkinson’s disease cont…
• Treatment Strategy:
– Restore balance between DA and Ach
• Activating DA receptors
• Blocking Ach receptors
• Overview of Drugs Employed
– Dopaminergic drugs
– Anticholinergic drugs

44. Parkinson’s disease
Classification of drugs
• 1. Drugs affecting brain dopaminergic system
– a. Dopamine precursors: levodopa
– b. Peripheral decarboxylase inhibitors: carbidopa &
benserazide
– c. Dopaminergic agonists: bromocriptine, pergolide,
ropinirole, cabergoline & pramipexole
– d. MAO-B inhibitors : Selgiline
– e. COMT inhibitors: Entacapone, tolcopone
– f. Dopamine facilitator : Amantidine

45. Parkinson’s disease
Classification of drugs cont…
• 2. Drugs affecting brain cholinergic system
– a. Anticholinergics: Benzotropine, benzhexol, Procyclidine,
biperiden
– b. Antihistamines: promethazine

46. Parkinson’s disease
Levodopa (L-DOPA)
• First-line treatment for PD
• Is the immediate metabolic precursor of dopamine
– Prodrug for DA and can cross BBB while DA does not
• More than 95% of oral dose is decarboxylated in periphery
tissue mainly in gut & liver to dopamine
– DA in periphery cause SE
– Peripheral DOPA decarboxylase inhibitor (carbidopa or
benserazide) ↓metabolism in periphery

47. Parkinson’s disease
Levodopa (L-DOPA) cont…
• Adverse effects
– Dyskinesia (involuntary writhing movements)
– On/off phenomenon
• Effectively improves mobility with marked dyskinesia (on - period)
• Rigidity & akinesia at the end of the dosing interval (off - period)
– Nausea & anorexia – Tolerance develops
– Postural hypotension, cardiac arrthymias & excerbation of
angina - β adrenergic action
– Psychological effects - Schizophrenia-like syndrome

48. Parkinson’s disease
Dopamine receptor agonists
• Lower incidence of on /off phenomenon & dyskinesias
• Do not require enzymatic conversion to active metabolite
• Selectively affect certain DA receptors (primarily D2)
• Used for patients who have largely lost the capacity to
synthesis, store & release dopamine from levodopa
• Have longer duration of action than that of levodopa
• Effective as monotherapy or as adjuncts to carbidopa

49. Parkinson’s disease
Dopamine receptor agonists cont…
• Bromocriptine (Ergot derivative)
–Potent D2 agonist & partial D1 agonist /antagonist
–High dose is needed if used alone
–Used only in late case as supplement to levodopa
–Low dose - For treatment of hyperprolactinemia
• Pergolide - More effective than bromocriptine and allow the
levodopa dose to be reduced
• Pramipexole - Scavenge hydrogen peroxide (neuroprotective)

50. Parkinson’s disease
Dopamine receptor agonists cont…
• Adverse effects
– Anorexia, nausea & vomiting, constipation, dyspepsia,
symptoms of reflux esophagitis
– Postural hypotension and cardiac arrhythmias
– Dyskinesias
– Confusion, hallucinations, delusions & other psychiatric
reactions

51. Parkinson’s disease
MAO-B inhibitors
• MAO-B - The predominant form of MAO in striatum
– Responsible for most of oxidative metabolism of DA in the brain
• Selegiline (deprenyl)
– At low to moderate doses ( < 10mg/day), it is selective &
irreversible MAO-B inhibitor
• It does not affect metabolism of peripheral catecholamines
• At dose > 10mg/day , MAO-A can be inhibited
– Used as adjunctive therapy for patients with declining or
fluctuating response to levodopa

52. Parkinson’s disease
COMT inhibitors
• Tolcapone (long duration) & entacapone (short duration)
• Inhibition of DOPA decarboxylase is associated with
activation of other levodopa metabolism pathways: such as
metabolism of L-DOPA by COMT
• Addition of COMT inhibitors to carbidopa / levodopa
combination delays ’’on/off’’ phenomenon of the L-DOPA
therapy

53. Parkinson’s disease
Muscarinic receptor antagonists
• Benzatropine, biperiden, orphenadrine, procyclidine
• ↓ the unbalanced cholinergic activity in striatum
• The only drugs effective in drug induced (phenothiazines
– anti-psychotics) parkinsonism – Benzatropine
• Start from small dose & gradually ↑ until benefit occurs or
SE limit further increment

54. 54
Antidepressant drugs

55. Depression
• Depression is defined as disorders of mood
which occurs for more than 6 weeks of time
• It is characterized by different symptoms
– Lack of interest in normal activities
– Insomnia, anorexia, low self esteem
– Fatigue & inability to concentrate
– Mental slowing, indecisiveness
– Lack of energy & libido
– Pessimism, feelings of guilt, ugliness

56. • Monoamine theory
–The theory states that depression is caused by
a functional deficit of monoamine transmitters
(NE &/or 5-HT) at certain sites in the brain
• So, most of the antidepressant drugs work by
facilitating adrenergic & serotonergic
neurotransmission in the CNS
– Inhibiting reuptake of NE & serotonin (5-HT)
– Inhibiting metabolism of NE & 5-HT
– Increasing release of NE & 5-HT

57. Classification of antidepressants
1. Tricyclic antidepressants (TCAs)
2. Selective serotonin reuptake inhibitors (SSRIs)
3. Monoamine oxidase inhibitors (MAOIs)
4. Miscellaneous ('atypical') antidepressants

58. I. Tricyclic or heterocyclic antidepressants (TCAs)
Were mainstays of depression treatment in earlier times
But now TCAs are not 1st line therapy for depression due to their
prominent side effects
• They can be classified into two based on their mechanism
A. NE & 5-HT reuptake inhibitors – Predominantly 5-HT
Imipramine Amitriptline
Trimipramine Dothiepin
Doxepin Clomipramine
B. Predominantly NE reuptake inhibitors
Amoxapine Desipramine
Nortriptyline Reboxetine

59. Mechanism of TCAs
• TCAs work by blocking reuptake of NE & 5-HT
– ↑these NTs concentration in the synaptic cleft
• Reuptake inhibition by the TCAs occurs within short
period after administration but therapeutic effect occurs
after 2-3 weeks of drug taking
• This delay of therapeutic effect has been hypothesized to
be due to
– On the 1st few weeks of treatment the increased NTs activate
presynaptic autoreceptors (α2, 5-HT1A & 5-HT1D)
– Activation of these receptors leads to decreased release of the
NTs
– But after 2-3 weeks these receptors are desensitized & NE &
5-HT are released well

60. • After long term administration of TCAs (2-3 wks)
– The drug desensitize presynaptic auto
receptors (α2, 5-HT1A & 5-HT1D)
– ↑concentration of NTs in synaptic cleft
– Increased sensitivity of postsynaptic receptors
– Hence, the net effect after long term therapy
is enhanced noradrenergic & serotonergic
transmission

61. Pharmacological actions of TCAs
• Well absorbed from the GIT
• Are highly lipid soluble & bound to plasma proteins
• They block several receptors other than their effect to
inhibit 5-HT & NE reuptake including
– Muscarinic receptors
– Histamine receptors
– α-1 adrenergic receptors
– D2 receptors (only Amoxapine)
• So the capacity of TCAs to inhibit multiple receptors is
the source for
– Most of their side effects & drug interactions

62. • Side effects
– Due to muscarinic receptor antagonism
• Dry mouth, constipation, urinary retention, blurred vision,
tachycardia
– Due to histamine receptor antagonism
• Sedation, weight gain
– Due to α1-antagonism
• Orthostatic hypotension
– Due to D2 antagonism (only for Amoxapine)
• Extrapyramidal effects, gynacomasteia, lactation
• TCAs can also cause life threatening seizures,
sexual dysfunction

63.  Drug interactions
 TCAs compete for binding sites of plasma proteins &
displaced by phenytoin, aspirin & phenothiazines
 Serious but rare interaction occurs b/n TCAs &
MAOIs
• Both are important for treatment of depression
• But coadministeration of a drug from each class leads to
Hyperpyrexia, convulsions, coma
• So, in TCAs resistant patients, it is advisable to discontinue
the TCAs drug for 2-3 weeks before initiation of a MAOI
therapy
• TCAs can also potentiate sedative effects of alcohol &
patients should be cautioned about this interaction

64. II. Selective serotonin reuptake inhibitors (SSRIs)
• Includes:
– Fluoxetine, fluvoxamine, paroxetine, sertraline,
citalopram, maprotiline, trazodone & nefazodone
• This class of antidepressants
– Has little/no affinity for cholinergic, adrenergic &
histaminergic receptors
– Don’t affect cardiac function, so they are well
tolerated by patients with cardiac problems

65. SSRIs
• MOA: inhibit reuptake of 5-HT into the neuron &
increase 5-HT concentration in the synapse
• 1st line drugs for management of depression
–Due to their relative safety & acceptability
• No seizure precipitating propensity & not inhibit
cardiac conduction
• They don’t cause weight gain

66. – For TCAs & SSRIs onset of action is slow, so:
•Treatment should be given for at least 4-6
weeks before concluding that the drug is
ineffective for the particular individual
• If there is a partial response, treatment should
be continued for several more weeks before
increasing the dose
•Treatment should continue for at least 4
months following subsidence of depression

67. • Side effects
– Anxiety/agitation
– Insomnia
– Nausea
– Loose stools
– Sexual dysfunctions
• Decreased libido, delayed ejaculation, anorgasmia
• Drug interaction – If combined with MAOIs, cause 5-HT syndrome –
Overstimulation of 5-HT receptor in brain stem and spinal cord
– Confusion, elevated or dysphoric mood, tremor, myoclonus, incoordination,
hyperthermia, and cardiovascular collapse

68. • Fluoxetine
– Prototype of the SSRIs
– Given in the morning to prevent night time insomnia
– Has slow elimination from the body after discontinuing the drug
– So we should weight 4-6 weeks of time before administering a
drug which could interact with it such as MAOIs
– Is potent inhibitor of CYP2D6 enzyme
• So it can increase the concentration of drugs metabolized by
this enzyme
• Note: from all SSRIs, Citalopram has the least
effect on the CYP450 enzymes & has the most
favorable profile regarding drug-drug interactions

69. III. Monoamine oxidase inhibitors (MAOIs)
• Two types of MAO enzymes
– MAO-A: metabolizes NE, 5-HT, DA & tyramine
– MAO-B: metabolizes DA
• So, there are two types of MAOIs
• Non selective MAOI
– Tranylcypromine, phenelzine & isocarboxide
– Older, irreversible, long-acting drugs
• Selective MAO-A inhibitor
– Moclobemide, clorgyline
– Newer, reversible & short acting agents

70. • MAOIs are as effective as TCAs & SSRIs as
antidepressant
• However, at least two forms of life threatening toxicities
have been associated with their long term use
– Hepatotoxicity
– Dietary tyramine induced hypertensive crises
• For these reasons MAOIs are not considered as 1st line
therapy for depression
• So, they are used for resistant type of depression
• Note: MAO-A inhibition is responsible for the
antidepressant effect of both the non selective &
selective inhibitors

71. • Adverse effects
– Hepatotoxicity
– Drug-food interactions
– Tremors, Sexual dysfunction
– Dry mouth, fatigue & weight gain
• Note:
– When switching from SSRIs to MAOIs, we should
allow drug free 3-4 weeks before starting the MAOIs
therapy
– A drug free period of 2 weeks is required before
switching to SSRIs
• To allow for regeneration of tissue MAO & elimination of
MAOIs

72. IV. Miscellaneous ('atypical') antidepressants
Venlafaxine
– Inhibits the reuptake of both NE & 5-HT
– Doesn’t have significant effects at muscarinic,
histaminic or α-adrenergic receptors
– Has minimal effects on CYP450 enzymes
– Has similar side effects as the SSRIs
Mirtazapine
– Enhances NE & 5-HT neurotransmission (promotes their
release) by blocking presynaptic α2 receptors
– Doesn’t inhibit neuronal reuptake of 5-HT & NE
– Doesn’t have significant effect on CYP450 enzymes
– SEs: weight gain, sedation( should be given at bed time)

73. Bupropion
– Weak inhibitor of DA & NE reuptake
– But is MOA as antidepressant isn’t well known
– It doesn’t inhibit other receptors such as:
• Muscarinic
• Histamine
• Adrenergic receptors
– It inhibits the CYP2D6 enzyme
– Unlike the SSRIs & Venlafaxine, Bupropion doesn’t
cause sexual dysfunction
– Side effects
• Restlessness, insomnia
• Risk of seizures
– So it is contraindicated in patients with history of seizure

74. Analgesic drugs
• Drugs eliminate pain by
– ↓ transmission of nociceptive impulses and pain perception
• Opioids
– ↓ the underlying cause of the pain
• Nonopioid analgesics - NSAIDs
– Miscellaneous
• Anti-depressants, adrenergic agonist, transcutaneous
electrical nerve stimulation, physical and massage therapy,
acupuncture, meditation, behavior modification

75. Analgesic drugs
Opioid (Narcotic) analgesics
• All compounds related to or derived from opium
– Opium - Extract of the juice of the poppy Papaver somniferum
• Opioid receptors – Three receptors
– µ (Mu)-receptors - Responsible for the analgesic and major SE
• Clinically used opioids relatively selective for µ
• ↑ Dose - Interact with additional receptor subtypes
–  (Delta) – Analgesia, peripheral effects, tolerance
–  (Kappa) – analgesia, psychomimetic, dysphoria
• Inhibit adenyl cyclase or Ca++ channel or activate K+ channel
– Inhibit nociceptive transmission

76. Analgesic drugs
Opioid analgesics cont…
• Class of opioid analgesics
– Strong agonists
• Phenanthrenes- Morphine, hydromorphone, heroin, oxymorphone
• Phenylheptylamines – Methadone
• Phenylpiperidines - Meperidine, fentanyl, sufentanil, alfentanil,
remifentanil, pethidine
• Morphinans - Levorphanol

77. Analgesic drugs
Opioid analgesics cont…
• Class of opioid analgesics
– Mild to moderate agonists
• Phenanthrenes - Codeine, oxycodone, dihydrocodeine, hydocodon
• Phenylheptylamines - Propoxyphene
• Phenylpiperidines - Diphenoxylate → Difenoxin, Loperamide
– Opioids with mixed receptor action
• Phenanthrenes - Nalbuphine, Buprenorphine
• Morphinans – Butorphanol
• Benzomorphans - Pentazocine

78. Analgesic drugs
Opioid analgesics cont…
• Class of opioid analgesics
– Antagonists - Naloxone, naltrexone, nalmefene
– Anti-tussives - Dextromethorphan, Codeine, Levopropoxyphene
– Miscellaneous - Tramadol

79. Analgesic drugs
Opioid analgesics
• Therapeutic uses
– Severe, constant pain
– Acute pulmonary edema
• ↓ Anxiety, ↓ cardiac preload and afterload
– Cough suppression
• Dextromethorphan, codeine, levopropoxyphene
– Diarrhea – Diphenoxylate, Loperamide
– Pre-anaesthetic medication

80. Analgesic drugs
Opioid analgesics cont…
• Adverse effects
– Respiratory depression
– Sedation
– Constipation
– Miosis
– Euphoria and physical dependence - Mu receptors
– Psychomimetic and dysphoria effect - Kappa receptors
Mu and Kappa receptors

81. Analgesic drugs
Nonsteriodal anti-inflammatory drugs (NSAIDs)
• Less effective than opioids
– Less chance of tolerance and physical dependence
• ↓ the formation of pain mediators (prostaglandins, PGs) in
PNS by inhibiting cyclooxygenase (COX) enzyme
– Arachidonic acid (AA) Prostanoids
• Prostanoids are involved
– Pain and Fever:- PGE, PGI
– Inflammatory responses in tissue:- PGE, TXA , PGD
– Maintenance of the gastric mucosal lining:- PGE, PGI
– Renal functions:- PGE, PGI, TXA

82. Analgesic drugs
NSAIDs cont…
• Classification of NSAIDs
– A. Non selective COX inhibitors
• Salicylates – Aspirin
• Propionic acid derivatives- Ibuprofen
• Acetic acid derivatives- Diclofenac, indomethacin
• Oxicam – Piroxicam
– B. Selective cox-2 inhibitors
• Coxibs – Celecoxib

83. Analgesic drugs
NSAIDs cont…
• Actions of NSAIDS
– Anti pyretic, Anti inflammatory, Analgesic
– Anti aggregatory (Reduce platelet plug and clot formation)
• Uses of NSAIDs
– Mild analgesic and anti-pyretics
– Anti-inflammatory
• Inflammation associated with arthritis in joints
– Anti-platelet agents

84. Analgesic drugs
NSAIDs cont…
• Adverse effects
– Gastrointestinal
• Local irritation because of their acidic nature
– High absorption at the stomach
• Inhibit the mucosal synthesis of PGI2 and PGE2
• ↓ the defense mechanisms of the GIT (mucus, bicarbonate
secretion, blood flow)

85. Analgesic drugs
NSAIDs cont…
• Adverse effects
– Bleeding time
• ↓ in TxA2 synthesis, will prevent platelet aggregation
– Renal
• Cause renal failure only if there is an underlying condition
that results in underperfusion of the kidney
– Pulmonary
• Bronchoconstriction-due to high production of leukotriene

86. Analgesic drugs
NSAIDs cont…
• 1. Salicylates - Aspirin, Diflunisal
– Aspirin
• Analgesic, Antipyretic, Antithrombotic (drug of choice for
being an antithrombotic)
• Anti-inflammatory
• Additional SE
– Reyes syndrome - Not recommended in children less than 14
years with chicken pox, measles and mumps as anti-pyretics
– Tinnitus and Uric acid retention

87. Analgesic drugs
NSAIDs cont…
• 2. Propionic acids - Naproxen, Ibuprofen
– More potent than aspirin
– Ibuprofen
• Anti-inflammatory, analgesic and antipyretic
• GI irritation less frequently than aspirin
• SE - Pruritus, rash, tinnitus, dizziness, fluid retention
– Rarely - Agranulocytosis, aplastic anemia
» Kideny (renal failure, interstitial nephritis, nephrotic
syndrome)

88. Analgesic drugs
NSAIDs cont…
• Ibuprofen indications
– Relief of signs and symptoms of rheumatoid arthritis
– Osteoarthritis
• Degenerative disease of joint which become stiff and painful
– Ankylosing spondylitis
• Inflammation of vertebrae and joints which become stiff
– Acute gouty arthritis
– Relief of mild to moderate pain and fever reduction
– Treatment of dysmenorrhea

89. Analgesic drugs
NSAIDs cont…
• 3. Acetic acids - Indomethacin, Diclofenac
– Indomethacin
• Has prominent antiinflammatory and analgesic-antipyretic
properties similar to those of the salicylates
• More potent inhibitor of COX than aspirin
• Patient intolerance (Due to its ulcerogenic effect) generally
limits its use to short-term dosing
• Used only for its anti inflammatory effect

90. Analgesic drugs
NSAIDs cont…
• Diclofenac
– Potent COX inhibitor
• Its potency against COX-2 is substantially greater than that
of indomethacin, naproxen, or several other NSAIDs
– Accumulates in synovial fluid
– Indications
• Acute or long-term treatment of mild to moderate pain,
including dysmenorrhea
• Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis

91. Analgesic drugs
NSAIDs cont…
• Acetaminophen (Paracetamol)
– Weak PG synthesis inhibitor in peripheral tissues and
possesses no significant anti-inflammatory effect
– Effective analgesic and antipyretic agent
– Use - Mild to moderate pain - Head ache, postpartum pain
– SE - Hepatotoxic, hemolytic anemia

92. Analgesic drugs
NSAIDs cont…
• Coxibs – Selective COX-2 inhibitors
– Meloxicam, celecoxib, etoricoxib, rofecoxib
– Reduces prostaglandins produced in pathological situations
– Analgesic, antipyretic and anti-inflammatory effect similar
to nonselective NSAIDs
• Less GIT adverse effects

93. Anti-rheumatoid drugs
• Rheumatoid arthritis (RA) is a long lasting autoimmune
disorder that primarily affects joints. It typically results in
warm, swollen, and painful joints
– NSAIDs
– Slow acting anti-rheumatoid drugs (SAARDs) or disease
modifying anti-rheumatoid drugs (DMARDs)
– Glucocorticoids

94. Anti-rheumatoid drugs
DMARDs
• Do not have general anti-inflammatory effects
• May take 6 weeks to 6 months to produce their effects
– They are slow-acting compared with NSAIDs
• Included in this category are
- Chloroquine
- Sulfasalazine
- Gold compounds
- Methotrexate
- Penicillamine

95. Anti-rheumatoid drugs
DMARDs cont…
• 1. Chloroquine
– Is used in the treatment of malaria
– Anti-inflammatory only in rheumatic disease
– Less adverse systemic effects but tends to seriously affect the eyes
• Cornea of the patient undergoing this treatment needs to be monitored. Retinopathy
may be irreversible, causing blindness
– Very slow onset (months)
• 2. Sulfasalazine
– A free radical scavenger?
• Free radicals cause cell injury and inflammation
– Has marked GI irritation - Only available with an enteric coating

96. Anti-rheumatoid drugs
DMARDs cont…
• 3. Gold compounds
– Aurothiomalate (IM), Auranofin (Oral, less common)
– MOA
• ↓ lymphocyte proliferation, ↓ lysosomal enzyme release
• ↓ superoxide production, ↓ neutrophil chemotaxis, ↓ IL-1 synthesis
– May take months to see a beneficial effect.
– Adverse effects
• Allergic type reactions at the skin and mucous membranes, Renal
injury
• Blood dyscrasias (any adverse change in blood function)

97. Anti-rheumatoid drugs
DMARDs cont…
• 4. Methotrexate
– Immunosuppresant (Folate antagonist)
• Also used to treat cancer
– Affects the functions of leucocytes and macrophages
• 5. Penicillamine
– Adverse effects similar to gold compounds
– Not effective, most probably be obsolete soon
– Once the effects of the above drugs are observed, they will slow
the disease progress, not just treating the inflammation

98. Gout
• Gout - Due to an accumulation of uric acid (a breakdown
product of adenosine)
– High concentrations of uric acid lead to crystallization and
deposition in the synovium of joints, resulting in arthritic pain
• Acute treatment of gout involves
– NSAIDs (NOT aspirin as it inhibits the excretion of uric acid)
– Colchicine
– Glucocorticoids
• Chronic treatment involves
– Allopurinol, Colchicine, Probenecid

99. Gout cont…
• Its difference from rheumatoid arthritis (RA)
– Gout usually occurs in the foot, most commonly at the base of
the big toe.
• RA can affect any joint on either side of the body, but most
commonly occurs in small joints of hands, wrists and feet
– Gout is always accompanied by redness, swelling, and intense,
agonizing pain
• A joint affected by RA also may become painful, but won’t
always be red or swollen.
• RA pain varies in quality and intensity – Mild to excruciating

100. Gout cont…
• Synthesis of uric acid

101. Drugs for Gout
• Colchicine
– Anti-mitotic agent (interferes with tubulin) which prevents
leukocyte migration
– Reduced leukocytes in synovial joints affected by gout
would reduce the pain and discomfort
– Can be used as an acute treatment
– Also can be used as a chronic treatment as prevention
(prophylactically) in conjunction with allopurinol

102. Drugs for Gout cont…
• Allopurinol
– Analogue of hypoxanthine which Inhibits xanthine oxidase
• Preventing hypoxanthine from binding
– Product of allopurinol with xanthine oxidase is alloxanthine
• Alloxanthine is an irreversible inhibitor of xanthine oxidase
• ↓ synthesis of uric acid and the concentrations fall
– Even though underexcretion rather than overproduction is
the underlying defect in most gout patients, allopurinol
remains effective therapy

103. Drugs for Gout cont…
• Probenecid
– Uricosuric agent (increases the excretion of uric acid)
– Inhibits the tubular reabsorption of uric acid in the kidneys
– Limited use, not as effective as allopurinol

104. Anesthetics agents
• Depress the nervous system, causing a loss of consciousness
(except for local and regional anesthetic agents) and relieving
pain during surgery
• Anesthetic agents are classified as
– General Anesthetic – Act on the CNS
• Used for surgery consists of one medication or a combination that
causes a temporary loss of consciousness
– Local Anesthetic
• Block specific nerve pathways in a region and result in temporary
analgesia and paralysis but no loss of consciousness

105. Anesthetics agents
Local anesthetic
• Blocks pain at the site where the medication is administered
• Used to render a specific portion of body insensitive to pain
– Interfere with nerve impulse transmission to specific areas of the
body
• Do not cause loss of consciousness
• Procaine, Tetracaine, Bupivacaine, Lidocaine
• It is used for
– Suturing lacerations, short-term localized surgery, spinal
anesthesia, diagnostic producers

106. Anesthetics agents
Local anesthetic
• Lidocaine
– Moderate-acting local anesthetic agent
– Systemically used for cardiac arrhythmia management
– Side effects
• CNS depression, convulsion and respiratory depression
• Main toxic actions are in the heart - Arrhythmias, decreased
contraction, hypotension, cardiovascular collapse
– Caution
• Dosage should be reduced for elderly, debilitated, acutely ill

107. Anesthetics agents
Local anesthetic
• Lidocaine
– Contraindications
• Do not use a vasoconstrictor on appendages such as fingers,
toes, earlobes, and penis.
• Use with caution with cardiac patients.
• Hypersensitivity to amide-type local anesthetics, arrhythmias
– Anesthetic solutions containing epinephrine should be used
with caution in peripheral or hypertensive vascular disease
and during or following potent general anesthesia

108. Anesthetics agents
General anesthetics
• Four stages of Anesthesia
– 1. Analgesia - Patient is conscious and able to converse, no pain
– 2. Excitement: Breathing ↑, BP ↑ and become irregular.
Delirium sets in and the patient may become violent
– 3. Surgical Anesthesia: Eye movement slows then stops as
breathing becomes regular. Skeletal muscles relax and surgery
begins
– 4. Medullary Paralysis: The respiratory center (medulla
oblongata) becomes paralyzed. Breathing and vital functions
cease. Death occurs

109. Anesthetics agents
General anesthetics cont…
• General anesthetics – IV or inhalational
• IV anesthetics
– To induce or maintain general anesthesia, To induce
amnesia, as an adjunct to inhalation-type anesthetics
– Includes
• Short acting barbiturates - Thiopental, methohexital
• Benzodiazepines - Midazolam, diazepam, Lorazepam
• Propofol
• Ketamine

110. Anesthetics agents
General anesthetics cont…
• Short acting barbiturates – Thiopental
– Short acting due to their redistribution phenomenon
– Produce rapid unconsciousness & amnesia
– Don’t produce analgesia & skeletal muscle relaxation
– MOA - They promote the action of GABA
– SE - CVS and respiratory depression, precipitation of drugs
• ↓ force of contraction & vasodilation

111. Anesthetics agents
General anesthetics cont…
• Benzodiazepines (BDZ)
– Midazolam is the most popular agent due to
• Its high water solubility
• Short duration of action (enables rapid recovery)
– Lorazepam is the most potent agent
– Lorazepam & diazepam are not water soluble
• Dissolved in propylene glycol which is irritant to vasculature

112. Anesthetics agents
General anesthetics cont…
• Benzodiazepines
– Produce unconsciousness & amnesia but not analgesia
– So they can be used in place of barbiturates
– Advantages of BDZs over barbiturates
• Produce lesser CVS & respiratory depression
• Have antagonist called flumazenil
– Used in the cases of BDZ overdosage

113. Anesthetics agents
General anesthetics cont…
• Propofol
– IV anesthetic which is rapidly metabolized (rapid recovery
from the anesthesia)
• Patients are able to ambulate earlier after general anesthesia
– It produces less postoperative nausea and vomiting
– It is used for induction and maintenance of anesthesia
– Effective to induce prolonged sedation for patients in
critical care settings (by applying prolonged infusion)

114. Anesthetics agents
General anesthetics cont…
• Ketamine
– Block glutamate activity on NMDA receptor
– The only IV anesthetic with analgesic effect
– It differs from the other IV anesthetics in two ways
• Produces dissociative anesthesia and cardiac stimulation
– Patient may seem awake & reactive but doesn’t respond to
sensory stimuli
– By stimulating SNS and by inhibiting NE/EP reuptake

115. Anesthetics agents
General anesthetics cont…
• Ketamine
– Side effects
• Most common side effects are post anesthesia effects
– Patients in the recovery period may
» Be agitated
» Hallucinate
» Cry
» Scream
• Vomiting, salivation, shivering

116. Anesthetics agents
General anesthetics cont…
• Inhalational anesthetics
– Halothane, isoflurane, sevoflurane, desflurane
– Other - Nitrous oxide, Ether
– Use - General anesthesia & severe refractory status
asthmaticus (rare indication)
• Mainly used for maintenance of anesthesia
– Contraindication: Malignant hyperthermia (MH)
– SE – Hypotension, respiratory depression, liver and kidney
damage, carcinogenesis, hematotoxicity

117. Anesthetics agents
General anesthetics cont…
• Halothane – Liver toxicity
• Nitrous oxide – Laughing gas – Bone marrow toxicity
– Analgesic action
• Enflurane – Some risk of epilepsy-like seizures
• Desflurane – Respiratory irritant – Cough and laryngospasm
• Isoflurane – Respiratory irritant and precipitate MI
• Sevoflurane – Lack respiratory irritation