This document discusses various sedative-hypnotic drugs including benzodiazepines, barbiturates, and other non-benzodiazepine sedatives. It covers their mechanisms of action, classifications, pharmacological effects, therapeutic uses, and side effects. The document also discusses antidepressant drugs for treating depression and mania, including monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and norepinephrine-dopamine reuptake inhibitors (NDRIs).

1. PSYCHOPHARMACOLOGY
Dr. Sakhile Ndlalane
Levy Mwanawasa Teaching hospital

2. SEDATIVE- HYPNOTICS
 Hypnotics are drugs which induces a state resembling natural sleep.
 Hypnotics in small doses are sedatives since they induces the calmness
without inducing sleep.
 Sedative agent reduce the anxiety and exert the calming effect.
 Hypnotic involve more pronounced depression of CNS than sedatives

3. SEDATIVE- HYPNOTICS
 Major subgroup: benzodiazepines
 Other groups still in use ; Barbiturates
 Miscellaneous agents: carbamates, alcohols, cyclic ethers

4. CONT..
Classes
 Benzodiazepines
Short, Intermediate and long action
 Barbiturates
Ultra-short, Short, long action
Miscellaneous agents
 Buspirone, chloral hydrate, eszopiclone, ramelteon, zaleplon, zolpidem

5. CONT..
Classification of barbiturates
Ultra Short-Acting
 duration of action of 15 to 30 minutes, administered IV to induce anesthesia
because of their high lipid solubility
 Examples: Methohexital, thiopental
Short acting
 Duration of action 2-4 hours
 taken orally the initial and short term treatment of insomnia
 for short term daytime sedation in patients who suffer from anxiety

6. CONT
Examples
 Pentobarbital
 Secobarbital
Intermediate-Acting
 duration of action: 4-6 hours .
 used for the initial and short term treatment of insomnia
 Example: Amobarbital
long acting :
 Duration 6-8hrs
 Ex, Phenobarbital and Mephobarbital
 With the exception of phenobarbital, which is partly unchanged in the urine,
most of the barbiturates are extensively metabolized

7. MOA
 Mechanism of action: increase the inhibitory activity of the GABA and GABA
mediated increase in chloride conductance
 Barbiturate potentiate the action of benzodiazepine probably by additive
effect

8. PHARMACOLOGICAL ACTION
CNS
 nervous system depression and death due to the depression of the vital
medullary center including the cardiovascular and respiratory center.
 Respiratory depression can occur in hypnotic doses in chronic lung patients
CVS
 Lower the blood pressure by reducing the cardiac output and inducing the
venodialatation.
 Higher doses depresses the vasomotor center and induces the marked
hypotension.

9. TOXICITY
 Characterised by respiratory failure, cardiovascular collapse, coma,renal
failure.
 Mostly suicidal thoughts
 Treatment include gastric lavage, artificial respiration and forced alkaline
diuresis with mannitol and sodium bicarbonate.
 In alkaline urine barbiturate get ionised and hence their tubular reabsorption
is prevented thats why excretion promoted

10. THERAPEUTIC USES
 Sedative hypnotics: seldom used now , previously short acting barbiturate
used.
 Anesthesia: ultra short acting barbiturates (thiopental sodium ) as inducing
agents...
 Anticonvulsants: long acting barbiturates as phenobarbitone..
 To treat hyperbilirubinemia of neonates as it increases its activity

11. BENZODIAZEPINES
MOA
 Potentiates GABA-A receptor by increasing chloride ion conductance
CLASSIFICATION
long acting :
 diazepam, flurazepam, clonazepam, chlordiazepoxide
Short acting:
 alprazolam, estazolam, temazepam,lorazepam,nitrazepam
Ultra shortacting:
 midazolam, triazolam, oxazepam

12. PHARMACOLOGICAL ACTION
CNS
 Hypnotic, sedative ,anxiolytic, anticonvulsant,and central muscle relaxant
actions..
 Benzodiazepines act cheifly on brain recticular activating systems, limbic
system nd median forebrain bundle and hypothalamus .
 Benzodiazepine shorten the time taken to go to sleep(sleep latency),decrease
intermitent awakening, and increase total sleep duration
 Flumazenil is an inverse antagonist at benzodiazepine receptor and reverses
CNS effects of BZPs

13. THERAPEUTIC USES
1.ANXIOLYTIC
 Most commonly used are
alprazolam,lorazepam,oxazepam,diazepam,chlordiazepoxide.
Alprazolam has anxiolytic and antidepressant property
 Dose
0.25 -.5 mg BD or TDS
Lorazepam
 for short lived anxiety states and compulsive obsessive neuroses and tension
induced psychosomatic symptoms
 Dose
1-6mg per day

14. CONT..
3.FOR PREANAESTHETIC MEDICATION AND INDUCTION OF ANAESTHESIA:
 Diazepam,lorazepam and midazoam are generally used for this purpose
 Midazolam most often used as a more rapid onset with shorter duration of
action.
4. AS SKELETAL MUSCLE RELAXANT:
 Diazepam prefered for relaxing effect in skeletal muscle.

15. DIs
 Potentiate the effect of of other CNS depressant such as alcohol,hypnotics
and neuroleptics.
 Smoking decreases the activity of benzodiazepines...
 Aminophylline antagonises the sedative effect of benzodiazepines.
 Enzyme inhibitors like cimetidine,and ketoconazole enhances the
benzodiazepine action

16. PKs of BZDPs
 Well absorbed and given orally.
 High lipid solubility
 bind strongly to plasma protein.
 metabollised and eventually removed as glucuronides.
 Several converted to active metabolite like nordazepam (n -desmethyl
diazepam) which has a half life of 60 hours and this responsible for the
cumulative effect of many diazepams.

17. OTHER NON-BENZODIAZEPINE SEDATIVES
 Tolerance and dependance much less as compaired to BZDS
 Dose reduction needed in the hepatic and elderly patients
ZOLPIDEM:
 Have t ½ of 2-3 hours
Dose
 10-20 mg at night time for transient insomnia.
ZOPICLONE:t
 Have t½ of 3-4 hrs
Dose
 7.5 mg noct. to treat transient insomnia

18. CONT..
 ZALEPLON:
 t ½ of 6-8 hrs
Dose:
 10-20 mg to treat short term insomnia
 Negligible muscle relaxant and anti convulsant action

19. MELATONIN AGONISTS
(ATYPICAL SEDATIVE-HYPNOTICS, Ramelton and Buspiron)
RAMELTEON:
 MT1 and MT2 melatonin receptor agonist class hypnotic for sleep onset
insomnia.
Dose:
 8 mg half hour before going to bed.
 It shown to hasten sleep onset and increase in sleep duration

20. OTHER HYPNOTICS AND SEDATIVES
BUSPIRONE:
 Partial agonist primarily at the brain 5HT1A Receptors .
 By selective activation of the inhibitory presynaptic 5HT1A recepter they
suppresses 5HT neurotransmission through neuronal system
Dose
 Buspirone 5-10 mg tds is used in anxiety state
 Usual anxiolytic action of buspirone is delayed for two weeks which make it
unsuitable for the management of the acute anxiety state.

21. CONT..
PROMETHAZINE:
 sedating antihistamine with antiemetic anti cholinergic property.
HYDROXYZINE:
 antihistamine with sedative hypnotic action are promoted for treating
insomnia.
 TRICLOFOS: for short term management of insomnia

22. SUMMARY

23. CONT..

24. MANIC DEPRESSIVE DISORDERS
Causes of depression
 Genetics
 Death/Abuse
 Medications
MONOAMINE OXIDASE (MAO) AND DEPRESSION
 MAO catalyze deamination of intracellular monoamines
 MAO-A oxidizes epinephrine, norepinephrine, serotonin
 MAO-B oxidizes phenylethylamine

25. CONT..
Types of MAOI
 MAO Inhibitors (nonselective)
 Phenelzine (Nardil)
 Tranylcypromine (Parnate)
 Isocarboxazid (Marplan)
 MAO-B Inhibitors (selective for MAO-B)
 Selegiline (Emsam)

26. CONT..
 MAOIS SIDE EFFECTS
 Constipation
 Decreased urine output
 Decreased sexual function
 Sleep disturbances
 Muscle twitching
 Weight gain
 Blurred vision

27. CONT..
MAOIS SIDE EFFECTS
 Side effects have put MAOIs in the second or third line of defense despite
superior efficacy
 MAO-A inhibitors interfere with breakdown of tyramine
 High tyramine levels cause hypertensive crisis (the “cheese effect”)
 Can be controlled with restricted diet
 MAOIs interact with certain drugs
 Serotonin syndrome (muscle rigidity, fever, seizures)
 Pain medications and SSRIs must be avoided

28. CONT..
Tricyclic antidepressants.
MOA
 inhibit serotonin, norepinephrine, and dopamine transporters, slowing
reuptake.
 Imipramine was first tried as an antipsychoti drug for schizophrenia
 proved to have antidepressant qualities, in 1950s
 Examples include
 Amitriptyline, Desipramine, imipramine, protriptyline
 Trimipramine, nortriptyline

29. Uses
 Amitriptyline – most widely used, most effectve
 Desipramine – active metabolite of imipramine, used for neuropathic pain
 Doxepin – used for depression and insomnia
 Imipramine – used for major depression and enuresis
 Protriptyline – depression
 Trimipramine – depression, insomnia, and pain
Side effects
 dry mouth, blurred vision, constipation, urinary retention and impotence
 sedation and weight gain
 postural hypotension

30. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
MOA
 Transport reuptake blockers
 Increases residence time of serotonin leading to mood elevation.
Examples
 citalopram (Celexa)
 dapoxetine (Priligy)
 escitalopram (Lexapro)
 fluoxetine (Prozac)
 paroxetine (Paxil)
 sertraline (Zoloft)

31. USES
 Citalopram: Major depression
 Dapoxetine: Premature Ejaculation
 Escitalopram: Major depression and various other anxiety disorders
 Fluxoetine: Major depression, OCD, bulimia, etc
 Fluvoxamine: OCD
 Paroxetine: Major depression or anxiety
 Sertraline: Major depression or anxiety

32. CONT..
 Side effects
 Apathy
 Nausea/vomiting
 Drowsiness or somnolence
 Headache
 Bruxism (involuntarily grinding of the teeth)
 Dizziness
 Fatigue
 Changes in sexual behavior
 Suicidal thoughts
 Side effects more manageable compared to MAOIs and TCAs

33. SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS (SNRIS)
 Slightly greater efficacy than SSRIs
 Slightly fewer adverse effects than SSRIs
 Mechanism of Action
 Very similar to SSRIs
 Works on both neurotransmitters
 Side effects
 Similar to SSRIs
 Current drugs
 Venlafaxine (Effexor)
 Duloxetine (Cymbalta)

34. NOREPINEPHRINE-DOPAMINE REUPTAKE
INHIBITORS (NDRIS)
 Bupropion (Wellbutrin)
 Mechanims of Action
 Similar to SSRIs and SNRIs
 More potent in inhibiting dopamine
 Adverse effects
 Lowers seizure threshold
 Suicide
 Does not cause weight gain or sexual dysfunction

35. MANIA
Symptoms of mania include
 distractibility
 racing thoughts
 impulsive actions and decisions
 elevated mood
 euphoria
 grandiosity
 irritability/hostility (easily angered)

36. Classification of Bipolar Disorders
Type Features
Bipolar disorder type 1
A manic episode ± major depressive
or mixed episode
Bipolar disorder type 2
A major depressive episode ±
hypomanic episode
Cyclothymic disorder
Chronic fluctuation between
subsyndromal and hyomanic episodes
(at least 2 years for adults)
Bipolar disorder not other wise
specified
Any bipolar disorder that does not
meet criteria for any specific bipolar
disorder
* From DSM iv

37. Theories of Bipolar disorder
Monoamine hypothesis
 An excess of catecholamines (primarily NE an DA) can cause mania.
 Deficit of monoamines (primarily NE , DA and/or 5-HT) can cause depression.
Cholinergic hypothesis
 Drug that increase cholinergic activity can decrease manic symptoms
Dysregulation of secondary messenger system
 Abnormal adenyl cyclase activity, abnormal phosphoinositide responses,
abnormal Na+, K+ and Ca++ channel exchanges

38. Drug of choice- LITHIUM
Main mechanisms of action
 Not fully understood but postulate to be actions on other second messenger
systems
 Inhibition of the activity of many receptors that are IP3/DAG linked.
 Li+ enhances GABAergic activity and reduces glutamatergic activity
 Li+ is classified as a mood-stabilizing drug because it can reduce both manic
and depressive symptoms of bipolar disorder

39. USES
 Manic phase of bipolar disorders (often with concurrent use of antipsychotics
or benzodiazepines during the first few days)
 Maintenance treatment of bipolar disorder (maintenance treatment can
prevents or diminishes the intensity of subsequent episodes of both mania and
depression. Treatment must be continued for at least 6-9 months; in severe
cases even for life).
 Schizoaffective disorder (together with antipsychotic drugs).
 Depressive disorder (augmenting agent for antidepressants)

40. Therapy for Bipolar Disorder
Disorder First Line Drugs Second Line Drugs
Acute Mania or mixed
states
Lithium
Valproate
Carbamazepine
Aripiprazole
Olanzapine
Quetiapine
Risperidone
Lamotrigine (for rapid
cycling)
Acute bipolar depression
Lithium
Lamotrigine
Carbamazepine
Valproate
Maintenance therapy
Lithium
Valproate
Lamotrigine
Olanzapine
Carbamazepine

41. Therapy for Bipolar Disorder
Hypomania
Lithium or valproate or carbamazepine
(if response is inadequate)
Lithium plus an anticonvulsant or an
atypical neuroleptic
Mania
Lithium or valproate plus lorazepam
(if response is inadequate)
Lithium plus an anticonvulsant plus an
atypical neuroleptic
Mild bipolar depression Lithium or lamotrigine
Severe bipolar depression
Lithium plus an SSRI
(if response is inadequate)
Lithium plus lamotrigine plus an SSRI

42. DEMENTIA
CAUSES
 Alzheimers Disease
 Vascular Dementia
 “Mixed” Dementia (Alzheimers Disease and Vascular Dementia)
 Parkinsons Disease with Dementia
 Others

43. Role of drug therapy
1. Cure disease
2. Prevent disease or delay onset
3. Slow progression of disease
4. Treat primary symptoms eg memory
5. Treat secondary symptoms eg depression, hallucinations

44. CONT..
CHOLINESTERASE INHIBITORS
 these drugs inhibit the breakdown of acetylcholine, an important
neurotransmitter in memory and cognition
 all show modest improvement in cognition and function, and behavioural
symptoms
 Howver, do not prevent progression of underlying disease

45. CONT..
 cholinesterase inhibitors:
 donepezil
 rivastigmine
 galantamine
 memantine
 ginkgo biloba

46.  donepezil (Aricept)
 given once daily, dosage of 5mg to 10mg
 rivastigmine (Exelon)
 given twice daily, dosages of 3mg to 12mg
 galantamine (Reminyl)
 given once daily, dosages of 8mg to 24mg (can also be given twice daily

47. CONT..
Side effects
 nausea, vomiting, diarrhoea,
 dizziness, headache, muscle cramps

48. Memantine
 glutamate is a transmitter in the brain that is affected by Alzheimers Disease
 memantine blocks the pathological effects of abnormal glutamate release
 indicated for moderate to severe AD
 trials show slowing in cognitive and functional decline and decrease in
agitation in treated group compared to placebo

49. Management of secondary symptoms of
dementia
 Antidepressants:
 specific serotonin reuptake inhibitors (citalopram, sertraline)
 antipsychotics:
 typical antipsychotics (haloperidol)
 atypical antipsychotics (risperidone)
 modest effect on symptoms
 watch for side-effects
 mood stabilisers:
 anticonvulsants (carbamazepine)

50. HIV DEMENTIA
 Common symptoms include decline in thinking, or "cognitive," functions such
as memory, reasoning, judgment, concentration, and problem solving.
 Depression
Symptoms may progress to
 Sleep disturbances
 Psychosis -- Severe mental and behavioral disorder, with features such as
extreme agitation, loss of contact with reality, inability to respond
appropriately to the environment, hallucinations, delusions
 Mania- Extreme restlessness, hyperactivity, very rapid speech, poor judgment
 Seizures

51. TREATMENT
Treat underlying cause.
Use of Combined antiretroviral treatment(CART) at early stage and aim to reduce
viral load.
 NNRTIs
 NRTIs
 PIs

52. Symptomatic management of HIV
dementia
Hallucinations –
 Antipsychotics- Haloperidol, risperidone
Depression –
 Antidepressants- fluoxetine,
Mood swings and apathy
 Mood stabilizers- carbamazepine

53. THANK YOU