anti-psychotic drugs

1. ANTI-PSYCHOTIC DRUGS
http://crisbertcualteros.page.tl

2. ANTI – PSYCHOTIC DRUGS
• NEUROLEPTIC DRUGS
• ANTI-SCHIZOPHRENIC DRUGS
• MAJOR TRANQUILIZERS
• DOPAMINE RECEPTOR
ANTAGONISTS

3. TYPES OF PSYCHOSIS
• SCHIZOPHRENIA
• AFFECTIVE DISORDERS
(DEPRESSION/MANIA)
• ORGANIC PSYCHOSES
(CAUSED BY HEAD INJURY,
ALCOHOLISM, OTHERS)

4. THE NATURE OF SCHIZOPHRENIA
• Begins at an early age
• Strong hereditary factor
POSITIVE SYMPTOMS
 Delusions / Hallucinations
Thought disorder
NEGATIVE SYMPTOMS
Withdrawal from social contacts
Flattening of emotional responses

5. THE DOPAMINE HYPOTHESIS
• SCHIZOPRENIA: WITH EXCESSIVE
DOPAMINIERGIC ACTIVITY
1. ANTIPSYCHOTIC DRUGS BLOCK
POSTSYNAPTIC D2 RECEPTORS IN CNS
2. DRUGS THAT INCREASE DOPA
AGGRAVATE SCHIZOPHRENIA

6. THE DOPAMINE HYPOTHESIS
3. DOPAMINE RECEPTOR DENSITY ↑ in
schizophrenia
4. POSITRON EMISSION TOMOGRAPHY
(PETS) ↑ DRD
5. HOMAVANILLIC ACID (HAV) change in
amount

7. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS
1. TYPICAL ANTIPSYCHOTICS
a. Phenothiazine derivatives
• Aliphatic Derivative: CHLORPROMAZINE
• Piperidine Derivative: THIORIDAZINE
• Piperazine Derivative: FLUPENAZINE,
PERPHENAZINE, TRIFLUOPERAZINE
b. Thioxanthene Derivative: THIOTHIXENE
c. Butyrophenone: HALOPERIDOL

8. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS
2. ATYPICAL ANTIPSYCHOTICS
• CLOZAPINE LOXAPINE
• OLANZAPINE
QUETIAPINE
• RISPERIDONE
MOLINDONE
• ZIPRASIDONE
• SERTINDOLE
ARIPIPRAZOLE

9. PHARMACOKINETICS
• READILY BUT INCOMPLETELY
ABSORBED
• FIRST PASS METABOLISM
• HIGHLY LIPID SOLUBLE
• LARGE V d > 7 L / kg
• PROTIEN BOUND
• COMPLETELY METABOLIZED
• LITTLE EXCRETED UNCHANGED
• T ½ is 10 -24 hours

10. MECHANISM OF ACTION
• DOPAMINE RECEPTOR-BLOCKING
ACTIVITY IN THE BRAIN
• SEROTONIN RECEPTOR-BLOCKING
ACTIVITY IN THE BRAIN
• BLOCK CHOLINERGIC,
ADRENERGIC & HISTAMINERGIC
RECEPTORS

11. DOPAMINERGIC SYSTEM
• MESOLIMBIC-MESOCORTICAL :
substancia nigra………>limbic system
BEHAVIOR
2. NIGROSTRIATAL : substancia
nigra,,,……...>caudate & putamen
VOLUNTARY MOVEMENTS
3.TUBEROINFUNDIBULAR: arcuate
nuclei & periventricular neurons,,,>
hypothalamus & post pituitary;
INHIBITS PROLACTIN SECRETION

12. DOPAMINERGIC SYSTEM
4.MEDULLARY-PERIVENTRICULAR :
motor nuclei of the vagus
EATING BEHAVIOR
5. INCERTOHYPOTHALAMUS : from
the medial zona incerta to the
hypothalamus and the amygdala
REGULATE THE ANTICIPATORY
MOTIVATIONAL PHASE OF
COPULATORY BEHAVIOR IN RATS

13. DOPAMINE RECEPTORS
• D1: CHROMOSOME 5; ↑ cAMP…>
activation of adenyl cyclase
• D5 : CHROMOSOME 4; ↑ cAMP
• D2: CHROMOSOMES 11: ↓ cAMP…>
blocks Ca ++ channels…> opens K +
channels
• D3: CHROMOSOME 11: ↓ cAMP
• D4: ↓ cAMP

14. DIFFERENCES AMONG
ANTIPSYCHOTIC DRUGS
CHLORPROMAZINE: a1=5HT2 >D2 >D1
HALOPERIDOL: D2>D1=D4>a1>5HT2
CLOZAPINE : D4=a1>5HT>D2=D1

15. DIFFERENCES AMONG
ANTIPSYCHOTIC DRUGS
OLANZAPINE: 5HT2A >D4 >D2 >a1 >D1
ARIPIPRAZOLE: D2 = 5HT 2A > D4 > a1
=H1 > > D1
QUETIAPINE: H1 >a1 > M1,3 > D2 > 5
HT2a

16. ANTIPSYCHOTIC AGENTS
• PSYCHOLOGICAL EFFECTS
> sleepiness, restlessness, impaired
performance & judgment
• NEUROPHYSIOLOGIC EFFECTS
> hypersyncrony focal /unilateral
• ENDOCRINE EFFECTS
> amenorrhea, galactorrhea, increase libido,
false( +) pregnancy tests
• ↓ libido in males, gynecomastia

17. ANTIPSYCHOTIC AGENTS
• CARDIOVASCULAR EFFECTS
orthostatic hypotension
 high resting pulse rate
↑ PR, ↓ stroke volume, ↓ mean
arterial pressure,
↓ peripheral resistance
NAUSEA & VOMITING
Block the chemoreceptor trigger zone

18. CLINICAL INDICATIONS
A. PSYCHIATRY INDICATIONS
• SCHIZOPHREMIA
• SCHIZOAFFECTIVE DISORDERS
• MANIC EPISODES IN BIPOLAR
DISORDERS
• GILLES DE TOURETTE SYNDROME
• SENILE DEMENTIA
B. NONPSYCHIATRIC INDICATIONS
>ANTI-EMETIC EFFECT (prochlorperazine)
>ANTI-PRURITIC EFFECTIphenothiazines)
>PREOPERATIVE
ANESTHESIA.promethazine
>NEUROLEPTIC ANESTHESIA..droperidol

19. SIDE EFFECTTS OF NEUROLEPTIC
DRUGS
A. NEUROLOGIC EFFECTS
1. ACUTE DYSTONIA : Spasm of muscles
tongue, face, neck, back, may mimic
seizures
• During the first 1 -5 days of Rx
• Mechanism unknown
• Rx: antiparkinson’s agents
2. AKATHISIA : Motor restlessness
• 5 -60 days
• Mechanism unknown; Rx with
diphenhydramine

20. 3. PARKINSONISM
 bradykinesia, rigidity, tremor, mask facies,
shuffling gait seen in 5-30 days
Mechanism is antagonism of Dopamine
Rx: Antiparkinson’s Agents
4. NEUROLEPTIC MALIGNANT SYNDROME:
catatonia, stupor, fever, unstable BP,
myoglobulinemia after weeks of treatment
Mechanism: Antagonism of Dopamine
Rx: Stop neuroleptic immediately; Dandrolene;
Bromocriptine, Antiparks not effective

21. 5. PERIODIC TREMOR (RABBIT SYNDROME)
Perioral tremors
 after months or years of treatment
Mechanism : unknown
Rx Antiparkinson’s Drugs
6. TARDIVE DYSKINESIA
oral-facial dyskinesia, choreoathetosis, dystonia
After months or years of Rx
Worse on withdrawal
Mechanism: excess function of dopamine
Rx: prevention crucial Rx unsatisfactory

22. ADVERSE EFFECTS
II. BEHAVIORAL EFFECTS:
• Pseudo-depression; toxic confusional state
III. AUTONOMIC NERVOUS SUSTEM EFFECTS :
• urinary retention,dry mouth, loss of
accommodation, constipation (MUSCARINIC
CHOLINERGIC BLOCKADE)
• orthostatic hypotension, impotence, failure to
ejaculate ( ALPHA ADRENORECEPTOR
BLOCKADE)

23. ADVERSE EFFECTS
IV. METABOLIC & ENDOCRINE EFFECTS
Weight gain, hyperglycemia, hyper -
prolactenemia, amenorrhea-galactorrhea
syndrome, infertility, impotence in males
V. TOXIC OR ALLERGIC REACTIONS
Agranulocytosis (clozapine) , cholestatic
jaundice, skin eruptions
VI. CARDIAC TOXICITY
Ventricular arrythmias (thioridazine)
VII. OCULAR COMPLICATIONS: “ browning
of vision”

24. ANTIMANIC AGENTS
• MOOD STABILIZING AGENT
• BIPOLAR DISORDERS (MANIC-
DEPRESSIVE)
• DISORDER WITH PREPONDERANCE OF
CATHECHOLAMINE RELATED ACTIVITY
• LITHIUM CARBONATE
• CARBAMAZEPINE, VALPROIC ACID

25. LITHIUM P’KINETICS
ABSORPTION : virtually complete
within 6 -8 hrs; peak plasma levels in 30 min
to 2 hrs
DISTRIBUTION: in total body water; slow
entry into intracellular compartment. No
protein binding
METABOLISM: None
EXCRETION: virtually entirely in urine; plasma
half life is about 20 hours

26. LITHIUM ‘ DYNAMICS
• EFFECTS ON ELECTROLYTES & IONS
TRANSPORT:
Substitute for sodium
• EFFECTS ON NEUROTRANSMITTER
 enhance effects of serotonin?
Decrease norepinephrine & dopamine
turnover
Block dopamine receptor
supersensitivity
Augment synthesis of acetylcholine?

27. LITHIUM PHARMACODYNAMICS
• EFFECTS ON SECOND MESSENGER
effect on IP3/ DAG
EFFECTS ON PHOSPHOINOSITOL
TURNOVER…..> EARLY RELATIVE
REDUCTION OF MYOINOSITOL IN HUMAN
BRAIN

28. LITHIUM ADVERSE EFFECTS
1. CNS EFFECTS; dizziness, mild ataxia
2. NEUROMUSCULAR EFECTS: fine tremors
3. CV EFFECTS: ventricular arrythmias
4. GIT EFFECTS: nausea, vomiting,
diarrhea
5. GUT EFFECTS: polyuria
6. ENDOCRINE EFFECTS: hypothyroidism
7. ALLERGIC REACTION: pruritus, rash
8. OVERDOSE TOXICITY: vomiting,
drowsiness, decrease consciousness
seizures
Rx: dialysis

29. LITHIUM CONTRAINDICATION
A. MARKED DEHYDRATION OR
SODIUM DEPLETION
B.SIGNIFICANT RENAL OR CARDIAC
DISEASES
C. PREGNANCY(W)
D. RENAL CONCENTRATION
ABILITY(W)
• Nephrogenic diabetes insipidus with
polyuria

30. DRUG INTERACTIONS
A. THIAZIDE DIURETICS: ↓ RENAL
CLEARANCE OF LITHIUM
B. NSAID: ↓ LITHIUM CLEARANCE
C. ANTIPYSCHOTIC AGENTS:
↑ NEUROTOXICITY

31. DEPRESSION
I.REACTIVE OR SECONDARY DEPRESSION
Core Depression Syndrome: depression, anxiety,
tension, bodily complaints, guilt (> 60%)
II.ENDOGENOUS DEPRESSION
Core Depression Syndrome plus ABNORMAL VS
rhythm of sleep, motor activity, livido,
decrease appetite ( 25%)
III. DEPRESSION ASSOCIATED WITH BIPOLAR
AFFECTIVE DISORDER
(10-15%)

32. ANTIDEPRESSANTS
I.TRICYCLIC ANTIDEPRESSANTS
IMIPRAMINE. AMITRYPTYLINE, DOXAPIN,
NORTRIPTYLLINE ,DESIPRAMINE.
CLOMIPRAMINE , PROTIPTYLINE,
TRIMIPRAMINE
B. HETEROCYCLIC, SECOND & THIRD
DEGENERATIONS
1. SECOND GENERATIONS
AMOXAPINE, MAPROTILINE
TRAZODON, BUPROPION
2. THIRD GENERATIONS
MIRTAZAPINE, VENLAFAZINE
NEFAXODONE

33. ANTIDEPRESSANTS
C. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRI)
• FLUOXETINE FLUVOXAMINE
• PAROXETINE ESCITALOPRAM
• SERTRALINE CITALOPRAM
D. MONOAMINE OXIDASE
INHIBITORS (MAOI)
• PHENELZINE, TRANYLCYPROMINE
• MOCLOBEMIDE

34. ANTIDEPRESSANTS PHARMADYNAMICS
A. ACTION OF ANTIDEPRESSANTS ON
BIOGENIC AMINE
NEUROTRANSMITTERS
 TRICYCLICS: BLOCK AMINE REUPTAKE
PUMPS
 MAOI: BLOCK DEGRADATIVE PATHWAY
FOR THE AMINE NEUROTRANSMITTERS
 TRAZODON, NEFAZODONE &
MIRTAZAPINE: SERETONIN RECEPTORS
ANTAGONIST

35. B.RECEPTOR & POSTRECEPTOR
EFFECTS
• SSRI: ↓ in norepinephrine cAMP &
in beta -adrenoreceptor binding
• MAOI: mixed action with
norepinephrine & serotonin
• ↑ serotonergic transmission
mediated through diverse
mechanisms

36. Drug Sedati Muscar NE 5HT reuptake
ve inicrBl reuptake block
ock Block
Amitryptyline +++ +++ ++ +++
Imipramine ++ + + ++
Amoxapine ++ + ++ +
Bupropion - - - -
Trazodone +++ - - ++
Mirtazepine +++ - - -
Venlafaxine - - +++ ++
Fluoxetine - + - +++

37. PHARMACOKINETICS
• A. TRICYCLICS
Incompletely reabsorbed
First pass metabolism
Large Vd
Metabolized
HETEROCYCLICS
Variable bioavailabilitiy
High protein binding
Variable and large Vd
Active metabolites

38. PHARMACOKINETICS
• SSRI : FLUOXETINE
• Well absorbed
• PPC: 4 – 8 hrs
• Inhibits drug metabolizing enzymes
• MAOI
• Readily absorbed

39. CLINICAL INDICATIONS
A. DEPRESSION
B. PANIC DISORDER
C. OBSESSIVE COMPULISVE
D. ENURESIS
E. CHRONIC PAIN
F. OTHERS: Eating Disorder(Bulemia)
Cataplexy asstd with Narcolepsy,
School Phobia, Attention Deficit
Syndrome

40. ADVERSE EFFECTS
• TRICYCLICS
Sedation: Sleepiness
Synpathomimetic; tremors,
insomnia
Antimuscarinic; blurred vision.
constipation
confusion,
urinary
incontinence

41. TRICYCLICS
Psychiatric: psychoses
aggravated
CVS: orthostatic
hypotension
Neurologic: Seizures
Metabolic-Endocrine: weight
gain, sexual
disturbance

42. ADVERSE EFFECTS
MAO INHIBITORS
headache, drowsiness, dry mouth,
weight gain, postural hypotension,
sexual distn
AMOXAPIN
 Tricyclic & antipsychotic effects
MAPROTILINE
Tricyclic Effects

43. ADVERSE EFFECTS
TRAZODONE & NEFAZODONE:
drowsiness, dizziness, insomnia,
nausea, agitation
BUPROPION
dizziness, dry mouth, tremor
FLUOXETINE
Anxiety, insomnia, tremors, decr
libido, GIT effects

44. Foods that interact with MAOI
• High in tyramine content:
BEER.
BROAD BEANS, LAVA BEANS
CHEESE.
CHICKEN LIVER
 SAUSAGES
 SNAILS WINE, RED WINE
YEAST

45. Drugs that Interact with MAOI
A.INDIRECTLY ACTING
SYMPATHOMIMETICS: amphetamines,
ephedrine, metaraminol,
phenylpropanolamine
B. OTHER ADRENORECEPTOR AGENTS &
RELATED AGENTS: levodopa, methyldopa,
guanethidine, reserpine
C. OPIOID ANALGESICS &
DERIVATIVES: morphine, codeine,
meperidine, dextromethorpham
D.MISCELLANEOUS DRUGS: buspirone,
fluoxetine, LSD