g
DR. Killua Zoldyck
CNS Module - 2nd year
Clinical Pharmachology
Opioid Narcotics
SubClass
MAO
■ Morphine ++ opiate receptors μ, κ,
δ in C.N.S & periphery:
1. ++ of these receptors ➩)--) adenyl
cyclase ➩ ↓ cAMP.
2. Presynaptically: block Ca++ channels
➩↓ excitatory transmitters e.g.
glutamate,substance P & PG.
3. Postsynaptically: open K+ channels ➩
hyperpolarization→inhibitory post
synaptic potential.
1. Morphine
■Strong Natural opioid
■Phenanthrene
Derivative
CNS Action
1. Depressant actons: ‫مهم‬
A. Analgesia
B. Narcosis.
C. Depresses R.C, cough center
D. (--) Heat regulatng center )κ
receptors)
E. ACTH, FSH & LH.
F. (--) of withdrawal refex
2. Stimulant effects:
a. Euphoria.
b. Miosis (PPP).
c. Bradycardia→ )++) )CIC)
d. vomiting→ )++) )CTZ).
e. Oliguria→ ↑ ADH release.
f. ↑ Monosynaptic reflex: stretch reflex
g. ↑ ICP.
2. Codeine
Natural pure Agonist
3.Meperidine
Synthetic pure Agonist
4. Naloxone
Pure Opioid Antagonist
Uses
Adverse Effects
CI
1- Pain:
1. CNS:
■ )--) RC → Resp depression ■ )--) VMC → Hypotension.
■ ++ CTZ → vomiting.
■ ↑ )ICP).
2. Respiratory system: BC.
3. GIT: Constipation.
4. Urinary: urine retention.
5. Allergy.
6. Dependence (Addiction).
7. Tolerance: No tolerance For Miosis P.P.P, Constipation
& Excitation.
ttt of Acute toxicity:
1. Extremities of age.
2. Head injuries Why?:
3. Increased intra-cranial
pressure & epilepsy.
4. Impaired pulmonary
functions: BA,COPD &
Emphysema.
5. Liver & Kidney Dz.
6. Alone in biliary or renal
colic.
7. Acute abdomen
8. During pregnancy &
lactation.
9. During labor.
10. Myxedema )↓ BMR).
11. Addison.
Cardiac pain (MI),Cancer pain,
Colic, Post-operative, Fracture:
but not in head.
2- Preanesthetic drug.
But has disadvantages:
Outlines the Disadvantages of
Morphine in Preanathetic
Medication? Q ‫سؤال نظري سنين‬
‫سابقة‬
a- Delay awakening from
anesthesia
b- Depresses R.C &VMC.
c- Post operative urine retention
& constipation
d- Bronchospasm.
e- Miosis (PPP).
f- Vomiting.
3- Pulmonary edema (acute left
ventricular failure):
↓ after load, ↓ preload,
↓Anxiety, ↓ over stimulated R.C
& cough center.
4- 1ry neurogenic shock:
5- Anesthesia.
1. Anti-tussive: dry cough.
2. Analgesic: moderate pain.
1- Pain: MI & colic
2- Preanesthetic
3- Labor: obstetric analgesia
1. tt of acute morphine
poisoning.
2. Neonatal asphyxia.
3. Diagnosis of opiate
Addiction.
1. Artificial respiration..
2. Stomach wash.
3. Naloxone or Nalmefene.
ttt of Chronic toxicity (Addiction)
1- Hospitalization & psychotherapy.
2- Gradual withdrawal of Morphine
3- Replacement morphine with Methadone or
Buprenorphine
4- Give reason: Use of methadone in morphine
addiction?Written Q
 As it has longer duration.
 Less withdrwal symptoms.
5- Clonidine: After Methadone .
6- Oral Naltrexone )μ antagonist):
 prevents recurrence.
 Maintenance: prevent desire for
morphine.[craving]
Q: Compare ( ) Morphine & Meperidine.
Chemistery
Bioavilability
Analgesic effect
Antitussive effect
Addiction
Effect on R.C
Anaethesia
Pupil Size
Morphine
Natural Opioid
30%
More
More
More
More R.c Depression
Genral
Miosis
Meperidine
Synthetic opioid agonist
50%
Less )1/10 of Morphine)
No antitussive effect
Less
less
Local
Mydriasis
g
DR. Killua Zoldyck
CNS Module - 2nd year
Clinical Pharmachology
Hypnotics






SubClass
MAO
Uses
Adverse Effects
1. Barbiturates
1. Binds to & ++ specific
binding site on GABA
receptor ➩↑binding of GABA
to its site➩opening of Clchannels with Cl- influx
➩postsynaptic
hyperpolarization & inhibition.
1- Anticonvulsants &
Antiepileptics:Phenobarbitone.
2- Anesthesia & preanesthetic:
■ IV thiopentone.
■ Hexobarbital rectally → basal anesthesia.
3- Hyperbilirubinaemia & kernicterus In
neonates MCQ.
■ Hepatic microsomal enzyme inducer➩↑
bilirubin metabolism.
1- Idiosyncrasy: excitation in elderly.
2- Idiosyncrasy: precipitate porphyria.
3- ↑ hepatic microsomal enzyme: ↑drugs
metabolism ☟to:
Tolerance, cross tolerance, ↑ metabolism
4- Interactions with other drugs:
a) Phenobarbitone P450 inducer
b) Potentiate CNS depressants
5- Allergy: skin rash.
6- Amnesia & Automatism,
7- Abnormal sleep : ↓ REM→ hang over &
rebound paradoxical sleep.
8- Extravasation of thiopental: gangrene.
9- Acute Barbiturates toxicity.
10- Addiction = dependence
1. Daytime sedation.
2. Dependence ➩ addiction.
3. Mental, psycho-motor & sexual effects.
4. Amnesia esp. short acting triazolam.
5. Elders: mental confusion & hypotension.
6. With Alcohol ➩ severe C.N.S inhibition.
7. Ataxia.
8. Allergy.
9. Amenorrhea,↓ ovulation, ↓ejaculation &
teratogenic.
10. ↑ Appetite → ↑ body weight.
11. Acute toxicity: rare.
Phenobarbital
Amobarbital
Phenobarbitone
Secobarbital
Thiopental
Methohexital
2. (--) release of excitatory
neurotransmitters
2.Benzodiazepines (BZd)









Alprazolam
Chlordiazepoxide
Clorazepate
Clonazepam
Diazepam
Flurazepam
Lorazepam
Midazolam
Triazolam
Flumazenil
5-HT agonist
 Buspirone
1. Bzd binds to specific
Actions = Uses
1. Anxiolytic = antianxiety = minor
tranquilizer
2. Hypnotic action.
3. Antiepileptics.
4. Antispasticity = sk ms relaxant: ■used in
multiple sclerosis & cerebral palsy.
5. Induction of anesthesia:
■ Selective & competitive Bzd
receptor blocker MCQ
■The specific antidote of Bnz
■ Partial agonist on
presynaptic )5-HT1A) in brain.
■ Anxioselective
1. Acute Bzd toxicity.
2. Awake patients from anesthesia.
3. In hepatic coma.
Advantages of (anxioselective)
1. No anticonvulsant 2.No ms relaxation.
3. No hypnosis 4.No rebound anxiety.
5. No tolerance or cross dependence.
6. Little dependence & least additive to
alcohol.
binding site on GABA
receptors➩☟
■Facilitate binding of GABA
to its binding site.
■Open of Cl- channels➩↑ Clinflux➩ hyperpolarization &
post synaptic inhibition.
2. Bzd & newer hypnotic
(zolpidem) bind to α & γ
subunits of the GABA receptor
➩ ↑ opening of Cl- channels.
■ Tachycardia, palpitation & nervousness.
■ If taken with MAOI → hypertension.
CI
1. Allergy to
barbiturates
2. Idiosyncrasy
(porphyria).
3. Head injury.
4. Hypotension
)shock).
5. Liver & kidney
6. Depressed RC.
7. Respiratory:
emphysema, BA.
g
DR. Killua Zoldyck
SubClass
1. Levodopa

Madopar
[levodopa + benserazide]
 Sinemet
[levodopa + carbidopa]
2. Bromocriptine,
pergolide
MAO
CNS Module - 2nd year
Drugs used in ttt Of Parkinsonism
Adverse Effects
1. Dopamine itself does not cross
BBBMCQ.
2. Its immediate precursor )levodopa) can
cross BBB where it is decarboxylated to
dopamine which replenishes stores.
3. It ↓↓ all clinical features of Parkinsonism
esp. bradykinesia.

Specific D2 receptors agonist
USES OF Bromocriptine:
1- Parkinsonism.
2- Inhibit lactation.
3- ttt of amenorrhea-galactorrhea➩
)induce ovulation)➩Blocks prolactin
secretion.
4- Pituitary tumors + hyperprolactinemia.
3. Selegiline
(Deprenyl)
4. Antimuscurinic
Agents
 Benztropine
 Trihexyphenidyl
 Biperiden
5. Amantadine


Clinical Pharmachology
Selective MAO-B inhibitor MCQ.
↑ Dopamine levels in the brain.
1. Block cholinergic transmission➩restore
balance ) ) dopaminergic /cholinergic
systems.
2. Improve tremors & rigidity.
3. A little effect on bradykinesia.
4. Effective in drug-induced parkinsonism
1. ↑ release of dopamine, )--) its uptake.
2. Slight anticholinergic effect.
3. ↓ bradykinesia & muscle rigidity.
4. Antiviral drug against influenza A2
1. Anorxia, nausea, vomiting )reduced by domperidone).
2. Postural hypotension & cardiac arrhythmias.
3. Brownish discoloration of urine.
4. Mydriasis.
5. Visual & auditory hallucinations & involuntary movements )dyskinesia).
6. Mood changes & depression.
7. Fluctuation of the response:
■ Wearing off effect: progressive ↓ in duration of benefit.
■ On-off effect: Swings from relative mobility to hypotonia & bradykinesia.
 Management:
a. ↑ frequency of intake of L-dopa.
b. Use of slow release preparations.
c. Add long-acting direct dopamine agonists➩bromocryptine.
d. Drug holiday for 3- 21 days.
1. Dyskinesia, mental disturbances.
2. Arrhythmia, digital vasospasm.
3. Erythromyalgia: swollen, red, hot & tender feet.
4. Anorexia, nausea, vomiting, dyspepsia, constipation, PU.
5. Postural hypotension:1st dose phenomenon )sudden collapse).
Advantages of bromocryptine over L-dopa: written Q
1. Does Not need synthesizing enzymes.
2. More specific on D2 receptors.
3. No active transport system.
4. No competition with amino acid.
5. Longer t1/2 so ➩ less fluctuation in response.

Related to ↑ levels of Dopamine.




Blurred vision-.
Dry mouth
Constipation
Urine retention
1. CNS: insomnia, hallucinations, rarely fits.
2. Skin: livedo-reticularis 3. Ankle edema.
4. Postural hypotension. 5.Dry mouth and urine retention.
6. Used with caution in patients with seizures & CHF.
CI
1. Closed angle glaucoma.
2. Coronary artery disease.
3. Severe psychosis
4. Melanoma
1. Psychiateric illness.
2.Peripheral vascular disease.
3. Peptic ulcer.
4. MI.
g
DR. Killua Zoldyck
SubClass
1. (SSRIs):





Fluxetine
Citalopram
Fluvoxamine
Paroxetin
Sertraline.
CNS Module - 2nd year
Antidepressant drugs
Uses
MAO
1. Specific inhibitor of 5-HT reuptake .
2. Have little ability to block dopamine
transporter.
3. SSRIs have little blocking activity at
muscurinic, alpha & histamine receptors.
1. Depression.
2. Obsessive compulsive disorder
(fluvoxamine)
3. Panic disorder.
4. Generalized anxiety
2. (TCAs)
1. TCA block both NE & 5-HT reuptake into
the neurons➩↑ level of monoamines in the
synaptic cleft.
2. They also block M, H and α receptors.
3. (MAOIs)
1. Irreversible inactivation of MAO➩ ↑
stores of NE, 5-HT & DA within the neurons.
2. Mild Amphetamine like stimulant effect.
1- Depression.
2- Phobias.
4.Atypical
antidepressants
1. Mirtazepine: Blocks 5-HT2 & α2 receptors
2. Nefozodone &Trazodone: blocks 5-HT1
1. Bupropion: ↓ craving for nicotine in
tobacco abusers.











Imipramine
Amitriptyline
Clomipramine
Doxepin
Desipramine
nortriptyline
Phenelzine
Tranylcypromine
Bupropion
Mirtazepine
Nefozodone
Trazodone
presynaptic, inhibits 5-HT reuptake.
Enumerate Drugs used in tt of Huntington’s
1. Reserpine.
2. Dopamine receptor antagonists:
Haloperidol , chloropromazine.
3. GABA agonist: Baclofen.
Clinical Pharmachology
Adverse Effects
1.
2.
3.
Sleep disturbances.
Sexual dysfunction.
Nausea, vomiting &
diarrhea.
1- Blurred vision, dry mouth,
retention of urine, constipation.
2- Orthostatic hypotension.
3- Sedation.
4- Sexual dysfunction.
5- ↑ catecholamines➩cardiac
overstimulation.
Drugs used in tt Alzheimer’s
1. Glucoma
2. Senile prostatic enlargement.
3. Myocardial infarction.
4. With MAOI.
1- ↑↑ CNS stimulation: tremors,
irritability, hyperthermia.
2- Postural hypotension.
3- Constipation, dry mouth.
4- Weight gain.
Drugs used in [ ‫ لو جت تيجي‬enumerate]
A. Acetylcholinestrase Inhibitors
Donepezil, Galantamine,
Rivastigmine & Tacrine
B. NMDA Antagonist:
Memantine
CI
Drug therapy of acute migraine
I- Triptans e.g, Somatriptan.
II- Ergotamine
III- Analgesics e.g NSAIDs
Drug Prophylaxis of Migraine
1. Beta Blockers: propranolol & nadolol.
2. Methysergide:MCQ
3. Pizotifen
4. Flunarizine: Calcium channel blocker.
5. Clonidine.
g
DR. Killua Zoldyck
CNS Module - 2nd year
Clinical Pharmachology
Antiepileptic drugs
SubClass
1. Phenytoin
MAO
1. Blocks Na+ channels.
2. At higher concentrations➩
blocks Ca++ channels & interferes
with release of neurotransmitters
+
2. Carbamazepine ■ Blocks Na channels ➩
↓propagation of abnormal
impulses in the brain.
Uses
1. Antiepileptic:
■ 1st choice in grand mal &
focal seizures.
■ Status epilepticus.
2. Ventricular arrhythmia.
1. Grand mal and focal
seizures.
2. Trigeminal neuralgia
3. Cerebral or nephrogenic D.I.
4. Mood stabilizer
3. Barbiturates &
related drugs
Selective anticonvulsant activity
Potentiate the inhibitory pathway
)GABA).
■ Partial & grand mal epilepsy &
febrile convulsion
4. Valproic acid
1. ↑ GABA in synaptic regions by:
■ Inhibition of GABA transaminase
■ Inhibition of GABA reuptake.
2. Blocks Na+ channels & T-Ca++
channels.
1. Broad spectrum aniepileptic:
■ effective in grand mal
epilepsy & partial seizures.
■ But it is not the drug of choice
)sedation & hepatotoxicity).
2. Petit mal epilepsy.
3. Febrile convulsion.
4. Myoclonus.
5. Prophylaxis of migraine.
 Phenobarbitone
 Primidone
Adverse Effects
1. C.N.S: nystagmus, ataxia, diplopia &
vertigo.
2. Gingival hyperplasia MCQ
3. G.I.T disturbances.
3.Chronic use )it interferes with vit D
hydroxylation & ↓ GIT Ca+2 absorption)
5. Megaloplastic anemia.
6. Hypersensetivity reactions.
7. Hirsutism & acne due to ↑androgen
8. TeratogenicityMCQ :
 cleft palate and hare lip )fetal
hydantoin syndrome)➩1st
Trimester.
 Hypoprothrombinemia of the baby
➩if taken before labor.
1. C.N.S: diplopia, ataxia & drowsiness.
2. G.I.T: nausea & vomiting.
3. Allergy: rash & photosensitivity.
4. Hyponatremia, water toxicity.
5. Aplastic anemia, Agranulocytosis.
6. Liver dysfunction.
1. Sedation, nystagmus, ataxia.
2. Megaloblastic anemia.
3. Osteomalacia.
4. Addiction.
1. G.I.T: anorexia, nausea & vomiting.
2. Hair loss.
3. Hepatotoxicity.
4. Teratogenic: Spina Bifida
CI / Precautions
Precautions
1. Serum level monitoring.
2. Oral hygiene.
3. Vit D and folate supplements.
Treatment of status
epilepticus
1.
2.
3.
Written Q.
Diazepam: slow intravenous
(1st choice).
IV phenytoin.
General anesthesia in
highly resistant
cases)thiopental IV,
intubation, muscle relaxant
& artificial respiration).
h
SubClass
I. Typical
Antipsychotic drugs antischizophrenic= neuroleptics =major tranquilizers
Uses
Adverse Effects
MAO
1. Typical drugs ☞block D2 receptors in
+ve symptoms mainly the mesolimbic system.
 Chloropromazine 2. Atypical drugs☞inhibition of 5-HT
receptors, block presynaptic D1 receptors.
 Haloperidol
3. Blocking dopamine receptors in:
 Droperidol
 Nigrostriatal pathway➩
 Flupentixol
extrapyramidal adverse effects.
II. Atypical
 Tubero-infandibular pathway➩
-ve symptoms mainly
↑prolactin secretion.
 C.T.Z. ➩antiemetic action.
 Clozapine
 Medullary periventricular pathway ➩
 Olanzepine
change eating behavior.
4. Block cholinergic, adrenergic &
histaminergic receptors.
MAO of General Anaethetic
Drugs
1. GABAA-receptor Cl- channels: ↑ GABA-
mediated ↑ in Cl- ➩hyperpolerization & )-) of neuronal membrane activity.
2. Lignad-gated K+ channels➩↑ K+
conductance➩hyperpolarization & )--)
neuronal membrane activity.
3. NMDA receptors: Anesthetics )e.g., NO
& ketamine)➩ )--) excitatory glutamate.
1- Schizophrenia, organic
psychosis, manic phase.
2- Antiemetic.
3- Persistant pruritis.
4- Hiccough.
5- Neuroleptanalgesia
)droperidol + fentanyl): for
minor procedure as endoscopy
6- Tics )haloperidol is used).
7- Hypothermic anesthetic
medication )lytic cocktail).
1- Extrapyramidal manifestations.
2- Anticholinergic side effects.
3- Orthostatic hypotension.
4- Cholestatic jaundice➩
chloropromazine.
5- Phenothiazines ➩urticaria,
dermatitis & photosensitivity.
6- Galactorrhoea, gynecomastia,
amenorrhoea.
7- ↑ appetite, weight gain.
8- Clozapine➩agranulocytosis.
Anesthesia
Enumerate Inhaled Anesthetic
Enumerate 2 IV
Anaethetics
I- Nitrous oxide [gas]
II- Halogenated Volatile anesthetics:
A. Halothane➩arrhythmias ,Hepatotoxic
B. Sevoflurane➩Nephrotoxic,
bronchodilator
C. Enflurane➩nephrotoxic, CNS
stimulant in high conc.
D. Isoflurane➩preserves cardiac output.
E. Desflurane➩irritating to the airway.
1. Propofol
2. Fospropofol [prodrug]
3. Thiopental )Barbiturates)
4. Midazolam
(Benzodiazepines):
5. Fentanyl, Sufentanil,
Remifentanil (opioid)
6. Ketamine
7. Etomidate
1- Epilepsy as antipsychotics
lower seizure threshold.
2- Agranulocytosis (avoid
clozapine).
3- Infertility.
4-Liver impairment
(chlorpromazine).
MAO of Local
Anaethetic Drugs
1. Block Na+ channels.
2. ↓ influx of Na+ ions.
3. Block the initiation &
propagation of action
potentials
CI
Enumerate 2 local
Anaethetics
Amides: Lidocaine,
Bupivacaine, Mepivacaine,
Prilocaine, Ropivacaine.
Esters : Procaine,
Tetracaine, Benzocaine,
Cocain.
Morphine not used in head injuries.
On Pharmachological Basis Give Reason: ‫مهم‬
1. ↑ ICP.
2. Miosis → Mask sign of lateralization.
1. As it has longer duration.
2. Less withdrwal symptoms.
Use of Naltrexone in Morphine
addiction?
Combining Levodopa with Benserazide
or carbidopa?
1. Prevents recurrence.
2. Prevent desire for morphine.[craving]
a. As They potentiate its action.
b. ↓daily levodopa req. by 75%.
c. ↓ side effects such as nausea, vomiting, risk
of cardiac arrhythmias & postural hypotension.
As they lower seizure threshold.
Adding Bromocryptine or Selegiline to
L-dopa in tt of parkinsonism?
1. ↓ required dose of levodopa.
2. improves on-off phenomena & wearing off.
Combining Fentanyl with Droperidol?
As Droperidol blocks the emetic effect
of fentanyl.
Epinepherine is often added to local
anesthetics ?
Anxioselective so effective in generalized
anxiety syndrome not in acute panic attacks?
As Its anxiolytic effect appears after 12 weeks.
TCAs shouldn’t be used with MAOIs ?
1. Localize the anesthetic to the site of
injection.
2. Slow its absorption and prolong its effect.
3. Minimizing the systemic toxicity.
As it can lead to hypertension crisis.
Use of methadone in morphine addiction?
Use of Morphine in Acute left vwntricular
failure (Pulmonary Edema)?
Antipsychotics are contraindicated in
Epilepsy?
a-↓ anxiety → ↓ after load.
b- Venodilatation →↓ preload.
c-↓ over stimulated R.C & cough center
 Advantages of Bzd over barbiturates as hypnotics
written Q
Barbiturates
Benzodiazepines
Sleep Patttern
Hepatic Microsomal
Enzs
Therapeutic
Index
Antidote
Marked )--) of REM:
a. Hang over
b. Rebound sleep
Induction:
a. Tolerance.
b. cross tolerance
c. Dependence
d. Drug interactions
↓ inhibition of REM:
a. ↓ hang over
b. ↓ rebound sleep
No Induction:
a. ↓ Tolerance.
b. ↓ cross tolerance
c. ↓ Dependence
d. ↓ interactions
Low )depress R.C) ➩
narrow safety margin
No
Higher )safe R.C) ➩ wide
safety margin
Flumazenil