CNS Acting Drugs

المعلومات بالداخل موثوق بها ألنها مراجعه و معتمده من

Certified from

Pharmacists_coffee magazine

Sedatives & Hypnotics

These are drugs that cause hypnosis by suppression of the reticular activating system (RAS) in the brain. These are classified as follows:

1. Barbiturate hypnotics: these are derivatives of barbituric acid, & can be classified as:

Type GIT absorption Duration of action Example

Long acting Slow 6-8 hrs Barbital, Phenobarbital

Intermediate Fairly rapid 4-6 hrs Amobarbital

Short acting Rapid 3 hrs Pentobarbital Secobarbital

Ultra-short Irregular 15 min Hexobarbital (used in IV anesthesia) Thiopental

– Overdose of barbiturates is treated by artificial respiration, IV fluids (dextran), alkalization of urine, forced diuresis & haemodialysis.

– Phenobarbital is used as the Na salt solubility.

– Thiopental is the most rapidly acting barbiturate (it is redistributed quickly).

2. Non-barbiturate hypnotics: They include: Cl3C – CH – (OH)2

Chloral hydrate: in body tissues, the drug is 1st metabolized to the active form, trichloro-ethanol, which is a potent hypnotic. It is the oxidized by the kidney & liver to the inactive form which is excreted. It is used as a hypnotic in children & elderly.

Paraldehyde: it is administered orally or parentrally. It is excreted unchanged through the lungs thus it is the hypnotic of choice in renal failure; however it is contraindicated in patients with liver or lung disease.

Glutathemide: is chemically related to phenobarbitone. It has a addiction potential.

Methyprylone: is used orally as a sedative & hypnotic depending on the dose used.

Morphine & related drugs.

Ethanol.

Carbromol.

Benzodiazepines

Glutathemide

O

CH2CH3

NO

• Substitution at C5 affects the lipid solubility, depending on:

Chain length Chain branching

Unsaturation Replacing aryl by alkyl

• The longer the chain at C5, the greater the lipid solubility (up to 9 carbon atoms, above

which activity ; thus marketed drugs have 6 – 9 carbon atoms).

• Polar substitution on C5 will drastically the activity.

• Phenyl substitution at C5 is important for anticonvulsant activity (e.g. phenobarbital).

• Replacing the C=O at C2, by C=S greatly enhances the lipid solubility; the onset of action

will be very quick, but the duration of action will be very short (e.g. thiopental).

• Alkylation of either N atoms will the lipid solubility (e.g. primadone).

Classification of barbiturates according to substitution at C2 & C5.

Type C2 C5

Ultra-short C=S Long, unsaturated or branched

Short C=O Long, unsaturated & branched

Intermediate C=O Short, saturated & branched

Long C=O Very short, saturated & branched

SAR of Barbiturates

Benzodiazepines inhibit the reticular formation system & the limbic system

Benzodiazepines: inhibit rapid eye movement (REM) in stage I of anesthesia.

They are not anti-depressants & are classified according to the duration of action:

– Diazepam (Valium) is the fastest acting.

– Triazolam (Halcion): has the shortest half-life (< 5 hrs); it is the shortest acting but is not the fastest acting. It acts in 15 min; it has no active metabolites.

– Temazepam (Restoril), oxazepam (Serax), lorazepam (Ativan) & alprazolam (Xanax) have half-lives < 15 hours; (medium acting).

– Nitrazepam & clonazepam (Rivotril) are intermediate acting.

– Diazepam, fluorazepam & chlordiazepoxide have long half-life (90 – 100 hrs).

• Fluorazepam: is the hypnotic of choice in insomnia.

• Chlordiazepoxide (Librium): is the fastest hypnotic. It has advantages over other members:

– It is the best agent in acute & chronic anxiety.

– It is used in alcohol withdrawal.

• In alcohol withdrawal: diazepam, oxazepam & chlordiazepoxide are used.

• Oxazepam & Lorazepam: produce non-active metabolites & could be used in elderly people with renal insufficiency.

• The Triazolo-benzodiazepines (e.g. alprazolam) are the most potent of the currently available derivatives with a single dose of 0.25 mg.

• Classification of Benzodiazepines

– Short acting Triazolam

– Medium acting Tetrazolam, Alprazolam, Lorazepam, Oxazepam, Temazepam

– Intermediate acting Nitrazepam, Clonazepam

– Long acting Diazepam, Chlordiazepoxide, Flurazepam

Benzodiazepines: enhance GABA transmission (act on GABA sites facilitating entry in neuron inhibitory effect). They are used as minor tranquilizers (anxioletics) rather than barbiturates. They open the chloride channels.

Drug R1 R2 R3 R4 X

Chlordiazepoxide -- NH – CH3 -- = O --

(Librium)

Diazepam CH3 = O -- -- -- (Valium)

Temazepam CH3 = O – OH -- -- (Restoril)

Oxazepam H = O – OH -- -- (Serax)

Lorazepam H = O – OH -- – Cl (Ativan)

Alprazolam -- -- -- -- (Xanax)

X

N

NCl

R1 R2

R3

R4

SAR of Benzodiazepines

Substitution at positions marked

R1, R2, R3, R4, & X results in

different drugs.

N

N

CH3

Benzodiazepines are divided into 2 gps depending on the substitution at position 2:

The 2-amino-4-oxides: e.g. chlordiazepoxide is the most potent of this gp.

• The methyl amino gp. is the most effective substitution at C2. Activity is when either no

substitution, a longer side chain, =O, or =S is attached to this carbon.

• The NO at position 4 is not essential for activity.

The 1,3-dihydro-2-ketones: e.g. diazepam, oxazepam, lorazepam, temazepam & piprazolam.

• A methyl gp on N1 is optimal for activity, as is either no substitution or methyl gp at C3.

Generally, in both groups:

Presence of a double bond at positions 4 & 5.

An electron withdrawing gp (NO2 > Br > Cl > F > H) at position 7 is important for anti-anxiety

efficacy. (An electron donating gp. decreases the activity).

Presence of a phenyl gp. at position 5 with an ortho-halide substitution enhances activity.

Any other substitution on the aryl ring (i.e. C6, C8, C9) activity.

At position 1: N-alkylation active metabolite.

Drugs Used in Treating Seizures• Barbiturates ( but have narrow safety margin )

• Deoxybarbiturates.

• Hydantoin ( Phenytoin. Mephenytoin )

• Succinamides ( Ethosuximide, Methosuximide, Phensuximide )

• Benzodiazepines ( Diazepam, Clonazepam [Revotril], Chlorazepate [Tranexene] )

• Other anticonvulsants ( Valproic acid, Dantroione)

Antiepileptics (anticonvulsants): There are three types of epilepsy:

1. Grand mal epilepsy (Tonic – clonic seizures): This is treated by:

Phenobarbital (Luminal).

Phenytoin (Epanutin).

Primidone (Mysoline) the best agent in grand mal seizures.

2. Petit mal epilepsy: (absence of seizures). This is treated by:

Ethosuximide (Zarontin). Methosuximide (Celontin).

Trimethadione (Tridione). Paramethadione (Paradione).

Clonazepam (Rivotril). Acetazolamide.

Valproic acid (Depakin).

N.B: Ethosuximide is the most effective in treating petit mal epilepsy; it is the drug of choice in treating such cases (or alternatively, valproic acid).

Phenobarbitone exaggerate petit mal epilepsy.

3. Psychomotor epilepsy: is treated by:

Primidone (Mysoline).

Phenytoin (Epanutin).

Methosuximide (Celontin).

Phenacemide (very toxic).

• Status epilepticus: is treated by:

Phenobarbital (Luminal), (the drug of choice in children).

Diphenyl hydantoin: Phenytoin (Epanutin).

Diazepam IV (the drug of choice in adults, because unlike phenobarbital it does not cause respiratory depression & unlike phenytoin it has no hypotensive effect).

• Early symptoms of epilepsy: A part of the brain is involved:

Sensory seizures or focal motor seizures

Patient is conscious.

The 3 drugs can disturb folic acid metabolism may cause abnormal mental status.

• Febrile seizures: is treated by:

Phenobarbital (Luminal).

Antipyretics.

• Gamma Amino Butyric Acid (GABA): is the main inhibitory neurotransmitter in the brain i.e. it prevents convulsions.

Phenobarbitone enhances transmission of GABA.

In vitamin B6 deficiency GABA convulsions.

• Valproic acid (Depakin)

– Is used to treat petit mal (absence of seizures) esp. in children, myo-clonic seizures & mixed type epilepsy.

– It levels of GABA through inhibiting the enzyme responsible for its metabolism.

– When added to Phenobarbital regimen, the serum levels of phenobarbital by 40%, thus to be used concomitantly, the dose of phenobarbital must be reduced.

• Phenytoin: Promotes Na+ efflux Na+ neural conc.

– after 1 year of treatment, the following side effects are reported:

Gingival hyperplasia. Hirsutism. Ataxia.

Megaloplastic anemia. Hepatitis. Gastric distress.

– Phenytoin inhibits insulin secretion hyperglycemia

– Folic acid enhances the metabolism of phenytoin.

Parkinsonism• Parkinson’s disease is a slow progressive degenerative neurologic disease characterized by

tremors, rigidity, bradykinesia (sluggish neuromuscular responses) & postural instability.

• It is due to dopamine defficiency in the nigrostatial pathway.

• Normally, there is a balance in the brain between acetylcholine & dopamine. In parkinsonism, this balance is disturbed, with an in acetylcholine levels & lack of dopamine.

• In treating parkinsonism the aim is to restore the dopamine : acetylcholine levels to normal (i.e. to dopamine conc. & acetylcholine conc. in brain.)

• Drug- (neuroleptic-) induced parkinsonism: (drugs with extra-pyramidal side effect), e.g.:

– Phenothiazine (chloropromazine). – Reserpine

– Butyrophenones (Dropridol, halopridol, triflupridol)

These antagonize the action of dopamine & prolong the action of acetylcholine.

• 70 – 80% of patients on neuroleptics: experience extra-pyramidal side effects which mimic Parkinson's disease. These include:

– Muscular rigidity/stiffness, short steps, ramped handwriting, tremors, akinesia (impaired voluntary muscle movement) drowsiness, convulsions, dry mouth & constipation.

• Drugs used in treating Parkinsonism include:

– Anticholinergics

– Dopamine precursors: Levo-dopa / Carbi-dopa

– Dopaminergic agonist: Ergot alkaloids Bromocriptin (Parlodel)

– Amantadine (Symmetral) releases dopamine (Inhibits its re-uptake).

– Selgeline inhibits the metabolism of dopamine.

– Antihistamines with anticholinergic effect (diphenylhydramine, Orphenidine)

– Phenothiazines ( only Ethopropazine)

– Benzodiazepines, Propranolol, Primadone

• Anticholinergic drugs used in the treatment of parkinsonism:

– Benzatropine (Cogentin) – Trihexyphenydil – Procyclidine

– Propantheline

– Anticholinergics cholinergic activity correct dopamine : acetylcholine imbalance.

• L-dopa: these are dopamine precursors & are used in the treatment of parkinsonism.

– It is contra-indicated in with vitamin B6 because B6 enhances the activity of L-dopa

decarboxylase enzyme which is essential for the conversion of L-dopa to dopamine before entering the brain. (dopamine itself cannot pass the BBB).

• L-dopa + Carbidopa (Sinemet) are adrenergic.

• Carbidopa: inhibits the L-dopa decarboxylase enzyme, peripheral deactivation of L-dopa before penetrating the BBB ( # vitamin B6)

• Tardive dyskinesia is: defective & painful voluntary movements.

– A side effect of long-term treatment of phenothiazines (antipsychotics) esp. if suddenly withdrawn (neuroleptic drug holiday). Phenothiazines block the dopamine receptors extra-pyramidal side effects.

– Treated by neuroleptics or large doses of L-dopa (desensitization, as receptors become very sensitive to dopamine, we give large doses of L-dopa).

– A contraindication for using anti-cholinergics.

• Symptoms of tardive dyskinesia:

– Orobuccal signs: Abnormal facial movements [involuntary movement of tongue (vermicular), lips & jaws]; this is the most important symptom.

– Fatigue – Tremors

• Mysthenia gravis: is an auto-immune disease, characterized by decreased amount of aceyl-choline & increased amount of cholinesterase weakness & rapid fatigue of muscles.

– It is treated with anti-cholinesterase: prostegmine (neostigmine).

– Edrophonium is used to diagnose myasthenia gravis.

N.B: Parkinsonism: is the opposite of myasthenia gravis.

• Muscle relaxants can be classified as:

– Non depolarizing neuromuscular blockers (competitive NMB):

Curare alkaloids (d-tubocurarine) Gallamine (Flaxedil)

Pancronium (Pavulon) Alcuronium (Alloferin)

– Depolarizing NMBs:

Succinylcholine (Suxamethonium) Decamethonium

Edrophonium Scaline.

• The use of neuromuscular blockers is:

– In surgery to provide muscular relaxation.

– In convulsions.

– In diagnosis of myasthenia gravis.

• Alzheimer’s disease: is a brain disorder in elderly due to acetylcholine deficiency. It is characterized by pre-senile dementia with hyaline degeneration of smaller brain blood vessels

• Fenfluoramine (Ponderax): is the only anorexogenic drug which causes CNS depression rather than stimulation.

• Nicotine (in small doses) or acetylcholine (n large doses) adrenaline release from adrenal medulla.

• Nicotine also release of vasopressin (ADH) diuresis

Antipsychotic Agents “Major Tranquilizers” “Neuroleptics”

1- Phenothiazines:

• Mechanism of Action: They block the dopamine receptors (thereby increasing the turn over rate of dopamine). In long-term therapy, they lead to extra pyramidal side effects parkinsonism (thus they are contraindicated in parkinsonism).

– Additionally, phenothiazines block serotonin, muscarinic, 1 adrenergic receptors & the

chemoreceptor trigger zone (CTZ) (used as anti-emetics).

• Phenothiazines include:

– Thioridazine (Melleril): is the phenothiazine with the least extra-pyramidal side effect.

– Methotriperazine: is the one with analgesic effect.

– Trifluoroperazine (Stelazine)

– Prochloroperazine (Stemetil)

– Ethopropazine (Parsidol): is the one with powerful anti-cholinergic effect, & can be used in treating tremors & rigidity of parkinsonism.

– Cloropromazine (Largectil): has anti-emetic effect

– Fluphenazine (Modecate / Anatensol)

– Promethazine (Phenergan): has antihistaminic effects

• Benzatropine (Cogentin): is an anticholinergic drug that is used concomittantly with phenothiazines, thus reducing the extrapyramidal side effects of phenothiazines.

2- Rawolfia Alkaloids: Reserpine.

3- Butyrophenones:

– Halopridol (the least sedating neuroleptic)

– Trifluopridol

– Dropridol

4- Thioxanthenes:

– Chlorothioxan (Taractan)

– Thiothixan (Navane)

Anti-anxiety Agents “Minor Tranquilizers”

1- Benzodiazepine derivatives:

• Mechanism of Action: They depress the limbic system, decrease reticular formation in the CNS by increasing GABA.

– Chlordiazepoxide (Librium)

– Diazepam (Valium)

– Oxazepam (Serax)

2- Propanediol derivatives: CNS depressants

– Meprobamate

– Carbamate

– Phenaglycodal

3- Diphenyl methane derivatives: H1 receptor blockers

– Hydroxyzine (Atarax) anti-anxiety with antihistaminic effect

– Benactyzine

4- Buspirone (Buspar) & Azaspirodecan: 5-HT S

– Buspar is the anti-anxiety product with the least sedative side effects

• Haloperidol, unlike chloropromazine, is not a phenothiazine. However both drugs share the ability of inducing parkinsonism (have extra-pyramidal side effects).

Analgesics: these are classified as follows:

1. Non-narcotic analgesics: e.g. ASA. These act on the thalamus.

2. Narcotic analgesics: e.g. Morphine. They act on both the thalamus & the cortex.

• Morphine: is an opium alkaloid.

– It is contraindicated in asthmatic patients, because it releases histamine & serotonin. It is also contraindicated in pulmonary heart disease.

– Morphine causes severe miosis & pin point eye pupil. This can be blocked by atropine.

– It does not affect the uterine contraction.

– Morphine & its isomer to be active should be in the (-) levo form.

– In case of morphine poisoning, gastric lavage is very important since morphine & its metabolites are excreted in the stomach.

• Oxymorphone: has the highest analgesic activity.

• Hydromorphone: is used as suppositories.

• Codeine: it is methyl morphine:

– It is weaker than morphine in analgesic activity (1/4 potency).

– Has little respiratory depression effect.

– Has little addiction.

– Not recommended in children

– Used as antitussive (cough sedative).

• Hydrocodone & oxycodone:

– They have analgesic effect like morphine.

– They are addictive.

– Can be used in the form of suppositories.

• Heroine: it is diacetyl morphine:

– It is class I controlled substance used for experimental work only.

– It is 10 times more potent than morphine as an analgesic (not used in clinical practice).

– It has less antitussive & constipating properties.

• Levorphanol:

– It is 5 times more potent than morphine.

– It has longer duration of action with a narcotic agonist activity.

– The dextro form (dextromethorphan) has excellent antitussive effects as codeine.

– It has no analgesic effect, it is non-addective.

– It is used IV in morphine poisoning.

• Ethyl morphine (Dionin):

– Is the least analgesic.

– It can be used in ophthalmic preparations.

• Meperidine (Pethedine or Demerol):

– It has 1/10 the analgesic activity of morphine. – It has shorter duration.

– It has some respiratory depression effect.

– It does not cause miosis. – It has no antitussive effect.

– It causes less constipation. – It is less addictive.

• Propoxyphene (Darvon):

– It is non-narcotic.

– It has the less analgesic activity of codeine & has no addictive properties.

– It is structurally related to methadone but 12 -15 times less potent.

• Others:

– Methadone – Pentazocine – Phenazocine

– Fentanyl (trasdermal patches)– Alfentanyl – Sufentanyl

– Diphenoxalate (Lomotil)

• Opiod receptor antagonists & partial antagonists

– Pure antagonists: Naloxone & Naltrexone (long-acting).

• Naloxone: is a pure narcotic antagonist (competitive) without analgesic activity. It is used as an antidote for narcotic analgesics (0.4 mg IV); it blocks all morphine’s pharmacological actions & reverses the respiratory depression of morphine.

– Partial Antagonists: Nalorphine Buprenorphine, Levallorphan, Butorphanol (Stadol), Nalbuphin (Nubain).

• Nalorphine: is narcotic partial antagonist with some analgesic activity.

• Morphine tolerant patients: are given methadone as a replacement therapy for morphine.

• Nausea associated with narcotics is due to stimulation of CTZ in the medulla.

• Non-opiod antitussive: Dextromethorphan.

• Patients with ulcerative colitis: if treated with morphine perforation of intestine ulcerative colitis that can be treated with vancomycin. (morphine causes constipation).

• Central Actions of Morphine:

Inhibition of neuronal activity analgesic antitussive

Respiratory depression Sedation change in mood

Nausea & vomiting ( CTZ) Miosis release of LH & FSH

• Peripheral Actions of Morphine:

Histamine release vasodilatation hypotension, flushing & loss of hair.

Contraction of biliary & bladder sphincters + tone of GIT, biliary tract & ureter intra-luminal pressures in these sphincters spasms

Ac ch release from mysentric plexus in peristaltic movement constipation

(Antidiarrheal effect of opioids)

General Anesthetics: these drugs are lipophilic in nature to cross the BBB. The chemistry

of most is: Hydrophilic gp + Ester or amide gp + Lipophilic moiety. They can be classified as:

1. Volatile anesthetics: These are inhaled as a gas or a vapor; e.g.:

Nitrous oxide (N2O). Halothane. Cyclopropane.

2. Non-volatile anesthetics: These are given parentrally, e.g.:

Short-acting barbiturates (thiopental).

Ketamine HCl.

Local Anesthetics: These act by stabilizing sensory nerve membranes, preventing ion

exchange No depolarization no conduction of impulse (blocks conduction).

• They possibly block nerve impulse conduction & interfere with the change in permeability to Na ions, probably by stabilizing cell membranes. They can be classified as:

– Ester linkage: e.g. procaine, tetracaine & cocaine.

They are short-acting & easily destroyed by choline-esterase enzyme.

Safe in liver disease (not metabolized in the liver).

Need ephedrine to prolong their action.

– Amide linkage: e.g. lidocaine ( HR used as antiarrhythmic).

They are long-acting & are not destroyed by choline-esterase enzyme.

Not used in liver disease (metabolized in the liver).

No need for ephedrine. +

R – CO – X – N (CH3)2 –X – NH (CH3)2

(Unionized portion penetration) (ionized portion blocks the nerve)

Both forms are essential for activity. While the unionized form has better penetration, the ionized form blocks the nerve (i.e. blocks the entry of Na+ without affecting the exit of

K+, attracting Cl-, NO2 (electron donating gp).

Lipophilic gp Connecting gp (ester) Hydrophilic gp

– Tetracaine is more toxic as it has a prolonged duration of action (because of substitution with a longer chain at the amino position).

At pH 7.5, hydrolysis occurs.

N. B. Phenytoin also is a Na+ Cannel blocker.

+

C4H9–NH COO–CH2–CH2 – N (CH3)2

NH2 COO–CH2–CH2 – N (C2H5)2 NH2 COOH + HO–CH2–CH2 – N (C2H5)2

• Stages of general anesthesia:

– Stage I Analgesia.

– Stage II Delirium.

– Stage III Surgical anesthesia.

– Stage IV Respiratory paralysis.

• Droperidol (Inapsine): is related to haloperidol. It is used as an adjuvant to general anesthetics to induce sedation & to reduce the incidence of post-operative nausea & vomiting.

• Inhalation anesthetics: are highly effective if:

– The CNS concentration is high.

– The anesthetic agent has a high partition coefficient in the CNS (lipophilic).

• Pre-anaesthetic treatment include:

– Narcotic analgesic (e.g. morphine) to provide analgesia.

– Benzodiazepines (diazepam) to reduce anxiety.

– Skeletal muscle relaxant.

– Anti-muscarinic agents (atropine & scopolamine): to block vagal reflexes salivary & respiratory secretions (as these cause dry mouth they are given at the time of induction of anesthesia rather than as pre-meditation).

• The objectives of pre-anesthesia treatment is to: are highly effective because:

Smooth introduction of anesthesia. Reduce side effects of anesthesia.

Reduce irritation. Skeletal muscle relaxation.

Drug Trade name IV Local Topical

Cocaine Dimethisoquin Dibucaine (Nupercaine) Tetracaine (Pontocaine) Mepivacaine Bupivacaine Ketamine Procaine (Novocaine) Lidocaine (Xylocaine)

N.B: The depth of anesthetic effect in inhalation anesthesia is proportional to the partial pressure of the anesthetic agent present in the brain (same as conc. in alveolar tissue 20 – 30%)

A vasoconstrictor (e.g. adrenaline) may be given 1 hr before inducing anesthesia to:

blood supply enhance the long action of anesthesia.

give smoother & good induction of anesthesia.

SAR of Sympathomimetic Amines:

• Sympathomimetic amines, to be active they should fit in the receptor.

• Phenyl ethylamine derivatives: where R1, R2 are H; e.g. epinephrine which is inactive orally &

must be given parentrally.

• Phenyl propylamine derivatives: where R2 ( position) is a methyl gp.; e.g. amphetamine &

ephedrine which can be given orally.

– This methyl substitution in the position will:

the pressor activity. the CNS activity. toxicity.

• Amino Substitution: As the size of the alkyl gp. (R3) increases, activity will shift from being

predominantly agonist, to being predominantly agonist, e.g.:

– R3 = H agonist

– R3 = CH3 & agonist

– R3 = CH3 – CH2 agonist for example

Ephedrine

Norephedrine

Phenyl ephrine

Isoprotrenol

• Phenylephrine ( stimulant) is used as eye / nasal drops. In large doses causes severe HT & can be counteracted by phentolamine ( blocker) or tolazocine.

• Oxymetazoline (Afrin): sympathomemetic nasal decongestant, derivative of naphazoline (Privine).

• Biosynthesis of Catecholamines:

– CH – CH – NH

R2 R3R1

– CH2 – CH – NH2

COOH

HO– CH2 – CH – NH2

COOH

HO

HO

– CH2 – CH2 – NH2HO

HO

– CH – CH2 – NH2

OH

HO

HO

L-Tyrosine L-Dopa

Noradrenalin Dopamine

Tyrosine Hydroxylase

Dopa Decarboxylase

Dopamine Hydroxylase

– CH – COOH

OH

HO

HO

– CH – CH2 – N

OH

HO

HO

CH3

H

MAO

Phenyl ethanolamine N-methyl transferase

3,4-dihidroxy mandelic acid L-Adrenaline

• The cataionic head { – N+ – (CH3)3 }

– If one methyl group is replaced by ethyl the resulting compound will have ¼ the activity of acetylcholine.

– The replacement of the 3 methyl groups by ethyl groups an antagonist

• Methylation of the side chain:

– The introduction of methyl group in the carbon gives a compound with a stronger muscarinic & weaker nicotinic action as methacholine.

– The introduction of methyl group in the carbon gives a compound with a stronger nicotinic & weaker muscarinic action.

Parasympatholytics

– Have anticholinergic effect: propantheline, trihexyphenidyl, procyclidine, benzatropine

– They prevent the action of acetylcholine on muscarinic receptors through competitive antagonism (i.e. synthetic antimuscarinic agents) used to treat parkinsonism.

– They are used to treat peptic ulcer (by decreasing gastric secretions).

– They are used as antispasmodics (decreases GIT motility) & in treating bladder spasm.

– High dose produce skeletal neuromuscular block.

– Side effects: dry mouth & dry skin.

– Propantheline is a synthetic anticholinergic with antimuscarinic effect (competitive Ac.ch blocker at cholinergic neuro-effector sites); also used as antacid.

– SAR of parasympathomemetics

CH3 – N – CH2 – CH2 – O – C – CH3

CH3

CH3

O

Para-sympathomimetics• Acetylcholine has 2 main actions:

– Nicotinic action in (in high doses):

Autonomic ganglia Neuromuscular junction Adrenal medulla

– Muscarinic action in: Post-ganglionic cholinergic endings.

• Acetylcholine: has a direct effect on the heart coronary vasodilatation.

SAR of Para-sympathomimetics:

• Acetylcholine: is a quaternary ammonium compound with the formula.

+Exhibits muscarinic activity

Antidepressants “Psycho-analeptics” these are classified as follows:

1. MAO Inhibitors: They increase the amount of biogenic amines (NE, dopamine, 5-hydroxy-tryptamine & serotonin) in the synaptic cleft by their destruction ( MAO breakdown of amines). They are used for atypical depression (unipolar depressive disorders) & include:

– Hydralazine derivatives: Phenelzine (Nordil)

Iproniazid (Morolide) Isocarboxazid (Morphan).

– Non-hydralazine derivatives: these have amphetamine like action

Tranylcypromine (Parnate) Paragyline Pergolin (Entomyl).

• Side effects of MAO-Is: insomnia, dry mouth, orthostatic hypotension, dizziness

• MAO-Is may interact with pressor amines as tyramine (in cheese, yogurt, beer, wine) accumulation of tyramine adrenaline hypertensive crisis.

• MAO-Is if used with guanithidine HT crisis. Guanithidine is an adrenergic neuron blocker & also depletes NE stores where NE is supposed to be deactivated by MAO. However The MAO-I will deactivation of NE NE HT crisis.

2. Tricyclic Antidepressants: They enhance the effect of biogenic catecholamines (adrenaline & noradrenalin) as a result of inhibiting their re-uptake into storage sites. They include:

Imipramine (Tofranil) Amitryptaline (Tryptizol)

Desipramine (Norpramine) Nortryptaline (Aventyl)

Doxepen (Sinequan) Protryptaline (Vivactyl)

3. 2nd Generation Antidepressants (Tetracyclic antidepressants): dibenzo bicyclo acetadienes

Amoxapin Maprotiline (Ludiomil)

4. Atypical Antidepressants: Selective 5-HT serotonin (inhibit serotonin reuptake)

Trazodone Bupropion Citalopram (Celexa)

Fluoxetine (Prozac) Paroxetine

Fluoxovamine Sertaline (Lustral Zoloft)

• Trazodone (Desyrel): is a cyclic antidepressant with much less anti-cholinergic & CV side effects than other members of the group. Unlike other members of the class, it acts mainly on the re-uptake of serotonin rather than norepinephrin.

5. L- Tryptophan.

6. Lithium carbonate (carbolith): is primarily indicated for treating bipolar affective disorders (manic episodes of depression & psychosis). It is not used to treat mild biogenic depression.

– Needs 2 – 3 week before its action is evident.

– It has a low therapeutic margin (0.8 – 1.5 mg / L).

– Not recommended in pts with renal or CV disease.

– Manic depression is a state of over activity of catecholamine transmission & lithium enhances the destruction of catecholamines.

– Patients should not restrict their Na dietary intake because if Na levels , the excretion of Li , leading to toxic levels of Li (which accumulates rapidly).

CNS Stimulants• Xanthene derivatives: e.g. caffeine, theophylline, theobromine.

– These AMP & cGMP by inhibition of phosphodiesterase enzyme.

• Amphetamine group:

– These the release of catecholamines, & their inactivation though inhibition of MAO.

– Amphetamine.

– Methamphetamine.

– Phenmetrazine.

– Fenfluoramine (Pondrax) CNS depressant

• Cocaine:

– It blocks the reuptake of NE, serotonin & dopamine.

• Methyl phenidate (Ritalin)

• Hallucinogens

– Lysergic acid diethylamide (LSD)

– Tetrahydocannabinol (THC)

– Phencyclidine (CP)

1. Which of the following agents act by competitive inhibition as a NMB (block NM junction):

a. Pancronium c. Succinyl choline

b. Edrophonium d. Tubocurrarine.

2. Alzheimer disease (brain disorder in elderly) may be due to deficiency of:

a. Acetylcholine b. Dopamine c. Serotonin

3. Of the following anti-anxiety agents, which possesses the greatest antihistaminic action:

a. Diazepam (Valium) d. Hydroxazine (Atarax)

b. Memprobamate (Miltown) e. Chlorodiazepoxide (Librium)

c. Oxazepam (Serax)

4. Symptoms associated with parkinsonism:

a. Dry mouth c. Drowsiness

b. Constipation d. Muscular rigidity & tremors at rest

5. Morphine usage is restricted only for:

a. Acute pain c. As an antispasmodic

b. As a cough sedative d. Antispasmodic

6. Long-term therapy with benzodiazepines will cause:

a. Potential drug abuse. d. Convulsions if suddenly withdrawn.

b. Disturbs normal sleep e. Has active metabolites

1. Reduce REM sleep. f. All of the above.

a. Codeine:

a. Has no analgesic activity. d. Best for children (less than 2 years).

b. Has no local anesthetic action

1. Unlikly to cause addiction when given as antitussive based on dose frequency.

b. Which of the following agents is most effective in absence of seizures:

1. Clonazipam. c. Phenytoin.

a. Valproic acid. d. Ethosuximide.

c. Which is a competitive inhibitor of acetylcholine esterase (anticholine esterase):

1. Carbacol. c. Edrophonium. e. Succinyl choline

a. Pancuronium. d. Tubocurrarine. f. Neosegmine

d. When anesthesia is given, partial pressure in the brain is due to:

1. Concentration of the anesthetic agent.

e. Which drug can cause peripheral parkinsonism like symptoms:

a. Clorpromazine. c. Haloperidol.

b. L-dopa.

12. The levo isomer of propoxyphene is used as:

a. Analgesic c. Anti-inflammatory

b. Antitussive d. Urinary antiseptic

13. Which drug is effective orally in parkinsonism:

a. Reserpine d. Halloperidol

b. Chloropromazine e. Amantadine (Symmetrel)

c. Dopamine f. L-dopa + Carbidopa (Senimet)

14. The action of inhalation anesthetics is dependent on:

a. Conc. in alveolar sac. b. Partial pressure in alveolar sac ???

b. Conc. in brain c. Partial pressure in brain

15. If phenylephrine (-receptor agonist) is given IM to BP, which agent can be used to B.P:

a. Beta receptor antagonist (propranolol)

b. Irreversible non-selective adrenoreceptor antagonist (phenoxybenzamine, diabenamine) (block -1 & -2 receptors)

c. Reversible -adrenoreceptor blocking e.g. phentolamine & tolazoline.

16. Pre-anesthetic treatment is given to:

a. Reduce anxiety. d. Muscle relaxant.

b. Relief pain e. Ensure smooth anesthesia

c. Decrease side effects f. All of the above

17. Which is true about codeine phosphate:

12. Contraindicated in children b. Used as antitussive.

a. Conc. of inhalation anesthetic is:

a. 5 – 10%. b. 15 – 20%.

12. 20 – 30%

b. Which type of local anesthetic is most effective:

a. The most lipophylic b. The most hydrophilic

12. Neostegmine is used for:

a. Parkinsonism b. Mysthenia gravis c. Antidote for curarrae

a. What is true about pancuronium:

12. Is a competitive non-depolarizing NMB b. It is a depolarizing NMB

b. Epilepsy is a result of:

a. GABA deficiency b. Acetylcholine deficiency

23. Select the CNS poison which is selectively toxic to the retina:

a. Methanol c. Warfarin

b. Arsenic d. Carbon tetrachloride

24. The neuroleptic drug with least sedating effect is:

a. Haloperidol c. Dropridol

b. Chlorothioxan

25. The shown structure is:

a. Antidepressant

b. Anticholinergic

c. Antibacterial

d. Narcotic analgesic

26. Which of the following agents is a competitive inhibitor of acetylcholine:

a. Carbacol c. Succinyl choline

b. Edrophonium d. Pancuronium

27. The most common side effects of neuroleptics are:

a. Tardive dyskinesia

b. Extra-pyramidal side effects

28. Which NMB is used safely in hepatic & renal failure:

23. Alcuronium b. Atracurium

a. Which is the fastest acting barbiturate:

a. Thiopental

23. Which is true about Li therapy:

a. Onset of action within 2-3 weeks c. Do not restrict Na during Li therapy

b. Used in manic episodes

24. Side effects of Li therapy include:

a. Hypothyroidism d. Obesity f. Ataxia

b. Dysrhythmia e. Diabetes insipidus g. Slurred speech

c. Skin eruptions (folliculitis)

25. Naloxone is used as:

a. Narcotic antagonist b. Antagonise morphine respiratory depression

a. Which agent stimulates the adrenal medulla to secrete norepinephrine:

23. Small doses of nicotine

24. Large doses of acetylcholine

34. Which of the following is not a side effect of anticholinergics:

a. Diarrhea b. Constipation

35. Which agent increases HR without significant effect on BP:

a. Isoproterenol b. Ephedrine c. Pilocarpine

36. The side effects of propantheline include:

a. Dry mouth b. Dry skin

37. Which agent is used in motion sickness:

a. Cyclizine b. Scopolamine

38. Which is the drug of choice in status epilepticus:

a. IV diazepam

39. Which is the drug of choice in petit mal epilepsy:

a. Ethosuximide b. Valproic acid c. Clonazepam

40. Which is the drug of choice in grand mal epilepsy:

a. Valproic acid c. Primadone (Mysoline) e. Carbamazepine

b. Phenytoin d. Phenobarbital

41. Epilepsy is a result of:

34. Excitatory neurotransmitters (AcCh, NE, histamine, cortico-tropine releasing factor)

a. Inhibitory neurotransmitters (GABA, Dopamine)

42. Action of anti-epileptics:

a. Inhibit excessive discharge & spread of excitation from CNS sensitive foci.

43. Which drug distributes easily in the CNS:

a. Thiopental b. Haloperidol c. Flurazepam

44. Structure of chloropromazine contains:

a. Phenothiazine ring b. Benzodiazepine ring

45. A patient is under phenytoin for treating epilepsy. The urine clearance of the drug is normal, but the patient still experiences side effects of headache & diziness. This may be due to:

a. Accumulation of metabolites c. Phenytoin induces hepatic enzymes

35. % of unbound phenytoin in plasma

a. Which is not a side effect of morphine:

35. Diarrhea c. Mydriasis

a. Hypotension d. Respiratory depression

b. Which is not a side effect of amitriptyline:

35. Blurred vision b. CNS stimulation

48. Complications of parkinsonism include:

a. Tremors c. Tardive dyskinesia

b. Dopamine deficiency d. Gene deficiency

49. Difference between dopamine & amphetamine is that amphetamine has:

a. 2 more OH & 2 more CH3 gps b. 1 OH less & 1 CH3 more

50. MAO I + Tyamine:

a. Hypertensive crysis

51. Interaction between phenytoin & folic acid:

a. Will decrease folic acid levels

52. All of the following can cross BBB except:

a. Nicotine c. GABA e. Serotonin

b. Bromocryptine d. Pancuronium

53. Amantadine is:

a. Antiviral c. Prophylactic against influenza

b. Used in parkinsonism d. Increases release of dopamine

54. Barbiturates have decreased popularity as sleeping aids because:

48. Increased abuse d. Narrow therapeutic index

49. Drug-drug interactions e. Affects REM

a. Discontinuation after long term use convulsions

a. The phenothiazine with least extra-pyramidal side effects:

48. Thioridazine b. Fluphenazine

b. The phenothiazine with anti-cholinergic effect:

48. Ethopropazine

c. The phenothiazine with sedative analgesic effect:

48. Methotriperazine

d. Diphenhydramine is:

48. Anticholinergic b. Anti-histaminic

e. Emetrol (transdermal scopolamine) is used in:

a. Motion sickness b. Vomiting

48. The metabolic product of primadone is:

a. Phenoparbitone

a. Which drug undergoes functional gp sulfoxidation in phase I:

48. Chlorpromazine

62. Tardive dyskinesia is:

a. A side effect of long term therapy with phenothiazines

b. Characterized by involuntary movement of tongue, & rigidity of jaws & lips

c. Treated with L-dopa in large doses

d. Anticholinergic treatment is useful

63. Carbamazipime is:

a. The drug of choice in trigeminal neuralgia, & simple & complex partial siezures

64. Tissue reabsorption makes which of the following anesthetics short acting:

a. Ether b. NO c. Halothane

65. Which of the following agents causes pain:

a. Bradykinin (the most potent algesic substance in the body)

66. Short-acting benzodiapine:

a. Diazepam b. Triazolam c. Nitrazepam

67. In morphine withdrawal, the drug of choice is:

a. Meperidine b. Naloxone c. Methadone (oral with juice)

68. Anti-cancer drugs induce vomiting by:

a. Stimulation of the chemoreceptor trigger zone (CTZ)

69. Which is a 5- receptor inhibitor:

62. Flutamine b. Finasteride

a. The antagonist for benzodiazepine is:

a. Flumazenil

62. The antagonist for tricyclic anti-depressant is:

a. Physostegmine

63. A neurotransmitter is:

a. Secreted & degraded outside the cell b. Easily passes BBB

64. What is true about GABA:

a. An inhibitory neurotransmitter

65. Which will increase the withdrawal symptoms of opiates:

a. Meperidine b. Naloxone c. Naltroxene

66. Aminophylline is: ???

a. CNS depressant (Stimulant) b. Diuretic

67. Drugs used in the treatment of schizophrenia:

a. Have a dopamine II antagonist action

77. The amount of gas reaching the CNS is determined by:

a. Partial pressure (PO2 , PCO2)

78. Which is the best choice for treating manic depression:

a. Lithim carbonate

79. Which of the following agents has short t ½ because of high degree of distribution in body fluids:

a. Thiopental b. Halotane c. Cyclopropane

80. Which of the following agents acts by opening Cl – channels:

a. Benzodiazepines

81. Opiod tolerance is induced by:

a. Decreased sensitivity of receptors to opiates & a need to increase dose

82. Which is a partial opiod antagonist:

a. Meperidine b. Naloxone c. Buterophanol

83. Which is an opiod agonist / antagonist:

a. Pentazocin

84. Which anticonvulsant when used for long time increases body clearance:

a. Barbiturates

85. Atropine is:

a. Parasympatholytic b. Parasympathomemetic

86. Convulsions can be caused by:

a. Strychnine b. Atropine

87. Diseases that can induce parkinsonism include:

a. Infections (syphylis, viral encephalitis) c. Arteriosclerosis

77. Wilson’s disease (degenerative CNS disease)

a. The use of NMBs is in:

77. Diagnosis of mysthenia gravis b. Treatment of mysthenia gravis

b. L-dopa is useful in parkinsonism because:

77. It better crosses the BBB than dopamine

a. A small portion crosses the BBB where it is metabolized to dopamine

77. Which of the following antidepressants is a selective serotonin (5HT) reuptake:

a. Fluxetine b. Trazodone

78. Which is a local anesthetic with a vasodilator activity:

a. Cocaine b. Tertacaine c. Lidocaine

92. Nocturnal enuresis in pediatrics is best treated by:

a. Imipramine (Tofranil) c. ADH

b. Oxybutrin d. Desmopressin (intranasal aerosol)

93. Benzodiazepines act on:

a. GABA a receptors d. Dopamine receptors

b. GABA b receptors e. Adrenergic receptors

c. Serotonin receptors

94. Which of the following agents is a MAO I:

a. Iproniazide c. Paragaline

b. Phenelzine d. Tranylcypromine

95. Which of the following agents is used in all kinds of depression:

a. Lithium (in manic depression due to over activity of of catecholamine)

96. Long-term treatment with diazepam or triazolam (Halocin) affects:

a. Decreased REM (dream sleep) c. Stages I & II

b. Stages III & IV

97. Which induces withdrawal symptoms in morphine tolerant patients:

a. Nalbuphane

98. An example of amide local anesthetic:

a. Dibucaine

a. Which of the following drugs antagonize the action of morphine :

92. Pure antagonist Naloxone

93. Partial antagonist Buterphanol, Buprenorphine, Nalbrophine, Dezocine

a. Mixed agonist antagonist Pentazocine

b. Atropine is:

92. Parasympatholytic b. Parasympathomemetic

c. Convulsions can be caused by:

a. Strychnine b. Atropine

92. Diseases that can induce parkinsonism include:

a. Infections (syphylis, viral encephalitis) c. Arteriosclerosis

92. Wilson’s disease (degenerative CNS disease)

a. The use of NMBs is in:

a. Diagnosis of mysthenia gravis b. Treatment of mysthenia gravis

92. L-dopa is useful in parkinsonism because:

a. It better crosses the BBB than dopamine

92. A small portion crosses the BBB where it is metabolized to dopamine

a. Which of the following antidepressants is a selective serotonin (5HT) reuptake:

a. Fluxetine b. Trazodone

92. Which is a local anesthetic with a vasodilator activity:

a. Cocaine b. Tertacaine c. Lidocaine