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INTRODUCTION TO CNS PHARMACOLOGY

Drugs affecting the CNS may act presynaptically by influencing the production, storage, or termination of neurotransmitters. Other agents may activate or block postsynaptic receptors.

An overview of the CNS with a focus on Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmitters mediating the physiological and pathological responses is essential for understanding neuropharmacology.

Ion channels & NT receptors


Voltage-gated channels Respond to AP Fast action potentials Include the sodium channels responsible for action potential propagation Ligand-gated channels (Inotropic) Chemically-gated Respond to chemical neurotransmitters (NTAs) that bind to receptor subunits of the channel

G-protein coupled receptors (Metabotropic) NTAs also bind to G protein-coupled receptors Direct opening voltage-channel through SM

CNS PHARMACOLOGY

TYPES OF RECEPTOR-CHANNEL COUPLING 1. Through a receptor that acts directly on the channel protein 2. Through a receptor that is coupled to the ion channel or change ion channel function through a G protein system.

CNS PHARMACOLOGY
ROLE OF THE ION CURRENT CARRIED BY THE CHANNEL SYNAPSE- communication
1. EXCITATORY POSTSYNAPTIC POTENTIALS 2. INHIBITORY POSTSYNAPTIC POTENTIALS

CNS PHARMACOLOGY
EXCITATORY POSTSYNAPTIC POTENTIALS (EPSPs) Depolarizing potential change Generated by Opening of sodium or calcium channels Closing of potassium channels

CNS PHARMACOLOGY
EXCITATORY POSTSYNAPTIC POTENTIALS (EPSPs) Na+, K+, Ca+2

-70 mV

CNS PHARMACOLOGY
INHIBITORY POSTSYNAPTIC POTENTIALS (IPSPs) Hyperpolarizing potential change Generated by Opening of potassium or chloride channels

CNS PHARMACOLOGY
INHIBITORY POSTSYNAPTIC POTENTIALS (IPSPs) K+ , Cl- at the postsynaptic , Ca+2 at the presynaptic

-70 mV

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION Some drugs exert their effect through direct interactions with molecular components of ion channels on axons Carbamazepine Phenytoin Local anesthetics and some drugs used for general anesthesia

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION

Most drugs exert their effect mainly at the synapses

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION
May alter Neurotransmitter Synthesis Storage Release Reuptake Metabolism

CNS PHARMACOLOGY
SITES AND MECHANISMS OF DRUG ACTION Activate or block Pre- and postsynaptic receptors for specific transmitters

CNS PHARMACOLOGY
CNS ORGANIZATION
Major excitatory transmitters Aspartate Glutamate

CNS PHARMACOLOGY
CNS ORGANIZATION 2 TYPES OF NEURONAL SYSTEM Major inhibitory transmitters: Gamma amino butyric acid (GABA) Glycine

CNS DRUGS CLASSIFICATION


Chemical structure
Benzodiazepines, Butyrophenones

Pharmacological
MAO inhibitors, SSRI,

Clinical use
Antidepressants, Antipsychotic agents

Classification
sedatives hypnotics drugs Drugs that reduce anxiety and cause sleep Examples Barbiturates, benzodiazepines

Classification
2. Antipsychotic drugs (neuroleptics, anti-schizophrenia Drugs that are effective in relieving symptoms of schizophrenic illness Examples Clozapine, Haloperidol

Classification
3. Antidepressant drugs Drugs that alleviate the symptoms of depressive illness Examples TCA, MAOI, SSRI

Classification
4. Psychomotor stimulants (Psychostimulants) Drugs that can cause wakefulness and euphoria Examples Amphetamines, Cocaine, and caffeine

5. Anticonvulsants: Drugs that prevent or suppress convulsions. 6.Analgesics: Drugs that relieve pain without causing loss of consciousness. 7. General anesthetics: Drugs that produce reversible depression of the CNS leading to loss of consciousness and loss of sensations surgical operations.

Sedative Hypnotics
Anxiety disorders Is unpleasant state of tension, apprehension or uneasiness . A fear that seems to arise from a sometimes unknown source . Most common mental disturbance.

Anxiety is a universal human characteristic which serves as adaptive mechanism to warn about an external threat by activating the sympathetic NS. Anxiety is in many cases secondary to organic disease (e.g MI,angina, peptic ulcers) which themselves require specific therapy. Or due to Drug-Induced. or Drug Withdrawal

Manifestations of anxiety:
Verbal complaints. The patient says he/she is anxious, nervous. Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, breathlessness, tremor, fatigue, disturbed sleep. . Social effects. Interference with normal productive activities.
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Anxiety become pathological when: 1.Fear is greatly out-of-proportion to risk/ severity of threat. 2.Response continues beyond existence of threat. 3.Social or occupational functioning is impaired.

SLEEP
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During sleep, the brain generates a patterned rhythmic activity that can be monitored bymeans of the electroencephalogram (EEG). Internal sleep cycles recur 45 times per night

Normal sleep
Normal sleep cyclic and repetitive, consists of distinct stages: Non-rapid eye movement(NREM) sleep: 70%-75% Stage 1,2 Stage 3,4:slow wave sleep, SWS Most sleep stage 2. Rapid eye movement(REM) sleep Recalled dreams. Both NREM & REM occur cyclically over an interval of about 90 min.

rapid eye movement (REM) sleep phase The REMstage is characterized by EEG activity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional REM stage is entered only after a preceding non-REM cycle.

insomnia is "difficulty initiating or maintaining sleep, or both" or the perception of poor quality sleep.

BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS


An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.

General anesthetic: the drug which causes reversible and controllable loss of consciousness associated with absence of response to pain. Sedation Hypnosis Anesthesia Coma and death. After progressive dose increments.

BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS


Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.
Graded dose-dependent depression of central nervous system function is a characteristic of sedative-hypnotics.

CHEMICAL CLASSIFICATION
1. Benzodiazepines: not to lead general anesthesia, raraly death. 2. Barbiturates: the older sedative-hypnotics, general depression of central nervous system. With such drugs, an increase in dose above that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, it may depress respiratory and vasomotor centers in the medulla, leading to coma and death.

DRUG A - BARBITURATES dose = CNS depression DRUG B - BENZODIAZEPINES - flatter dose response curve - greater margin of safety

Classification of anxiolytic and hypnotic drugs


1. Benzodiazepines most important class
2. Buspirone 5-HT1A R- agonist. And Hydroxyzine H1 blocker. 3. receptor antagonist propranolol. Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe. 4. barbiturates

SEDATIVE/HYPNOTICS ANXYOLITICS
BENZODIAZEPINES BARBITURATES

GABAergic SYSTEM
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Enhance GABAergic Transmission


frequency of openings of GABAergic channels. Benzodiazepines opening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBS

.Benzodiazepines

Classification Short acting e.g. Midazolam Intermediate acting e.g. Alprazolam Long acting e.g. Diazepam
The BNZ for most part, end in pam or lam

MOA:

MOA: GABA (-amino butyric acid) is an inhibitory neurotransmitter Binding of GABA to its receptor on cell membrane trigger an opening of Clchannel Influx of Cl- leads to hyperpolarization

BZ binds to specific receptor adjacent to GABA receptor This binding potentiate binding of GABA on its receptor

BZ receptors are found only in the CNS

Pharmacokinetics

Most of these drugs are lipid-soluble & are absorbed from GIT Good distribution to the brain Metabolism: most BZ metabolized by hepatic Cyt-P450 to compounds that are also active

Therapeutic Uses of BDZs


1. Anxiety disorders: for continued sever anxiety and NOT to alleviate the normal stress of every day of life. Only for short period. Addiction potential.

Benzodiazepines with intermediate or long durations of action are favored Alprazolam for Phobic and panic attacks

Therapeutic Uses of(BDZ) cont.


3. Sleep disorders: latency of sleep onset is decreased. total duration of sleep is increased. Both effects decline after prolonged use. Relatively slight decrease in REM and slight rebound after stoppage.

Tolerence , dependence and hangover. Tolerance occurs after 1-2 weeks.

Therapeutic Uses of(BDZ)


4. Anticonvulsant: clonazepam diazepam and lorazepam. 5. Preanesthetic medication: to produce amnesia in anxiety provoking and unpleasant procedures as endoscopy and dental procedures. (The pt. is receptive for instructions). 6. Control of ethanol and other hypnotic withdrawal less dependence and less resp. and CV effects.

Adverse effects

Day time drowsiness Cognitive impairment Blurred vision & confusion Tolerence and dependence (physical and psycological). Specially in high dose for long period. Withdrawal manifestation are more with BDZ of short duration.

Long-term Effects
Tolerance develops, resulting in dependence
Must have more and more of the drug to feel an even minor effects Higher risk of overdose

Withdrawal
This leads to dependence as well No one wants to feel the unpleasant withdrawal effects, so continues use (2)

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BZs antagonists Flumazenil reverse the effects of BZs This drug is available by I.V. administration only Has rapid onset

.BARBITURATES They were formerly used to sedate the patient; today they have been replaced by BZ because:
1. 2. 3. 4. BZ are safer (wide therapeutic index) BZ have risk of physical dependence BZ have drug-drug interaction (less induction of liver enzymes) BZs have less withdrawal symptoms

.BARBITURATES
Classification
(1)Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental is used I.V. to induce anesthesia (2)Long-acting barbiturates: have a duration of action greater than 6h. Such as Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents for long term management of Tonic-Clonic seizure & status epilepticus

MECHANISM OF ACTION
Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABAreceptor/chloride channel, and their action seems to prolong the duration of the opening of GABA-activated chloride channels.

S/Es CNS: Drowsiness, impaired concentration Respiratory depression: in dose that may lead to death

Benzodiazepines vs. Barbiturates


Criteria
Relative Safety

BZ

Barb.

High Low

Maximal CNS depression


Respiratory Depression

Low High
Low High

Suicide Potential
Abuse Potential Antagonist Available?

Low High
Low High Yes No

Other agents E.g.: Buspirone MOA: It is mediated by serotonin (5-HT1A) receptors Uses: Treatment of generalized anxiety disorders Lack anticonvulsant & muscle relaxant properties

Other anxiolytic agent: Hydroxyzine: an antihistamine that is useful for patients with anxiety disorders who have history of drug abuse. often used for sedation prior dental procedure or surgery. Drowsiness is possible adverse effects

-Adrenoreceptor Antagonists (eg. Propranolol)


Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe. Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.
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