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Lec #10 introduction to CNS pharmacology _________________________ This lecture Is the first lecture In the second exam. Drugs that are used to treat CNS disorders in order to be useful, should reach the site of action , they should penetrate the BBB (blood brain barrier) , just to remind u , the characteristics for a drug to penetrate the BBB : 1. High lipid solubility 2. Small molecular weight 3. Unionized - How drugs alter the CNS function or action or what is the mechanism ?? they will affect neurotransmitters in which they alter their (min 4:17 (***) ) , either the storage , the metabolism, for example the re-uptake process by different mechanisms , OR maybe they will act directly on ion channels , either NA CHANNELS , CA CHANNELS . NOW , the type of the channels or the receptor interaction either : 1.

VOLTAGE- GATED : in which a receptor is directly bound to a channel by stimulation or inhibition of this channel then I'll have opening and closing of this channel this type I call ION GATED OR VOLTAGE GATED in which they produce a fast action potential (AP) it's rapid , I don't have a secondary messenger need a time , just a receptor bind to it's ligand , in which this will initiate opening or closing of the channel . FOR EXAMPLE : Drugs that affecting the sodium channel , one of the important drugs for you is the local anesthetic , as you know the NA channel opening will induce the AP and initiate the neuronal propagation , so if I block the NA channels I'll prevent the neuronal excitation and AP propagation . CA channel is another example of this type .

2.

LIGAND-GATED ION CHANNELS (Inotropic) : It's chemically gated , I have receptor site for the neurotransmitter , now the binding of the neurotransmitter to it's receptor , will initiate the opening and closing of the channel , Y3NI chemically neurotransmitter bind to such receptors not present in the channel itself and by this binding I'll initiate for example the opening of the channel

3. G-protein coupled receptors (Metabotropic) : That type which leads to formation of secondary messenger , it will be slow AP This figure can be skipped it's not highly important , as the DR said

NOTE: **sometimes the opening of a cahnnel will initiate AP , and sometimes the closing of a channel initiates AP , depending on the channel type ** The figures are not highly important as the DR said , then she started to talk a little bit about them , and there wasn't any additions to the previous information .

GABA is : gamma amino butyric acid , and it's the major inhibitory neurotransmitter in the CNS . HOW ? now GABA BINDS TO IT'S RECEPTOR , by it's binding it will enhance or initiate the opening of the chloride channels , and the opening of the chloride channels will cause neuronal hypo-polarization(neuronal inhibition) , It will inhibit AP formation, how ?? it's ligand-gated effect .

NOW , how drugs and imma-drugs acts directly on the ion channel ?? We'll have an example : ***drugs can produce their action through a receptors that is coupled to ion channel , that we call ligand gated type , in which a drug bind to a receptor coupled to ion channels, either directly bind to ion channel or to a receptor coupled to ion channel to produce it's effect , or through a G Protein action , each affect at subtile of the receptor . We have either : EXCITATORY POSTSYNAPTIC POTENTIALS INHIBITORY POSTSYNAPTIC POTENTIALS Now from physiology , * how can we get excitation ?? by opening of NA channel or CA channel or by closing potassium channel _ opening of CA channel in the presynaptic neuron will enhance releasing of neurotransmitter this will enhance neuronal propagation. *How can we get neuronal inhibition (neuronal hyper-polarization) ? by potassium channel OR chloride channel opening , in which we have K or CL efflux. 1.

Site of actions of the drugs : * those examples are repeated , essentially u'll know them , we'll talk about them a lot . - Drugs that directly act on ion channels , for example : 1. anti-epileptic drugs , they directly block NA channel , 2. or the local anesthetics in which they act directly on the channel .

it will Regulate the influx of NA , influx of NA will induce neuronal excitation

Anticonvulsant: they are useful drugs forthe treatment of epilepsy

Now, neurotransmitter (NS )regulated channels ( ligand gated ion channels ) as you'll see , there is a receptor in which a NS binds , binding of the NS will initiate the opening of the channel , and we'll have an example which is : SEDATIVE-HYPNOTICS . -some drugs act directly on the NS in the CNS affecting : NS synthesis , storage , re-uptake process , termination or metabolism .

now in general we either block or activate pre-synaptic or post-synaptic receptors and that depends on pre or post-synaptic . just to remind you : -alpha 2 receptors are pre-synaptic , by their activation It'll inhibit sympathetic outflow so some drugs can act on pre-synaptic receptors •



-in our CNS we have multiple neurotransmitters , some have excitatory effect , some have inhibitory effect and some have both effects depending on the type of receptor in which they act . *most famous excitatory transmitters are : – 1. Aspartate – 2. Glutamate – – *And the most important or the Major inhibitory transmitters are : – 1. Gamma amino butyric acid (GABA) – 2. Glycine

HOW drugs in the CNS are classified ? they can be classified depending on their : – 1. chemical structure : like Benzodiazepines, Butyrophenon 2. Mechanism of action , I can say MAO (mono amino oxidase ) inhibitors OR SSRI (selective serotonin re-uptake ) inhibitor 3. Depending on their therapeutical use or clinical use , I can say this drug is antiepileptic which means it's used to treat epilepsy , or I can say antidepressant , used to treat depression Classification of drugs : 1. sedative-hypnotics (depending on the structure ): " drugs that's used for induction of sleep and relieving of anxiety " Examples : : Barbiturates, benzodiazepine 2. Antipsychotic drugs (neuroleptics, anti-schizophrenia ) ( Depending on their therapeutical use or clinical use) “Drugs that are effective in relieving symptoms of schizophrenic illness or ” Examples: Clozapine , Haloperidol 3. Antidepressant drugs (depending on their Mechanism of action ) : “ Drugs that are used for the management of depression or alleviate the symptoms of depressive illness” Examples : TCA(try-cyclin anti-depressant ) , MAOI (mono amino oxidase inhibitors) , SSRI (selective serotonin re-uptake inhibitor ) 4. Psychomotor stimulants (Psychostimulants) “Drugs that can cause wakefulness and induce euphoria” Examples : Amphetamines, Cocaine, and caffeine 5. Anticonvulsants: Drugs that prevent or suppress convulsions( used as treatment of epilepsy ) 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 by relaxation of the muscles . **We'll mention them almost with every upcoming disease so it will be much easier on you :D Beginning with the first disease disorder , which is treatment of: ANXIETY Anxiety : means tension , fear ‫ قلق‬, it can be defined as an unpleasant state of tension, apprehension or uneasiness in which an individual or the patient can say about him self : I'm anxious . anxiety is associated with over activation of the sympathetic nervous system , tachycardia , sweating , tremor and many other sympathetic symptoms . it's one of the common mental disorders . it might be due: 1. to a secondary disease , for example a patient who have a chronic disease and he or she is afraid from his situation , 2. OR maybe due to drug abuse (some drugs can induce anxiety ) 3. or due to Drug Withdrawal , some drugs if they were stopped suddenly , might cause anxiety . Anxiety might be chronic in which it lasts for weeks and months and this require medical intervention . but in some cases just like you when you feel afraid because you have an exam or interview or seminar it's then trans-anxiety and here no need for medical intervention Manifestations of anxiety : • Verbal complaints: The patient says he/she is anxious, nervous , anger , aggressive • • Somatic and autonomic effects. The patient is restless and agitated, has tachycardia, increased sweating, breathlessness, tremor, fatigue, disturbed sleep. •

Social effects. Interference with normal social activities.

*When the anxiety can be considered a disorder or pathological ?? 1.if Fear or tension is greatly out-of-proportion to risk the patient is in ( over estimation) / severity of threat. 2.Response continues beyond existence of threat. 3.Social or occupational functioning is impaired. Anxiety itself can induce sleep disturbances and VICE VERSA , insomnia may induce anxiety Sleep cycle : We have 2 stages , REM AND NON-REM they occur in a cycle over 90 min . in the beginning of the sleep we'll go on the NREM (NON Rapid eye movement) cycle AND it's composed of 4 stages : stage 1 , stage 2 ( counts for about 70% of the NREM ) , stage 3 +4 ( they are known as the slow wave sleep ) . now in the end of the NREM sleep we'll go to the REM stage , in the REM cycle in which dreams occur and it's easy to wake up while you are in this stage . insomnia is "difficulty initiating or staying sleep or maintaining sleep , or both" or the perception of poor quality sleep" Which the patient will say either have difficulty in initiating sleep , he stays awake for 1 hour before he can sleep OR patients will be awake 6 times

during the night OR total time of sleep is less than 6 hours and it was repeated for four times per week then it's insomnia . now to help patients in sleeping we might ask them to avoid noise and caffeine and smoking and taking a shower might also help in relaxation and inducing the sleep , even reading might be helpful . now starting with the sedative drugs : sedative drugs are anxio-lytic drugs , drugs that will reduce anxiety and calm the patient mostly or often without interference with motor or mental function . • hypnotic drugs : a drug that produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. They found that sedative drugs also have an effect on sleep (induce sleep ) if they were used In high doses , as I increase the dose the CNS inhibition will be more. • SO , CNS depression is dose dependant , increasing the dose leads to anesthesia or sometimes COMA and increasing more and more will lead to death . Now look at this figure :

Q: Which drug is safer ?? A: drug B Drug B is BENZODIAZEPINES and has a large therapeutic index , so if I increase the dose I'll not reach coma or death and that’s why it's safer . while drug A IS BARBITURATES in which by increasing the dose I'll get more and more CNS depression and can lead to death . examples of anxio-lytic and hypnotic drugs : 1. Benzodiazepines 2. Buspirone agonist: It acts on different types of receptor but mainly serotonin type 1 receptors , And Hydroxyzine (anti-histamine drug) H1 blocker . the first choice for the DR or the pharmacist for an individual having problems with sleeping is the anti-histamine like alerfine or serrous in which they have an effect which the block histamine receptors and they are SAFER than Benzodiazepines and BARBITURATES . 3. β – receptor • Effective to release symptoms of anxiety due to sympathetic stimulation

• 4. barbiturates. BARBITURATES and Benzodiazepines they act on GABA-ergic system . they found that Benzodiazepines will increase the frequency of chloride channel opening . while BARBITURATES will increase the duration of the chloride channel opening . and BOTH of them will enhance GABA action , will increase GABA affinity to GABA receptors.

Benzodiazepines the characteristic for it : suffix ends up with lam or pam • • •

Short acting  e.g. Midazolam Intermediate acting  e.g. Alprazolam Long acting  e.g. Diazepam ( most common one and famous) and their effect last for 24 hours , can be used once daily.

Mechanism of action :

At first the receptor is empty , so no chloride efflux because of the closed CL channels , Then after GABA binds to its receptor CL channels will open and that all leads to hyperpolarization . benzodiazepine they have their own receptors that present in the CNS , not periphery , in the brain and the spinal cord , now if we receive benzodiazepine and if benzodiazepine binds to its receptors the effect is that they will increase or they will enhance the binding of GABA to it's own receptors , more GABA binding means more CL channel opening , more CL entrance , more inhibition.

Pharmacokinetics OF Benzodiazepine - Most of these drugs are highly lipid-soluble in order to penetrate the BBB , - are absorbed from GIT - Good distribution to the brain - Most of them after metabolism are Converted to active metabolize, and this explain why some BZ have long duration of action

Therapeutic Uses of BDZs 1. Anxiety disorders: -for continued sever anxiety and NOT to alleviate the normal stress of every day of life. And should be used Only for short period to avoid drug dependence and Addiction . BZ are Addiction potential . Where do you think it causes more addiction in short acting BZ or long acting ?* Short acting , because of more frequent administration 2. One of Benzodiazepines derivatives is Alprazolam which is used for Phobic and panic attacks. **Anxiety has many types: 1. Phobia , agro-phobia or from certain animals. 2. Panic attacks , people afraid of highest for example or some people say they afraid to go out their homes , because they afraid they are going to die 3. Generalized anxiety disorder , tension and apprehension that last for long periods. 4. Obsessive compulsive disorders , these patients have repetitive ideas which they think can be removed by some of their behaviors , for example some patients are highly highly afraid by microbs ,so they directly wash their hands after hand-shaking ! )‫(الوسواس القهري‬

3. Sleep disorders: Mechanisim of action : As we said before taking a high dose of Benzo will induce sleep a. Latency of sleep onset is decreased (the time they will go into a sleep) . b. They suppress REM in the same time this will increase the duration of non-REM c. Total duration of sleep is increased "Both effects decline after prolonged use." If the patiend has stopped suddenly taking it , rebound REM phenomena will approve ( increasing of REM Aafter stoppage ), the patient will be back to insomnia . Tolerence , dependence and hangover occurs if usage is more than 1-2 weeks .

4.

Anticonvulsant: clonazepam diazepam and lorazepam. they are effective in relieving and controlling epilepsy. 5. Preanesthetic medication: to produce amnesia before any medical procedure in endoscopy and dental procedures to relieve anxiety and calm the patient . ( Amnesia is impairment of short term memory in the same time the patient cannot fall or get a new information ) 6. Control of ethanol and other hypnotic withdrawal symptoms from drug or other CNS depressants or alcohol addiction .

Adverse effects of BDZ a. Day time drowsiness or drug hangover effect ( If you take the drug today , tomorrow you will feel tired and confused with drowsiness . b. Cognitive impairment especially eldery patients c. Blurred vision & confusion d. Tolerence and dependence (physical and psycological). Phsyological in which the patient cant stop taking the drug suddenly due to the )‫ ( األعراض االنسحابية‬development of sever withdrawal symptoms. The psychological dependence in which the patient keep taking the drug to avoid emotional discomfort , it is the ADDICTION. Specially in high dose for long period. Withdrawal manifestation are more with BDZ of short duration. " Tolerance is : decreasing in drug response with repetitive use , some of the causes is receptors up regulation or down regulation , where the normal dose become insufficient and the patient become to take higher dose which may leads to toxicity " BZs antagonists ( THIS IS IMPORTANT ) Flumazenil reverse the effects of BZs , ( use for the treatment of BDZ overdose ) This drug is available by I.V. administration only Has rapid onset and short duration of action , use repeatedly to overcome BDZ toxicity.

Ⅱ.BARBITURATE They were formerly used to sedate the patient; today they have been replaced by BZ because: BZ are safer (wide therapeutic index), Barbiturate have smaller therapeutic index BZ have ↓ risk of physical dependence BZ have ↓ drug-drug interaction (less induction of liver enzymes) BZs have less withdrawal symptoms Barbiturate are hepatic enzyme inducer which means they increase metabolizim of other drugs .

CLASSIFICATION : 1. Ultra-short-acting barbiturates: Thiopental, 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 long duration of action 20-24 h. Such as Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents for long term management of Tonic-Clonic seizure in children & status epilepticus ( emergency type of epilepsy )

Mechanisim of action : Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel, and their action seems to prolong the duration of the opening of GABA-activated chloride channels on the other hand BDZ=will increase the frequency of Cl channels opening . They find that barbiturate in high dose can open Cl channels directly and block Na channels .

Side Effects :

-CNS: Drowsiness, impaired concentration -Respiratory depression: in ↑ dose that may lead to death They are highly toxic.

Benzodiazepines vs. Barbiturates Criteria

BZ

Barb.

Relative Safety

High Low

Maximal CNS depression

Low High

Respiratory Depression

Low High

Suicide Potential

Low High

Abuse Potential

Low High

Antagonist Available?

Yes

No

Hydroxyzine: A drug that is commonly used for dentists , it is H1 blocker , it blocks histamine receptors "its an antihistamine that is useful for patients with anxiety disorders who have history of drug abuse and induce sleep ." often used for sedation prior dental procedure or surgery. Drowsiness is possible adverse effects. We have talked about Beta Blockers.

Epilepsy and antiepileptic drugs -Epilepsy “ multiple seizure attack “ : is a very common chronic disorder characterized by recurrent seizures. -Seizure: excessive discharge of cortical neuron , excess CNS excitation -Convulsion: involuntary contraction of voluntary muscles . Patients may have epilepsy or seizure disorders without convulsions. Atonic Seizure , it happens once , with no convulsion when it presents the patient fall down . Imbalance in the CNS orders : CNS excitation >> CNS inhibition , that’s why our aim in treatment is to stop the epileptic attack and reduce the frequency of recurrence.

Types of Ion channels :

Ca and Na channels by opening will increase neuronal excitation, Glutamate channel is excitatory, and Gaba channel is inhibitory K and Cl channels are inhibitory.

Types of epilepsy is important to choose the proper therapeutic drug: a. Partial “focal” : In which the discharge involves one part of the cortex. 1.Simple: consciousness is preserved 2.Complex: consciousness is impaired Some seizures are partiel but secondrly generlised b. Generalized In which the discharge involves the whole cortex 1. Tonic-Clonic: Grandmal seizures ( HYS ) Tonic: alteration and abrupt loss of consciousness (less than 1 min) Clonic: jerking of body muscles with lip or tongue biting, fecal & urinary incontinence , contraction and relaxation , respiration attack Post-ictal phase : confused lethargy .

2. 2.Absence or petit mal: altering of consciousness, onset of this type occurs from ages 3-16 years , eye blinking or staring suddenly lasting for 10-30 seconds after that the individual will continue his activity .

3. Myoclonic: Single or Multiple muscle jerk c. Status epilepticus: it is a type of Clonic tonic seizure, Series of seizures without recovery of consciousness between attacks It is life threatening emergency.

*sorry for being late , bs we had network issues .. if u find any mistake , plz share It on the group so we all can get benefit

DONE by : Sundos abu-zaid Aya shahrouri

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