Lec.11 PHARMACOLOGY College of DentistryDr. Zainab Ghalib Al-Jassim Baghdad University

INTRODUCTION TO THE PHARMACOLOGY OF CNS DRUGS

CENTRAL NEUROTRANSMITTERSA vast number of small molecules have been isolated from the brain. A brief summary for some of these compounds follows.

Amino AcidsThe amino acids of primary interest to the pharmacologist fall into two categories:

The acidic amino acid glutamate → Excitatory neurotransmitter The neutral amino acids glycine and GABA → inhibitory

neurotransmittersAll of these compounds are present in high concentrations in the CNS.

Acetylcholine

Acetylcholine was the first compound to be identified pharmacologically as a transmitter in the CNS. Cholinergic pathways appear to play an important role in cognitive functions, especially memory.

Monoamines

Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine (serotonin). These compounds are present in very small amounts in the CNS.

A. DOPAMINEFive dopamine receptors have been identified, and they fall into two categories: D1-like (D1 and D5) and D2-like (D2, D3, D4). Dopamine generally exerts a slow inhibitory action on CNS neurons.

B. NOREPINEPHRINE

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Norepinephrine actually enhances excitatory inputs on CNS. Many of the behavioral processes thought to involve noradrenergic pathways, eg, ↑ attention and arousal.

C. 5-HYDROXYTRYPTAMINE (Serotonin)In most areas of the CNS, 5-HT has a strong inhibitory action. 5-HT has regulatory functions in CNS include sleep, temperature, appetite, and neuroendocrine control.

Peptides

Many of the peptides have been discoverd and include opioid peptides (eg, enkephalins, endorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. Glutamate and substance P play an important role in transmitting pain stimuli.

Nitric Oxide

The CNS contains a substantial amount of nitric oxide, which is found within certain classes of neurons. NO was found to promote the development of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease and other CNS disorders.

Endocannabinoids

Cannabinoids may affect memory, cognition, and pain perception. The primary psychoactive ingredient in cannabis, tetrahydrocannabinol (THC), affects the brain mainly by activating a specific cannabinoid receptor, CB1.

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SEDATIVE-HYPNOTIC DRUGSAssignment of a drug to the sedative-hypnotic class indicates that it is able to cause sedation (with concomitant relief of anxiety) or to encourage sleep.

Anxiety states and sleep disorders are common problems, and sedative-hypnotics are widely prescribed drugs worldwide.

BASIC PHARMACOLOGY OF SEDATIVE-HYPNOTICS

An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system depression caused by a sedative should be the minimum consistent with therapeutic efficacy.

A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with many drugs in this class simply by increasing the dose. Graded dose-dependent depression of central nervous system function is a characteristic of most sedative-hypnotics.

An increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death.

CLASSIFICATION

BENZODIAZEPINESAlprazolam XanaxChlordiazepoxide LIBRIUM Clonazepam Clorazepate Diazepam VALIUM Estazolam Flurazepam Lorazepam ATIVANMidazolam Oxazepam Quazepam

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Temazepam Triazolam

BARBITURATESAmobarbital Pentobarbital Phenobarbital LUMINAL Secobarbital Thiopental

OTHER HYPNOTIC AGENTSAntihistamines Chloral hydrate Eszopiclone Ethanol (alcohol, grain alcohol) Ramelteon Zaleplon Zolpidem Glutethimide Meprobamate BuspironeAntipsychotics Antidepressants

All sedative-hypnotics cross the placental barrier during pregnancy. If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant.

GABA and GABA receptors:

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the central nervous system.

There are two classes of GABA receptors: GABAA and GABAB.

The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopiclone, and many other drugs bind to molecular components of the GABAA

receptor in neuronal membranes in the central nervous system. This

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receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA.

Barbiturates bind to GABAA receptor but at different sites from those with which benzodiazepines interact. In contrast to benzodiazepines, zolpidem, zaleplon, and eszopiclone bind more selectively because these drugs interact only with GABAA-receptor isoforms.

In contrast to GABA itself, benzodiazepines and other sedative-hypnotics have a low affinity for GABAB receptors, which are activated by the spasmolytic drug baclofen.

Benzodiazepines (BZD)

Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti- anxiety), anticonvulsant, and muscle relaxant properties. Benzodiazepines are categorized as either short-, intermediate-, or long-acting.

Short ˂ 8 hours, e.g. Alprazolam.

Medium 8-16 hours, e.g. lorazepam.

Long > 16 hours, e.g. chlordiazipoxide, diazepam (Valium), clonazepam.

Mechanism:

Binds directly to GABAA receptor and increases the potency of endogenous GABA signaling: ↑ frequency of Cl – channel openings → membrane hyperpolarization and ↓ excitability.

The benzodiazepines do not substitute for GABA but appear to enhance GABA's effects without directly activating GABAA receptors.

Uses:

• Anxiolytic, sedative-hypnotic.• Epilpsy.• Muscle relaxant.

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Side effects:

Drowsiness, ↓ motor skills, tolerance and high potential for dependence.

Interactions: barbiturates, ethanol (can potentiate these drugs and lead to fatal CNS and respiratory depression).

Withdrawal

GI discomfort , Diaphoresis, pulse, BP, Tremor, Restlessness, insomnia, irritability, anxiety, depression, delirium, panic, hallucinations, abnormal muscular moves and Seizures.

☺☻Note: Flumazenil is a benzodiazepine antagonist that competitively inhibits the actions of benzodiazepines. It can rapidly reverse benzodiazepine overdose.

Barbiturates

Mechanism: Binds directly to GABAA receptor and increases the efficacy of endogenous GABA signaling: ↑ frequency of Cl – channel openings → membrane hyperpolarization and ↓ exitability.

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Uses:

• Sedative-hpnotic.• Preanesthetic sedative.• Epilpsy.• Muscle relaxant.

Side effects:

Drowsiness, ↓ motor skills, tolerance and high potential for dependence.

Interactions: With other sedatives (can potentiate these drugs and lead to fatal CNS and respiratory depression).

Zaleplon, Zolpidem, EszopicloneActivate GABAA receptor and have primarily sedative effects with less muscle relaxant and anticonvulsant activity.

RamelteonRamelteon is an agonist at the melatonin receptors type1 and type 2 of the brain. Melatonin is a hormone secreted from the pineal gland that regulates the sleep-wake cycle.

BuspironeBuspirone has selective anxiolytic effects. Buspirone relieves anxiety without causing marked sedative, hypnotic, or euphoric effects. It may exert its anxiolytic effects by acting as a partial agonist at brain 5-HT1A

receptors.

BaclofenSelectively activates GABAB receptors in the CNS → ↓ tonic neural stimulation to muscles.Uses: spasmolytic in patient with multiple scelrosis (MS) or spinal cord lesions and in interactable hiccups.

Propofol

is a highly lipophic agent that potentiates GABA neurotransmittion. Used for anesthetia induction due to its rapid onset.

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ANTISEIZURE DRUGSApproximately 1% of the world's population has epilepsy, the second most common neurologic disorder after stroke. Although standard therapy permits control of seizures in 80% of these patients, millions have uncontrolled epilepsy.

Epilepsy is a heterogeneous symptom complex a chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. The causes of seizures are many and include the full range of neurologic diseases from infection to neoplasm and head injury. In some subgroups, heredity has proved to be a predominant factor.

New antiseizure drugs can act by one of three mechanisms:

(1) enhancement of GABAergic (inhibitory) transmission,

(2)diminution of excitatory (usually glutamatergic) transmission,

(3)modification of ionic conductances.

Drugs Used in the Management of EpilepsyCarbamazepine TEGRETOLDiazepam VALIUMDivalproex Ethosuximide Felbamate Gabapentin NEURONTINLacosamide Lamotrigine Levetiracetam Lorazepam ATIVANOxcarbazepine Phenobarbital LUMINALPhenytoin Fosphenytoin Primidone Rufinamide Tiagabine Topiramate Vigabatrin Zonisamide

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Phenytoin

Mechanism: block of voltage gated sodium channels → inhibits generation of high frequency repetitive action potentials.

Uses: partial seizures and generalized tonic-clonic seizures. (1st line therapy)

Side effects: Nystagmus, Diplopia, ataxia, sedation, Gingival hyperplasia and hirsutism. Long-term use may also result in abnormalities of vitamin D metabolism, leading to osteomalacia.

Lamotrigine also acts on Na+ channels and used primarily to treat partial seizures.

Carpamazepine also acts on Na+ channels, and used in partial seizures and generalized tonic-clonic seizures. (1st line therapy). Carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well.

Topiramate

Inhibits excitatory neuronal transmission by 3 mechanisms: Blockage of glutamate receptors. Blockage of voltage gated sensitive Na+ channels. It may also potentiate inhibitory GABA-ergic neuronal transmission.

Valproic acid

Broad spectrum antiepileptic that act by multiple mechanisms, including Enhances GABA accumulation (uncertain mechanism). Inhibits voltage gated sensitive Na+ channels. Inhibition of Ca+2 channel.

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Gabapentin & Pregabalin

Gabapentin is an amino acid, an analog of GABA that is effective against partial seizures. Originally planned as a spasmolytic, it was found to be more effective as an antiseizure drug.

Pregabalin is another GABA analog, closely related to gabapentin. This drug was recently approved for both antiseizure activity and for its analgesic properties.

Mechanism of Action:In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act directly on GABA receptors. They may, however, modify the release of GABA leading to an increase in brain GABA concentration. Gabapentin and pregabalin bind and inhibit voltage-gated Ca2+ channels. They also act presynaptically to decrease the release of glutamate.

Phenobarbital

is a long acting barbiturates that enhances endogenous GABA inhibitory neurotransmission by binding directly to GABAA.

It is used to treat tonic-clonic and partial seizures in children and

it is the antiepileptic of choice in pregnant women.

Side effect: sedation is the major limiting side effect.

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ANTIDEPRESSANTS& ANTIPSYCOTICS

Depression ??

An affective disorder characterized by loss of interest or pleasure in almost all a person’s usual activities or pastimes.

Symptoms Associated With Depression:

• Sadness, Despair, Guilt, Pessimism

• Decrease in energy

• Decrease in sex drive

• Insomnia and fatigue

• Thoughts of death and suicide

• Mental slowing, lack of concentration

Although the underlying pathophysiology of depression has not been clearly defined, preclinical and clinical evidence suggest disturbances in Serotonin (5-HT), Norepinephrine (NE), and Dopamine (DA) neurotransmission in the central nervous system.

→ 5-HT deficiency is related to anxiety, obsessions, sleep, and appetite;

→ reduced NE neurotransmission is associated with decreased alertness, low energy, problems of inattention, concentration, and cognitive ability;

→ dysfunctional dopamine (DA) activity is implicated in problems of motivation, attention, and pleasure.

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Treatment of Depression

Virtually all currently available antidepressants act on one or more of the following mechanisms:

I. inhibition of reuptake of 5-HT or NE and DA,

II. antagonism of inhibitory presynaptic 5-HT or NE receptors,

III. Inhibition of monoamine oxidases (MAO) (enzymes that catalyze the oxidation and  inactivation of monoamines like 5-HT, NE, and DA).

All of these mechanisms result in an enhanced neurotransmission of 5-HT and/or NE.

Classes of Antidepressants:

1) Selective serotonin reuptake inhibitors (SSRIs)

2) Serotonin-norepinephrine reuptake inhibitors (SNRIs)

3) Tricyclic antidepressants (TCAs)

4) Monoamine oxidase inhibitors (MAOIs)

5) Atypical agents

Selective Serotonin Reuptake Inhibitors (SSRIs)  

-Are the most commonly prescribed antidepressants.

-They are highly effective and generally cause fewer side effects than the other antidepressants.

Mechanism: SSRIs help to alleviate symptoms of depression by blocking the reabsorption or reuptake of serotonin in the brain.

Examples on SSRIs: citalopram, escitalopram, fluoxetine (Prozac), paroxetine, sertraline.

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Side effects: nausea, vomiting, diarrhea, sexual dysfunction, headache, weight gain, anxiety, dizziness, dry mouth, trouble sleeping, abnormal bleeding when used with blood thinners, and suicidal thoughts .

SEROTONIN SYNDROME

Serotonin syndrome is a serious medical condition that can occur when medications that alter the concentration of serotonin in the brain are taken together. Symptoms of serotonin syndrome may include anxiety, restlessness, sweating, muscle spasms, shaking, fever, rapid heartbeat, vomiting, and diarrhea.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)  

Mechanism: work by blocking the reabsorption of the neurotransmitters serotonin and norepinephrine in the brain. They may also have an effect on other neurotransmitters.

Examples on SNRIs: duloxetine, venlafaxine, and milnacipran.

Side effects: nausea, dizziness, sweating, sexual dysfunction, tiredness, constipation, insomnia, anxiety, headache, loss of appetite, and suicidal thoughts.

Tricyclic Antidepressants (TCAs)

Are the first approved antidepressants. Although they are effective, they have been replaced by newer antidepressants that generally cause fewer side effects.

Mechanism: Like SNRIs, TCAs work by blocking the reabsorption of the neurotransmitters serotonin and norepinephrine in the brain. Additionally, they block muscarinic M1, histamine H1, and alpha-adrenergic receptors.

Examples on TCAs: amitriptyline, desipramine, Imipramine, clomipramine, and maprotiline.

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Side effects: TCAs affect several neurotransmitters in the brain and, as a result, cause numerous side effects: dry mouth, constipation, blurred vision, urinary retention, dizziness, tachycardia, memory impairment, delirium, orthostatic hypotension, weight gain, seizures, bone fractures, sexual dysfunction, increased sweating, increased or irregular heartbeats, and Suicidal thoughts.

Contraindication: TCAs should not be used within 14 days of taking an MAOI.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs have many drug and food interactions and cause significant side effects in comparison to the new antidepressants. As such, MAOIs have been replaced by newer antidepressants that are safer and cause fewer side effects.

Mechanism: MAOIs block the activity of monoamine oxidase, an enzyme that breaks down norepinephrine, serotonin, and dopamine in the brain and other parts of the body.

Examples on MAOIs: phenelzine, selegiline, and tranylcypromine.

Side effects: postural hypotension, weight gain, sexual side effects, and suicidal thoughts.

Hypertensive crisis: Taking MAOIs with tyramine-containing foods or beverages may cause dangerous elevations in blood pressure. Foods that should be avoided include wine, aged cheese, sauerkraut, cured meats, draft beer, soy products, and others.

Atypical Antidepressants

Atypical antidepressants are considered “atypical” because these agents do not fit into any of the other classes of antidepressants. Each medicine in this category has a unique mechanism of action in the body. However,

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like other antidepressants, atypical antidepressants affect the levels of dopamine, serotonin, and norepinephrine in the brain. 

Examples on Atypical antidepressants: bupropion, mirtazapine, nefazodone, vilazodone.

Side effects: Since medications in this class have unique properties, their side effect profile also varies. Some common side effects include dry mouth, constipation, dizziness, lightheadedness, and suicidal thoughts.

Mirtazapine and trazodone cause drowsiness and are usually taken at bedtime.

Bupropion generally does not cause weight gain or sexual problems. Bupropion may also be used to help quit smoking.

vilazodone is not associated with significant weight gain or sexual dysfunction.

NATURAL ANTIDEPRESSANTS

Exercise and pleasurable activities. Foods high in omega-3-fatty acids may increase serotonin levels in

the brain. Increasing exposure to light.

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ANTIPSYCHOTIC DRUGSPSYCHOSIS is a mental disorder characterized by an impaired relationship with reality, hallucinations or delusions.

Types of psychosis

1) Brief psychotic disorder due to stress.2) Drug- or alcohol-related psychosis (drug like

methamphetamine and cocaine)3) Organic psychosis A head injury or an illness or infection that affects

the brain.4) Psychotic disorders (bipolar disorder, Delusional disorder, Psychotic

depression, Schizophrenia, and Split personality )

Psychotic Disorders:

Bipolar disorder In bipolar disorder, moods swing from very high to very low. When their mood is high and positive,they may feel extremely good and believe they have special powers. When their mood is depressed, the individual may have psychotic symptoms that make them feel angry, sad, or frightened.

Delusional disorder A person strongly believes in things that are not real.

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Psychotic depression Person has major depression with psychotic symptoms.

Schizophrenia People with schizophrenia slowly lose contact with reality and often have delusions or hallucinations.

Split personality (Note: some people think schizophrenia is a split personality. In fact, schizophrenia and split personality are two different disorders)

It is believed that some psychotic symptoms are caused by brain producing too much of the neurotransmitter “dopamine”. Most antipsychotic drugs are known to block some of the dopamine receptors in the brain – this reduces the flow of messages, which may be too frequent in psychotic states.

Most antipsychotics are known to affect other brain chemicals too, such as the neurotransmitters serotonin and noradrenaline, which are both thought to be involved in regulating mood.

-The long-term use of antipsychotics is associated with side effects such as involuntary movement disorders, gynecomastia, and metabolic syndrome.

ANTIPSYCHOTICS

Antipsychotic drugs tend to fall into one of two categories: 

First generation or Typical antipsychotics (older)

Second generation  or Atypical antipsychotics (newer)

* Both generations of medication tend to block receptors in the brain's dopamine pathways, but atypicals tend to act on serotonin receptors as well.

1) First generation (typical) antipsychotics:

Mostly developed and first licensed in the 1950s

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These divide into various chemical groups which all act in a very similar way and can cause very similar side effects, including severe neuromuscular and movement disorders. Also, lead to drowsiness.

Chlorpromazine (Typical)

Mechanism: D2 receptor antagonist.

Side effects:

Cholinergic blockade→ dry mouth, constipation, urinary retention, visual problems. α-blockade→ postural hypotension, impotence, sedation.Histamine blockade→sedationDA blockade→ extrapyramidal dysfunction: parkinsonism, akathisia, dystonia, tardive dyskinesia, hyperpyrexia, increase prolactin(amenorrhea, infertility), and increase risk of arrhythmias.Haloperidol (Typical)

Mechanism: high affinity D2 receptor antagonist.

Side effects:

DA blockade→ extrapyramidal dysfunction: parkinsonism, akathisia, dystonia, tardive dyskinesia, hyperpyrexia, increase prolactin(amenorrhea, infertility), and increase risk of arrhythmias.

Other examples: Loxapine, Thioridazine and trifluoroperazine.

2) Second generation (Atypical) antipsychotics

o Mostly developed and first licensed in the 1990s.

o In general these cause less severe neuromuscular and sexual side effects than first generation antipsychotics. However, second generation antipsychotics are more likely to cause serious metabolic side effects, including rapid weight gain.

Olanzapine, Clozapine, Risperidone (Atypical)

Mechanism: D2 dopamine receptor blockade, and serotonin (5-HT2a) blockade.

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Side effects: extrapyramidal dysfunction, somnolence, and hypotension, weight gain, and diabetes mellitus. Clozapine can also cause agranulocytosis.

Quetiapine (Atypical)

Inhibits D2, 5-HT2a, H1(histamine), α1, and M1 receptors and, thus associated mainly with sedation and hypotension.

Other agents used in psychotic disorders:

-Lithium: its mechanism is not well known, used mainly in the treatment of bipolar disorder.

-All types of Antidepressants also can be used to decrease symptoms.

PARKINSON'S DISEASE

* is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms are shaking, rigidity, slowness of movement, and difficulty with walking.

**The cause of Parkinson's disease is generally unknown, but believed to involve both genetic and environmental factors.

***In parkinsons, the dopaminergic neurons was found to be lost.

****Treatment is with dopamine agonists. Examples: levodopa, pramipexole.

Also, we can use COMT enzyme inhibitors (ex, Entacapone)

and MAO enzyme inhibitors (ex, Selegiline)

Obsessive-Compulsive Disorder (OCD)

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OCD is a common, chronic and long-lasting disorder in which a person has uncontrollable, reoccurring thoughts (obsessions) and behaviors (compulsions) that he or she feels the urge to repeat over and over.

Selective serotonin reuptake inhibitors (SSRIs) are used to help reduce OCD symptoms. 

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