1st Edition of BigBrother CNS Pharmacology TextBook

CNS

PHARMACOLOGY For 3rd year

General anesthetics 1

✔ Classification of general anesthetics

✔ mechanism of action of general anesthetics

✔ pharmacological actions of general anesthetics

✔ toxicity of general anesthetics

✔ pre-anesthetic medication and anesthetic adjuvants

Definition

Anesthesia means loss of sensation.

General Anesthetics: A drug that brings about a reversible loss of consciousness and all modalities of sensations. Generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.

The neurophysiologic state produced by general anesthetics is characterized by five primary effects: unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation. None of the currently available anesthetic agents when used alone can achieve all five of these desired effects.

An ideal anesthetic drug Should induce:

• Rapid

• Smooth loss of consciousness

• Rapidly reversible discontinuation

• Wide margin of safety.

The modern practice of anesthesiology relies on the use of combinations of intravenous and inhaled drugs (balanced anesthesia techniques) to take advantage of the favorable properties of each agent while minimizing their adverse effects.

Classification

According to the channel of administration:

1. Inhalation Anesthetics:

• Volatile liquids (Halogenated hydrocarbons): Halothane, Enflurane, Isoflurane, Desflurane, Sevoflurane.

• Gasses (Nitrous oxide)

2. Intravenous Anesthetics:

• Ultrashort-acting barbiturates (thiopental).

• Non- barbiturates (Ketamine, propofol, etomidate)

The molecular and cellular mechanisms by which general anesthetics produce their effects have remained one of the great mysteries of pharmacology.

1. The unitary theory of anesthesia: anesthesia is produced by interruption of the physical properties of cell membranes.

2. Meyer-Overton rule: the greater is the lipid solubility of the compound the greater is its anesthetic potency.

3. Cellular mechanism of anesthesia: Inhalation anesthesia cause hyperpolarization of the neurons and together with intravenous anesthesia they inhibit synaptic transmission and action potential generation or propagation.

4. Molecular actions of general anesthesia: A variety of ligand-gated ion channels, receptors and signal transduction proteins are modulated by general anesthetics. Of these, the GABAA and NMDA receptors and the two-pore K+ channels

• Potentiation of inhibitory receptors.

- GABAA (Inhalational & intravenous anesthetics)

- Glycine

- activate K channels (two-pore domain K – channels)

• Inhibition of excitatory receptors (Ketamine & Nitrous Oxide).

- NMDA (glutamate)

Stages

MOA

• Analgesia without amnesia

II. Excitement

• Nausea vomiting, hyperreactivity, irregular respiration

III. Surgical anesthesia

• Sleep, normal respiration, and blood pressure IV. Medullary depression

• Depression of vasomotor and respiratory centers, coma and death

Pharmacological actions

CNS

• Irregular progressive descending depression of the CNS.

• Medullary centers are the last to be affected.

• Order of involvement is (cortex, basal ganglia and cerebellum, spinal cord and medullary centers).

Respiration

• Respiratory depression and decrease ventilation (hypercarbia and sometimes to hypoxia).

• NB: Toxic doses are fatal due to respiratory failure.

• Hypotension due to direct vasodilatation, depression of myocardium and depression of the vasomotor Centre.

• General anesthetics are depressants to the cardiac muscle.

• Halothane sensitizes the myocardium to arrhythmia induced by catecholamine.

• All inhalational anesthetics produce dose-dependent reduction in renal blood flow and glomerular filtration rate.

• All inhalational anesthetics decrease hepatic blood flow.

• Halothane increases the risk of postoperative hepatitis.

Muscles

• The halogenated anesthetics produce varying degrees of skeletal muscle relaxation

• Enflurane and isoflurane have additional effect on NMJ.

• All halogenated inhalational anesthetics potentiate the effects of competitive neuromuscular blockers.

• Halothane, enflurane and isoflurane are uterine muscle relaxants. This is an advantage if intrauterine fetal manipulation during delivery is required but it is a disadvantage as it may prolong the process of delivery and increase blood loss.

Metabolism

• Hypothermia: due to: 1. Increased heat loss (peripheral vasodilatation). 2. Decreased heat production (relaxation of skeletal muscles, depression of heat regulatory center).

• Hyperglycemia: due to the release of catecholamines with the resultant decrease in peripheral glucose utilization and mobilization of hepatic glycogen as glucose.

• Acidosis: due to CO2 retention and reduced tissue perfusion.

Toxicity

Nephrotoxicity

• enflurane and sevoflurane: Generate nephrotoxic fluoride ions

• Sevoflurane: degraded by CO2 absorbents in anaesthetic machine (produce nephrotic compound A which cause tubular necrosis.

Hematotoxicity

• nitrous oxide: decreases methionine synthase activity (megaloblastic anemia)

• All inhaled anesthetics: produce carbon monoxide which binds to hemoglobin, reducing oxygen delivery to tissues.

• halothane hepatitis: due to immune response to hepatic proteins.

• Hepatic dysfunction following surgery and general anesthesia is most Likely caused by hypovolemic shock, infection conferred by blood transfusion, or other surgical stresses rather than by volatile anesthetic toxicity. A heritable genetic disorder of skeletal muscle occur in susceptible individuals exposed to volatile anesthetics while undergoing general anesthesia. (depolarizing muscle relaxant exaggerate it)

Manifestation • Muscle rigidity • Hyperthermia • Tachycardia & hypercapnia • Hyperkalemia & metabolic acidosis N.B: The specific biochemical abnormality is an increase in free cytosolic calcium concentration in skeletal muscle cells.

Treatment

• Dantrolene (reduce calcium release from sarcoplasmic reticulum) • Appropriate Measures to reduce temperature and restore electrolyte and acid base balance 1. Nausea and vomiting: action on the CTZ and brainstem vomiting center. 2. Hypertension and tachycardia: sympathetic nervous system regains its tone and is enhanced by pain. 3. Emergence excitement: restlessness, crying. 4. Postanesthetic shievering: due to hypothermia (stopped by small dose of meperidine).

5. Pain ( stopped by analgesic drugs “opioids – NSAID”).

1. Inhalation anesthetics

A. Gases: Nitrous oxide (Laughing gas)

• Very rapid induction and recovery.

• It is weak anesthetic. So, it's primarily used as adjunct to other inhalational or intravenous anesthetics.

• It produces analgesia (dental & Obstetric analgesia).

B. Volatile liquids:

1. Halothane:

• Slow induction and lengthened recovery (accumulate in fat and tissues during prolonged administration lengthened recovery).

• Used in children because it is well tolerated.

❖ Side Effects:

1. Dose-dependent hypotension

2. Sensitize myocardium to arrhythmogenic effects of epinephrine.

3. Inadequate relaxation of skeletal muscle

4. Fulminant hepatic necrosis. Up to 80 % of it is eliminated unchanged via lungs. Remaning biotransformed by hepatic CYPs leading to formation of trifluoroacetic acid.

2. Enflurane:

• Induction and recovery are relatively slow.

• Good muscle relaxation.

• Safer than halothane (Regarding the liver and the heart).

• Produce EEG pattern of seizure activity.

• Metabolized to a modest extent in the liver with the generation of fluoride ions that are potentially nephrotoxic.

3. Isoflurane:

• Induction and recovery are rapid.

• Produce hypotension (Unlike halothane, cardiac output is well maintained with isoflurane)

• Potent coronary vasodilator.

• Unlike Enflurane ( No convulsant action).

• Unlike Halothane:

- Not sensitize the heart to dysrhythmic effect of catecholamine

- No serious effect on the liver.

4. Desflurane:

• Induction and recovery are very rapid. Desflurane is a widely used anesthetic for outpatient surgery because of its rapid onset of action and rapid recovery.

• No nephrotoxicity and hepatotoxicity.

• Drug irritates tracheobronchial tree and can provoke coughing, salivation & bronchospasm.

5. Sevoflurane:

• Induction and recovery are rapid.

• Hepatic metabolism of sevoflurane also produces inorganic fluoride.

• Not irritating to the airway and is potent bronchodilator.

• Nephrotoxicity of compound A, the degradation product produced by interaction of sevoflurane with the CO2 absorbent soda lime in anesthesia machine.

N.B Soda lime is a mixture of chemicals, remove carbon dioxide from breathing gases to prevent CO2 retention and carbon dioxide poisoning.

2. Intravenous anesthetics

These drugs can be used:



As sole agents for diagnostic minor surgical procedures. 

As induction agents followed by maintenance with inhalational anesthetics for longer operations.

Intravenous anesthetics (except ketamine) produce reduction in cerebral blood flow and cerebral oxygen consumption accompanied with decrease in intracranial pressure.

1. Thiopental (Ultrashort-Acting Barbiturates):

• Induction: rapid pleasant.

• Recovery: small doses (smooth rapid), large or repeated doses (delay recovery).

• Short duration due to rapid tissue redistribution.

❖ Side effects: respiratory depression, coughing, laryngospasm and bronchospasm.



It is used only for induction. As a sole agent for anesthesia, it is not recommended because of the respiratory depression and slow recovery associated with the use of large doses.

2. Propofol:

• Rapid induction and recovery.

• Following induction, respiration is depressed, particularly with bolus doses, that apnea may occur for 30-60 seconds.

• Used for induction and maintenance of minor surgery.

• As sedative agent in the intensive care unit

3. Etomidate:

• Rapid induction and recovery.

• Cardiovascular and respiratory depressions usually do not occur and is suited to maintain cardiovascular stability.

❖ Adverse effects: pain on injection, involuntary movements during induction, nausea and vomiting during recovery especially with opioid use.

 There is a possible risk of adrenocortical suppression even after a single injection.

4. Ketamine:

• Induction: Rapid during which the patient feels as if he is dissociated from his environment (dissociative anesthesia).

• Recovery: Slow and is frequently accompanied by bad dreams and hallucinations.

• Block NMDA receptor (Produces marked analgesia and amnesia).

• Unlike other anesthetics, it stimulates the cardiovascular system through inhibiting the uptake of norepinephrine. Heart rate, blood pressure and cardiac output are increased (This makes it useful in hypovolemic or cardiogenic shock).

• It increases cerebral blood flow and intracranial pressure.

• Given by I.V., also effective by I.M. and rectal routes.

Adjuvants

A general anesthetic is rarely given as the sole agent. Anesthetic adjuncts usually are used to augment specific components of anesthesia, permitting lower doses of general anesthetics with fewer side effects.

1. Analgesics:

• Nonsteroidal anti-inflammatory drugs (for minor surgery)

• Opioid analgesics:

- morphine, meperidine, fentanyl (primary analgesics used during perioperative period.

- Meperidine reduce shivering.

- Intrathecal opioids, with or without local anesthetic can produce profound analgesia but respiratory depression and pruritus usually limit their use to major operations.

2. Benzodiazepine (Midazolam, diazepam & lorazepam).

• Midazolam is preferred because its potency is greater, has rapid onset and shorter duration of action.

• Produce sedation and anterograde amnesia

3. Dexmedetomidine (highly selective α2-adrenergic agonist) that produces both sedation and analgesia with minimal respiratory depression.

4. Neuromuscular Blocking Agents

Depolarizing and non-depolarizing muscle relaxants often are administered during e induction of anesthesia to relax muscles of the jaw, neck, and airway and thereby facilitate laryngoscopy and endotracheal intubation.

5. Antihistaminic (HI-antagonists) eg, diphenhydraminc to prevent allergic reactions.

6. H2-blockers (ranitidine) to reduce gastric acidity and avoid acid reflux.

7. Atropine or scopolamine to prevent bradycardia and reduce respiratory secretion.

Local Anesthetics 2

Outlines

✓ Define local anesthetics.

✓ Explain the mechanism of action of local anesthetics

✓ Recognize adverse effects of local anesthetics.

✓ Recognize techniques of local anesthesia.

✓ Classify local anesthetics

Introduction

Definition

Local anesthetics are the drugs which cause reversible loss of pain sensation without the loss of consciousness or the impairment of central control of vital functions.

Uses

They may be used as:

• sole form of anesthesia

• in combination with general anesthesia

• provide postoperative analgesia

MOA

Local anesthetics act at the cell membrane to prevent the generation and the conduction of nerve impulses. Local anesthetics block conduction by decreasing

the large transient increase in the permeability of excitable membranes to Na+ by direct interaction with voltage gated Na+ channels.

Local anesthetics bind more readily to the Na+ channel during depolarization (when it is open or activated).

At higher concentrations, local anesthetics can block:

• k+ channels.

• Ca+2 channels

Note

The primary mechanism of action of local anesthetics is blockade of voltage-gated sodium channels especially the open sodium channel.

The receptor site is located at the cytoplasmic portion of the sodium channel.

Undesired effects

In addition to blocking conduction in nerve axons in the peripheral nervous system, local anesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. The danger of such adverse reactions is proportional to the concentration of local anesthetic achieved in the circulation.

CNS

low concentrations

• Sleepiness

• light headedness

• visual disturbances

• auditory disturbances

• restlessness

early symptom of toxicity

• Circumoral numbness

• tongue numbness

• metallic taste.

higher concentrations

• nystagmus

• muscle twitching followed by overt tonic clonic convulsions

Local anesthetics apparently cause depression of cortical inhibitory pathways thereby allowing unopposed activity of excitatory neuronal pathways. This transitional stage of unbalanced excitation (i.e: seizure activity) is then followed by generalized CNS depression.

Neurotoxicity

Occur at excessively high concentrations. Chloroprocaine and lidocaine are more neurotoxic than other local anesthetics when used for spinal anesthesia, producing transient neuropathic symptoms.

CVS

Local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability and conduction. Except cocaine, they also depress the strength of cardiac contraction and cause arteriolar dilatation (hypotension).

Cardiovascular collapse is rare but has been reported after large doses of (bupivacaine and ropivacaine).

Lidocaine has a high degree of effectiveness in arrhythmias associated with acute myocardial

Note

Cocaine differs from other Local Anesthetics in its cardiovascular effects:

• Vasoconstriction

• Hypertension

• cardiac arrhythmias

infarction by blocking activated and inactivated sodium channels in cells with long action potentials such as Purkinje and ventricular cells

Hematologic effects

The administration of large doses (>8mg/kg) of prilocaine during regional anesthesia may lead to accumulation of its metabolite leading to methemoglobinemia.

Smooth muscles

They depress contractions initially in:

• Gastrointestinal smooth muscle

• vascular smooth muscle

• bronchial smooth muscle

Although low concentrations initially may produce contraction.

Allergic reactions

Esters

Local Anesthetics

Amides

metabolized to para-aminobenzoic acid derivatives.

These metabolites are responsible for allergic reactions in a small percentage of the patient population.

not metabolized to p-aminobenzoic acid.

An allergic reactions to amide local anesthetics are extremely rare.

Classification

Amides:

Lidocaine

According to the duration of action: • Short acting: procaine • Intermediate acting: lidocaine, prilocaine, mepivacaine, cocaine. • Long acting: Tetracaine, bupivacaine, levobupivacaine, ropivacaine.

• Lidocaine (Xylocaine): o prototype of amide local anesthetic. o alternative choice for individuals sensitive to ester type local anesthetics.

• Mepivacaine: o More toxic to neonate so not used in obstetric anesthesia. o not effective topically.

• Prilocaine: Its metabolite o-toluidine causes methemoglobinemia which is dose dependent usually appearing after a dose of 8mg/kg.

• Bupivacaine: o Has long duration of action and tendency to provide more sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period. o cardiotoxic than equieffective doses of lidocaine.

14

s-enantiomer of bupivacaine, have the same efficacy and potency but less cardiotoxic

• Ropivacaine:

o Slightly less potent than bupivacaine.

o In clinical studies, it appears to be suitable for both epidural and regional anesthesia with duration of action similar to that of bupivacaine and even more motor sparing than bupivacaine.

Procaine (Novocain):

• first synthetic LA.

• hydrolysis in vivo produces p-aminobenzoic acid, which inhibits the action of sulfonamides.

• use now is confined to infiltration anesthesia and occasionally for diagnostic nerve blocks.

Cocaine: toxicity and potential for abuse have decreased the clinical utility of cocaine.

Esters

Benzocaine:

Applied directly to wounds and ulcerated surfaces producing sustained anesthetic action.

Tetracaine (Pontocaine):

• widely used in spinal anesthesia when a drug of long duration is needed

• also incorporated into several topical anesthetic preparations.

Surface Infiltration

uses Way of technique

Anesthesia of the skin and mucous membranes of the nose, mouth, throat, tracheobronchial tree, esophagus and genitourinary tract.

injection of LA directly into tissue without taking into consideration the course of cutaneous nerves.

Nerve block

Injection of LA into or around individual peripheral nerves or nerve plexuses.

Blockade of mixed peripheral nerves and nerve plexuses also usually anesthetizes somatic motor nerves

anesthetizes somatic motor nerves producing skeletal muscle relaxation which is essential for some surgical procedures (e.g: brachial plexus block for procedures on the upper limb).

Spinal

Injection of LA into the subarachnoid space. It is performed through one of the vertebral interspaces between the 2nd and 5th lumbar levels.

Epidural

anesthesia

IV regional

Injection of LA into epidural space.

It produced by IV injection of the anesthetic agent into a distal vein while the circulation of the limb is isolated with a proximally placed tourniquet.

safe and effective technique, Specially, during surgery involving • lower abdomen • lower extremities

• perineum.

for short surgical procedures (<60 min) involving: • upper extremities • lower extremities

3. Others:

A. Barbiturates. B. Chloral hydrate (rarely used). C. Antipsychotics. D. Antidepressant drugs. (in chronic anxiety disorders).  antihistaminic agents: 1. diphenhydramine 2. hydroxyzine 3. promethazine  cause sedation but commonly also exert marked effects on the peripheral autonomic nervous system  Antihistaminic drugs with sedative effects are available as counter sleep aids

β- adrenergic blockers when sympathetic is over activate

Benzodiazepines

Chemistry

The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B).

Mechanism

it interacts with its receptors ➡️ ⬆️ inhibitory effect mediated by GABA ➡️ opens CL channels ➡️ ⬆️ CL enter the cell ➡️ hyperpolarization of the cell and ⬇️ excitation.

A B

NOTE

GABA-A receptors are responsible for most inhibitory neurotransmission in CNS

Pharmacological Properties

all effects of benzodiazepines result from their actions on CNS

The most prominent of these effects are 1. sedation 2. hypnosis 3. decreased anxiety 4. muscle relaxation 5. anterograde amnesia 6. anticonvulsant activity

Only two effects of benzodiazepines result from peripheral actions: 1. coronary vasodilation, seen after intravenous administration of therapeutic doses of certain benzodiazepines 2. neuromuscular blockade, seen only with very high doses

CNS

⬆️ dose of benzodiazepine ➡️ sedation progresses to hypnosis ➡️then to stupor.

But do not cause a true general anesthesia because awareness usually persists, and immobility sufficient to allow surgery cannot be achieved.  But cause preanesthetic: there is amnesia for events subsequent to administration of the drug.

Antianxiety: in small doses.

Hypnotic:

 ⬇️sleep latency especially when first used.  ⬇️ number of awakenings.  ⬇️ time spent in stage 0 (a stage of wakefulness before sleep).  ⬇️Time in stage 1 (descending drowsiness) of NREM sleep.  ⬇️ time in slow-wave sleep (Stages 3 and 4).

⬇️ nightmares and night terrors  ⬇️ time spent in REM sleep.  ⬆️number of cycles of REM sleep.

⬆️Total sleep time by ⬆️Stage 2 (which is the major fraction of NREM sleep).

N.B: Zolpidem and zaleplon suppress REM sleep to a lesser extent than do benzodiazepines and thus may be superior to benzodiazepines for use as hypnotics.

Skeletal muscle relaxation:  induce hypotonia without interfering with normal locomotion.  ⬇️ rigidity that associated with cerebral palsy.  Tolerance may occur.  hypotonia is possibly due to central effect that is not related to their sedative- hypnotic action.

Anticonvulsant:

⬇️ seizure activity induced by either pentylenetetrazol or picrotoxin or ethanol

Examples:

Clonazepam.

Nitrazepam.

Nordazepam

They have more selective anticonvulsant activity than most other benzodiazepines

Tolerance may occur ➡️ limit usefulness of benzodiazepines in treatment of recurrent seizure.

analgesic effects: only transient in humans (intravenous)

may cause amnesia.

Unlike barbiturates, benzodiazepines do not cause hyperalgesia.

Respiratory system

Hypnotic doses ➡️ no effect

At higher doses (preanesthetic doses) ➡️slightly depress alveolar ventilation ➡️ cause respiratory acidosis

especially in patients with COPD or administered with respiratory depressant drugs as morphine

preanesthetic doses:

blood pressure

heart rate

coronary flow

produces -ve inotropic effects due to accumulation of adenosine (cardio depressant metabolite)

Midazolam (large doses):

cerebral blood flow

improve anxiety related GIT disorders as, stress ulcers

4. Long-acting agents:  t1/2: >24 hours  Examples: 1. flurazepam 2. diazepam 3. quazepam 4. Lorazepam

benzodiazepines have high lipid solubility, so they cross BBB easily

Benzodiazepines are metabolized in the liver by: 1. oxidation 2. conjugation

Some of Benzodiazepines give active metabolites like the parent drug:  diazepam converted into➡️nordazepam which changes into➡️ oxazepam  Both metabolites are active as hypnotic and anxiolytic similar to diazepam

Formation of active metabolites with some Benzodiazepines makes no correlation between the clinical duration of action and actual half-life of the parent drug  Example: flurazepam half-life = 3hrs but its active metabolite (n-desalkylflurazepam) has a half-life of 50 hours

All the benzodiazepines cross the placental barrier

Nursing infants may also become exposed to the drugs in breast milk.

Because benzodiazepines do not induce synthesis of hepatic CYPs, their chronic administration does not result in ⬆️ metabolism of other substances

USES

1. Anxiety:

longer acting benzodiazepines preferred to treat it as anxiety require treatment for prolonged time

Alprazolam:  used in treatment of  panic disorders

agoraphobia

more selective in these conditions than other benzodiazepines

2. Sleep disorders:

An ideal hypnotic agent has a rapid onset of action when taken at bedtime

facilitate sleep all the night

no residual action by the following morning

Example:  triazolam useful in initial insomnia (difficult to enter into sleep)

temazepam and flurazepam which both are suitable in latent insomnia (early awakening)

One of disadvantages: relatively rapid rate of disappearance, including the early morning insomnia

3. Seizure:

Benzodiazepines that are useful as anticonvulsants and treat status epilepticus have:

a long t1/2

rapid entry into brain

Clonazepam is useful in absence seizures

diazepam used in status epilepticus

SIDE EFFECTS

 temporary intensification of problems that originally prompted their use (e.g., insomnia or anxiety).  Dysphoria.  Irritability.  Sweating.  Unpleasant dreams.  Tremors.  Anorexia.  Faintness.  Dizziness.

Occur especially when benzodiazepine withdrawn abruptly So, it should be withdrawn gradually  Despite their side effects benzodiazepine relatively safe drugs  Even huge doses are rarely fatal unless other drugs are taken concomitantly  Ethanol is a common contributor to deaths involving benzodiazepines.  Although overdosage with a benzodiazepine rarely causes severe cardiovascular or respiratory depression.  therapeutic doses can compromise respiration in patients with COPD or obstructive sleep apnea.  serious allergic, hepatotoxic, and hematologic reactions to benzodiazepines may occur, but the incidence is quite low.  Large doses taken before or during labor may cause:  Hypothermia.  Hypotonia.  Mild respiratory depression in neonate.

 Abuse by pregnant mother can result in a withdrawal syndrome in newborn.

pharmacodynamic interactions interactions between benzodiazepines and other drugs have been infrequent.

Interactions between benzodiazepines and other drugs have been infrequent.

1. Ethanol + benzodiazepines:  ⬆️ rate of absorption of benzodiazepines.  ⬆️ associated CNS depression.

2. Valproate + benzodiazepines:  ➡️ psychotic episodes.

Ethanol : ⬆️ rate of absorption of benzodiazepines ⬆️ associated CNS depression.

Valproate + benzodiazepines cause ➡️ psychotic episodes

Adverse effects

Z compounds were initially promoted as having less potential for dependence and abuse than traditional benzodiazepines.

Over dose

Overdose with Z compounds are similar to that of benzodiazepine overdose and can be treated with the benzodiazepine antagonist flumazenil. 

Zaleplon and zolpidem

Zaleplon and zolpidem are effective in relieving sleep-onset insomnia.  Both drugs have been approved by the FDA for use for up to 7-10 days at a time. 

Zaleplon and zolpidem have sustained hypnotic efficacy without occurrence of rebound insomnia on abrupt discontinuation. 

Zaleplon and zolpidem have similar degrees of efficacy. 

Zolpidem has at 1/2 of 2 hours, which is sufficient to cover most of a typical 8-hour sleep period, and is presently approved for bedtime use only. 

Zaleplon has a shorter t 1/2 1 hour, which offers the possibility for safe dosing later in the night. 

Zaleplon and zolpidem differ in residual side effects; late-night administration of zolpidem has been associated with morning sedation, delayed reaction time, and anterograde amnesia, whereas zaleplon does not differ from placebo.

Flumazenil: A Benzodiazepine Receptor Antagonist

Flumazenil binds with high affinity to specific sites on the GABA A receptor, where it competitively antagonizes the binding and effects of benzodiazepines and other ligands; it antagonizes both the effects of agonist and inverse-agonist. 

Flumazenil is available only for intravenous administration. On intravenous administration, flumazenil is eliminated almost entirely by hepatic metabolism to inactive products with a t1/2 of 1 hour; the duration of clinical effects usually is only 30-60 minutes. 

Although absorbed rapidly after oral administration, <25% of the drug reaches

the systemic circulation owing to extensive first-pass hepatic metabolism.  The primary indications for the use of flumazenil are the management of suspected benzodiazepine overdose and the reversal of sedative effects produced by benzodiazepines administered during either general anesthesia or diagnostic and/or therapeutic procedures. 

The administration of a series of small injections is preferred to a single bolus injection. 

A total of 1 mg flumazenil given over 1-3 minutes usually is sufficient to abolish the effects of therapeutic doses of benzodiazepines. 

Lack of response to 5 mg flumazenil strongly suggests that a benzodiazepine is not the major cause of sedation. 

Flumazenil is not effective in single-drug overdoses with either barbiturates or tricyclic antidepressants. To the contrary, the administration of flumazenil in these settings may be associated with the onset of seizures.

Ramelteon: Melatonin Congeners

MOA

Melatonin receptors are thought to be involved in maintaining circadian rhythms underlying the sleep-wake cycle. 

Ramelteon, a novel hypnotic drug specifically useful for patients who have difficulty in falling asleep, is an agonist at MT 1 and MT 2 melatonin receptors located in the suprachiasmatic nuclei of the brain. 

The drug has no direct effects on GABAergic neurotransmission in the central nervous system. 

Ramelteon reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. 

The drug is rapidly absorbed after oral administration and undergoes extensive first-pass metabolism, forming an active metabolite with longer half-life (2–5 hours) than the parent drug. Metabolized by cytochrome p 450. 

The drug should be used with caution in patients with liver dysfunction. 

The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite. 

Adverse effects

Adverse effects of ramelteon include dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin. 

Ramelteon has minimal potential for abuse.

Buspirone: 5HT 1A Receptor Agonist

It selectively binds to 5HT 1A (serotonin) receptor acting as a partial agonist.

Following oral administration, it is rapidly and completely absorbed from GIT, undergoes first pass effect and highly bound to plasma protein metabolized in the liver by CYP 3A4.

It has no interaction with benzodiazepines receptor or facilitates the action of the GABA.

It has no hypnotic or anticonvulsant or muscle relaxant effects.

MOA Uses

Its anxiolytic effect does not appear before 2-4 weeks of its administration. So it is suitable for chronic anxiety but not acute anxiety states.

Also, it is not effective in severe form of anxiety especially if associated with panic attacks.

Adverse effects

Side effects may include restlessness and dysphoria

Tolerance to its effect does not occur, little potential to abuse and no withdrawal symptoms develop after abrupt withdrawal.

 Introduction about Disorders:

Affective disorders

psychic disturbances characterized primarily by changes of mood (depression or mania).

1. Depression: In endogenous depression (melancholia), mood is persistently low.

2. Mania: refers to the opposite condition of depression.

3. Bipolar affective disorder (manic-depressive illness): Characterized by episodes of mania alternative withdepression.

 Although the patient may have suicidal thoughts, psychomotor retarda prevents suicidal impulses from being carried out.

DRUGS USED IN AFFECTIVE DISORDERS:

1. ANTIDEPRESSANTS

2. MOOD STABILISERS

The nature of schizophrenia

Psychotic disorders

Psychosis: is a severe mental disorder affecting about 0.5-1.0 % of populations, in which thepatient behaves out of touch of reality with illogical and bizarre thinking, lives in his own world

1-Schizophrenia. 2-Manic phase of bipolar (manicdepressive) illness.

3-Acute idiopathic psychotic illnesses (Psychoses). 4-Other conditions marked by severe agitation.

Symptoms of psychoses: a) false beliefs (delusion) b) Abnormal sensation (hallucination). Psychoses have two components: a) Organic component (dopamine hypothesis): suggests that psychoses may be due to over-activity of dopaminergic action in mesolimbic system of the brain. b) Psychic component: due to psychological and social stress. component.

 Schizophrenia has a strong genetic component.

 Psychotic illness characterised by : 1-delusions, hallucinations and thought disorder (positive symptoms). 2. Flattening of emotional responses (negative symptoms).

 Its incidence is about 1% of population.



Dopamine theory:

• Pharmacological evidence is generaly consistent with dopamine overactivity theory.

• According to dopamine theory in schizophrenics hyperactivity of dopamine at D2 receptors in limbic system occurs.

Note

Antipsychotics do not cure psychoses. They often reduce the need for institutional care and enable patients to maintain relatively stable lives.

a) Behavioral effects:

 Due to blocking D2 receptors (competitive antagonist) in mesolimbic system.

 aggressive and impulsive behavior and the patient become motionless, silent and he answers questions in a slow and monotonous voice.

 spontaneous motor activity.

 In high doses cataleptic effect (the body and the limbs are molded in various postures and remain immobile for long time).

b) Antiemetic effect:

 Blocking D2 receptors in chemoreceptor trigger zone (CTZ) powerful antiemetic action.

 It is not effective in vomiting due to vestibular stimulation (motion sickness) or that caused by local gastrointestinal tract irritation.

c) Extrapyramidal effects:

 Blocking D2 receptors in basal ganglia extrapyramidal side effects.  L- Dopa (precursor of dopamine) thus exacerbates symptoms of schizopherenia.

d) Hyperprolactinemic effect:  Blocking D2 receptors in hypothalamus anterior pituitary axis hyperprolactinemia (galactorrhea in female and decreased libido and impotence in male).

IV.Endocrinal

effects

 Chlorpromazine block dopaminergic receptors in hypothalamicadenohypophyseal axis:

1- In female: galactorrhea, inhibit ovulation, infertility and suppress menses.

2.In male: decrease libido and decrease testicular weight

V- Skeletal muscles

 relaxant effect due to central mechanism in medulla or basal ganglia.

VI- Antihiccough



Chlorpromazine is highly effective in the treatment of intractable hiccough.

Pharmacokinetics

 Erratically absorbed from GIT.

 Highly lipophilic and concentrated in the brain.

 Highly bound to plasma protein.  Elimination half-lives ranged from 12-24h .

 Once daily dosing.

 Metabolized in the liver by liver microsomal enzyme system through 2 steps “oxidation followed by conjugation with glucuronic acid”.

 Metabolites are excreted in the urine and persist in the body for long time and so can be detected in the urine even after several months after drug stoppage

Therapeutic uses

1.Psychoses:

 Phenothiazines are most effective in excited psychotic patients & in split mind (schizophrenia).

 Schizophrenia responds well to phenothiazine and electroconvulsive (ECT).

 Phenothiazine do not cure scizophrenic patient but just quiten and make him more co-operative and acceptable.

 The onset may be delayed to 2-5 weeks.

2.Behavioral disorders in children and senile:

 Children with aggressive destructive behavior sometimes are improved by phenothiazine.

 Senile patient’s behavior can be controlled by phenothiazine.

3.Antiemetics and antihiccough:

 Chlorpromazine control vomiting of central origin because it blocks D2 receptors in CTZ but does not control motion sickness.

 It is effective in the treatment of intractable hiccough (mechanism unknown).

Side effects

:an

1-Neurological or Extrapyramidal adverse effects:

a) Parkinsonian syndrome with muscle rigidity, tremors, mask face.

b) Akathisia (motor restlessness): compelling need of the patient to be in constant movement.

c) Acute dystonic reaction: spasm of muscles of face and neck leading to facial grimacing and torticollis.

d) Neuroleptic malignant syndrome manifested by catatonia, extra pyramidal signs, unstable blood pressure, altered consciousness and hyperpyrexia. ,

e) Perioral tremor (rabbit syndrome).

f) Tardive dyskinesia that is stereotyped involuntary movements of tongue, lips, jaws and extremities.

 The first four reactions usually appear soon after administration of the drug while the last two appear following prolonged treatment.

2-Anticholinergic side effects including:

dry mouth, blurred vision, urinary retention particularly in old patients with senile prostate, delayed gastric emptying.

3-Postural hypotension and sexual dysfunction.

4-Allergic manifestations in the form of:

a) skin rash, contact dermatitis, photosensitivity, b) b-intrahepatic obstructive jaundice.

c) blood dyscriasis in form of leucocytosis, leucopenia and agranulocytosis.

5-Abnormal pigmentation in regions exposed to the sun and with high doses pigmentary retinopathy has been reported.

6-Gynecomastia, menstrual irregularities and lactation.

B) OTHER DRUG CLASSES