1. Prof. Faris Abachi College of Pharmacy University of Mosul
CNS Depressants
Prof. Faris Abachi
College of Pharmacy
University of Mosul

2. Classifications 1- General Anesthesia 2- Sedative – Hypnotics
3- Anti – psychotic drugs
4- Anti – Consultants drugs. .

3. Mode of Action
Positive modulation of the action of γ – amino butyric acid (GABA) at GABAA receptor .Except anti consultants has been associated with neuronal voltage - gated sodium channel block , leading to decrease neuronal excitation .

5. What are General Anesthetics?
A drug that brings about a reversible loss of consciousness.
These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery.
Can be viewed as a pharmacological intervention used to prevent psychological and somatic adverse effects of surgical trauma and also to create convenient conditions for surgery.

7. Background General anesthesia was absent until the mid-1800’s
William Morton administered ether to a patient having a neck tumor removed at the Massachusetts General Hospital, Boston, in October 1846.
The discovery of the diethyl ether as general anesthesia was the result of a search for means of eliminating a patient’s pain perception and responses to painful stimuli.
Yet, the most famous contribution by the United States to medical progress at this period was undoubtedly the introduction of general anesthesia. Drugs of various kinds have been used for many centuries to reduce the distress of surgical operations. It was a procedure that not only liberated the patient form the fearful pain of surgery, but also enabled the surgeon to perform more extensive operations.
Now, known as one of the most important discoveries in medical science, Morton’s technique quickly reached Europe, and establishing the practice of anesthesiology. Safely has improved greatly, less than one death per 200,000 procedures occurs currently.
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8. HISTORY OF ANESTHESIA INHALATION AGENTS
Nitrous Oxide
1799 Davy
1824 Hickman
1844 Wells
Ether
1842 Long
1847 Snow
NITROUS OXIDE
Davy - Worked at a laboratory in Bristol, England. Study Nitrous Oxide and Carbon Dioxide. Named Nitrous Oxide laughing gas and understood it “destroyed” physical pain.
Hickman - A young doctor from Ludlow, England. Successfully anesthetized animals with a mixture of nitrous oxide and oxygen and performed amputations.
Wells - Dentist from Hartford, Connecticut. Used nitrous oxide for painless tooth extractions. Fell into disfavor, became deranged and an ether addict. (Killed himself in prison.)
ETHER
Long - Used vapors of ether to painlessly removed a large tumor from a patient’s neck in Jefferson, Georgia. The population of Jefferson threatened to lynch him. He stopped the use of ether and moved his practice to Athens, Georgia.
Snow - From London, England. First physician to specialize in anesthesia. Developed the “Clinical signs of Anesthesia.” He sought to understand the process of anesthesia and appreciated the significance of reduced oxygen and the problem of carbon dioxide. Also demonstrated for the first time that Cholera was transmitted by water.

9. Anesthetics divide into 2 classes:
Inhalation Anesthetics
Gasses or Vapors
Usually Halogenated
Intravenous Anesthetics
Injections
Anesthetics or induction agents
Drugs given to induce or maintain general anesthesia are either given as: inhalation or intravenous!
 Basically extremely diverse group of chemicals which produce a similar endpoint!!!!
The most commonly used methods of administering general anesthetics are inhalation, in which the patient breathes a gas or vapor into the lungs, from which the anesthetic can enter the bloodstream; and injection with a hypodermic needle, usually into a vein.
 Most commonly there two forms are combined, although its is possible to deliver anesthesia solely by inhalation or injection.

10. Inhaled Anesthetics Halothane Enflurane Isoflurane Desflurane
Inhalational anesthetics refers to the delivery of gases or vapors form the respiratory system to produce anesthesia.
 Special set of physical principles govern absorption, distribution, and elimination.
Halogenated compounds:
Contain Fluorine and/or bromide
Simple, small molecules

11. Nomenclature Halothane
is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane.

12. Stages of Anesthesia 1- Stage I :Cortical stage
2- Stage II :Excitement
3- Stage III :surgical Anesthesia
4- Stage IV :Modularly Paralysis

13. Component of general anesthesia
1-Uncinicousness ( Hypnosis )
2- Analgesia
3- Muscles relaxants .

14. Routine Monitors ECG. BP. Oximetry (2 wavelengths , red and infrared)
End Tidal CO2 .
Temperature (axillary vs. core).
FUTURE : Depth of anesthesia - BIS (Bispectral index EEG) -scale from 0 to 100
BIS > 65  deepen. 14

15. Physical and Chemical Properties of Inhaled Anesthetics
Although halogenations of hydrocarbons and ethers increase anesthetic potency, it also increase the potential for inducing cardiac arrhythmias in the following order F<Cl<Br.1
Ethers that have an asymmetric halogenated carbon tend to be good anesthetics (such as Enflurane).
Halogenated methyl ethyl ethers (Enflurane and Isoflurane) are more stable, are more potent, and have better clinical profile than halogenated diethyl ethers.
fluorination decrease flammibity and increase stability of adjacent halogenated carbons.
Complete halogenations of alkane and ethers or full halogenations of end methyl groups decrease potency and enhances convulsant activity. Flurorthyl (CF3CH2OCH2CF3) is a potent convulsant, with a median effective dose (ED50) for convulsions in mice of atm.
The presence of double bonds tends to increase chemical reactivity and toxicity.

16. SAR for Inhalated Gases

17. Intravenous Anesthetics
Used in combination with Inhaled anesthetics to:
Supplement general anesthesia
Maintain general anesthesia
Provide sedation
Control blood pressure
Protect the brain

18. Intravenous Anesthetics
Thiopental Sodium ( Ultrashort acting barbiturates), 3D-structure ;

19. Benzodiazepines
Alone cant produce surgical anesthesia, i.v. used to introduce anesthesia.Relaxant.

20. Uses of Benzodiazepines
Benzodiazepines generally share the same pharmacological properties, such as anxiolytic, sedative, hypnotic, skeletal muscle relaxant, amnesic and anticonvulsant (hypertension in combination with other anti hypertension medications).

21. Propofol ( Diprivan ) It is a 2 , 6 diisopropylphenol (Emulsion )
Used o inducion and maintenance of anesthesia . Has lipid / water P.C.
The drug binds alloster
ically o GABA A2

25. Ketamine Hydrochloride ( Ketalar)
± 2- ( o-chlorophenyl) -2- methyl amino cyclohexanone HCI . ( racemic mixtures )
Ketamine produces a sense of dissociation from events being experienced , followed by anesthesia , analgesia and sometimes amnesia.

28. Essential Components of Anesthesia
Analgesia- perception of pain eliminated
Hypnosis- unconsciousness
Depression of spinal motor reflexes
Muscle relation
* These terms together emphasize the role of immobility and of insensibility!
According to the American Society of Anesthesiologists, in general anesthesia the patient is unconscious and has no awareness or other sensations while, in addition the patient is carefully monitored, controlled and treated by the anesthesiologist.
 By identifying these signs anesthesia can be measured.
The relationship between the amount of general anesthetic administered and the depression of the brain's sensory responsiveness is arbitrarily, but usefully divided into stages to describe the depth of anesthesia.1,3,5 Furthermore, the following four stages can recognize both during induction of and recovery from general anesthesia.

29. Hypotheses of General Anesthesia
Lipid Theory: based on the fact that anesthetic action is correlated with the oil/gas coefficients.
The higher the solubility of anesthetics is in oil, the greater is the anesthetic potency.
Meyer and Overton Correlations
Irrelevant
2. Protein (Receptor) Theory: based on the fact that anesthetic potency is correlated with the ability of anesthetics to inhibit enzymes activity of a pure, soluble protein. Also, attempts to explain the GABAA receptor is a potential target of anesthetics acton.
Importantly, Morton’s technique proved that a chemical substance can achieve all of the actions of general anesthesia that have been considered clinically essential. Nevertheless, many attempts have been made to produce a single explanation of action that would embrace all anesthetics. Although these compounds have a common chemical structure, consequently no structure-activity relationships have been recognized. Throughout decades of debates, most of the theories have made attempts to correlate anesthesia potency with some physical property of the anesthetic agents.
PROTEIN-BASED: theory that anesthetics bind to hydrophobic/lipophilic sites of proteins.
It is thought that anesthetics act on the membrane protein to cause it to be change by:  inducie/prevent conformation change, alter kinetics of conformational changes, and compete with ligands (competitive antagonsim) !!!!!!!!!!

30. Other Theories included
Binding theory:
Anesthetics bind to hydrophobic portion of the ion channel
Studies of individual cells in the brain during anesthesia have begun to pin down at least what anesthetics do, if not how they do it. All anesthetics appear to shut off the brain from external stimuli. One way they can do this is by altering the chemistry of the synapes. Which are the gaps between nerve cells.
Chemicals called neurotransmitters normally act as MESSAGERS, crossing the synapse to relay a nerve signal. Other brain chemicals, in particular once called GABA, tend to shut off the signal. Many anesthetics appear to block the excitatory neurotransmitters or enhance the natural effect of GABA.
Yet, precisely how they do this remains unclear!!!

31. Mechanism of Action UNKNOWN!! Most Recent Studies:
General Anesthetics acts on the CNS by modifying the electrical activity of neurons at a molecular level by modifying functions of ION CHANNELS.
This may occur by anesthetic molecules binding directly to ion channels or by their disrupting the functions of molecules that maintain ion channels.
Although despite decades of research, the efforts to characterize the mechanism of action by which general anesthetics produce loss of consciousness remain mysterious
Clearly, a general anesthetic is a drug that has the ability to bring about a reversible loss of consciousness, by act on the central nervous system (CNS) via shutting off the brain from external stimuli.5,7.

32. Cont on Mechanism
Scientists have cloned forms of receptors in the past decades, adding greatly to knowledge of the proteins involved in neuronal excitability. These include:
Voltage-gated ion channels, such as sodium, potassium, and calcium channels
Ligand-gated ion channel superfamily and
G protein-coupled receptors superfamily.

33. Anesthetic Suppression of Physiological Response to Surgery
Basically this picture helps to show what is thought to be the mode of action!
In the nervous system a general anesthetic changes the nerve cells so that normal communication among many of them is closed off for a time. Anesthetics can achieve this is by altering the chemistry of the synapses, the gaps between the nerve cells. 5,7 Therefore, sensations of all kinds are temporarily blocked from reaching the brain. At the same time, the person under anesthesia cannot move parts of the body. The muscles are completely relaxed, making surgery easier. At any point along this branching nerve system, the pain message can be blocked.5 Ultimately, what all anesthetics do is block the signal for pain.

34. Pharmacokinetics of Inhaled Anesthetics
Amount that reaches the brain
Indicated by oil:gas ratio (lipid solubility)
Partial Pressure of anesthetics
5% anesthetics = 38 mmHg
Solubility of gas into blood
The lower the blood:gas ratio, the more anesthetics will arrive at the brain
Cardiac Output
Increased CO= greater Induction time
Factors influencing the effects of inhaled anesthetics included:

35. Rate of Entry into the Brain: Influence of Blood and Lipid Solubility
LOW solubility in blood= fast induction and recovery
HIGH solubility in blood= slower induction and recovery.

36. Increase in Anesthetic Partial Pressure in Blood is Related to its Solubility
Significance of solubility
Agents of low solubility in blood included
-nitrous oxide
-desflurane
-Sevoflurane
With low solubility the partial pressure in blood rises quickly
Agents of medium solubility in blood included:’
-halothane
Isofulane
With medium solubility in blood partial pressure in blood raises slowly

37. General Actions of Inhaled Anesthetics
Respiration
Depressed respiration and response to CO2
Kidney
Depression of renal blood flow and urine output
Muscle
High enough concentrations will relax skeletal muscle
General anesthetics work by altering the flow of sodium molecules in to nerve cells or neurons through the cell membrane. Exactly how they do this is not understand since the drug apparently does not bind

38. Cont’ Cardiovascular System Central Nervous System
Generalized reduction in arterial pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents
Central Nervous System
Increased cerebral blood flow and decreased cerebral metabolism