Drugs affecting the central nervous system

Anesthetic agents 1. General anesthetic agents

General anesthesia is used mainly for operative procedures.

Anesthesia involves: . narcosis – putting the patient into the state of unconsciousness . analgesia – elimination of pain . autonomic blockade – decreasing the patient’s reaction to stimuli . decreasing the tension of the striate muscles. The following groups of drugs are used as general anesthetic agents

. inhalational anesthetics – nitrous oxide, ether and halogenated anesthetics – halothane, enflurane, isoflurane, desflurane, sevoflurane

. intravenous anesthetic agents –to prepare the patient for operative procedures or for general anesthesia. Intravenous anesthetic drugs include:

 General anesthetics – ketamine, propanidid, etomidate and propofol  Hypnotic drugs – barbiturates: thiopental and methohexital  Opioid analgesic drugs – fentanyl, alfentanil, sufentanil, remifentanil  Anxiolytic drugs – eliminating emotional tension: diazepam, flurazepam, midazolam  Neuroleptics - mainly droperidol  Drugs causing muscle relaxation - mainly pancuronium The ideal anesthetic agent should meet many requirements, such as:

. good analgesic and anesthetic properties . slight influence on breathing and circulation . lack of irritative action on the skin . biotransformation without creating harmful metabolites . low toxicity and a high therapeutic index . rapid start and end of action when administration is stopped . appropriate physicochemical properties (stability, non- flammability and non-explosiveness) . environmental safety. General inhalational anesthetics

Nitrous oxide. It is a common inhalational anesthetic with weak hypnotic and strong analgesic action. Nitrous oxide is slightly toxic.

Depression of the respiratory tract is the main danger during the use of nitrous oxide. This problem may be avoided when nitrous oxide is administered in a mixture with oxygen (70% N2O + 30% oxygen).

Nitrous oxide does not act harmfully on the parenchymatous organs, does not irritate the mucous membrane of the upper airways and does not impair intestinal peristalsis. It is most often used with halothane.

Nitrous oxide does not induce skeletal muscle relaxation. It is also known as laughing gas because of causing short, very pleasant periods of excitation. Ethyl ether (H3C-CH2-O-CH2-CH3). It is a flammable liquid, susceptible to oxidation producing explosive peroxides. Ether for anesthesia is stabilized by ethanol. Ethyl ether has many advantages: a wide therapeutic range, ease of use, strong hypnotic, analgesic and relaxing action, and a low price. However, it is being withdrawn form therapy because of its explosive properties and unfavourable metabolic action, which is caused by inhibition of lactate dehydrogenase and leads to metabolic acidosis. Halogenated anesthetics are volatile liquids with a distinctive odour. They have dfifferent blood:gas partition coefficients (desflurane – 0.42, sevoflurane – 0.59, isoflurane – 1.40, enflurane – 1.91, halothane – 2.30, methoxyflurane - 12), which is important for their accumulation in the blood and tissues, the onset of general anesthesia and elimination time. The more easily a drug dissolves in the blood, the greater its concentration in the blood and tissues before it reaches the desired partial pressure in the brain and the more slowly it is eliminated from the body. Halothane Cl HALAN, NARCOTAN CF3 Br

Isoflurane, FORANE Halogenated anesthetics F Cl F O CF3

F F Desflurane, SUPRANE

F O CF3

F Cl F Enflurane, EFRANE O F F F

Cl F Methoxyflurane, METOFANE CH3 O Cl F

CF3 Sevoflurane, SEVOFRANE F O CF3 The main pathway of elimination of inhalational anesthetics is the lungs.

Only a small part is metabolized in the liver and eliminated by the kidneys.

The degree of biotransformation is crucial for their toxicity.

Isoflurane, in contrast to other inhalational anesthetics, undergoes biotransformation to a small degree. 18-20% of halothane, 2.9% of enflurane and sevoflurane and 0.02% of isoflurane (to fluoride and non-volatile fluoride-organic compounds) undergoes biotransformation in the liver. Cl F CH3 O Cl F The nephrotoxic action of methoxyflurane is caused by its biotransformation leading to significant amounts of fluoride and oxalate acid.

The halogenated anesthetics differ in their power of action and unwanted effects.

The most powerful action is demonstrated by methoxyflurane. Its good solubility in fats results in a long induction period of 20-30 min and a long withdrawal from anesthesia. The anesthetic action of desflurane and sevoflurane is weaker than that of isoflurane. Isoflurane has a higher therapeutic index than halothane.

The halogenated anesthetics cause some unwanted effects:

. respiratory depression . hepatotoxicity and nephrotoxicity . cardiotoxicity (negative inotropic action, arrhythmogenic action, hypotension) . malignant hyperthermia (uncontrolled increase of body temperature, which may lead to death and is caused by generalized muscle tension, during which excessive heat is produced and a huge amount of oxygen is used). Dantrolene is a drug which prevents malignant hyperthermia. It inhibits the release of calcium ions from sarcoplasmic reticulum and prevents muscular contraction.

H O N O N O 2 Dantrolene O N N General intravenous anesthetic agents

Ketamine is a structural analog of phencyclidine. There is an asymmetric carbon atom in position C2 of the cyclohexane ring. Although in therapy racemate is used, the potency of S(+)-ketamine is greater than that of racemate and the R(-)-isomer and fewer unwanted effects are observed.

Cl O Ketamine, KETANEST

N H 2-(2-Chlorophenyl)-2-(methylamino)- CH 3 cyclohexanon Ketamine acts analgetically, anesthetically, locally anesthetically, sympathomimetically (inhibits the reuptake of NA, DA and 5- HT), and parasympathomimetically (increases glandular secretion).

S(+)-Ketamine acts by binding with opioid receptors and places which bind the phencyclidine (PCP) of NMDA receptors.

The R(-)-isomer shows lower affinity for opioid receptors and places binding the phencyclidine of NMDA receptors. ANALGESY

Opioid and NMDA receptors

-stimulation NMDA NEURO- BRONCHOLYSIS KETAMINE receptors PROTECTION

NMDA receptors

ANALGESY

Figure The action of ketamine (according to M. Bastgkeit: Pharm. Ztg. 1997, 142 (no 4), p. 40). Ketamine:

 inhibits the reuptake of NA, DA and 5-HT by neurons, which increases indirectly the stimulation of particular receptors  acts parasympathomimetically (increases glandular secretion by influencing nicotinic and muscarinic cholinergic receptors)  affects voltage-dependent ion channels (mainly sodium, potassium and calcium channels)

 affects the GABAA-chlorine channel.

The mechanism of all that action remains unexplained. While the affinity of ketamine for -opioid receptors determines its hypnotic action, its affinity for -opioid receptors determines its analgetic action. The analgetic action of ketamine is similar to petidine, an opioid analgetic. The analgetic action of S(+)-ketamine is approx. 70% greater than that of racemate. The depressive action of S(+)-ketamine is weaker than that of racemate. R(-)-Ketamine binds mainly with -opioid receptors, which explains its unwanted cardiologic effects and the patient’s agitation after awakening. S(+)-Ketamine acts as a noncompetitive NMDA receptor agonist and demonstrates neuroprotective and possibly, anesthetic action.

The anesthetic action of S(+)-ketamine is twice as strong as that of racemate.

It is believed that the neuroprotective action of ketamine is caused by the trapping of free radicals, which act neurotoxically, central sympatholytic action and the increased DA degradation in the nucleus caudatus. S(+)-Ketamine has 4 times greater affinity for places binding PCP (phencyclidine) than the R(-)-isomer. The places binding PCP are located inside the ion channel, which is connected with the NMDA receptor.

They are responsible for memory processes.

S(+)-Ketamine inhibits the extraneuronal trapping and transport of catecholamines.

R(-)-Ketamine inhibits weakly the transport of catecholamines but its inhibition of serotonin transport is twice as strong as that of the S(+)-isomer. The superiority of S(+)-ketamine over R(-)-ketamine consists in:

. stronger analgesic and anesthetic action . 2.5 times greater therapeutic index . lower spontaneous response and arrhythmia . shorter phase of awakening . insignificant influence on the patient’s attention . insignificant degree of amnesia.

The bioavailability of ketamine after oral or rectal administration is 20% and 93% after IM administration. The action of ketamine is observed: . immediately on IV administration . after 5 minutes on IM administration . after 20 minutes on oral administration . after 10-15 minutes after rectal administration. Ketamine demonstrates the following kinds of action in terms of duration time:

 anesthetic: 10-15 minutes  analgesic: 40 minutes  amnesia: 1-2 h.

In the presence of barbiturates, benzodiazepines and neuroleptics the duration of action of ketamine is prolonged.

In the liver, under the influence of cytochrome P-450 ketamine undergoes N-demethylation to active norketamine. Hydroxyderivatives are the next products of biotransformation. H3C OH CH3 Propofol, DEPRIVAN H C 3 CH3 2,6-Bis(1-methylethyl)phenol

Propofol is a short-acting agent with a very fast start of action (~30 s) and a short time needed to recover consciousness after anesthesia. It is metabolized in the liver where it conjugates with glucuronic acid (~50% of a dose) and is hydroxylated. Its inactive metabolites are eliminated in the urine. Propofol penetrates the placenta and may cause circulatory and respiratory depression in newborn babies. Propofol is used to induce and maintain anesthesia. H3C Etomidate, O HYPNOMIDATE, N H3C O N Etomidate is a strong-acting agent, causing anesthesia without analgesia.

Its anesthetic effect appears similarly to what is observed after IV administration of thiopental and methohexital (~30 s) but its potency is 12 times greater than that of thiopental and 4-5 times than that of methohexital.

The time of awakening depends on the dose and is significantly shorter than after administration of thiopental and slightly shorter than after using methohexital (3-12 minutes after a single dose). H3C O N H3C O N

Etomidate acts depressively on the CNS through GABA. Only the D-isomer is active anesthetically.

It is metabolized in the liver. 85% of the dose is eliminated in the urine as inactive metabolites and 10-13% in bile.

Etomidate inhibits the activity of the adrenal cortex and is an inhibitor of plasma cholinesterase. CH3 O O O Propanidid, EPONTOL, PROPANTAN N O H3C H3C O CH3

Propanidid is used only in short-lasting, minor procedures, eg. an incision of an abscess. At present its use is becoming less common. Intravenous hypnotic agents – barbiturates

At present methohexital and thiopental are used most often in general anesthesia. They demonstrate hypnotic and anesthetic action but do not demonstrate analgesic action and do not relax skeletal muscles. They decrease the brain blood circulation, demand for oxygen in the brain and intracranial pressure.

CH3 CH3 O N O O N S 1 1 6 2 6 2 R1 5 3 R 5 4 N H 1 4 3N H R 2 R2 O O

R1 = -CH2-CH=CH2 R = - CH -CH R2 = -CH(CH3)-CC-CH2-CH3, Methohexital 1 2 3 R2 = -CH(CH3)-CH2-CH2-CH3, Thiopental, THIOPENTAL Intravenous hypnotic agents – barbiturates

Methohexital acts 3 times more strongly than thiopental. After IV administration of either drug its action lasts 5-15 min.

Awakening is faster after methohexital.

Thiopental has very high solubility in lipids and is slowly eliminated from the body. These properties may cause drug accumulation when administration is repeated.

CH3 CH3 O N O O N S 1 1 6 2 6 2 R1 5 3 R 5 4 N H 1 4 3N H R 2 R2 O O

R1 = -CH2-CH=CH2 R = - CH -CH R2 = -CH(CH3)-CC-CH2-CH3, Methohexital 1 2 3 R2 = -CH(CH3)-CH2-CH2-CH3, Thiopental, THIOPENTAL The barbiturates undergo biotransformation, mainly in the liver (thiopental 99% of the dose) and to a lesser degree in the brain and kidneys.

Thiopental may release histamine whereas methohexital is the only barbiturate which may cause convulsions in patients with psychomotor epilepsy. Analgesic drugs

Such opioid analgesics as fentanyl, alfentanil, sufentanil and remifentanil are commonly used IV for general anesthesia.

They have different times of reaching the maximal effect of the dose and different duration of anesthesia.

Fentanyl and sufentanil rapidly reach maximal action (after 2.5 and 5 min, respectively).

The action of fentanyl is short-lasting (~1 h) and of sufentanil long-lasting (9 h). 2. Local anesthetics

A local anesthetic agent is a drug that when administered either topically or parenterally to a localized area produces a state of local anesthesia by reversibly blocking the nerve conductances that transmit the feeling of pain from this locus to the brain. The mechanism of action

The mechanism of action involves the blocking of sodium channels. As a result of this process the permeability of the cell membrane for Na+ ions is decreased and in spite of the fact that the rest potential and the potential threshold do not change as a result of the decreased speed of depolarization, the threshold of the action potential is not achieved. The transfer of the action potential is not observed and, as a result, the nerve is blocked. It is believed that the blockade of sodium channels is caused by the binding of a local anesthetic with a specific receptor place which is connected with the sodium channel. There are several hypotheses explaining the sodium channel blockade.

A commonly accepted one is the theory of a modulated receptor, according to which the anesthetic’s affinity for the receptor is modulated by the open, inactive or rest state of the sodium channel.

Normally when the action potential is created, the state of the sodium channel changes from rest-close to open-active and, finally, to close-inactive. When the nerve is exposed to local anesthetics, the sodium channels after reducing the action potential return more slowly to the initial state than when no drug has been administered, so the time between the next action potentials of the nerve may be insufficient for it to achieve total polarization.

During the state of action potential, when the sodium channels are open, local anesthetics demonstrate high affinity for the receptor. When the action potential disappears, the sodium channels have lower affinity and dissociation of the drug-receptor complex is observed. If the next action potential is reached before total dissociation of the drug-receptor complex, the blockade is increased. Therefore as the frequency of stimulation increases, the intensity of the blockade increases too.

This phenomenon is called the frequency-sensitive blockade of a local anesthetic. The intensity and duration of that kind of blockade are related to the relative affinity of a local anesthetic for the receptor conjugated with the sodium channel and to the drug’s access to this receptor. According to another hypothesis, the affinity of a local anesthetic for the receptor is always high and does not depend on the conformation state of the sodium channel.

What limits the access of the drug to the receptor is the ‘gates’ of the sodium channel. Nerve fibres differ in the speed of conductivity, which is in proportion to the size of the fibre.

Generally, the longer is the fibre, the greater must be the concentration of a local anesthetic to obtain the blockade of conductivity. The chemical structure and action of local anesthetics

Nearly all of the local anesthetics consist of hydrophilic and hydrophobic components, which are separated by an intermediate chain.

The hydrophilic group is mainly a second- or third-order amine and the hydrophobic one is an aromatic rest.

Intermediate Aromatic part Amine group chain

Hydrophobic Hydrophilic component component The classification of local anesthetics is based on the type of the connection of the aromatic group with the intermediate chain.

Two kinds of local anesthetics are distinguished: the ester derivatives (procaine, chlorprocaine, tetracaine) and the amide derivatives (lidocaine, mepivacaine, bupivacaine, etidocaine).

Intermediate Aromatic part Amine group chain

Hydrophobic Hydrophilic component component O CH3 O O Cocaine H N CH3 Benzocaine, 2 O H3C N O

O O CH3 H N N Procaine 2 O CH3 CH3 R O N CH Lidocaine, HN 3 Chlorprocaine, R = -Cl H C CH3 Hydroxyprocaine, R = -OH 3 Mepivacaine, R = -CH3 H3C O R N O H

Tetracaine, R = -CH2-CH2-N(CH3)2; PANTOCAIN CH3 N R = N CH3 Paridocaine, N R H O CH3

O CH3 N Bupivacaine, R = -CH2-CH2-CH2-CH3 O CH3 Edan, BUPIVACAINUM HYDROCHLORICUM O O Ropivacaine, R = -CH2-CH2-CH2 CH3 N O CH3 Cinchocaine, CH3 N CH O N 3 H

O S CH O 3 O H3C N H Articaine, H N H3C CH3 The kind of the connection between the aromatic group and the intermediate chain determines the biotransfomation of the local anesthetics. The ester compounds are easily hydrolized in plasma under the influence of pseudocholinesterases. The amides are more slowly metabolized in the liver than the ester compounds.

Local anesthetic action is also demonstrated by drugs which do not have an amide or ester group, for example fomocaine.

O

O N

Fomocaine O

O N

Fomocaine is used mainly to treat pain in burns and ulceration caused by X-ray irradiation. Modifications of the chemical structure of the local anesthetics change their physicochemical properties, which may influence the potency of anesthetic action, time of action and toxicity.

The effect of a local anesthetic depends on its solubility in lipids, binding with proteins and the dissociation constant. Generally, local anesthetics with high solubility in lipids demonstrate stronger and longer activity. A butyl or amine substituent in the aromatic group significantly increases drug solubility in lipids. Because of that tetracaine demonstrates 8 times greater activity than procaine and bupivacaine 4 times greater than its methyl derivative, mepivacaine. The lengthening of the intermediate chain increases activity but after exceeding its critical length the power of action decreases.

Intermediate Aromatic part Amine group chain CH3 N Hydrophobic Hydrophilic N component R component H O H3C O R CH3 N Tetracaine, R = -CH2-CH2-N(CH3)2 O H Mepivacaine, R = -CH3

O CH3 H2N N Bupivacaine, R = -CH2-CH2-CH2-CH3 O Procaine CH3 R The greater the body’s potential for binding proteins, the longer the time of anesthetic action. It is believed that there is a relationship between binding with plasma proteins and the proteins of the neuronal membrane.

The local anesthetics are weak bases. Their pKa values range form 7.6 to 8.9. Drugs with a lower pKa value at the value of physiological pH are ionized to a smaller degree, so the amount of the non-ionized drug able to permeate the cell membrane is greater and the start of action is faster. The local anesthetics are divided into three groups depending on the power and time of action:

 drugs with low potency and short time of action (procaine, chlorprocaine),

 drugs with medium potency and time of action (lidocaine, mepivacaine, prilocaine, cocaine),

 drugs with high potency and long time of action (bupivacaine, tetracaine, etidocaine). The application of local anesthetics

The local anesthetic are used in the following types of anesthesia:

 permeation anesthesia (benzocaine, tetracaine, fomocaine),  conduction anesthesia (etidocaine),  conduction and infiltration anesthesia (procaine, lidocaine, prilocaine, mepivacaine, S-ropivacaine and articaine),  all kinds (bupivacaine). The physicochemical properties and relative potency of local anesthetics (selection)

Drug pKa (25oC) Distribution Binding with Relative potency coefficient plasma proteins,%

Procaine 8.9 0.02 1 Chloroprocaine 8.7 0.14 1 Tetracaine 8.,5 4.1 8 Prilocaine 7.9 0.9 2 Mepivacaine 7.6 0.8 75 2 Lidocaine 7.9 2.9 60-75 2 Bupivacaine 8.1 28 90-97 8 Etidocaine 7.7 14.1 94-97 6