Local & General Anesthetics

Anesthetic

It is an agent that causes partial or complete loss of sensation, with or without loss of consciousness, i.e., anesthesia.

 

Anesthesia
It is a partial or complete loss of sensation, with or without loss of consciousness, as a result of disease, injury, or administration of an anesthetic agent, usually by injection or inhalation.

 

 

 

Classification of Aesthetics
Generally there are two types of anesthetics. Such as-

 

1. Local anesthetics
2. General anesthetics

 

 

 

Local Anesthetics

 

Clinically, local anesthetics are those anesthetics which are used to block pain sensation from—or sympathetic vasoconstrictor impulses to—specific areas of the body.

 

Local anesthetics reversibly block impulse conduction along nerve axons and other excitable membranes that utilize sodium channels as the primary means of action potential generation.

 

The first local anesthetic introduced into medical practice, cocaine, was isolated by Niemann in 1860 and introduced into practice by Koller in 1884 as an ophthalmic anesthetic.

 

 

 Chemistry of LA

 

Most of local anesthetic agents consist of a lipophilic group (an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine).

 

Local anesthetics are weak bases. For therapeutic application, they are usually made available as salts because of solubility and stability.

 

Factors on pKa

 

In the body, they exist either as the uncharged base or as a cation. According to Henderson-Hasselbalch equation the relative proportions of these two forms is given by-

 

log (Cationic form)/(Uncharged form)=〖pK〗_a- pH

 

Because the pKa of most local anesthetics is in the range of 8.0–9.0, the larger percentage in body fluids at physiologic pH will be the charged (cationic form).

 

 

 

[Note to know: The cationic form is the most active form at the receptor site because it cannot readily exit from closed channels. However, the uncharged form is important for rapid penetration of biologic membranes and producing a clinical effect, since the local anesthetic receptor is not readily accessible from the external side of the cell membrane. Therefore, local anesthetics are much less effective when they are injected into infected tissues because a smaller percentage of the local anesthetic is nonionized and available for diffusion across the membrane in an environment with a low extracellular pH.]

 

 

 

Pharmacodynamics (M/A of LA)

 

Local anesthetics prevent the initiation and propagation of the nerve impulse (action potential). By reducing the passage of sodium through voltage-gated Na ion channels they raise the threshold of excitability (the transmembrane potential -90 - -60mv changed to +40mv); in consequence, conduction is blocked at afferent nerve endings, and by sensory and motor nerve fibers. The fibers in nerve trunks are affected in order of size, the smallest (autonomic, sensory) first, probably because they have a proportionately greater surface area then the larger (motor) fibers. Paradoxically, the effect in the CNS is stimulation. A related flow chart is given below-

 

Uses of LA

 

1. LA is generally used when loss of consciousness is neither necessary nor desirable and also as an adjunct to major surgery to avoid high dose of GA.
2. It can be used for major surgery, with sedation, though many patients prefer unconsciousness.
3. It can also be used topically for short periods to give relief from local pain or itching (but skin allergy is common).

 

 Pharmacokinetics

 

LA are usually used by injection into the area of the nerve fibers to be blocked, and sometimes also topically.

 

Absorption

 

Systemic absorption of injected local anesthetics from the site of administration depends on several factors including-

 

• Dosage
• Site of injection
• Drug-tissue binding
• Presence of vasoconstricting substances
• Physicochemicals and pharmacologic properties of drug

 

[vasoconstrictor substances such as epinephrine reduce systemic absorption of local anesthetics from the depot site by decreasing regional blood flow in these area.]

 

 

 

Distribution

 

The amide local anesthetics are widely distributed after intravenous bolus administration. The distribution rate of a single dose of a local anesthetic is determined by diffusion into tissues with concentrations approximately in relation to blood flow (blood t1/2 only a few minutes).

 

 

 

Metabolism and Excretion

 

The local anesthetics are converted in the liver or in plasma to more water-soluble metabolites and then excreted in the urine. Since LA in the uncharged form diffuse readily through lipid, little or no urinary excretion of the neutral form occurs. Ester like LA hydrolyzed very rapidly in the blood by butyrylcholinesterase (pseudocholinesterase) to have very short plasma half-lives. Decreased hepatic removal of local anesthetics should also be anticipated in patients with reduced hepatic blood flow.

 

 

 

Basic Administration of Local Anesthetics

 

Topical (Surface)- skin and mucosa

 

 

 

Infiltration – direct injection intradermal or sc (eg. knee)

 

for: joint pain

 

 

 

Peripheral Nerve Block – injected close to nerve trunks (eg. brachial)

 

for: surgical procedures, severe, chronic pain (eg. cancer)

 

 

 

Spinal – injection into subarachnoid space near spinal cord

 

for: surgery

 

 

 

Epidural – injection just above dura surrounding spinal cord, near spinal nerve roots

 

for: OB, surgery

 

 

 

Factors Affecting the Pharmacokinetics of Local Anesthetics

 

Lipid solubility (hydrophobicity)

 

• All local anesthetics have weak bases. Increasing the lipid solubility leads to faster nerve penetration, block sodium channels, and speed up the onset of action.

 

• The more tightly local anesthetics bind its target, the longer the duration of onset action.

 

• Local anesthetics have two forms, ionized and nonionized. The nonionized form can cross the membranes, but the ionized form binds more strongly to sodium channels.

 

pH influence

 

• Usually at range 7.6 – 8.9

 

• Decrease in pH shifts equilibrium toward the ionized form, delaying the onset action.

 

• Lower pH, solution more acidic, gives slower onset of action

 

 

 

Vasodilation

 

• Vasoconstrictor is a substance used to keep the anesthetic solution in place at a longer period and prolongs the action of the drug

 

• Vasoconstrictor delays the absorption which slows down the absorption into the bloodstream

 

• Lower vasodilator activity of a local anesthetic leads to a slower absorption and longer duration of action

 

• Vasoconstrictor used is usually epinephrine

 

 

Adverse effects (toxicity)

 

There are some adverse effects of LA on our different bodily mechanisms, such as-

 

On CNS

 

_ Euphoria (cocaine)

 

- sleepiness

 

- visual and auditory disturbance

 

- Nystagmus, shivering convulsions

 

- CNS depression leading to respiratory depression

 

On PNS

 

- Neurotoxicity (sensory and motor deficits)

 

On CVS

 

_ myocardial depression

 

- vasodilatation, hypotension

 

- Qunidine like action (antiarrythmic)

 

- hypertension (cocaine)

 

On blood

 

- Methaemoglobinaemia

 

Allergic

 

- rash

 

- asthma

 

- Anaphylactic Shock

 

Others

 

- Myasthenia gravis

 

- vomiting

 

- Mydriasis

 

- Pyrexia

 

- hallucination

 

- addiction etc.

 

 

 

General Anesthetics

 

General anesthetics are the agents that produce reversible unconsciousness with loss of pain and reflexes along with adequate muscle relaxation. GA do not act by any receptors because they are all nonspecific drugs and since they have got no antagonist.

 

 

 

Effects

 

The effects GAs include are-

 

Analgesia

 

Amnesia

 

Loss of consciousness

 

Inhibition of sensory and autonomic reflexes

 

Skeletal muscle relaxation

 

Types of GA

 

GA agents fall into following two types-

 

Inhalation agents or volatile anesthetics

 

Intravenous agents or non-volatile anesthetics

 

 

 

Inhalation Anesthetics

 

The anesthetics which enter and leave the body through the lungs are inhalation anesthetics. Anesthetics can easily cross the alveolar membrane as they are all lipid soluble molecules.

 

Intravenous Anesthetics

 

These anesthetics are administered intravenously. These produce anesthesia without excitement and produce unconsciousness in about 20 seconds.

 

Pre-anesthetic Medication

 

In addition to GA agents there are considerable numbers of drugs that are used before and during surgical operation for sedation and analgesia. This use of drugs is called pre-anesthetic medication, and the drugs are called adjuvant anesthetics.

 

Drugs used in Pre-anesthetic Medication

 

1. For sedation and amnesia

 

- Diazepam, Phenobarbitone

 

2. For suppressing respiratory and salivary secretion (anticholinergic agents) and reflex excitability

 

- Atropine sulphate

 

3. To prevent bronchospasm, hypotension and vomiting (antiemetics)

 

- Promethazine hydrochloride, Chlorpheneramine maleate

 

4. To relief pain (opioid analgesics) and production of sedation

 

- Inj. Pethidine, Morphine

 

5. Barbiturates (as sedative, hypnotic agents)

 

 

 

Balanced Anesthesia

 

Balanced anesthesia is one in which each drug being selected for one specific purpose and the whole combination providing the most effective and comfortable but the least hazardous anesthetic experience for the patient and the best operating condition for the surgeon.

 

An example is given below-

 

1. Pre-anesthetic medication with a basal anesthetic (barbiturate), a narcotic-analgesic (pethidine), and a vagal inhibitor (atropine)

 

2. Induction by short acting barbiturates (thiopentone, methohexitone)

 

3. Maintenance of unconsciousness, analgesia and reflex inhibition by an anesthetic gas (N2O with O2 and halothane) and an intravenous narcotic analgesic (pethidine)

 

4. Maintenance of muscle relaxation by neuromuscular blocking agents.

 

 

 

Patient Factors in Selection of Anesthesia

 

The selection of anesthesia administered preoperatively depends on two factors-

 

1. Status of organ system

 

2. Concomitant use of drugs

 

Status of organ system

 

Liver and kidney

 

Liver and kidneys help in distribution and clearance of various anesthetic agents , and also the target organs of toxic effects. The repeated administration of anesthetic agents cause rapid release of chloride, fluoride, bromide which affect the organs.

 

Respiratory system

 

The RS is affected when inhalation anesthetics are administered. It becomes complicated for a patient of asthma or perfusion abnormalities. Because, it depress the RS; additionally, they are bronchodilators.

 

CVS

 

Ischemic injury of tissues reduces perfusion pressure because of the hypotensive effect of the most anesthetics. If a hypotensive condition necessitates treatment during operation, a vasoactive agent is administered considering the possibility of sensitization of heart to the arrhythmogenic effects.

 

Nervous system

 

Various neurologic disorders, i.e., epilepsy or myasthenia gravis demand the right selection of an anesthetic, even having sensitivity to halogenated hydrocarbon-induced malignant hyperthermia, too.

 

Pregnancy

 

Selecting an anesthetic is very sensitive for a pregnant woman. There is a report that transient use of nitrous oxide can cause aplastic anemia in the unborn child. Oral clefts have occurred in the fetuses of women who have received benzodiazepines. Diazepam should not be used routinely during labor, because it results in temporary hypotonia and altered thermoregulation in the newborn.

 

 

 

Concomitant use of drug

 

- Multiple adjunct agents

 

Commonly surgical patients receive one or more preanesthetic medications , such as – antiemetic agents, anticholinergic agents, antiallergic agents, analgesics etc. to facilitate smooth induction of anesthesia. Such coadministration can also enhance undesirable anesthetic effects (i.e., hypoventilation), and it may produce negative effects that are not observed when each drug is given individually.

 

- Concomitant use of additional non-anesthetic drugs

 

Surgical patients may be chronically exposed to agents for the treatment of the underlying disease as well as to drugs of abuse that alter the response to anesthetics.

 

 

 

Stages of Anesthesia

 

Surgical anesthesia classically divided in four well-defined stages when a slowly acting anesthetic (such as ether) is used. The stages are-

 

Stage 1- Analgesia

 

Analgesia is partial until stage 2 is about to be reached. Consciousness and sense of touch are retained and sense of hearing is increased.

 

Stage 2-Excietment

 

 The patient experiences delirium and possibly violent, combative behavior.

 

 There is a rise or irregularity in blood pressure.

 

 The respiratory rate may increase.

 

To avoid this stage, a short-acting barbiturate (such as thiopental) is given intravenously before inhalation anesthesia is administered.

 

Stage 3- Surgical Anesthesia

 

 Regular respiration and relaxation of the skeletal muscles occur in this stage.

 

 Eye reflexes decrease progressively, until the eye movements cease and the pupil is fixed.

 

 Surgery may proceed during this stage.

 

Stage 4- Medullary Paralysis

 

 Severe depression of the respiratory and vasomotor centers occur during this stage.

 

 All reflexes activities lost and pupil widely dilated.

 

 Death can rapidly ensue unless measures are taken to maintain circulation and respiration.

 

 

 

Induction, Maintenance and Recovery from Anesthesia

 

Anesthesia can be divided into three major stages-

 

Induction

 

It is defined as the period of time from the onset of administration of the anesthetic to the development of effective surgical anesthesia in the patient. During induction, it is essential to avoid the dangerous excitatory phase (delirium). GA is normally induced with an I/v anesthetic like thiopental, which produces unconsciousness within 25 seconds after injection. Then additional proper anesthetic combination can be administered to get desired surgical stage of anesthesia (stage iii). For children, without intravenous access, nonpungent agents, such as halothane or sevoflurane, are used to induce GA. This is termed inhalation induction.

 

Maintenance

 

It is the period during which the patient is surgically anesthesized. Then the anesthesiologist monitors the patient during the whole period of surgical procedure to balance the amount of drug inhaled and/or infused with the depth of anesthesia. Anesthesia is usually maintained by the administration of volatile anesthetics, because these agents offer good minute-to-minute control over the depth of anesthesia. Opioid, such as fentanyl, are often used for pain along with inhalation agents.

 

 

Recovery

 

Postoperatively, the anesthesiologist withdraws the anesthetic mixture and monitors the patient carefully until he/she is fully recovered from unconsciousness. Patients are observed for the delayed toxic reactions, such as hepatotoxicity caused by halogenated hydrocarbons.

 

 

Depth of Anesthesia

 

It has been divided into four sequential stages. Each stage characterized by increased CNS depression, which is caused by accumulation of the anesthetic drug in the brain. The stages are-

 

1. Stage 1- Analgesia

 

2. Stage 2-Excietment

 

3. Stage 3- Surgical Anesthesia

 

4. Stage 4- Medullary Paralysis