PART-IX-CNS STIMULANTS-COFFEE AND SMOKING

CENTRAL STIMULANTS-COFFEE &SMOKING

CNS stimulants are drugs inducing increased motor activities, excitement, and decrease the feelings of tiredness.

1.METHYLXANTHINES

1.Caffeine

2.Theophylline

3.Theobromine

Theobromine is of little interest and it is mostly found in cocoa butter.

These drugs stimulate the CNS by a series of chemical and biological pathways involving an increase in cyclic guanosine monophosphate and cyclic adenosine monophosphate the two nucleotides which are increasing intracellular signaling to exhibit an increased motor activity and thereby stimulating the CNS.

Caffeine:-

 

The pharmacodynamical effects of caffeine are as follows:-

1. Centrally caffeine increases motor activity and alertness.

2.Heart and Bloodvessels-Caffeine increases heart rate (+chronotrophic) and contractility (+inotrophic)

3. Caffeine and its derivatives relax the smooth muscles of the bronchioles and dilate them to facilitate good ventilation. Hence drinking a cup of coffee would be beneficial during an attack of cold and asthma.

4. Caffeine is a weak diuretic and increases the excretion of sodium+,potassium+, and chloride-ions in the urine. Hence over a drink of coffee may lead to heavy loss of these ions.

5. Caffeine stimulates gastric secretions and thereby enhance acidity in the stomach. Hence care should be taken by those who suffer from peptic ulcers to avoid coffee drinks.

Side Effects

1.Insomnia

2.Agitation

3.Nausea and Vomiting

4.Convulsions

5.Cardiac Arrhythmias

Theophylline

 

Theophylline is already dealt with in detail in the post describes Asthma in this blog. Please refer to it.

2.NICOTINE

 

Physiology

Nicotine is having double action on the preganglionic receptors. Because of its specific actions at the preganglionic receptors the receptors are known as nicotinic receptors.

At low dosage it causes ganglionic stimulation by depolarization through acetylcholine. At high doses it causes ganglionic blockade.

At low dosage it causes arousal, relaxation, and improved attention through ganglionic stimulation.

At high doses it causes respiratory depression through medullary suppression through the ganglionic blockade.

Pharmacology

At Low Dose

Nicotine at a low dosage increases heart rate. constricting the blood vessels and thereby elevate B.P.

At High Dose:-

1. At a high dose, it slows the heart rate, dilates the blood vessels and thereby lower the B.P.

2. It causes many dysfunctions in our digestive system.

Nicotine increases acid secretions in the stomach and causes peptic and duodenum ulcers by impairing the secretions of sodium bicarbonate from the pancreas. 

Nicotine increases the stomach's susceptibility to H.pylori.

Nicotine weakens L.E.S.and thereby causes heartburn and G.E.R.D.

Nicotine causes the liver's ability to metabolize various toxic wastes and drugs ingested.

Nicotine causes Crohn's disease.

3. Nicotine causes severe urinary incontinence.

All the above effects are due to the ganglionic blockade of nicotine at high doses.

Clinical Uses

Fortunately nicotine has no therapeutic uses.

Kinetics

Nicotine is rapidly absorbed through the buccal mucosa, by inhalation, and by the skin.

Side Effects

1.Irritability

2.Tremors

3.Intestinal cramps

3.Diarrhea

4.Increased heart rate and B.P.

Withdrawal Symptoms For Addicts

1.Craving

2.Irritability

3.Restlessness

4.Anxiety

5.Stomach pain.

 

CNS DEPRESSANTS-PART-VIII-LOCAL ANESTHETICS

LOCAL ANESTHETICS

Local anesthetics are partial anesthetics that do not anesthetize the entire body. This is particularly useful for carrying out a surgical operation at a particular area of the body which can easily be desensitized without affecting the rest of the body. Also they are useful to reduce the pain impulses at an injured part of the body such as tooth pain.

TYPES OF LOCAL ANESTHETICS

In general there are two types of local anesthetics divided by their chemical structure. Structurally there are two portions in their molecule such as lipophilic (Affinity for fat) and hydrophilic (Affinity for water). There are two types of local anesthetics available determined by the bond linking the hydrophilic part to the lipophilic part.

They are either esters or amides

Esters

1.Cocaine

2.Benzocaine

3.Procaine

4.Tetracaine

Amides

1.Lidocaine (Xylocaine,or Lignocaine)

2.Mepivacaine

3.Bupivacaine

4.Prilocaine

Mechanism

Local anesthetics block the nerve conduction of pain impulses by inhibiting the voltage-gated sodium channels of the nerve cell membrane.

Small unmyelinated nerves that conduct pain,  heat, and autonomic activity are affected first.

With increasing concentration Pain fibers(A and C fibers) sensory(A-fibers) fibers followed by motor fibers(A-fibers) which are myelinated get affected.

Metabolism

Esters are more electrophilic and more rapidly metabolized by blood and tissue esterases and hence they have a shorter half-life and less toxic.

Amides are less electrophilic and slowly metabolized in the liver and hence they have a longer half-life and more toxic.

Clinical Indications

1.For surface anesthesia

2.Nerve blocks

3.Spinal and Epidural anesthesia

4. Lidocaine is also used as an antiarrhythmic systemically

With Epinephrine

To increase the duration of action of local anesthetics epinephrine is added which blocks the area to be anesthetized by vasoconstriction effects and thereby reduces the systemic absorption and enhances the local anesthetic actions.

Side Effects

1. Systemic effects will result in high doses and long time continuous use.

Cardiovascular effects like Depression of myocardial contraction(negative inotropic)

and hypotension.

But on the contrary cocaine causes systemic vasoconstriction and hypertension.

2.Lightheadedness(Headache)

3.Sensory disturbances

4.Convulsions

5. At high dose coma and death can occur.

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ANESTHETICS-Contd...

DISSOCIATIVE AGENTS AND HALLUCINOGENS

These agents are employed as adjuncts with the inhalation agents to attain anesthesia rapidly. These agents are psychotic products and induce withdrawal symptoms, through hallucinations and delusions. They are usually given by I.V.routes.

1.PROPOFOL (Diprivan)

This drug is clinically used for the induction of anesthesia.

Pharmacology:-

This drug is very similar to the opioid thiopental as high-fat solubility. Hence it easily crosses the blood-brain barrier to produce ultrafast CNS effects. Higher affinity and readily distribute into highly vascularised tissues like the brain followed by rapid redistributing back into the blood. Hence its onset of action is ultra-fast with a short duration of action.

Benefits Over Thiopental

1. Ultra-fast in the induction of anesthesia similar to thiopental but recovery is very sooner than thiopental.

2.Less nausea and vomiting

3.No cumulative effect or delay in recovery even after a prolonged infusion.

Metabolism and Kinetics

Metabolized by liver-enzymes like CYP-450-2-B6 through glucuronidation and extrahepatic enzymes present in kidneys. The metabolism is very faster than that of thiopental. Usually the I.V. anesthetics are not eliminated through lungs. The metabolites are excreted in the urine.

Side Effects

1.Hypotension

2.Negative inotropic effects(Weaken the muscle contractions especially that of the heart)

3.The pain of injection.

KETAMINE

Ketamine because of the prominent cardiovascular support it is mostly used in relieving the patients from fear of surgery and radiotherapies and post-operative traumas.

It is very useful in relieving traumas of children during dressing changes of burns and radiological procedures.

Ketamine is a dissociative agent to produce anesthesia associated with catatonia, amnesia, and analgesia without actual loss of consciousness.

Pharmacology

Ketamine's cardiovascular support during anesthesia is accounted for by its sympathetic stimulant action. Ketamine causes an increase in catecholamine releases and thereby causes a series of sympathomimetic effects such as increased heart rate, B.P, and cardiac output.

Warning:-

Ketamine should not be given as an analgesic in patients with head injuries as it increases cerebral blood flow oxygen consumption and intracranial pressure.

Side Effects

1.Disorientation

2.Sensory and perceptual illusions

3.Vivid and unpleasant dreams.

The side effects can be minimized or nullified by the concomitant or 5 to 10 minutes prior administration of diazepam

Routes of Administration:-

1. Intra muscularly

2.Intra venously.

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ANESTHETICS-I.V.-Contd...

2.BENZODIAZEPINES

For detailed information regarding benzodiazepines see Post under the heading Anxiolytics in this blog.

In anesthetic practice the most commonly used benzodiazepines are as follows:-

1.Midazolam

2.Diazepam

3.Lorazepam

These agents are used for preoperative sedation, intraoperative sedation for procedure not requiring analgesias such as colonoscopy and cardioversion, and as adjuncts with other agents to produce anesthesia.

Mechanism

As we already know that benzodiazepines bind at their own receptors very adjacent to the GABA-A receptor and thereby enhance the binding of GABA and its effect of chloride ion influx and thereby make neurons to be hyperpolarized which leads to the prevention of the action potential and the result is neuronal relax. Unlike barbiturates that act directly on the GABA, receptors benzodiazepines have slow onset of action.

Midazolam is useful as a preoperative anesthetic as it reduces the post-operative trauma by causing loss of memory of events (Amnesia) to calm the patient. Midazolam has the advantage of faster onset of action, greater potency, and faster elimination when compared with diazepam and other benzodiazepines.

Side Effects

1.Moderate to severe respiratory depression

2.Withdrawal symptoms

3. Contraindicated with opioids as the combination can produce cardiac and respiratory arrest.

Antagonist

Flumazenil is used to reverse benzodiazepine poisoning. As the drug is short-acting and the dose should be repeated every one hour.

3.OPIOIDS

Opioids are opium alkaloids available naturally as morphine and its derivatives.

Most commonly used opioids as anesthetic agents are as follows:-

1.Fentanyl

2.Morphine

Opioids are used as anesthetics in cardiac surgery and other major surgeries in which cardiac reverse is limited.

Fentanyl is more frequently used than morphine because of its greater potency and its lesser impact on the respiratory system than does morphine.

Side Effects

1.I.V.opioids will cause chest block so that expiration is difficult.

2.Respiratory depression

3.Postoperative trauma.

Antagonist

Naloxone is used as an antagonist to reverse opioid poisoning

4.INNOVAR

Innovar is generical droperidol, a butyrophenone, often combined with fentanyl and nitrous oxide to produce neurolept anesthesia, combined analgesia with amnesia.

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ANESTHETICS-Contd...

INTRAVENOUS ANESTHETICS:-

The followings are the general anesthetics that are unlike inhalers that can be given through the intravenous route to produce anesthesia.

Classes of I.V. Anesthetics:-

1.Barbiturates

2.Benzodiazepines

3.Opioids

4.Other Hallucinogens and Dissociative agents

1.BARBITURATES:-

As we have already known barbiturates are derivatives of barbituric acid either as salts or esters(a product with any alcohol). But salts are mostly used in practice.

Thiopental

An ultra short-acting barbiturates widely used as an adjunct with inhalation anesthetics or with any other.

It rapidly induces anesthesia in combination with other anesthetics. It has a fast onset of induction, and anesthesia occurs within 10 to 30 seconds after the injection.

Mechanism:-

As a barbiturates thiopental acting by binding at GABA-A receptor and thereby opening the chloride ion influx to produce hyperpolarization of the neuron beyond the threshold so that an action potential is nullified and the neurons are inhibited to relax.

The ultrashort duration of activity is accounted for by the high lipid solubility of thiopental which leads to the quick entry of the blood-brain barrier into the CNS and produces the anesthetic effect.

The effect lasts so rapidly because of the lipid solubility which results in rapid elimination from the CNS and the drug gets redistributed into the highly vascularised other muscles and fat and the effect lasts. 

Metabolism:

Thiopental is metabolized in the liver more slowly than its redistribution and hence after a prolonged infusion the recovery may be slow.

100% drug is metabolized in the liver.

Thiopental is a teratogenic drug and hence it can cross into the placenta.

Thiopental, after metabolized, is excreted in the urine.

Side Effects:-

1.On Cardio Vascular System:-

Thiopental lowers B.P. and cardiac output. Peripheral vascular resistance is not affected.

2.On Respiratory System:-

Thiopental depresses the respiratory center in the brain.

It decreases carbon dioxide response to the center and causes hypoxia. It reduces cerebral blood flow and thereby decreases the oxygen demand by the brain. This effect is useful in treating patients who has cerebral edema.

3.Laryngospasm

4.Bronchospasm

5.Acute porphyric crisis by inducing the synthesis of delta-aminolevulinic acid in the liver.

CNS-PART-VII-ANESTHETICS-Contd..

ANESTHETICS-Contd...

General Anesthetics-1.Inhalers:-

1.Halothane

2.Enflurane

3.Isoflurane

4.Desflurane

5.Sevoflurane

6.Nitrous Oxide

MINIMUM ALVEOLAR CONCENTRATION(MAC):-

The concept of MAC is used to define the potency of the inhaler anesthetics.

MAC is the minimum alveolar concentration of the anesthetics necessary to suppress movements among 50% of the individuals challenged by a Standardised Skin Surgical Stimulus at a steady-state(assuming at a minimum concentration for 15 minutes remained in the alveolar chamber) at 1 atmosphere (at sea level) 

The potency is calculated as an inverse proportion to the MAC. That means the greater the MAC for an agent the higher the amount of the agent needed to eliminate the movements of the individual in constant time and the lower the potency. (e.g.-Nitrous Oxide)

The MAC of a safer agent can be reduced by concomitant administration of some adjuncts such as analgesics or opioids.

1.HALOTHANE

The first generation halogenated anesthetic available in the market. Chemically it is Bromo- chlorotrifluoromethane.

It is a colorless, pleasant smelling halogenated ethane, unstable towards the light, and is stored in dark brown colored bottle mixed with thymol as a stabilizer. It is the only brominated anesthetic and because of its bromine content which increases its toxicity it is mostly replaced in developed countries by many modern inhalers.

Clinical Use:-

Because of its pleasant smell and lack of liver toxicity it is still used in pediatrics.

Kinetics and Metabolism:-

80% of the drug is eliminated in the expired air unchanged. The remaining 20% is metabolized in the liver to trifluoroacetic acid which may rarely cause (1 in 10,000) cause liver injury. Trifluoroacetic acid is excreted by the kidneys.

MAC of Halothane

MAC = 0.75%

Side Effects:-

1.Arrhythmia (by sensitizing the heart muscles to catecholamines.)

2.Decrease heart rate

3. Decrease cardiac output.

4.Hypotension with reduced peripheral resistance

5.Malignant hyperthermia-a common reaction of inhaled anesthetics composed of higher temperature, metabolic acidosis, tachycardia, and accelerated muscle contraction. Malignant Hyperthermia can be controlled by the administration of Dantrolene.

6.Liver toxicity particularly in adults (Halothane Hepatitis)

2.ENFLURANE:-

Enflurane is used to induce rapid anesthesia.

Metabolism and Kinetics

Approximately 2% of the drug is metabolized to a fluoride ion which is then excreted by the kidney.

The 98% remained is eliminated by expired air unchanged.

MAC of Enflurane

MAC = 1.6%

Side Effects:-

1.Cardio-Vascular-Decreased heart rate, Peripheral vascular resistance, and B.P.

Unlike halothane enflurane does not cause arrhythmias as it does not sensitize the myocardium to catecholamines.

2.Kidney damage by the fluoride ion after prolonged uses

Enflurane is contraindicated to those who have already kidney failure.

3.ISOFLURANE

Almost 100% of this drug is eliminated by expired air and is very safe as it does not pass into the system unless a fraction.

MAC=1.4%

Cardiovascular Effects

1.Increased heart rate

2.Decrease B.P by decreasing peripheral resistance

3.Malignant hyperthermia

Isoflurane does not sensitize the myocardium to catecholamines and hence does not cause 

arrhythmias.

4.DESFLURANE

Very similar to isoflurane this drug also 100% eliminated through expired air unless a fraction can enter into the system on prolonged use.

MAC = 6%

Side Effects:-

1. Cardiovascular effects are similar to isoflurane

2.Higher risk of Malignant Hyperthermia

5.SEVOFLURANE

Metabolism is very similar to enflurane as a small quantity can enter into the system and the remaining portion is eliminated by the expired air unchanged. But it differs from enflurane it does no cause nephrotoxicity as it is hypothesized that it is not excreted by the kidneys.

MAC=2%

Side Effects

1.Cardiovascular-Increase heart rate, lower B.P by reducing peripheral resistance,

It does not cause arrhythmias as with enflurane.

2.Malignant hyperthermia.

6.NITROUS OXIDE 

As it is a weaker anesthetic it is mostly used as an adjunct to induce anesthesia.

It can be administered either by inhalation or by I.V.

Nitrous oxide is expelled out without change as it is not metabolized.

MAC=100%, very weak as even if 100% nitrous oxide is given to the patients it does not attain the stage of surgical anesthesia.

Toxicity

1.Minimal cardiovascular effects

2.Bone marrow suppression if used for a long time

3.Neuropathies.

Contraindication

Pneumothorax-a condition in which there are closed cavities in the lung and the gas cannot escape out and will diffuse within the cavities to increase internal cavity pressure.

Precaution

The patient must be administered with sufficient oxygen during the recovery phase as nitrous oxide from the blood will diffuse into the alveoli and entirely replace the oxygen.

CNS-PART-VII-ANESTHETICS

ANESTHETICS-INTRODUCTORY

Anesthesia can be defined as a medical state which is composed of one or more of the following components of states such as analgesia(relief from the pain), state of muscle relaxation(paralysis), and loss of consciousness.

The patient who is given an anesthetic agent is said to be Anesthetized.

A nursing staff who is not a professional if give an anesthetic to a patient is known as an Anesthetist as in U.S.and North America (including Canada)

A professional who gives an anesthetic to a patient is known as Anesthesiologist.

Medical anesthesia can be divided into two types as 1. General and 2.Local.

General anesthetics are usually given by inhalation or through intravenous.

Local anesthetics are generally injected at the operative site to block the nerve conduction.

Stages of General Anesthesia

1.Analgesia or Stage of Induction:-

Loss of senses to feel pain. Consciousness is retained. The patient can talk.

2.Stage of Excitation:-

Delirium, a mental state of excitement, restlessness, incoherence with sweat.

3.Stage of Surgical Anesthesia:-

The patient is unconscious sufficiently to conduct surgery on him. Regular respiration is safely retained, with muscle paralysis and decreased vasomotor responses to painful impulses.

4.Stage of Medullary Paralysis:-

An irreversible stage if unattended, in which respiratory depression followed by coma and death occurs.

The pharmacokinetics of drugs plays an important role in attaining the different stages.

A slow-acting anesthetic like ether can give a well-distinguished stage. A fast-acting anesthetic would lead to the rapid occurring of the stages.

Induction of Anesthesia can be well defined as from the time of administration of the anesthetic 

up to the achievement of the state of surgical anesthesia.

The induction goal can be achieved as quickly as the drug reaches the central nervous system (CNS)

The complication of inducing anesthesia can be avoided by first injecting an ultra fast-acting and ultra short-lived anesthetic such as Propofol through I.V. so that the patient will rapidly progress through the first and second stages so that the anesthesia can easily enter into the state of surgical anesthesia.

The recovery from the anesthesia is the reverse process of induction. This depends on how fast the drug is removed from the CNS.

There are five factors influence the inhalation anesthesia as follows:-

1.Solubility

2.Pulmonary ventilation

3.The partial pressure of the inhaled drug

4.Alveolar blood flow.

5.Arteriovenous concentration gradient.

1. Solubility-This factor affects the rate of induction by the blood-gas partition coefficient. A low coefficient implies low solubility and a low soluble agent require fewer molecules to raise the partial pressure of the agent in the blood. Thus the equilibrium between the arterial partial pressure and the alveolar partial pressure is attained rapidly which leads to rapid induction. Recovery is similarly hastened by discontinuing the agent.

2. Pulmonary Ventilation-The rate and depth of lung ventilation (the minute ventilation) affect the rate of increase in the partial pressure of the anesthetic in the blood. An increase in minute ventilation results in an increased amount of agent and this effect is very important for agents with low solubility because they require a higher amount of the agent to attain equilibrium.

3. Partial Pressure-An increased concentration of the drug in the inhaled air mixture leads to higher concentration in the alveoli and thus increases the arterial partial pressure of the drug. Therefore a greater concentration is given initially to speed induction and then it is reduced to a maintenance level.

4. Alveolar Blood Flow-Increased blood flow causes more rapid uptake of the agent which attain quicker effect on the CNS.

5. Arterio-Venous Concentration Gradient-This depend on the tissue uptake of the drug. If more tissue uptake of the agent is there then there is a decrease venous concentration of the agent, which leads to a longer time to achieve an equilibrium between the arteriovenous concentration.

Factors Affecting Tissue Uptake Of the Anesthetics:-

1.Blood Partition Coefficient

2.Rate of blood flow to the tissue

3.Concentration Gradients between artery and vein.

Highly perfused tissues like the brain, heart, liver, and kidneys will exert greater influence on the arteriovenous concentration gradient.

Skin and skeletal muscles are low perfused and hence they exert a low influence.

Mechanism

The mechanism of action of the GA depends upon the availability of the agent in molecules. All anesthetics are assumed by acting on the action potential by nullifying them through increasing the threshold. Also acting by inhibiting the entry of sodium ion by decreasing the membrane permeability to them. The mechanism is not clear but on assumption, only.No receptors are involved inbound up with anesthetics.

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