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Amphetamines are central stimulants but they are frequently used as drugs of abuse. This we will see in a separate article in the other blog 'MAS PHARMACY AND HEALTH REVIEW'
Amphetamine is generally an equal mixture of the two enantiomers the Levo and dextro amphetamines
Further amphetamines are available in the market as follows:-
Amphetamines are chemically a derivative of the endogenous phenylethylamine.
Mechanism
Amphetamines are powerful central stimulants work by releasing norepinephrine and dopamine from their storage.
Physiology
Amphetamines by stimulating CNS through the release of catecholamines they mainly affect sleep centers of the hypothalamus which regulates the sleep cycles.
1. Amphetamine causes euphoria to the individuals who are addict to it. Euphoria is a kind of daydream or imagination of impossible thoughts associated with belief and confidence.
2. CNS stimulation reduces tiredness and fatigue, improves alertness, and cognitive ability.
3. Elevate B.P-Hypertension.
4.Elevate breathing
5. Blunts hungry.
6. Amphetamine is an aphrodisiac, a drug that stimulates sexual desire.
Clinical Use
1.To improve sleep disorders(Anti-Narcoleptic)
2.Attention Deficit Hyperactivity Disorders(ADHD)
3.Appetite Control.
Route Of Administration
Oral
Metabolism and Kinetics
Amphetamine is well absorbed orally and 75 % is bioavailable in case of dextroamphetamine.
Amphetamine is a weak base with a pH of 9.9 and in the alkaline gut, it easily gets dissociated into the highly lipid-soluble free base and easily absorbed by the fatty gut villus.
15 to 40% are absorbed by the plasma proteins
Amphetamine is metabolized in the liver and excreted in the urine.
Amphetamine is eliminated by the body within two days of the last dosage taken.
Elimination is increased and the half-life is decreased by acid diets and vice versa.
Contraindication
Amphetamine should not be taken by those who are using MAOIs for their mobility disorders. Because MAO should not be inhibited any way if amphetamine is in usage as amphetamine is acting by releasing catecholamines from their stores which are metabolized by MAO. Inhibiting MAO will result in an excessive adrenergic crisis.
Adrenergic Crisis Treatments
Chlorpromazine a neuroleptic is the drug of choice to neutralize amphetamine poisoning as it effectively blocks the alpha-adrenergic receptors which are responsible for CNS disturbances and hypertension.
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.
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.
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 throughglucuronidation 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
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.
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-Areceptor 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.
