Pharmacology 3rd stage
General anesthesia
Usually it involves the following : analgesia ,amnesia ,loss of consciousness ,inhibition of sensory and autonomic reflexes and skeletal muscles relaxation. Usually we can't produce all these effects with a single drug without causing major side effects ;therefore; in practice of general anesthesia ; we use combination of different drugs .
Drugs that are used in practice of G.A. include
1)Drugs used before surgery (pre-operative ) .
The principle aims are to provide the following :
A)Sedation :- We started with them as soon as possible ,because anxious patients with high levels of adrenalin and raised BMR is more liable to cardiac arrhythmias ,and more difficult to be anesthetized, include Benzodiazepines e.g. Diazepam ;Promethazine (antihistamine),chloral-hydrate(in children) .
B) analgesia :- they are used when there's an existing pain or as a supplement to an anesthetic agent having low analgesic effect like Morphine and Pethidine (Opioids) .
C) inhibition of parasympathetic nervous system to produce the following
1-decrease salivation and bronchial secretion ,which might increased by some irritant anesthetic agents .
2- decrease any tendency to bronchospasm .
3- decrease reflex bradycardia and hypotension ;all this can achieve by using Atropine and Scopolamine
D) for stomach ; as prophylaxis against aspiration pneumonia caused by aspiration of acid content of the stomach ,can use the following either :
- A single dose of an antacid .
- H2 receptor blockers (as Ranitidine, Cimetidine ,… )
2- Drugs used during surgery :-
The principle aims are to provide the following1- loss of consciousness .
2-analgesia .
3- muscular relaxation .
Typical G.A. is consist of :-
1)Induction ; achieved by short acting Thiopentone I.V. with Suxamethonium ,if
endotracheal tubation is intended .
2) maintenance :- achieved by
a- Nitrous oxide + volatile agent as Halothane or Ether .
b- Nitrous oxide + I.V. analgesia (as Morphine or Pethidine ) +NM. Blockers (Tubocurarine ).
3) Drugs used after surgery to ensure that :-
a) the effects of NM blocking agents and opioids induced respiratory depression have either worn off or reversed by an antagonist Neostigmine .b) re-gaining of consciousness .
c) relief of pain ( by NSAIDs or by Opioids ) .
Mechanism of action of G.A. :-
The principle site of action of G.A. at the neuronal lipid membranes , interfering with the movement of cat ions through ion channels , mainly sodium and potassium channels which are associated with action potential .Types of G.A. :- 2 types ; inhalation and I.V. agents .
Pharmacokinetic of Inhalation agents :-
The level of anesthesia is correlated with the tension of the anesthetic drugs in the brain tissue and this is depend on the development of tension gradient from high partial pressure delivered to the alveoli ,then through the blood to the brain and other tissues .
Factors that affect the uptake and distribution of anesthesia . :-
1) Solubility ; anesthetic gas which has high solubility in blood (as Ether ) when given at a steady concentration will provide slow induction because the blood act as a reservoir for the drug ; so that it doesn’t enter the brain easily until the blood reservoir has been filled ;while agents with low solubility as( NO or Halothane )will provide rapid induction because the reservoir is small and the gas is available to pass to the brain sooner .
2) Anesthetic concentration (tension) in inspired air ;this affect the maximum tension that could be achieved in alveoli and the rate of increase in tension in the arterial blood .
3) pulmonary ventilation ; the rate of raise in the anesthetic conc. In arterial blood is dependent on the rate and depth of ventilation ; hyperventilation that is induced by mechanical control of respiration will increase speed of induction ; hypoventilation induced by opioids will decrease the speed of anesthesia (onset of action ) .
4) pulmonary blood flow ; an increase in the pulmonary blood flow will slow the rate of rise the arterial tension especially for gases with high blood solubility . This occur because in this case there is increase of the amount of blood needed to be saturated (slow induction ) .
Elimination:-
The major rout of elimination is inhalation of elimination depend on the lungs and is affected by
1)solubility :- agents with high solubility → slow elimination (slow recovery ), while insoluble agents are eliminated at faster rate which may cause ( diffusion hypoxia ) because insoluble agents displace oxygen by fast accumulation in alveoli .
2) duration of exposure to anesthesia .
3) pulmonary blood flow .
4) ventilation .
Effects of G.A. :-
1) Sympathetic nervous system ; stimulation is produced by Ether , Cyclopropane and Nitrous oxide ;while it is inhibited by halogenated anesthetics as Halothane .
2)Parasympathetic nervous system ; Cyclopropane and Halothane are vagul stimulation that lead to bradycardia .
3)Cardiovascular system :-
Heart → all G.A. cause (dose related ) negative inotropic effect because of the membrane stabilizing action on the cells of the heart ,but there are difference between G.A. e.g. Halothane is more than Ether ; G.A. ;causes sensitization of the heart to the catecholamine ;so any exogenous catecholamine may lead to cardiac arrhythmia ..
Cyclopropane and Halothane are the most powerful negative inotropic effect .
On blood pressure :-
Ether lead to increase the blood pressure due to its ability to liberate catecholamine .Halothane ,Enflurane, Isoflurane lead to decrease the mean arterial blood pressure .
Halothane and Enflurane decrease the blood pressure due to decrease cardiac output ;while Isoflurane due to decrease systemic resistance with little effect on C.O.
Respiratory system :-
All inhaled anesthetics are respiratory system ;G.A. ,decrease tidal volume and increase respiratory rate except Nitric oxide and Ether .Isoflurane is the most potent respiratory depressant ;they depress mucocilliary function of airways → lead to lung collapse and respiratory infection .
They have a bronchodilator effect especially Halothane .
On renal system :-
They decrease GFR . and decrease the effective blood flow through the kidney ;so they will decrease renal function .On liver:-
They decrease the hepatic blood flow ;Halothane is hepatotoxic (sever hepatitis, may be fetal
On uterine smooth muscles:-
Nitric oxide have little effect on uterine smooth muscles ;Halothane ,Isoflurane and Enflurane are potent muscle relaxants ,but they may cause postpartum hemorrhage and they are may be used in intrauterine fetal manipulation .
Miscellaneous effects :-
They cause nausea and vomiting especially Ether and Cyclopropane .
They decrease temperature due to hypothalamic depression .
Halothane cause malignant hyperthermia and acidosis .
Individual anesthetics :-
divided into 1) Gaseous anesthetics . 2) volatile liquid anesthetics ;both types by inhalation rout .
Gaseous anesthesia :- they are gases at room temperature like NITRIC OXIDE .
Nitric oxide :-
It is gas at room temperature ,sweet odour , cause laugh .
Advantages :-
1)It reduces the requirement of more potent and toxic general anesthetics (called second gas effect ) .
2) Rapid induction and recovery .
3) Neither inflammable nor explosive ,
4) Has strong analgesic action .
5) It produces light anesthesia without demonstrable depressing the respiratory or vasomotor centre .
Disadvantages:-
Nitric oxide has little muscle relaxing effect ,so, it must be administrated with more potent anesthetics and muscle relaxant to produce a state of full surgical anesthesia .Clinical uses :-
1) Maintenance of surgical anesthesia in combination with other surgical general anesthetics and muscle relaxants .
2) In sub anesthetic does to maintain analgesia in obstetric practice .
3) Emergency management of injuries .
4) During post operative physiotherapy .
5) For refractory pain in terminal illnesses .
Contraindication s:-
1)Intestinal obstruction
2) Occlusion of middle ear .
3) Chronic obstructive airway disease
4) Arterial air embolism
Nitric oxide cause diffusion hypoxia because the recovery is very rapid ,so getting off the gas will take oxygen with it leading to diffusion hypoxia . ( a continued administration of O2 may be necessary during recovery especially in elderly .
Adverse effects :-
1)nausea and vomiting .2) prolong and repeated exposure may be associated with bone marrow depression.
Drug interactions :-
Addition of 50% of NO and O2 mixture to another inhalation anesthesia like Halothane will reduce the required dose of this drug by 50% and this is called (second gas effect ) .
Volatile liquid agents :-
Ether (diethyl ether ); it is irritant ,inflammable, bad odour , colorless and highly volatile .
Advantages :-
1) potent and reliable anesthetic .
2) vasomotor centre is resistance to the dose required for full anesthesia .
3) Full muscle relaxation achieved in deep anesthesia .
4) It is a bronchodilator used to treat bronchospasm resistant to other drugs ,but it is irritant to upper respiratory tract .
5) Doesn’t sensitized the heart to catecholamine or other sympathomimetic agents (no fair of arrhythmia ) .
Disadvantages :-
1)Explosive and flammable ;so contraindication in dithermy .
2) Irritant , leading to excessive bronchial and salivary gland secretion which can be stopped by Atropine .
3) bad odour .
4) Frequent post operative nausea and vomiting .
5) Induction and recovery period are very long ;because it is highly soluble in blood .
Clinical uses :-
It was used in induction and maintenance of anesthesia in surgery .Contraindications :-
1)Sever hepatic disease .
2) Raised CSF pressure .
Precautions :-
1-In febrile children ,it increases the risk of convulsion .
2- Dangerous use of dithermy with it .(flammable, explosive).
3-In pregnancy lead respiratory depression in fetus and postpartum hemorrhage due to relaxation and loss of uterine tone .
Drugs interactions :-
1) It potentiates neuromuscular blockers because it is muscle relaxant .2) With β –blockers lead to myocardial depression ;because Ether is heart depressant .
Halogenated agents:-
1)Halothane :-
colorless ,volatile ,non irritant ,sweet odour ,neither inflammable nor explosive ,liquid at room temperature .
Advantages :-
1-Potant non inflammable .
2- Smooth and rapid indication and rapid recovery from anesthesia due to low solubility .
3- No effect on bronchial and salivary secretion (non irritant )
4- Low incidence of post operative nausea and vomiting .
Disadvantages :-
1-Sever hepatitis ( may be fatal ) .
2- In anesthetic dose ,it depresses both cerebral function and sympathetic activity .3- Should be combined with NO, to produce surgical anesthesia (due to its cardio depressant effect ) .
4- Should be combined with muscle relaxants to prepare patients for surgery .
5- It suppresses sympathetic activity ,but sensitized the heart to catecholamine .
Adverse effects :-
1)Cardiac arrhythmias .2) Hepatic damage .
Drug interactions :-
1-It potentiates anti hypertensive drugs (cardio depressant ) .
2- Giving Atropine to reduce the risk of hypotension .
2)Enflurane :-
Less potent , cardio respiratory depressant; less metabolized than Halothane ,not sensitized the heart to catecholamine .
3)Isoflurane :-
Intermediate potency between Halothane and Enflurane; stabilizes heart rhythm ; it decrease the systolic blood pressure due to decrease the vascular resistance .
I.V. anesthesia :-
They are highly lipid soluble ;reach to CNS rapidly ;so they have extremely rapid induction . I.V. anesthesia can be eliminated by redistribution to adipose tissue where they are inactive .Thiopentone ( Thiopental) :-
Very short acting barbiturate ;extensively bound to plasma plasma proteins ;administered
parent rally (i. v.) ;rapidly induces hypnosis and anesthesia without analgesia ;it distributed extensively in highly vascular tissue of brain ,then subsequently diffuses selectively into fatty tissues where it is pharmacologically inactive .
Advantages :-
1)Acting quickly (within about 30 seconds ) .
2) The anesthetic effect last for 4-7 minutes (useful in brief operation ) .
3) Anesthesia induced pleasantly without excitement .
Disadvantages :-
1)Insignificant analgesic effect .2) Very short muscle relaxant effect .
3) Cannot be used alone as anesthetic due to short period of action .
Clinical uses :-
Induction of anesthesia prior to administration of inhalational and other anesthetic .Contraindications :-
1)Allergy to Barbiturates .2) Sever cardiovascular diseases or hypotension .
3) Obstructive air way diseases like in status asthmatics .
4) Addison's disease .
5) hepatic dysfunction .
6) Myxoedema .
Side effects :-
1)Short period of apnea .
2) Rapid injection lead to sever hypotension .3) Coughing , sneezing and laryngeal spasm .
4) Very irritant if it outside the veins .
Ketamine :-
In anesthetic dose it produces a special type of anesthesia known as ( dissociative anesthesia ) ,which is a state of analgesia with light hypnosis .Anesthesia produced by Ketamine is not potent or effective .Advantages :-
1)Produce anesthesia for 15 min. which is characterized by profound analgesia .2) Less vomiting incidence .
3) production of anesthesia is associated with sympathomimetic effect ( help in blood pressure maintenance ) .
4) It rarely induces bronchospasm ( useful in asthmatic patients ) .
Disadvantages :-
1) No muscle relaxing effect .2) Hallucination can occur during recovery .
3) It increase the heart and increase the intracranial pressure and I.O.P. ( due to its sympathomimetic activity ) .
Clinical uses :-
1)Sub anesthetic dose used to provide analgesia for painful procedures of short duration e.g. bone marrow sampling and radio therapeutic procedures .
2) Used for indication and maintenance of anesthesia for short lasting procedures that don't require muscle relaxation .
Contraindications :-
1)Moderate and sever hypertension .2) Congestive heart failure .
3) History of C.V.A. or cerebral trauma or any condition associated with increase I.C.P. .
4) Chronic alcoholism .
5) eye injury and increase the I.O.P.
6) Psychiatric disorder e.g. Schizophrenia .