Pharmacokinetics of inhalational agents relavant to anaestheist
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Pharmacokinetics of inhalational agents relavant to anaestheist

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  • 1. PHARMACOKINETICS OF INHALATIONAL AGENTS RELAVANT TO ANAESTHEIST
  • 2.
    • BY
    • Dr.NARASIMHA REDDY M.D,D.A,
    • PROFESSOR AND HOD,
    • DEPT OF ANAESTHESIOLOGY,
    • KURNOOL MEDICAL COLLEGE,
    • KURNOOL.
  • 3. PARMACOKINETICS contd
    • INTRODUCTION
    • HISTORY
    • PHARMACOKINETICS
  • 4. INTRODUCTION
    • History started with
    • inhalational anaesthetic agents.
    • Modern equipment
    • Electronic gadgets
  • 5. HISTORY
    • In 1951 – Seymour Kety
    • In 1963 – Concept of MAC by Merkel and
    • Eger.
    • In 1974 – Redefinition by Eger.
    • Other people who contributed
    • Severinghaus, Mapleson and Epstein.
  • 6. DEFINITIONS
    • Pharmacokinetics: what the body is doing to the drug.
    • Pharmacodynamics: what the drug is doing to the body.
  • 7.
    • Def. of some symbols:
    • P D – Delivered partial pressure (tension)
    • F D – Delivered concentraion (fraction)
    • P I – Inspired partial pressure
    • P A – Alveolar partial pressure
    • F A – Alveolar concentration
    • P a – Arterial blood partial pressure
    • P CNS – Brain partial pressure
  • 8. PARMACOKINETICS contd
    • Anaesthetist manipulates concentration of anaesthetic agent in the brain indirectly.
    • A series of partial pressure gradients exists from the anaesthetic machine to brain tissue.
    • Partial pressure of anaesthetic agent in the alveoli determines the partial pressure of anaesthetic agent in the brain.
  • 9.  
  • 10. PARMACOKINETICS contd
    • The factors involved for difference in tension are:
    • Ventilation
    • Uptake
    • Concentration
    • The factors which influence the input of anaesthetic agents – INFLOW FACTORS
    • The factors which influence the loss of anaesthetic agents from alveoli- OUTFLOW FACTORS .
  • 11. INFLOW FACTORS
    • Flow rate of carrier gas.
    • Conc. delivered by vaporizer.
    • Breathing systems.
    • a) Non rebreathing VS rebreathing.
    • b) Total volume of the system.
    • c) Arrangement of components.
    • d) Agent solubility in components.
  • 12. INFLOW FACTORS CONTD.
    • 4) Effective alveolar ventilation
    • Tidal volume
    • sponta vs controlled
    • Breath rate
    • Dead space
    • FRC
    • 5) Conc. Effect and Second gas effect.
  • 13. FLOW RATE OF GAS/VAPORIZERS
    • FLOW RATE OF CARRIER GAS :
    • Precision flow meters which can deliver 100ml – 10lt/min
    • Fine needle valves
    • Flow meters are specific for each gas.
    • VAPORIZERS :
    • Compensated for back pressure and barometric pressure.
    • The outflow depends on saturated vapour pressure and carrier gas splitting ratio.
  • 14.  
  • 15. FLOW FROM COMMON GAS OUTLET
    • Factors which influence the conc. Of anae. agent delivered from common gas outlet:
    • Total gas flow rate (vol/time)
    • Conc of anaesthetic agent (vol/cent)
  • 16. TENSION OF ANA. AGENT IN THE INSPIRED GAS
    • Corrugated rubber tubing
    • 1) Non- rebreathing
    • 2) Partial rebreathing
    • 3) Total rebreathing
    • In rebreathing the gas mixtures may be diluted by residual gases in the system.
    • Vol. of circle system is 4-5lts. Reservoir bag 2lts.
    • To wash out this vol. at 5lts/min may take 5-6minutes.
    • The arrangement of components in the circle system is designed to give highest conc. Of the anaesthetic agent and oxygen.
  • 17. TENSION OF ANAE. AGENT IN ALVEOLAR GAS
    • Depends on 2 factors:
    • Conc. Of anae. Agent
    • Alveolar ventilation
    • If ventilation is controlled or assisted the conc. Of anae. agent raises rapidly. Denitrogneation enhances this effect.
    • Alveolar ventilation is a function of
    • a) tidal vol.
    • b) dead space
    • c) ventilatory rate
    • The tidal vol. and ventilatory rate can be manipulated by assist or controlled ventilation.
    • The dead space is increased by certain drugs and position.
  • 18. FRC
    • FRC is less in supine position, abd distension, pregnancy and obesity.
    • ↓ FRC -> Induction and recovery.
    • ↓ FRC -> Hypoxia at a faster rate
    • “ Of the steps between delivered and brain anae. Partial pressure none is more pivotal than that between the inspired conc. and alvoelar gases”.
  • 19. CONCENTRATION EFFECT
    • when a high conc of an anaesthetic agent is administered in the inspired gases a very large conc gradient between the alveoli and blood exists especially if partial denitrogenation is done, regardless of the solubility of the anaesthetic agent.
    • Nitrous oxide is less soluble but 30 times more soluble than nitrogen.
    • The total volume of nitrous oxide absorbed into the body over 1-2.5hrs after anaesthesia can be up to 30lts, 5-6lts being absorbed in the first 10minutes.
    • “ The rate of raise of FA/F1 ration is determined by Fi and alveolar ventilation”
  • 20.  
  • 21. CONCENTRATING EFFECT
    • As half of N 2 O is removed from the lung the conc of second gas increases from 1-1.7 although the absolute volume does not change. The relative conc increases because of the reduction in total lung volume.
  • 22.  
  • 23. SECOND GAS EFFECT
    • The second gas effect has two components
    • one concentrating effect and
    • Second one is – if lung is not allowed to collapse but is replenished with gas containing same conc then more of second gas is brought in to the lung. According to Epstein the increased inspiratory ventilation is the second part of second gas effect. The imp. of conc. vs increased inspired ventilation to the second gas effect depends on the solubility of the second gas. If solubility is more the explanation lies in increased ventilation and if solubility is less the concentrating effect is imp.
  • 24. OUTFLOW FACTORS
    • The gradient in the anaesthetic agent pps from the alveoli to the CNS can be divided into two steps:
    • 1)from the tension of anaesthetic agent in the alveolar gas to tension of anaesthetic agent in the arterial blood.
    • 2) from the tension of anaesthetic agent in the arterial blood to the tension in the CNS.
    • “ The partial pressure of the anaesthetic agent in the alveoli governs the PP of the anaesthetic in the body tissues including Brain.”
  • 25. MAC
    • Def: conc of an agent in the alveoli at 1 atm that prevents skeletal muscle movement in 50% of patients in response to supramaximal stimulus.
    • It is used as an index to measure the potency and relate the potency of other agents.
    • MAC 1 corresponds to ED55.
    • MAC usually expressed as vol % and it does not change with altitude. Usually 1.3 to 1.5 times MAC is necessary for operations and this is equal to ED95.
    • MAC bar: is the alveolar conc required to “block autonomic reflexes”. It is 1.5-2times the MAC.
    • MAC awake: It is return of consciousness MAC 0.5.
    • MAC 0.2 is patient responding to commands.
    • “ MAC is a concentration but anaesthetic effect is produced by partial pressures”.
  • 26. MAC contd
    • Factors that raise the MAC:
    • 1) Hyperthermia
    • 2) Ch. Alcohol abuse.
    • 3) Abuse of CNS depressants.
    • 4) Cocaine and amphetamines
  • 27. MAC contd
    • Factors that decrease MAC:
    • 1) Old age
    • 2) Hypothermia
    • 3) Pregnancy
    • 4) Hypotension
    • 5) Lithium
    • 6) α-2 adrenergic agonists
    • 7) Lidocaine
    • 8) Opioids
    • 9) Benzodiazepines
    • 10) Barbiturates
    • 11) Calcium channel blockers
    • 12) N 2 O.
  • 28. TEN. OF ANAE. ARTERIAL BLOOD
    • The uptake of anaesthetic agent from the alveoli which has the effect of lowering the agent is a product of three factors:
    • 1) Solubility of the agent in the blood (blood/ gas par coefficient)
    • 2) Pul blood flow
    • 3) Alveolar to mixed venous PP difference
  • 29. SOLUBILITY OF THE AGENT
    • A partition coefficient expresses the ratio of the solubilities of an agent in each 2 phases i.e such as blood and gas.(table).
    • According to blood gas par. coefficients the inhaled anaesthetics can be grouped as:
    • 1) poorly soluble anaesthetics
    • 2) moderately soluble anaesthetics.
  • 30.  
  • 31.  
  • 32.  
  • 33. EQUILIBRIUM
    • Def: condition where no difference in partial pressures of agent exists between two phases such as gas phase in alveoli and the dissolved phase in blood.
    • Expressed in conc. and not as partial pressures.
    • The larger the blood/gas par coefficient the more soluble the agent in the blood and larger the uptake by the blood and reduction in partial pressure in the alveoli(PA) and consequent reduction in Pa and Pcns.
  • 34. OVER PRESSURE EFFECT
    • More soluble the agent higher conc required during induction than normally required for maintenance.
    • Poorly soluble agents demonstrate a more rapid raise of FA/FI during induction and reach equilibrium at a faster rate and changes in ventilation have little effect.
    • “ When partial pressures are at
    • equilibrium between two phases
    • concentration may be dissimilar ”
  • 35.  
  • 36. PULMONARY BLOOD FLOW
    • Increase in cardiac output slows down the raise of alveolar conc even though the equilibrium is attained faster in between tissue compartments
    • Effect of increase in cardiac output on FA/FI ratio is more pronounced with soluble agents. Decrease in co with soluble agents can cause high FA/FI ratio and sudden increase in PP in CNS. This is further complicated by increase in alveolar ventilation. Profound depression of CVS and CNS can occur.
  • 37.  
  • 38. ALVEOLAR TO MIXED VENOUS PP DIFFERENCE
    • Highest during induction and gradually comes down.
    • Reflects the total tissue uptake of anaesthetic agent over time .
    • tissue saturation with anaesthetic agent -> gradual raise in PP and FA/FI ratio also increases. PA/PI approaches equilibrium and concomitantly Pa/PA also reaches equilibrium
    • “ Increased pul blood flow and increased
    • blood solubility have more pronounced
    • effects with more soluble agents”
  • 39. VENTILATION/PERFUSION MISMATCH
    • In rt to lt shunts a portion of the pul. blood flow will not come in contact with inspired gas producing a great gradient between alveolar to arterial anaesthetic agent.
    • The gradient depends on the size of the shunt.
    • The partial pressure (Pa ) is less and so the Pcns.
    • In VA/VQ abnormalities the anaesthetic effect with poorly soluble agents is delayed than the more soluble agents
  • 40.  
  • 41. FRC
    • In obese patients ERV and FRC are reduced, more so in supine position nearly to closing volumes producing true rt to left shunt.
    • Smaller FRC theoretically must produce faster equilibration between PI, PA and pa but because of collapse of alveoli and shunting there is a delay in uptake of anaesthetic agent so that Pa/PA ratio is reduced and so induction is delayed.
  • 42. TENSION OF ANAESTHETIC AGENTS IN CNS:(PCNS )
    • several characteristics of the body tissues regulate the amount of anaesthetic agent reached from the blood :
    • 1) Solubility in particular tissue and
    • 2) Blood flow through the tissue
    • 3) Volume of the tissue
    • 4) Gradient between arterial to tissue concs.
  • 43.
    • Tissues are categorized according to perfusion and solubility characteristics into 4 groups:
    • 1) Vessel rich group (VRG)
    • 2) Muscle group (MG)
    • 3) Vessel poor group (VPG)
    • 4) Fat group (FG).
  • 44.  
  • 45.
    • 1) VRG: Brain, heart, kidney, liver and endocrine glands.
    • Mass is < 10% of body wt but they receive 75%
    • of CO.
    • Perfusion ratio is 70ml/100ml of tissue/min.
    • Takes large amount of anaesthetic while induction.
    • Equilibration with arterial pp of anaesthetic is>
    • 90% complete with in 8 mts.
    • 2) MG: After 8minutes the tissue uptake of anaesthetic
    • agent is mainly by muscle and skin.
    • MG is 50% of body wt and receives 20% of CO.
    • Perfusion rate is 3ml/100gm/min.
    • Takes longer time to get equilibrium may be 3-
    • 4hrs.
  • 46.
    • 3) FG: Acts as final large reservoir of anaesthetic
    • agent.
    • Affinity is 25-75 times> affinity of blood.
    • FG 20% of body wt and receives 6% of
    • COP.
    • Perfusion ratio of 3ml/100ml/min.
    • Equilibration may not occur in clinical
    • anesthesia.
  • 47. Distribution to CNS
    • various areas of brain and spinal cord play an important role in getting equilibrium with anaesthetic agent and by which end result occurs, like loss of consciousness movement, analgesia, depression and blockade of autonomic reflexes and relaxation.
    • Since brain tissue is highly perfused and raise of tension of anaesethic agent is rapid and uptake ceases with in a short period, the raise is more with poorly soluble agents but depends on pressure gradient between agent, PA, Pcns and CBF.
    • “ Tissue uptake of anaesthetic is governed by tissue solubility, perfusion, tissue size and tissue saturation” .
  • 48. RECOVERY FROM ANAESTHESIA
    • Nearly all the factors that govern the rate at which the alveolar conc raises in induction apply to recovery.
    • The immediate decline of the anaesthetic level is rapid because of the wash out of the FRC.
    • As the ventilation removes the anaesthetic from the alveoli more and more anaesthetic gets washed into the alveoli from the tissues. This depends on the venous alveolar anesthetic gradient which will be higher for more soluble agents. So the fall in alveolar levels will be slow when compared to less soluble agents.
  • 49. DIFFERENCES BETWEEN INDUCTION AND RECOVERY
    • Mainly two:
    • 1) There is no such counterpart for an overpressure effect and the elimination of anaesthetic depends on the return of the agent from the tissues.
    • 2) Since all tissues do not have the same PP at recovery and although the vessel rich group may be getting depleted of its anesthetic content, fat may still take up anaesthetic agent in the blood.
  • 50. DIFFUSION HYPOXIA
    • Patient if allowed to breath room air on discontinuation of anaesthesia with nitrous oxide hypoxia can occur.
    • On recovery from anaesthesia large volumes of nitrous oxide flood the alveoli; this dilutes the gases inside the alveoli including oxygen.
    • As large volumes of nitrous oxide is washed out it takes carbon dioxide also suppressing the respiratory stimulation.
    • Hence diffusion hypoxia is due to dilution of alveolar gases and respiratory depression.
    • This problem exists for the first 5-10min during recovery and this is more important in a pt with existing respiratory disease.
    • This can be managed by discontinuing of nitrous oxide few minutes before and giving 100% oxygen for some time.
  • 51.  
  • 52. THANK YOU