Pharmacokinetics and Pharmacodynamics of Drugs on CPB
Pharmacokinetics - The study of how the body processes the drugs including metabolism and excretion is called pharmacokinetics (what the body does to the drug).
Pharmacodynamics - The study of how drugs interact with cells to produce effects is called pharmacodynamics (what the drug does to the body).
Changes in Pharmacokinetics of drugs –
1)Hemodilution:- occurs as a result of priming of CPB circuit which leads to-
As a result of this changes- pharmacokinetics are altered through following mechanisms-
Non- pulsatile flows alter tissue perfusion
4)Acid Base status:-
Drugs are taken up by various components by CPB circuit itself.
Oxygenators take up -
PMP Oxygenators – has decreased diffusion coefficient for volatile agents than polypropylene oxygenators
This makes use of volatile gases with PMP oxygenators problematic causing increased perfusion pressure.
RBCs – may serve as reservoir of drugs
Hemofiltration – Heparin/Aprotinin/Cephazolin are not removed by hemofiltration.
Factors influencing movement of drugs across the membrane :-
Changes in pharmacodynamics during CPB:-
The ability of drug to produce its effect depends on the ability of free unbound drug to reach its receptors and bind to it to transduce the signal.
The factors that may affect this are –
In blood, drug exists in free (unbound) form in equilibrium with bound drug
Drug binds with plasma proteins: albumin (acidic drugs) & alpha1 glycoprotein (basic drugs)
Free drug penetrates tissues
There it binds with tissue proteins like heart and lungs which act as drug reservoir
In elderly patients organ function,drug clearance is decreased, decreased adipose tissue so pharmacodynamics are altered
CNS sensitivity to drugs is altered so less drug is required
In infants and children- Altered drug effects as :
Hysteresis may be seen, which means effect and peak plasma level discrepancy.
Hypothermia decreases anaesthetic requirements due to
6) Acid- Base & Electrolytes:-
Altered tissue flow causes acidosis. This changes response to catacholamines protein binding and degree of ionization.
Number of receptors available- determines the effect of drug
So if patient with Congestive heart failure: beta receptor downregulation which causes defect in receptor transduction and impaired synthesis and reuptake of noradrenaline so beta agonists may have reduced effect during or following CPB.
SIRS has a significant impact on drug pharmacokinetics and pharmacodynamics:-
CPB and cardiac surgery initiate a systemic inflammatory response as a consequence of blood contact with a foreign surface and complement activation, development of ischemia and reperfusion injury, and the presence of endotoxin.
The magnitude of SIRS depends on -
As part of the response cytokines are released including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, IL-2, IL-8, IL-10, and nitric oxide.
TNF-alpha, IL-1, and IL-6 reduce free drug levels and IL-6 and nitric oxide may alter distribution of drugs.
Activation of neutrophils with generation of oxygen-derived free radicals may injure tissue, particularly endothelium, leading to a capillary leak syndrome, which may affect volume of distribution for drugs and penetration to receptors.
Reductions in liver blood flow may reduce clearance of drugs with a high hepatic extraction ratio (e.g., fentanyl).
Cytokines may inhibit reticuloendothelial function and thus impair drug metabolism.
TNF-alpha, IL-1beta, and IL-6 are endogenous pyrogens that may produce an anesthetic-sparing effect.
Specific drugs with CPB influenced properties:-
Opioids &Intravenous anaesthetic like (benzodiazepines,propofol,barbiturates) - Concentrations decrease with onset of CPB but free drug concentration rapidly return to baseline.
Neuromuscular blockers- effects markedly influenced by hypothermia.
Antibiotics- have variable tissue penetration.
Lignocaine- higher loading dose is indicated(2.5mg/kg).
References : Richard I.Hall, Cardiopulmonary Bypass: Principles and Practice by Glenn P. Gravlee.