PHARMACOKINETICS AND PHARMACODYNAMICS OF DRUGS ON CPB

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-

1. Decrease protein binding as decrease in albumin and alpha 1 glycoprotein which has implications for protein binding of drugs due to alterations in bound to free drug ratio.
2. Decrease RBCs – for drugs that are sequestrated in RBCs
3. Decrease in amount of free drug
4. Alteration in organ blood flow

2)Hypothermia:-

• Shifts fluid from intravascular to interstitial spaces,this alters volume of distribution
• It also activates autonomic and endocrine reflexes producing peripheral vasoconstriction,this alters to distribution of blood flow
• It decreases metabolism by inhibiting enzyme function

As a result of this changes- pharmacokinetics are altered through following mechanisms-

1. Peripheral vasoconstriction decrease absorption of drugs
2. Decreased absorption of drugs given by other than intravenous route
3. Fluid extravasation cause drug movement from central to peripheral compartment
4. Vasoconstriction decreases the reuptake of these drugs from peripheral to central compartment back
5. Hypothermia induced enzyme inhibition  decreases clearance and increases half life of drugs.
6. Decrease renal blood flow  decreases GFR and decreases tubular secretion.Therefore, alters drug excretion.
7. Hypothermia increases solubility of drugs and volatile agents.
8. Drugs like - Esmolol, Clevidipine, Remifentanil, Atracurium,Cis-atracurium.All depend on enzyme degradation so altered clearance.
9. Muscle relaxants- concentration may increase as volume of distribution altered
10. Opioids- sequestrated ,may come in central compartment on rewarming and postoperatively and increase plasma concentration.
11. Clearance of digoxin, fentanyl &cephalosporins is reduced after CPB.
12. Altered CNS drug penetration
13. Reduced biotransformation rate with decreased clearance and increased elimination half life

3) Perfusion:-

Non- pulsatile flows alter tissue perfusion

1. Lungs- during CPB lungs are excluded from circulation
2. Opoids, propofol,diazepam are sequestrated in lungs and lungs form reservoir once normal circulation is established
3. Liver – hepatic blood flow altered and metabolism of following drugs is altered:
   • Vasopressin
   • Dopamine
   • Dobutamine
   • NTG
   • Anaesthetic agents like propofol,fentanyl

4)Acid Base status:-

• There are marked changes in acid base balance during CPB resulting in changes in ionized and unionized drug concentration affecting drug binding.
• Changes in pH as in pH stat or alpha stat may alter blood flow in organs like cerebral blood flow in pH stat.
• pH stat – may affect the degree of ionization and protein binding causing increase/decrease in free active drug concentration.

5) Sequestration:-

Drugs are taken up by various components by CPB circuit itself.

Oxygenators take up -

• Volatile anaesthetic agents
• Propofol
• Opoids
• Barbiturates
• Antibiotics
• Benzodiazepines
• NTG
• Nifedipine
• Nimodipine

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 :-

1. Protein binding
2. Volume of distribution
3. Solute & membrane interaction
4. Solute charge
5. Protein concentration
6. Ultrafiltration line suction
7. Blood flow through hemofilter
8. Viscosity of blood & degree of hypothermia
9. Length & diameter of tubing
10. Venous resistance
11. Filter – surface area & properties

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 –

1)Protein Binding:-

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)

• Albumin binding –thiopentone, diazepam, phenytoin
• Alpha1glycoprotein- lignocaine,quinidine, propranolol
• Renal & liver diseases- decrease albumin concentration
• Heparin releases free fatty acids - These FFA displaces drugs from protein binding and increase free drug concentration and gives more effects

2)Tissue Binding:-

Free drug penetrates tissues

There it binds with tissue proteins like heart and lungs which act as drug reservoir

3)Age:-

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 :

• Body fat distribution is different
• Immature organ function
• Immature clearance

4)CNS Penetration:-

Hysteresis may be seen, which means effect and peak plasma level discrepancy.

5)Temperatures:-

Hypothermia decreases anaesthetic requirements due to

• Changes in receptor affinity
• Decreased release of excitatory amino acids : glutamate & aspartate therefore exerting cardioprotective effect.

6) Acid- Base & Electrolytes:-

Altered tissue flow causes acidosis. This changes response to catacholamines protein binding and degree of ionization.

7)Receptor Density:-

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 -

• composition of the priming solution
• presence of pulsatile perfusion
• use of mechanical filtration
• type of oxygenator
• type of extracorporeal circuit
• temperature during CPB
• or by the avoidance of the use of CPB.

 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.

- by Dr Amarja