Introduction to Pharmacokinetics
Objectives:
- introduction to pharmacokinetics in drug dosing and therapeutic management
- To understand the 4 main components of pharmackinetics (ADME)
- Preparation for attendant PK workshops in ELM2 clin pharmacology next week
Objective based questioning:
Content:
What is pharmacokinetics?
It is how the body moves and processes drugs.
The sequence of clinical pharmacological events
- Drug dose into body
- Pharmacokinetics (how the body moves and processes drugs)
- drug concentration at the site of action
- Pharmacodynamics (How the drug effects the body)
- Drug effects
Pharmacokinetic principles
ADME
Absorption Distribution Split between the blood and the body compartments Metabolism (Part of Clearance) Excretion (Part of Clearance) ABDCs Administration This is related to the route dose and adherence by the patient Bioavailability absorption first pass metabolism and activation Distribution (This then feeds onto pharmacodynamics and clearance simulatanously) diffusion and transport Clearance how much is metabolised and cleared
Drug dosing
Optimal therapeutic range is between the minimum toxic concentration and minimum effective concentration
Pharmacokinetic profile over time
Generally you want the dosing to stay within this range. The time of concentration within the optimal theraputic range is called the effective duration
AUC
If you track the area under the curve you can get the amount of drug in the plasma and therefore fraction that reached the blood stream
Dosing regimes in relation to sustaining OTR
Multidose oral to keep a drug sustainably in the Optimal Theraputic Range.
Enteral vs Parenteral (not enteral)
Enteral
- Oral sublingual and rectal Parenteral
- Systemic delivery (iv bolus/infusion etc)
- Nonsystemic (topical and inhalation)
Enteral vs Parenteral
Cost benefits of enteral delivery
| Route of delivery | Advantages | Disadvantages |
|---|---|---|
| Oral delivery | Easy to administer Inexpensive formulation | Possibly slow onset, • Impossible in unconscious/ vomiting; • Harsh GI environment; • Subj. to 1st pass metabolism. |
| Subligual delivery | • Rapid absorption into buccal venous drainage • Avoids 1st pass metabolism | • Patient may swallow the drug! |
| Rectal delivery | • Rapidly Effective in unconscious patient • 50% of drug avoids hepatic 1st pass metabolism. | • Absorption can be irregular and incomplete; • Certain drugs can cause irritation of rectal mucosa. |
Cost benefits of parenteral delivery
| Route | Advantages | Disadvantages |
|---|---|---|
| Intravascular delivery - Bolus (small vol.). - Infusion (maintenance). | • Rapid delivery & effect; • Useful for drugs poorly absorbed or unstable in GI tract; • Avoids 1st pass metabolism | • Can be difficult to reverse; • Risk of Infection; • Needs skill in admin (particularly with IA route). |
| - Subcutaneous (SC) e.g. insulin | • Rapid, easy delivery | • Small vols. only |
| - Intramuscular (IM) E.g. adrenaline | • Mod. quick delivery; • Allows larger vol. than sub cut. | • Can be painful with risk of bleeding |
| inhalation | Direct and rapid brochial delivery Rapid exchange across pulmonary membrane allows for immediate control of plasma concentration |
Pharmacokinetic Terms and calculations
Fraction of dose (F)
F for an IV drug is 1
F for oral drug is calculated by dividing the oral AUC by the IV AUC and multiplying by 100
eg fusnimide has an oral availability of 55%
the reason why oral availability is lower is bc oral delivery is subject to first pass metabolism tough GI environment and membranes to pass through gastric ph drug lipid solubility drug Pka surface area etc
First pass metabolism is dependant of a few things
gastric ph and gastric motility
metabolic enzymes in gut lumen wall and liver which clear the drug
hepatic mass
other drugs occupying pathways
Transport of drugs
chemical properties of the drug determine its transport
How does physiochemical properties affect bioavailablility
molecular weight and size hydrophilic lipophillic pKa and ionisation status of drug NEED TO BE UNIONISED AT PHYSIOLOGICAL PH to pass through neutral membranes most drugs for weak acids or bases
for gastric absorption drug should be neutral at gastric pH for absorption
Clearance.
clearance is dependant of excretion and metablosim cl total is the sum of cl of all other organs and tissues
Clearance is calculated with dose and AUC. more AUC less clearance etc We can calculate by logarizing the the Concentration in plasma over time
NOTE
once absorbed into the plasma the drug is absorbed into the tissues of the body at various rated
we can also calculate the half life of drug with our logrithmised graph
Loading dose
Understanding Vd and Cl
with these 2 variables calculate the halflife of the drug and therefore with this data make the accurate loading dosage,
half life
