Pharmocokinetics & Pharmocodynamics Flashcards
What is pharmacokinetics and pharmacodynamics?
Pharmacokinetics - study of how the organism affect drugs
- Absorption
- Distribution
- Elimination (Metabolism + Excretion)
Pharmacodynamics - Study of how drugs affect organism
- relationship of drug conc and response
What is the rate of the absorption of drugs affected by?
- Route of administration
IV (bolus) > IV( (infusion) > Intramuscular > Oral (tablet) > Oral (extended release tablet) [conc. vs time graph] - Chemical properties of a drug
- MW and structure
- Solubility: PARTITION COEFFICIENT - drug conc in oil vs drug conc in h2o layer; P(o/w) increases as lipid solubility incr
- Ionization: uncharged form of drug can diffuse across membrane, only free unbound drug cross membranes - Patient & physiological factors for absorption
- Adherence or compliance ex. elderly/psychiatric
- Oral drugs depend on GI FUNCTION ex. pH
- Physiological changes ex. age
- Environment ex. herbal products
How is the drugs distributed in the body?
- Drugs may be distributed from circulation ➔ body/target tissues
- Highly-perfused organs (liver, kidney, brain) first, then to less-perfused organs (muscle, fat, etc)
What properties of the drug influence distribution of drugs?
Molecular size & structure
Lipid solubility
Degree of ionization
Movement across membranes
Tissue perfusion
PROTEIN BINDING
What does protein binding have to do with distribution of drugs?
Acidic drugs bind to albumin
Basic drugs bind to alpha-1-acid glycoprotein (AAG)
Drugs binds to plasma proteins usually in a reversible non-covalent interaction and can be saturated
Only free (unbound) drug produces a pharmacological effect
What is the effect of binding protein conc. on free drug conc?
- Albumin may decrease in liver diseases, critically ill and malnourished
- AAG (an acute phase reactant) increases conc. during inflammatory conditions
- Co-administered drugs may compete for binding sites on binding protein which increase free drug concentration
- Free drug concentration = increased pharmacologic effect & maybe increase toxicity threshold
What organs are responsible for drug metabolism?
Liver (main)
Intestine
Lungs
Kidneys
Skin Eye
How is drug metabolism categorized?
- Hepatic microsomal
- Non-microsomal
- Extra-hepatic metabolism
Parent cmpd ➔ metabolites (mayb active/inactive)
What are the elimination routes for drugs?
Kidney ➔ urine
Liver ➔ bile and excreted as feces
Breath, breastmilk, saliva, sweat, tears, hair
What factors affect renal and hepatic elimination of drugs?
- Perfusion and function of organs - renal fcn changes GFR
- Protein binding
- FREE DRUGS filtered by glomerulus
- BOUND DRUGS prolong half-life - Urine pH & reabsorption in the renal tubules - alters ionization and solubility of drug
Define and describe the term volume of distribution. What is it used for? How to calculate apparent Vd?
Theoretical volume of total body fluid in which all of the drugs in the body is distributed.
Used to compare the distribution of a drug with volumes of water compartment in the body.
Total amt of drug in the body (dosage)/initial plasma drug conc
How does knowing Vd help?
- Predict where drug might be distributed (plasma vs tissue)
- Predicting plasma drug conc when dose of drug administered is known (look up Vd in database)
- To decide whether useful to use hemodialysis in poisonings
Define and describe the term bioavailability. What does it measure? What % is useful for oral drugs? What is it affected by?
The fraction or % of drug that enters the circulation an unchanged form after administration of the drug
Measures EXTENT of absorption not RATE
70%
1st-pass effect
Define and describe the term first pass effect. Where does it occur mainly?
Biotransformation of a drug (to pharmacologically active/inactive metabolites before it reaches its site of action or systemic circulation. This significantly decreases the oral bioavailability of a highly metabolized drug.
Liver
What are factors affecting biotransformation?
- GENETIC POLYMORPHISM
- Single nucleotide polymorphism can incr/dec enzyme activity
- Genetic polymorphism in specific drug metabolizing enzymes leads to functionally slow metabolizer or fast metabolizer - Physiological factors ex. age
- Environmental factors
- DRUG-DRUG INTERACTION
- Can lead to enzyme induction (incr expression) and inhibition
- Induction ➔ incr enzyme synthesis ➔ incr metablism ➔ decr drug conc.
- Inhibition ➔ decr enzyme synthesis ➔ decr met ➔ increase drug conc
What is the effect of cytochrome P450 induction or inhibition on drug conc curves?
Induction ➔ conc lower & eliminated faster
Inhibition ➔ conc higher and eliminated slower
What are examples of inducers?
- Acetaminophen and ethanol
- CYP2E1 substrates include APAP and ethanol
- Alcohol + acetaminophen increases formation of NAPQI - Coffee + smokers
- CYP1A2 substrates include caffiene
- CYP1A2 can be induced by polycyclic aromatic hydrocarbons found in cigarette smoke
- Increases metabolism of caffeine, decreases duration of effect - Grapefruit juice and medication
- CYP3A4/5 metabolize ~50% of therapeutic drug
- Grapefruit juice inhibits CYP3A4
Define and describe the term elimination half-life. Formula? What is the general rule of thumb for drug elimination?
Amount of time required for conc to decrease by 50%
- Sum of metabolism + excretion
- Assumes absorption and distribution phase is complete
- Determines length of effect of drug
half-life = 0.693 x Vd/Clearance
5-7 half lives to eliminate drug from body once administration stops
Define potency and efficacy.
Potency
- Dose/conc required for specific effect
- Effective dose values can be used to compare relative potency
- Higher potency, less drug required to give given effect
Efficacy
- Max effect a drug can have
- Higher maximal response, more efficacious the drug
- Reflects how the drug works in ideal situations
Describe characteristics of agonists and antagonists.
Agonist - bind to receptor and produce a biological response tht mimics tht of endogenous ligand
Antagonist - Bind to a receptor but has no activity itself
- May block endogenous ligands from binding
- Attenuates the effect of agonists
What is therapeutic index? How to calculate the therapeutic index of a drug? What does a low or high TI mean?
Comparison of a drug that causes therapeutic effect to toxicity
TI = LD50/ED50
Low TI = little difference between toxic and therapeutic dose, require TDM to help adjust dose
High TI = favourable safety profile
Define TDM and the goals of TDM.
Therapeutic drug monitoring is the measurement of drug concentration in the blood.
Goals of TDM
1. Provide objective info to guide clinicians to achieve optimal treatment dosing
2. Ensure patient gets right dose at the right time in the right circumstance
What are examples of TDM drugs?
Phenytoin
Digoxin
Tacrolimus
How is Phenytoin distributed in the body? How is it metabolized, and how is it excreted?
Distribution - 90% protein bound to albumin
Metabolism - Hepatic (CYP2C9 & CYP2C19)
Excretion - renal and hepatic
