Session 2 Flashcards
Difference between Pharmacokinetics and Pharmacodynamics?
pharmacodynamics is the study of how a drug affects an organism, whereas pharmacokinetics is the study of how the organism affects the drug
Key factors that pharmaceutical companies look at when a new drug is released.
Key factors: Bioavailability Half-life Drug elimination Inter-subject variability Drug-drug interactions Safe dose required to achieved the desired plasma conc. in the right tissue.
Things to consider when thinking about pharmacokinetics
Renal function Stress Pyrexia Alcohol Smoking (multiple drugs) Age Sex Exercise Infection Diet Occupational exposure Lactation Liver function Albumin Cardiovascular function Circadian and seasonal variations Immunisation Barometric pressure GI function Pregnancy
Define bioavailability and what affects it.
• Measure of drug absorption where it can be used – Bioavailability (F) • Drug administered via intravenous bolus is said to have 100% bioavailability • For other routes referenced as a fraction of i .v. Bioavailability affected by : • Absorption - Formulation - Age (luminal changes) - Food (chelation, gastric emptying) - Vomiting/malabsorption (Crohn’s) • First pass metabolism - metabolism before reaching systemic circulation (gut lumen, gut wall, liver)
How is rate of absorption shown graphically
• Plasma concentration-time graphs – distinct phases • Rate of absorption dictates visibility of distribution and elimination phases Insert 8 slide
What is modified release preparation?
Insert slide 9 and 10 use Panopto • Plasma concentration determination shifts more towards rate of absorption • Adherence – taking medication
Distribution
Distribution • Adequate plasma levels and reach the target organ • Factors affecting therapeutic agents Blood flow, capillary structure Lipophilicity and hydrophilicity Protein binding Albumin – acidic drugs Globulins – hormones Lipoproteins – basic drugs Glycoproteins – basic drugs Volume of distribution (V d ) – see later
Multiple compartments
• Rate of distribution and equilibration from i .v. administration typically follows multiple compartment model
Drug-protein binding and distribution
• Typically only free drug will be able to afford response and or be eliminated • Displacement of a drug from binding site can result in Protein Binding Drug Interaction • Clinically important if: - highly protein bound - narrow therapeutic index - Low Vd • Increased free drug - will be able to afford response and or be eliminated • Second drug displaced first drug from binding proteins B BB • More free first drug to elicit a response BB • Potentially causing harm – Target receptor - Pregnancy (fluid balance), renal Target receptor failure, hypoalbuminemia…….
Volume of distribution
• Proportionality factor! • Only plasma (blood) concentration can be measured easily Concentration is amount of substance per unit of volume. • Vd = Dose/[Drug]plasma In general a smaller apparent Vd suggests drug confined to plasma and extracellular fluid a larger apparent Vd suggests drug is distributed throughout tissues
Levels of drug metabolism
• Several sites of activity, liver having the most numerous and diverse metabolic enzymes • Size, lipophilicity, hydrophobicity, structural complexity affect route and mechanism • Phase I converts drugs into lipophilic metabolites, may alter PK/PD?! Insert slide 19
Cytochrome P450 (CYPs)
• Majority of phase I catalysed reactions utilise the P450 system – equally important for endogenous substances • Numerous genes that encode these enzymes, few CYP families deal with most reactions (see pharmacogenetics lecture) Insert slide 20 Importance of CYP450 enzymes • active → inactive - most drugs inactive → active - perindopril → perindoprilat, levodopa → dopamine active → active – codeine → morphine, diazepam → oxazepam • CYPs can be induced or inhibited by endogenous/exogenous compounds affecting phase I metabolism • age hepatic disease blood flow alcohol cigarette smoking…
Enzyme inhibition and drug interactions
• Grapefruit/juice and statin therapy - CYP3A4 inhibition e.g. CYP 2D6 • Absent in ~ 7% Caucasians • Hyperactive/increased induction in ~ 30% East Africans • Substrates include β-blockers, many SSRIs some opioids • Inhibited by some SSRIs, other antiarrhythmic agents and other antidepressants Clinical importance • Important for drug prescribing (lots of drugs) • Over the counter preparations • Other factors (generally): Race (see pharmacogenetics lecture) Sex - women slower ethanol metabolisers Species - drug development, interpretation of evidence • Carbamazepine St John’s Wort - mood stabiliser and has big impact on cytochrome p450• Self induced metabolism - can cause metabolism of itself see Panopto
Drug elimination
• Primarily via the kidney (~25% of systemic blood flow) • Other possible routes: Fluids - sweat, tears, genital secretions, saliva, breast milk Solids - faeces, hair Gases - volatile compounds
Renal drug elimination
• Typically low molecular weight polar metabolites • Affected by: 1 GFR and protein binding (gentamicin) 2 Competition for transporters (penicillin) 3 lipid solubility, pH, flow rate (aspirin) • Clearance of drug from the body - clearance from all routes – both metabolism and excretion taken together by definition (mL/min) • mostly GFR • Manipulation of pH in poisoning
Hepatic drug elimination
• Typically high molecular weight - conjugated with glucuronic acid • Bile important route for conjugates • Elimination in faeces or reabsorbed • Enterohepatic circulation Endogenous examples? • Antibiotic drug interactions - Warfarin, morphine….
First and zero order kinetics
Insert slide
Half life
Half-life (t 1/2 ) – first order kinetics • More intuitive than rate constant 1/time • Independent of concentration • For a drug and a pharmacokinetic process • Elimination half-lives range from minutes to days (and weeks) • 2 t1/2s?
Clearance
Slide 30 • Constant proportion not amount
Elimination rate and clearance
• Volume of blood cleared per unit time (mL/min) Slide 31 • Drug concentration high – more drug in the same volume cleared – elimination rate increased - amount/time (mg/min)
Elimination rate constant and that familiar formula
Elimination α 1/V d k = CL/V d k = 0.693/t 1/2 substitute k for CL/V gives us t1/2 = 0.693 x Vd d CL • Relationship between half-life, volume of distribution and clearance clinically useful (see next slide) • Long half-life results from?
Clinical significance of elimination rate relation to Vd
Slide 33
Elimination kinetics
• Most drugs exhibit first order kinetics at therapeutic doses (t1/2 is constant) • High doses and alcohol, salicylic acid and phenytoin - zero order • Important consideration for toxicity and dosing For zero order - • Dose change can produce unpredictable change in [plasma] • t1/2 not calculable
Clinically – importance of drug monitoring
• Zero order kinetics • Long half-life • Narrow therapeutic window • Drug-(drug) interactions (metabolic/genetic) measure plasma conc.? • Reported or expected toxic effects • Therapeutic effect – response that is expected/desired?
