Pharmacokinetics (flipped lecture) 1 Flashcards
What is the difference between pharmacodynamics and pharmocokinetics?
While Pharmacodynamics concerns itself with what a drug DOES to the body
Pharmacokinetics put simply deals with what a body DOES to a drug! (absorption, distribution etc…)
What does drug effect depend on? (2)
Pharmacodynamics
Concentration (Pharmacokinetics)
What 4 factors influence Pharmacokinetics? (4)
PADME - regulate concentration of drug in body
Pharmacokinetics
Absorption - from site of administration
Distribution - within the body
Metabolism
Excretion
What are the two types of transport for drugs in the body? (2)
-Bulk flow, transfer of drug through bloodstream and around body
-Diffusion, aqueous diffusion carries drugs to and from hydrophobic barriers
What is the diffusion coefficient proportionate to?
1/ square root of molecular weight
What are the barriers in the body? (4)
-(Plasma membrane) separates extra-intracellular compartment
-(Epithelial layer) epithelial cells gastrointestinal mucosa or renal tubule, consists of a layer of cells tightly connected
-(Vascular endothelium) is more complicated, its anatomical disposition and permeability varying from one tissue to another
-(Central nervous system) (CNS) and the placenta, tight junctions between the cells, and the endothelium is encased in an impermeable layer of periendothelial cells (pericytes)
How do large molecules cross the BBB?
Carrier channels
What factors effect drug crossing plasma membrane? (3)
Size – larger molecules have more difficulty getting across
Diffusion coefficient = 1/square root of molecular weight
Charge – repels if charged
Whah happens in bulk flow via pinocytosis?
Membrane invaginates and traps molecules in extracellular fluid, they then come into cell and via trannsitosis, vesicle may fuse and release onto other side of cell
(Used with large proteins, insulin or antibodies across BBB)
What does diffusion across lipids depend on? (2)
And what do these factors depends on? (2)
Concentration gradient - depends on lipid-water partition coefficient
Diffusion coefficient - depends on chemical properties of the drug
What is partition coefficient ?
Partition coefficient is how readily molecule dissolves into water vs oil
(The more lipophilic the more easily it can enter plasma membrane)
What do most drugs tend to be? (ph wise) (2)
-Weak acids and bases, so readily form salts, easier like this rather than oils
Which equation shows charged and uncharged form of drug?
Henderson–Hasselbalch equation
e.g. weak acid HA -> H+ + A-
(pH = pKₐ + log([A⁻]/[HA]))
What is the equation for pKa?
pKa = pH + log10(HA/A-)
What pKa value do weak acids and bases tend to have? (2)
-Weak acid always has PKA value below 7
-Weak bases above 7
How do we determine if associated or dissociated form of drug is favoured? (2)
Salts when placed in aqueous environment it can split into positively charge H ion and negative anion
-There is an excess of H ions in acid environment, equilibrium forced left, favours associated form
-In basic environment, less H ions, forced right and favors dissociated form of acid
How can Ph be used to remove poison? (4)
-Basic environments (ie. pH > 7) favour dissociation of acids
-Weak acids become ‘trapped’ in basic compartments eg. renal tubules
-Urinary acidification slows excretion of weak acids
-Increasing plasma pH (eg. sodium bicarbonate) causes weakly acidic drugs to be extracted from CNS into plasma where they get ‘trapped’
-This means they can go to other parts of body or be extracted
Routes of administration affect drug absorption, what are the different routes of administration? (9)
-(Intravenous) (injected in) administration is the MOST direct (reliable) route, fastest acting….used in emergencies
-(Subcutaneous or Intramuscular injection) (avoids digestive system)next fastest, variable absorption depending on site of injection and local blood flow
-(Intrathecal injection) –lumbar puncture used to produce regional aneasthesia (very local effect)
-(Oral route) is most common, easiest, most drug absorption occurs not in the stomach but in the gut (larger surface area) by passive diffusion
-(Rectal administration) - this route also used if want local effect (eg. colitis) or where oral administration difficult eg. children
-(Sublingual administration) (absorption from oral cavity) avoids portal blood system and exposure to gastric pH and metabolism…but may taste horrible!
-(Cutaneous administration) (skin patches, cornea eye drops, nasal mucosa cold remedies and some peptide hormones)…useful when want local effect (although some can enter circulation)
-(Inhalation) - restricted to gases….but large surface area so get fast absorption and also elimination.
Used for gen anaesthetics and for local effects eg. administration of broncodilators in asthma
-(Percutaneous injection), through skin, avoids digestive system, slow delivery, of drug, used in anti smoking drugs like nicotine, slow and constant supply, creams used as well for slow delivery
What does rate of absorption really depend on (stomach)? (5)
-Gut motility
-Presence of food
-Particle size of the tablet
-Encasing of the tablet eg. slow melting coatings
-Physiochmical factors (eg. binding, lipophilicity etc.)
What factors affect absorption of drug? (5)
-Site/method of administration
-Molecular weight – affects rate of diffusion (inverse to infusion coefficient)
-Lipid solubility – ability to cross lipid membrane by diffusion
-pH and ionisation - only uncharge molecules can cross
-Carrier mediated transport – passive or active
What are the two types of carriers? (2)
-Solute carrier (SLC) transporters (passive) (include OCTs organic cation transporters)
-ATP-binding cassette (ABC) transporters (active)
What are the major body compositions in drug distribution? (4)
Extracellular fluids
-plasma 4.5% b.w.
-interstitial fluid 16%
-lymph 1-2%
-Intracellular fluids -30-40%
-Transcellular fluids (e.g. CSF) – 2.5%
-Fat – 20%
What does distribution of drug at equilibrium across major body compartments depends on? (4)
-Permeability across tissue barriers
-Binding within compartment
-pH partition
-Fat:water partition
What is the “volume of distribution” of a drug?
Volume of distribution of a drug (Vd) is a measure of the volume of fluid that would be required to hold the amount of drug in the body
How do you calculate volume of distribution? (Vd)
And what is Cp?
Vd = Dose/cp
Cp - concentration of plasma after equilibrated in its volume of distrobution but before significant elimination
Why could drug distribution be limited across BBB?
What types of molecules can pass through?
-Endothelial cells lining blood vessels in CNS form tight junctions impermeable to water soluble molecules
-Small lipid soluble (large drugs used carrier)
How does binding to plasma proteins affect drug distribution?
-Free drug is active drug, drug concentration required for therapeutic effect approached binding capacity of albumin
-We need to monitor levels of free drug and protein binding; drugs compete for albumin so may displace each other
(binds
How can Partition into specific tissues (e.g body fat) affect drug distribution?
Body Fat acts as ‘drug reservoir’
Can achieve higher conc in lower fat animal
Easier to remove from skinnier animal
Harder to control levels with higher body fat
(especially of lipophillic drugs like anaesthetics that need to be specific)
What does binding of drug to plasma proteins result in in terms of relationship between drug dose and active drug?
Can result in non-linear relationship between dose and active drug concentration as a result of saturation, slows elimination
What is Pinocytosis?
Movement of drugs between compartments usually involves penetration of lipid diffusion barriers (ie. cell membranes) which determines where and for how long a drug will be present in the body after administration
What happens to weak bases in acidic environments?
What happens to weak acids in alkaline environments?
What is the effect of this known as?
-They dissociate (so can’t travel across membrane)
-Ionic trapping (important as drug can travel in plasma, could then alter ph to make more of drug dissociate and travel through body)
What is the Henderson Hasselbach equation, used to calculate drug ionisation in different compartments?
pH = pKₐ + log([A⁻]/[HA])
How might a drug be excreted too soon?
Portal blood system
What does meningitis do to BBB?
More permeable, larger gaps
What happens when plasma proteins bind in bulk flow?
High Protein binding in plasma proteins?
Unexpected large increases in concentration of drug as protein binding sites become saturated.
How does high fat effect drug distribution?
High fat in body drugs gets trapped in fat cells
