Lecture 10.1 and Lecture 11 Flashcards
Distinguish between pharmacodynamics and pharmacokinetics
- Pharmacokinetics – what the body does to the drugs
- Pharmacodynamics – what the drugs do to the body
What are the four main processes in pharmacokinetics?
- Drug in:
I. Absorption
II. Distribution
- Drug out: Elimination
I. Metabolism
II. Excretion
What are the two groups of drug administration?
- Enteral – delivery into internal environment of body (GI tract). Enter the body via the highly vascularised surface area of the GI tract, then on to the rest of the body through the cardiovascular system
- Paraenteral – delivery via all other routes that are not the GI (very important in acut medicine, also used to overcome problems presented by GI absorbtion)
Identify the different types of drug administration
- Paraenteral: intrathecal, intramuscular, transdermal, inhalation, intravenous, subcutaneous
- Enteral: rectal, oral, sublingual (placing the drug under your tongue to dissolve it into the blood and tissues there)
Mnemonic: OI, IT IS SIR
How are drugs absorbed?
Drug mixes with chyme, then enters small intestine where most absorption occurs
What things in the SI helps with absorption?
- Pilica circularis
- Very large surface area (villi and microvilli)
- Constant GI moving - mixing - presenting drug moleucles to GI epithelia for absorption
Why do some drugs have an enteric coating?
Some drugs are pH sensitive, helps to avoid denautring of pH by stomach acid
What is the typical transit time in the small intestine? Why can this increase or decrease? What is the pH?
Typical Transit Time
- 3-5 hrs Varying motility
- 1-10 hrs Weakly acidic pH pH
- pH 6 -7 (weakly acidic pH)
Why does little absorption occur in the stomach?
Due to the thick mucosa layer in the stomach
Which processes facilitate drug absorption?
- Passive diffusion
- Facilitated diffusion
- Primary / secondary active transport
- Pinocytosis
Describe drug absorption through passive diffusion
Lipophilic drugs e.g. steroids, weak acids/bases diffuse passively into GI capillaries, diffuse directly down concentration gradient into GI capillaries
This works are large blood flow to small intestine, so concentration gradient is maintained
- not strongly ionic
- small molecular etc
More detail - how do weak acids move across the membrane, explain in detail
Many drugs in solution are weakly acidic or weakly basic in nature. That is at physiological pH, if they are acidic they will release a proton H+ to go from HA to H+ and A- .
A weak acid:
HA ⇌ H+ + A-
(HA is the neutral form, so HA can diffuse across)
- The ionised form of the drug cannot diffuse directly through the lipid bilayer (although can be carried via facilitated diffusion - see below). Importantly, the rate of uptake of weak acids or bases depends on the pKa or pKb of the drug. For weak acids, the pKa represent the pH value at which the drug as a weak acid exists in the 50% ionised A- and 50% unionised form AH.
- In brief, the proportion of the drug that exists in the unionised (lipid soluble)/ ionised (lipid insoluble) in the gut lumen determines the rate of diffusion across from the gut lumen into the epithelial cells. This tells us that irrespective of the actual concentration of a drug that acts as a weak acid or base in the gut, some percentage of it will exist in the unionised form.
- E.g. Valproate has a pKa of 5, this means that at pH 5, 50% of it is in the ionisied form (A-) and 50% of it is in the unionised form (HA). In the surrounding area was the small intestine, e.g. pH 6-7, the small intestine is …. ??? ask about this
More detail about weak bases moving across the membrane
B + H+ ⇌ BH+
B is the unionised form, it is lipophillic and can move over the small intestine…
If the pKb of the base is 8, the pH is 6-7 (more acidic environment), this means there is lots of H+ around, much more likely to be protonated, so BH+ and therefore be in the ionised form.
Similarly for weak bases, the pKb represent the pH value at which the drug as a weak base acid exists in the 50% ionised BH+ and 50% unionised form B. In brief, the proportion of the drug that exists in the unionised (lipid soluble)/ ionised (lipid insoluble) in the gut lumen determines the rate of diffusion across from the gut lumen into the epithelial cells. This tells us that irrespective of the actual concentration of a drug that acts as a weak acid or base in the gut, some percentage of it will exist in the unionised form. This unionised form is able to diffuse across the very large surface area offered to it by the gut. Pharmacokinetically even if this is small, say less than 1% of the total drug molecule, this proportion can then leave the gut lumen
Describe drug absorption through facilitated diffusion
- Molecules with net ionic charge can be carried across GI epithelia
- Passive process based on electrochemical gradients
- Solute carrier transporters are either OATs(carry negative ions) and OCTs(carry positive ions) which are highly expressed in GI, Hepatic and Renal Epithelia (OATs and OCTs are highly important for absorbtion from GI tract, but as cover later, elimination requiring hepatic and renal epithelia transport)
Describe drug absorption through secondary active transport
- SLCs facilitate this process (no ATP)
- Transport driven by pre-existing electrochemical gradient across GI epithelial membrane
Example of secondary active transport for drug absorption
- Fluoxetine/Prozac - SSRI antidepressant co-transported with Na+ ion (move by OATs)
- Penicillins - co-transported with H+ ion (move by OATs)
Factors affecting drug absorption:
What are the physicochemical factors affecting drug absorption?
- Surface area and GI length
- Drug lipophilicity and pKa
- Density of SLC expression in GI
Factors affecting drug absorption:
What are the physiological factors affecting drug absorption?
- Blood Flow: increases after a meal, blood dlow drasitically reduces due to shock/anxiety/exercise
- GI Motility: decreases after a meal, this is rapid with diahoorea (this means that if the drug is in the GI tract, may be glushed out with diahorrea and not absorbed)
- Food/pH: Food can reduce/increase uptake. Low pH destroys some drugs
Factors affecting drug absorption:
What are the factors affecting drug absorption in terms of First Pass Metabolism by GI and Liver?
- Gut Lumen: enzymes can denature drugs
- Gut Wall Cytochrome P450s (Phase 1 enzymes) and Conjugating (Phase 2 enzymes) (has to be absorbed to be acted on by P450s…)
- Liver Cytochrome P450s (Phase 1 enzymes) and Conjugating (Phase 2 enzymes)
MORE DETAILS IN GROUP WORK
What is bioavailability?
Bioavailability is the fraction of a defined dose which reaches its way into a specific body compartment
CVS (Circulation) is most common reference compartment
For CVS/Circulatory Compartment Bioavailability Reference - IV bolus = 100%
- No physical/metabolic barriers to overcome
We compare e.g. a drug taken orally to an IV drug, as know that with an IV, 100% reaches circulation as there are no physical circulation as there are no physical, metabolic to overcome
What is the most common means of calculating bioavailability?
- CVS (circulation) is most common reference compartment
- Most common comparison is (O)/(IV)
(i.e. oral over IV) - look at next slide for equation
How does one calculate oral bioavailability?
It is the amount of drug administered (AUC) via the oral route divided by the AUC via the IV route
Foral = AUC<u>Oral</u>
AUCIV
F = Amount reaching systemic circulation
Total drug given IV
F lies between 0 and 1
This calculation informs choice of administration (i.e. if F is very high, can be taken orally, if F is very high e.g. between 0.9 and 1.0, meaning most of it when giving orally gets through into the systemic circulation.)
Why do drugs distribute?
To reach and interact with therapeutic and non-therapeutic target
Outline the processes involved in the first stage of drug distribution
- Bulk flow – large distance via arteries → capillaries
- Diffusion – capillaries → interstitial fluid → cell membranes → targets (occurs over much shorter distances)
(this occurs rapidly and over large distances)
What are the major factors affecting drug distribution?
- Drug molecule hydrophilicity
I. Lipophilic drugs freely move across cell membrane
II. Hydrophilic drugs dependent on electrochemical gradients
- Drug binding to plasma and/or tissue proteins e.g. albumin, lipoproteins, glycoproteins
- Local permeability of capillaries
- Non-target binding
How do capillaries affect drug distribution? Types of capillaries
- Differing levels of capillary permeability
- Variation in entry by charged drugs into tissue interstitial fluid/target site
- Capillary membrane also express endogenous Transporter & OATs/OCTs
Types of capillaries:
- Continuous capillaries - near impossible for non-lipophillic molecules to diffuse without an OAT/OCT, these are therefore barriers to charged particles
- Fenestrated capillaries - Fenestrations allow movement of large proteins and charged molecules
- Sinusoid capillaries - Can even squeeze through, highly permeable to charged molecules
Factors affecting drug distribution - e.g. Affect of albumin
- Only free drug molecule can bind to target site(s)
- Binding in plasma/tissue decreases free drug available for binding
- Plasma/Tissue protein bound drug acts as ‘dynamic reservoir’
- Multiple Binding Sites on HSA
- Binding forces not strong – bound/unbound in equilibrium
- Binding for given drug can • be up to approximately 100% (Aspirin approximately 50%)
- Varying number of binding sites for given drug • Competition for binding site affects free plasma conc and Pharmacodynamics
If give a patient two drugs in the ‘same’ group, i.e. bind to the same domain on the albumin, they will be competitng to bind e.g. diazepam and ibuprofen (then will affect free drug concentration)
Major factors affecting drug distribution:
Drug molecule Lipophilicity/Hydrophilicity
- If drug is largely lipophilic can freely move across membrane barriers
- If drug is largely hydrophilic journey across membrane barriers dependent on factors described for Absorption
Major factors affecting drug distribution:
Describe drug binding to plasma and/or tissue proteins
In circulation many drugs bind to proteins e.g.
Albumin - Globulins (AS AN EXAMPLE)
Lipoproteins - Acid glycoproteins
- Only free drug molecule can bind to target site(s)
- Binding in plasma/tissue decreases free drug available for binding
- Binding forces not strong (bound/unbound in equilibrium)
What are the three main body fluid compartments?
male, 70kg:
Simple model of drug movement between the three body fluid compartments -
e.g. Heparin - acts as an anticoagulant, doesn’t move across capillary membrane, so stick in the plasma membrane compartment (e.g. red arrow)
e.g. Propofol - an anaethetic, this is highly lipophillic, this can diffuse easily from:
plasma -> interstitial -> intracellular
Simple Models of Drug Movement Between Body Fluid Compartments - showing the carriers in the membrane
Many drug targets are found on the target tissue membrane i.e. these drugs only therefore need to get through the plasma interstial membrane (the capillary membrane barrier)
- Circle in the middle of intracellular fluid compartment represents intracellular targets
Cytochrome P450 Enzymes - more detail about the families
Cytochrome P450 enzymes include three superfamilies
• Three superfamilies CYP 1, 2 and 3
• Isozyme members in each family coded by suffix: e.g. CYP3A4
• Six isozymes metabolise
90% prescription drugs
• Other isozymes exhibit very variable hepatic expression
• Each isozyme optimally metabolise specific drugs but do show overlap
(Don’t need to learn the table attached)
Talk about genetic polymorphism with codeine and CYP2D6
‘Pro-drugs’ activated by Phase I metabolism to active species
Earlier example: Codeine to Morphine
• CYP2D6 gene highly polymorphic
• CYP2D6 variants categorized into: poor; normal/high; ultrarapid metabolisers
Poor - codeine to morphine - may not experience pain relief
Ultrarapid - codeine to morphine - lead to morphine intoxication/ADRs
What processes are involved in renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive tubular reabsorption
Renal capillaries are fenestrated
Briefly describe glomerular filtration
Glomeruls ⇌ 20% renal blood flow
Unbound drug enters glomerulus via Bowman’s capsule for filtration
Metabolites diffuse through capillary slits into the Bowman’s capsule
Briefly describe proximal tubular secretion
- Remaining 80% blood via peritubular capillaries
- High Expression of OATs and OCTs
- Water reabsorbed along tube length
- Carry ionised molecules out of the plasma, into the tubules and out in the urine
- Low affinity/High Capacity OATs and OCTs
- Competitive transport (if two species e.g. two anionic species are metabolised, they will be competing for the same transporter to get out)
- Reverse of process in Small Intestine
Distal tubular Reabsorption
As water is resorbed along the length of the tubule, drug metabolite concentration increases. If this is in a lipophilic form, then it will pass out back into the bloodstream being reabsorbed passively as it goes back down its concentration gradient resulting in a lower rate of effective elimination.
• Along total tubule length water resorbed
• Along tubular length [Solutes]
• If drug/metabolite still lipophilic - pass back into blood
• What about drug/metabolites with weak acid/base characteristics ?
pKa ⇌ 4-7
pKb ⇌ 7-9
• Same process as in the small intestine - but reversed follow the proton!
pH changes in the tubule (not proper name…can’t think…), what would the effect by of decreasing and increasing pH on weak acids and weak bases being reabsorped?
What is the optimal pH and the normal health pH of urine?
pH therefore really affects drug elimination
Weak acids:
HA ⇌ H+ + A-
If an acidic environment (below it’s pKa): reaction is more shifted (not fully) to producing more HA, so increases absorption (as more in HA form)
If weak acid is in alkaline conditions, proton poor environment, more likely to release the proton and be in the ionised form, decreasing absorption
Weak bases:
B + H+ ⇌ BH+
What is Drug Half Life (t1/2)?
Drug half life is the amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it had when it was first measured
Plotting concentration against T1/2, not log curve, what does the curve look like?
What happens when you turn conc. curve against t1/2 into a log curve?
Becomes linear
Because y-axis now exponentially compressed
Log [Plasma] vsTime now linear
Linear Elimination Kinetics
Explain the principles of linear elimination kinetics
The rate of metabolism / excretion is proportional to [drug] per unit time
• The rate of Metabolism or Excretion is proportional to Plasma concentration of Drug (i.e. higher plasma conc = higher rate of metabolism i.e. for it to be eliminated)
• That is - if there is Large Functional Reserve
- Plenty of Phase I/II Enzyme sites
- Plenty of OAT/OCT Transporters
• Then the rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time
Outline the features of zero order kinetics and graph to show this
- Drugs at/near therapeutic dose with saturation kinetics
- Fixed rate of elimination per unit time
- Relatively small dose changes can produce large increments in plasma [drug]
First order kinetics and zero order kinetics (caused by dose of drug increasing beyond saturated level) - graph
- Low doses - First order
- High doses - Zero order
- As dose or [drug] first increases Rate of elimination also increases
- At increasingly higher doses approach natural finite limit of functional reserve - Only so many enzymes/carriers
- Above this drug dose/concentration Cannot go any faster – Saturated Like maximal rate of revision
- This has important clinical implications
What is the effect of first order and zero order reactions?
1st order kinetics - predictable
therapeutic response from dose increases (most drugs behave like this) - therapeutic effect is usually proportional to dose = linear
2nd order kinetics - Not predictable
therapeutic reponse can suddenly escalate, elimination mechanisms satruate (examples - alcohol, MDMA)
