Drug Therapy Flashcards
pharmacokinetics
the movement of drugs through the body
pharmacodynamics
the body’s biological response to drugs
safe and effective medications
balance between safety and efficacy - fine line with toxicity
bioavailability
the extent and rate at which the drug enters systemic circulation, thereby accessing the site of action
what does the effect of a drug depend on
- affinity
- intrinsic efficacy
- pharmalogical effect also dependent on residence time
what can different drugs still do
ellicit the same response - due to different mechanisms/pathways
What are different receptors which have the same function in different people called
polymorphic variation - diff sequence of genes code for same receptor
what mechanism of binding occurs in endogenous receptors
lock and key - either on same site, or allosteric site
agonist drug
inc proportion of activated receptors
antagonist drugs
dec proportion of activated recptors - prevent activation
what 2 mechanisms can inhibition occur by
competetive or non-competetive
what is a drug steady state
when the quantity of drug eliminated equals the quantity of the drug that reaches the systemic circulation - kinda like equilibrium
what are allosteric modulators
drug binds to different site, changing the shape of the receptor site for the endogenous ligand - can inc or dec efficacy
Biophase
the effect site of the drug (physical region in which the drug target is located
what is the bioavailability if we inject a drug directly into the circulation (e.g. IV route)
100%
what is a downside of non IV routes
some drug is lost (e.g. gut tissues etc. and passed on for excretion)
what is first pass metabolism
drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation - amount of drug removed before it reaches systemic circulation
Cmax
max plasma conc of drug achieved
drug: half-life
time taked for conc in plasma to fall to 1/2 original value
therapeutic index
ratio that compares the blood concentration at which a drug causes a therapeutic effect to the amount that causes death or toxicity
where will drugs go from the plasma
plasma –> ISF —> ICF (or other trancellular fluid)
what must drugs do to cross compartemnts and what are the 2 ways they go about this
Must cross barriers:
* Paracellular (filtration) - filter between cells
* Transcellular - through cells
3 types of barrier, and what makes them different in terms of drug absorption
Continous - hard for drugs to cross
Fenestrated - more holey
Sinusoid - incomplete basement membrane with intercellular gaps
Describe the meachanisms which drugs can use to travel from the plasma to tissues
- diffusion
- facilitated diffusion
- active transport
- endocytosis
what does the uptake of blood into tissues depend on
Key flashcard
- Lipophilicity - can easily diffuse across cell membrane
- Blood supply (perfusion) - inc blood supply, inc rate of drug delivery
- Ion trapping? - if ionic then hard to cross capillary/cell membrane so “trapped” there
if drugs are lipid soluble (lipophilic) what os diffusion driven by (instead of pumps/channels etc.)
conc gradient
what are tissue compartments
grouping tissues that show similar conc vs time profile
xenobiotic
chemical substances that are foreign to animal life and thus includes such examples as plant constituents, drugs, pesticides, cosmetics, flavorings, fragrances, food additives, industrial chemicals and environmental pollutants
what is the purpose of drug metabolism
+ what are the steps
make the metabolite more polar than the parent compound and thus, more easily excreted
Phase 1 (functionalisation) and phase 2 (synthetic)
what can characteristics that facilitate absorption and diistribution do to excretion
inhibit it - lipophilic dugs more easily reabsorbed
How is the liver important in drug metabolism
- Main site of metabolism/excretion
- CYP450 = enzyme that helps with M/E
- polymorphic variation
- liver health impacts rate of excretion
- Liver toxicity = inc risk of toxicity (impacts safety and efficacy)
briefly summarise pathway of xenobiotic to excretion
Xenobiotic –Phase1–> active metabolite –Phase2–> conjugate —-> Excretion
can skip 1, skip 2, do 2 then 1 or 1 then 2 or none ;)
biliary excretion
active secretion of drug molecules or their metabolites from hepatocytes into the bile
What are the main routs of drug administration
- IV: bioavailability = 100
- Oral (most common)
- Subcutaneous
- Intramuscular (IM)
- Nasal
- Inhaled
- Transdermal
- other GI (rectal, sublingual)
benefit of sublingual drug administration
bypasses first pass metabolism
Define each bit of ADME
Absorption: how a chemical enters the body. Absorption relates to the movement of a chemical from the administration site to the bloodstream.
Distribution: drug moves from the absorption site to tissues around the body via the bloodstream, but can also occur from cell-to-cell.
Metabolism: biotransformation of drug by tissues/organs so the drug can be excreted.
Excretion: the process by which the metabolized drug compound is eliminated from the body.
what are the mechanisms of ADME
normal physiological mechanisms we exploit when developing mediecations
bulk flow
the movement of fluids down a pressure or temperature gradient
2 important organs in drug elimination and toxicity
Kidney and liver
absorption
process of mass transefer from site of administration to bloodstream
what does the extent and rate of drug absorption depend on
- physiochemical properties of the drug (e.g. size, lipophilicity, ionic…)
- Dosage form
- Anatomical/physiological factors
are all drugs absorbed
No, some (e.g. topical) arn’t absorbed
do topical drugs reach systemic circulation
Yes, some can
why would we not want a drug to be absorpbed into systemic circulation
Only want to effect site of application (e.g. local anaesthetics)
How do we administer local anaesthetics to avoid them reaching systemic circulation
- Don’t inject into circulation
- Avoid highly vascular tissues
- Co-administer with adrenaline - causes vascoconstriction
what is half -life
check
tiem take for Cmax to reach half value
Factors to affect oral absorption
- solubility affected by gut’s contents
- Gastic emptying time (e.g. poo before absorpted)
- pH change throughout gut - ionize
- Guit flora
- First pass metabolism
Ficks first law of diffusion
the rate of diffusion of a substance across unit area (such as a surface or membrane) is proportional to the concentration gradient
things affecting fick’s first law (diffusion)
- Diffusion coefficient
- size etc.
- partion coefficient
- thickness of membrane
- membrane area
- Drug concentration
First order kinetics
occur when a constant proportion of the drug is eliminated per unit time. Rate of elimination is proportional to the amount of drug in the body. The higher the concentration, the greater the amount of drug eliminated per unit time. For every half life that passes the drug concentration is halved. - more drug in the body, the faster it is removed
Facilitated diffusion
for large or lipophobic molecules?
Eventually saturable so inc dose does not inc rate of absorption
What are some additional barrier to distribution
protected tissues: brain, testis, ovary, placenta
BBB
Plasma protein binding
- Happens in distribution
- The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form.
- Affects drug’s half life
- Essentialy drugs bound to protein (e.g. Albumin) and circulate in bloodstream until free drug used. Then bound drug released and cycle continues until all is used up
free drug hypothesis
assumes that the unbound drug concentration in blood is the same as that in the site of action at steady state
Is plasma protein bound drug active
No
volume of distribution
apparent volume into which the drug is distributed to provide the same concentration as it currently is in blood plasma
Proportionality constant between the total amount of drug in the body and the amount in the plasma at any one time - total inc bound drugs and assumes instantaneous equilibration
Drugs with low Vd
remain in plasma (less distribution)
drugs with high Vd
leave the plasma (more distribution)
what does drug plasma concentration drive
the therapeutic effect
overall what does Vd influence
[plasma]
half-life property of drugs with high Vd
Drugs with high Vd tend to have longer elimination half-life
What can Vd be used to calculate
loading dose
steady state
every time administer dose, get peaks and troughs (loading dose) until steady state achieved where have constant concentration
con of inhaled medication
much is swallowed and only 5% ends up in lungs
Apart from dose of drugs what else can we manipulate
Dosage form: e.g. hexamers vs monomers, fast vs long acting…
???
medical importance of first pass metabolism
educe the total exposure of the body to drug
factors to affect bioavailability
- chemical composition
- how it is administered
- patient’s physiology
effect of plasma protein binding on bioavailability
It can limit the bioavailability of active compounds by controlling their passage through biological membranes; however, binding to plasma proteins allows hydrophobic drugs to be transported in the aqueous environment of the human organism
zero order kinetics
Zero-order kinetics undergo constant elimination regardless of the plasma concentration, following a linear elimination phase as the system becomes saturated.
tmax
The time it takes for a drug to reach the maximum concentration (Cmax) after administration of a drug that needs to be absorbed
AUC
Are under curve: area under the plot of plasma concentration of a drug versus time after dosage
drug clearance
the rate at which a drug is removed from plasma(mg/min) divided by the concentration of that drug in the plasma (mg/mL).
Specific barriers (e.g. BBB, testes, placenta, ovarie)
Have continouse membranes
(no fenestrations or sinezoids)
Xenobiotics
compounds other than those with a well-defined physiological role
what are endogenous compounds administered at concentrationsoutside the normal physiological range classed as
xenobiotics
Ways of physical removal of drugs from body
urine, bile, sweat, perspiration
Biotransformation
Processing of increasing polarity of molecule making it less likely to be reabsorbed: Phase 1 and Phase 2
Biotransformatio: phase 1 reactions
Creating a functional group or modifying an existing one: largely oxidisation and conducted by CYP450s but could also be hydrolysis
Metabolisation
Where does Phase 1 of biotransformation (metabolisation) occur
Liver (also extrahepatic activity) and in gut/small intestine/lungs/kidney
Where in the cell is CYP450 found
membrane protien in mitochondria and cytosol, much in the SER
Toxicity of Phase 1
small number of phase 1 metabolites are toxic: Quinones and quinone analogues
Activation of prodrugs dec toxicity
what can be seen in cytochrome p450
mutations and polymorphism
cytochrome P450 with broad substrate specificity
3A4
Phase 2 biotransformation
- Products less active, larger and more hydrophilic so more likely to be exreted
- Tend to be weak ions - ion trapping
- More likley to bind to albumin
- Need cofactors - glucuronic acid
food-drug interactiong with CYP450
- CYP3A4 and grapefruit juice
- Omepraxole induces CYP3A4
Polymorhic variation
what is warfarin metabolised by
CYP2C9
Drug elimination
final removal of drug from body. Includes metabolism and excretion
Do drugs have to be metabolised before being excreted
not always
excretion
rateof drug removal from body
Define clearance
volume of plasma from which the drug would be totally removed per unit time
first order process
factors to affect [drug] in plasma
bioavailability and clearance
what is total clearance
renal + hepatic + lung… etc.
Renal clearance includes:
3
- Glomerular filtration
- active tubular secretion
- tubular reabsorption
Explain the process of fibtration and the conditions which must be met
- drug must be in plasma (and free)
- Depends on Vd and protein binding as well as size and charge
total renal clearance
maybe don’t bother learning
No secretion/reabsorption
what is active renal secretion
- occurs in proximal tubule
- clears drugs too large to filter
- depends of drug flow, free drug
- saturable
what + what = renal clearance
secretion +GFR
passive tubular reabsorption
passive process whereby drugs are reabsorbed into the systemic circulation from the lumen of the distal tubules - depends on urin flow rate and pH - ion trapping
wht is renal clearance proportional to
GFR
briefly describbe hepatic clearance
- perfusion important here
- dependent on efficiency of removal of drug from blood
what does hepatic clearnce equal
hepatic clearance = hepatic blood floow x hepatic extraction ratio
Intrinsic clearance capacity
a measure of the maximal ability of the liver to metabolize a drug in the absence of protein binding or blood flow limitations
High: hepatic clearance is perfusion limited
enterohepatic recirculation
- poorly reabsorbed
- enzymes expressed bu gut microbiota can de-conjugate and allow its reabsorption
- secondary drug absorption —> prolonged drug action
what does renal disease increase the risk of
drug toxicity
how can renal disease increaseing the risk of drug toxicity be accounted for
by alterations in the dosing strategy
