Basic Pharmacology Flashcards
Why do dentists need to know about the principles of drug action ?
To be able to use and prescribe drugs rationally
Dental patients might already be taking drugs
To be able to keep up with the latest developments in therapeutics
What is pharmacology ?
What the drug does to the body
What the body does to the drug
What is pharmacodynamics ?
the effect of the drug on the body
includes the molecular interactions and the effect of the concentration on the magnitude of the response
What does the study of pharmacodynamics allow us to do ?
allows us to determine the correct dosage
allows us to compare drugs effectiveness
What is pharmacokinetics ?
the effect of the body on the drug
What are the 4 disciplines of pharmacokinetics ?
absorption
distribution
metabolism
excretion
What is absorption ?
how the drug travels from the site of administration to the blood via the stomach, small intestine, liver and then the systemic circulation.
What is distribution ?
drugs can leave the bloodstream and travel in the interstitial fluid or in the intracellular fluid
What is metabolism ?
the body can inactivate the drug via enzymatic action
What is excretion ?
Drug can be eliminated from the body in the urine, faeces or bile. Kidney removes the drug from the blood.
What does the study of pharmacokinetics allow us to do ?
determine the route of administration
the frequency of the drug administration
the duration of the treatment
What are the 2 sources of drugs ?
Naturally occuring
Synthetic drugs
What are biologics ?
chemically produced biological entities
What 2 properties determine the ability of a dug to bind to its target ?q
the shape of the drug and whether it is complementary to the target receptor
charge distribution- determines the forces that will hold the drug to the target
What are the 4 types of interactions that can happen between the drug and the receptor ?
van der waals forces
hydrogen bonds
ionic interactions
covalent bonds
What are further considerations that should be made regarding the properties of the drug ?
hydrophobicity
ionisation- change charge in solutions
conformation
stereochemistry- isomers
What are the 4 types of proteins that are targets ?
receptors
ion channels
enzymes
carriers
What is an example of a receptor ?
B2 adrenoreceptor
drug salbutamol works on it
asthma
What is an example of an ion channel ?
voltage gated sodium channel
lidocaine acts on this to block a sodium influx
acts as a local anaesthetic
What is an example of an enzyme ?
cyloxygenase
aspirin works on it
analgesic
What is an example of a carrier ?
proton pump
omeprazole works on it- pumps out protons
anti-ulcer
How can drugs work without a target interaction ?
by virtue of their physico-chemical properties
What are some examples of drugs that work via their physico-chemical properties ?
Osmotic laxatives- lactulose
Antidotes-acetylcysteine for paracetamol poisoning
antacids- aluminium hydroxides in indigestion
What are targets fro drug action ?
receptors
enzymes
ion channels
carrier molecules
What does agonist do ?
activate the receptor
What does an antagonist do ?
block the action of the antagonist- inhibit
How can drugs act to change ion channles ?
block the ion channel from opening
modulate the frequency of opening and closing
(change frequency or capacity)
How can drugs act on enzymes ?
inhibiting the enzyme
act as a false substrate for the enzyme
How can drugs act on carrier molecules ?
they can be transported instead of the endogenous substrate or inhibit carrier transport
What is GABA and what does it do ?
GABA is a neurotransmitter which causes hyperpolarisation by increasing chloride permeability
this leads to a decrease in excitability
How do benzodiazepines work ?
they work in the presence of GABA - enhancing the effects of GABA
benzodiazepine binds to an allosteric site which changes the conformation of the GABA receptor and increases the chances of GABA binding as well
What is benzodiazepine used for ?
anti-anxiety
What is an orthosteric site ?
natural normal binding sure for the endogenous product like a hormone or neurotransmitter- the active site
What is the allosteric site ?
a different binding site other than the active site
drugs bind to the allosteric site and not the orthosteric site.
What is an example of an NSAID ?
Ibuprofen
What is the normal pathway for cell injury leading to symptoms ?
Immune activation and cell injury
phospholipids in the plasma membrane convered to arachidonic acid by Phospholipase A2
Arachadonic acid converted to prostaglandinsm cause inflammation via cyclooxygenase
How do NSAIDs work ?
they interact with the enzyme cascade (Cyclooxygenase and Phospholipse A2)
prevent cyclooxygenase converting arachadonic acid into prostaglandinds
stops pro-inflammatory meditors
What are the 4 types of receptor ?
ligand gated ion channels (ionotropic)
G protein coupled receptor (metabotropic)
Enzyme linked receptor (kinase)
intracellular receptors
What are the 2 types of ionotropic receptors ?
voltage gated and ligand gated
What are ligand gated receptor channels ?
require an agonist to bind and open a channel
binding leads to change in conformation
channel opens
Where can you find ligand gated channels ?
nervosu system - eg. acetylcholine receptor
What are voltage gated channels ?
they require a change in membrane potential to open and close
What is an example of a voltage gated channel ?
voltage gated Na channels
lidocaine works by binding to these channels and blocking their action to work as an anaesthetic
What is the structure of ionotropic receptors ?
pentimetric- 5 parts
have an inward kin which keeps them closed usually
agonist binding leads to conformational change
What are nictonic Ach receptor agonsits used for ?
muscle relaxants
What are examples of GPCRs ?
Alpha and beta adrenorecepetors
What does GPCR activation lead to ?
second messenger activation
What is the structure of a GPCR ?
7 pass transmembrane structure
consists of alpha, beta and gamma sub units
have a ligand binding domain and a G-protein binding domain
How can the alpha subunits be specified ?
they can be classified as Gs (stimulatory)
Gi (inhibitory) and Gq and G0
these determine the second messenger system
What is the action of Gs sub units ?
they activate adenylyl cyclase and calcium channels
What is the action of Gi sub units ?
inhibit adenylyl cyclase and activate potassium channels
What is the action of Gq sub sub units ?
activate phospholipase C
In the inactive state which G-protein is bound ?
GDP
In the active state which G-protein is bound ?
GTP
What happens when a drug binds to a GPCR ?
leads to conformational change
alpha subunit changes conformation
exchange of GDP for GTP
trigger second mesenger system
What are the classes of adrenoreceptors ?
alpha 1 alpha 2 beta 1 beta 2 these will have the various G subunits
What does the alpha 1 adrenrecetor do ?
it has the Gq subunit
this will activate adenylyl cyclase
lead to vasoconstriction
What does the alpha 2 adrenreceptor do ?
it has the Gi subunit
this inhibits adenylyl cyclase
leads to auto-inhibition of neurotransmitter release
What does the beta 2 adrenoreceptor do ?
it has the Gq subunit
this will activate adenylyl cylase
lead to accelerated HR
What does the beta 2 adrenoreceptor do ?
has the Gs subunit
stimulates adenylyl cyclase
leads to bronchodilation
What is atenolol ?
beta 1 adrenoreceptor antagonist
What is salbutamol ?
beta 2 adrenoreceptor agonist- will lead to bronchodilation in asthma patients
What is the purpose of kinase linked receptors ?
they enhance phosphorylation of proteins to activate processes like protein synthesis
What is the structure of kinase linked receptors ?
they have a large extracellular ligand binding domain - made of alpha units and an intracellular binding domain made of beta units
single membrane spanning helix
What is an example of a kinase linked receptor ?
receptor tyrosine kinase
the receptor for insulin
What happens when a ligand binds to a kinase linked receptor
a ligand binding event leads to the dimerisation and the combining of 2 transmembrane helices - this leads to autophosphorylation.
What happens when insulin binds to a receptor tyrosine kinase ?
insulin binding to receptor tyrosine kinase activates the intracellular beta unit
tyrosine is phosphorylated by the beta unit
other molecules are phosphorylated - IRS
phosphorylated IRS lead to the effects of insulin
What are agonists ?
They mimic the actions of endogenous chemical messengers - the bind to receptors and elicit a cellular response
What is an antagonist ?
a drug which blocks the response to the agonist
they block the action of the endogenous product
Give an example of an agonist ?
histamine acts at the H1 receptor in smooth muscle to increase local blood flow
Give an example of an antagonist to histamine ?
terefenadine
acts as an antagonist at the H1 receptor, - blocks histamine and decreases local blood flow
How can we identify receptor sub types ?
ligand binding essays
cloning techniques
What are the 4 histamine receptor sub types ?
H1
H2
H3
H4
What is the antagonist to H1 receptor ?
terfenidine
What is the antagonist to the H2 receptor ?
cimetidine
What is the antagonist to the H3 receptor ?
thioperamide
What is the antagonist to the H4 receptor ?
Thioperamide
Give an example of intracellular receptors ?
oestrogen receptors
What is the purpose of intracellular receptors ?
leads to changes in gene transcription and protein synthesis
How many different intracellular receptors are there ?
48 - divided into class I and class II
What are class I intracellular receptors ?
located in the cytoplasm
form homodimers- made of 2 identical proteins
ligands are endocrine
What are class II intracellular receptors ?
located in the nucleus
form heterodimers
ligands are lipids
What properties must a drug have to bind to intracellular receptors ?
lipid soluble to bind to nuclear receptors and cause conformational change
What is the mechanism of action of an intracellular receptor ?
drug binds to nuclear receptors
causes conformational change
drug goes to the nucleus and allows gene transcription to occur by unwinding chromatin
mRNA is translated
Most receptor operated channels have how many binding sites ?
multiple
binding at one site will allow binding at another
How many binding sites do Ach homomers have ?
5
How many binding sites do Ach heteromers have ?
2
What is the mechanism of action of salbutamol ?
salbutamol binds to beta 2 adrenoreceptor
leads to complex
activates adenylyl cyclase (Gq of alpha unit)
increased cyclic cAMP
leads to bronchodilation
What is the concentration of a drug ?
the concentration in the plasma
Why is dose important ?
wrong drugs give toxic effects
different dosages are sub therapeutic for different conditions
What is the shape of a dose response curve that has agonist concnetration on the x axis and percentage response on the y axis ?
hyperbolic curve
What is the shape of a dose response curve that has agonist concentration on the x axis and percentage response on the y axis ?
sigmoid curve
What is the advantage of using logarithims ?
shows threshold - when activity starts
shows linear response
shows max response
What are the 2 types of dose-response curves ?
quantal and graded
What do graded response curves show ?
show response of a particular isolated system or tissue
its measured against agonist concentration
What do quantal response curves show ?
population based effectd
specific response determined in each member of the population
cumulative on the y axis
Why plot a dose response curve ?
estimation of the emax
estimation of the Ec50
allow efficacy and potency to be measured
What is the EC50 ?
estimation of the concentration of drug required to produce a 50% maximal response
the further to the left the curve is …
the more potent the drug is
What is affinity ?
the strength at which an agonist and drug will bind to the receptor
What does the 2 state hypothesis predict ?
at any given point the receptor can be rested or active and there is a balance between the 2
What happens to balance between rested or active when a drug binds ?
if a drug binds depending on its affinity will bind to a receptor and change conformation, destroy the equilibrium and lead to an activated receptor.
What is the B max ?
maximum saturation of binding sites
What are the values of k1 and k-1 ?
k1- rate of association of agonist with the receptor
k-1- rate of AR complex dissociation
How do we quantify affinity ?
k1/k-1= Kd
Will a high affinity drug have a larger K1 or K-1 ?
larger K1
What is Kd ?
The concentration of ligand needed to occupy 50% or receptors
it is a constant and is the same for that specific drug receptor combination in any tissue
What can Kd values be used to compare ?
the affinity of different drugs for the same receptor
What is the relationship between ligand-receptor interaction and Kd ?
the lower the Kd the tighter the ligand/receptor interaction
inverse relationship
How can we measure Kd on a dose-response curve ?
find the Ec50
the further to the left the lower the Kd value and therefore the greater the affinity
What does potency depend on ?
affinity of the drug
efficacy of the drug
receptor density
efficiency of the stimulus
What is potency ?
the amount of drug needed to produce a given effect (50% of emax)
the lower the ec50 the greater the potency
How is potency represented graphically ?
percentage response on the y axis agaisnt log conc
How is efficacy represented graphically ?
binding on the y axis agaisnt log conc
Why is binding not a good measure of effectiveness of a drug ?
only a small number receptors might be needed to elicit a response- leads to spare receptors
many receptors amplify signals
What does efficacy describe ?
ability of an agonist to activate a receptor
What is a full agonist ?
they have a high efficacy and an activated receptor is likely. They produce a max response whilst only occupying a small number of receptors.
What is a partial agonist ?
have a low efficacy and AR is less likely
unable to produce a maximal response even when occupying all receptors
they have a different receptor-signal mechanism
the max response is short of the max response the system is capable of producing
What is the use of partial agonists ?
they are used to alleviate side effects
they bind to the orthosteric site and prevent the full agonist binding
reduces the number of side effects
Give an example of a partial agonist ?
vereniciline- partial agonist for the nicotine receptor
What are the limitations of the 2 state hypothesis ?
some receptors can be activated in the absence of ligands - constitutive activity
some receptors bind to other receptors leading to G-protein activation which actually activates the receptor
What are inverse agonists ?
they have a higher affinity for the inactive state than for the active state.
How do inverse agonists work ?
they work by stimulating and turning off rather than acting like an antagonist and blocking.
What are allosteric modulators ?
the bind to the allosteric site and alter the efficacy and the affinity of the agonist for the orthosteric site
How do positive allosteric modulators work ?
they dont act alone
increase the affinity and the efficacy of the agonist
eg. Benzo will bind to the allosteric site increasing the affinity and efficacy of GABA to the orhtosteric site
How do negative allosteric modualators work ?
not active alone
decrease affinity and efficacy of endogenous agents
What happens with continual repeated administrations of the drug ?
effect of the drug reduces internalisation of the receptor stops the potential for binding long periods lead to desensitisation reapplying the drug can lead to a heightened response
What is an antagonist ?
drug which blocks response to the agonist
binds to the receptor and prevents the endogenous product binding
What is the mechanism of action of antagonists ?
they dont have a mechanism of action, they just bind to the receptor and prevent the agonist binding
What are the 3 classes of antagonists ?
chemical
physiological
pharmacological
What are chemical antagonists ?
binding of 2 agents to make an active drug inactive
known as chelating agents
Give an example of chemical antagonism ?
heparin (-) binds to potamine (+) this stops the risk of bleeding
What is physiological antagonism ?
two agents with opposite effects that can cancel each other out
Give an example of physiological antagonism ?
glucorticoids have a risk of inducing hyperglycaemia so they are administered with insulin
What is pharmacological antagonism ?
binds to receptor and blocks the normal action of agonist on the receptor
What are the 2 types of receptor antagonists ?
allosteric binding
active site binding
At the binding sites anatagonists can bind …. ?
reversibly or irreversibly
What is a reversible active site antagonist called ?
competitive antagonist - binds at the orthosteric site- comeptes with the agonist
What is an irreversible active site anatagonist called ?
non-comeptitive active site antagonist- works at the allosteric site so the orthosteric site is still avaialble so endogenous product can still bind. - there is no competitive element
What are allosteric binding antagonists called ?
non-competitive antagonists - they dont compete for the orthosteric site
Does the agonist have any efficacy ?
no because it does not result in the AR* state
What is competitive orthosteric antagonism ?
antagonist will bind to receptor and prevent agonist binding but this can be overcome with increased agonist concentrations.
How is competitive orthosteric antagonism visible on the dose response curve ? (competitive antagonist)
parallel shift to the right of the agonist curve
How is non competitive orthosteric antagonism visible on the dose response curve ? (non-competitive active site antagonist)
the antagonist binds irreversibly to the orthosteric site
this is due to irreversible covalent bonds forming
this is visible as a shift to the right and a reduced maximal assymptote
What are non receptor antagonists ?
they dont bind to orthosteric sites but they still manage to inhibit the ability of the agonist to produce a response.
it occurs at the molecular level and works by inhibiting downstream molecules in a pathway
How are non receptor antagonists visible on the dose response curve ?
reduced slope
reduced maximal assymptote
With competitive antagonists how is the dose response curve produced ?
you cant measure antagonist response so you have to measure the agonist and the antagonist response
Why is the curve shifted to the right for competitive antagonists ?
because more agonist is needed to get the same response
the curve has the same form and max response because the antagonist binds irreversibly.
How do we work out the dose ratio ?
Antagonist + Agonist EC50 / Agonist EC50
What is the schild equation used for ?
calculated for different antagonists and then plotted as a straight line- where the line intercepts the x axis- amount of antagonist needed to reduce the agonist by 50%
What can we use schild values for ?
comapring the effectiveness of antagonists
What are pH2 values ?
they are the negative logarithim of the molar concentration of antagonsit required to make a dose ratio of 2
When can you only use schild plot values?
if a linear relationship and schild plot= 1
What does the extent of antagonist inhibition depend on ?
the amount of competing antagonist
actual amount of antagonist- differences between individuals
What does the irrevesible antagonist dose response curve look like ?
curve doesnt have the same form
shifted to the right
reduced maximal response
increased EC50
Why is the curve different for irreversible antagonism ?
antagonist binds with the orthosteric site irreversibly reducing the max reponse - cant be overcome by increasing agonist concentrations
How is the duration of the effects of irreversible antagonism determined ?
the longer it takes for receptors to turn over the longer the effect of the irreversible antagonist
What is the curve for irreversible agonists similar to ?
the curve for partial agonsits
How can you determine if something is an irreversible antagonist or a partial agonist based on the dose response curves ?
if you know the experimental conditions- know if antagonist was purposefully added
Which antagonists are more common ?
competitive antagonists
Give an example of a competitive antagonist ?
tamoxifen at the oestrogen receptor
Give an example of an irreversible antagonist ?
phenoxybenzamine at the alpha 1 adrenoreceptor
What does the curve look like for non-competitive antagonists ?
reduced slope
rediced maximal effect
Give an example of a non-competitive antagonist ?
nitedipine
How do we measure the therapeutic index ?
TD50/LD50 - therapeutic/lethal
Why do we have the therapeutic index ?
to give the range of concentrations of therapeutic and toxic effects
What does a large therapeutic index mean ?
there is a large gap between the theraputic doses and the lethal doses - not likely to get toxic
What is pharmcokinetics ?
mathematics of processes ADME which govern the amount of drug in the body and how this changes with time
What is absorption ?
movement of the drug across membranes
What is metabolism ?
how the drug is broken down
What is distribution ?
where the drug goes in the body
What is excretion ?
how the drug is removed from the body
What happens in absorption ?
transfer of an exogenous compound from the site of administration to the systemic circulation
Which type of compounds are likely to be absorbed ?
lipid soluble and unionised
Is the stomach important in drug absorption ?
no - weak acids and alcohols are absorbed here
How can substances pass across membranes ?
passive diffusion and active transport
Why is the rate of gastric emptying important ?
it determines the delivery of drugs to the small intestine and absorption there
Why is the small intestine significant ?
it is the site of absorption of most drugs
Why is the small intestine a good site of absorption ?
large
highly vascularised
permeable
What type of drugs are absorbed in the small intestine ?
weak basic drugs
What is the range of pH in the small intestine ?
6 in the duodenum and 7.4 in the terminal ileum
Why are enterocytes significant ?
site of drug metabolising enzymes
transporters
What are the factors affecting GI absorption ?
Gut motility
gut pH
physico-chemical interactions
particle size and formulation
Why is gut motility important ?
decreased motility leads to decreased absorption
excessive rapid movement leads to reduced absorption
Why is gut pH important ?
strong bases and acids are poorly absorbed
Why are physico-chemical interactions important ?
eg. tetracycline can bind to calcium rich foods
Why is particle size and formulation important ?
drugs are prepared to have a certain absorption
like resistant coatings
What is bioavailability ?
the fraction of the adminstred dose that enters the systemic circulation
What is first pass metabolism ?
metabolism that occurs in the liver and small intestine first before reaching the systemic circulation
What is a parameter of absorption ?
area under the curve
How do we work out area under the curve ?
Add concentrations and divide by 2
multiply by time
trapezium rule
What is another way of representing bioavailbility ?
F
What is the F for an intravenous dose ?
1 - goes straight into the systemic circulation
What is the F for an extracellular dose ?
less than 1
What are the disadvantages of using F as a parameter?
does not consider rate of absorption
What is the C max ?
the maximum concentration of a compound after it has been administered
What is the t max ?
the time taken to get to C max
What is sublingual administration ?
placing under the tongue
goes straight into the superior vena cava
avoids first pass metabolism
What is the rectal/vaginal route ?
bypasses the GI/hepatic systems
rapid absorption
useful if patient is vomiting
What is the venous drainage from the rectum ?
two thirds systemic - middle and inferior veins
one third liver- superior rectal vein
What are advantages of IV injection ?
very rapid
alternative to IM
What are the disadvantages of IV injection ?
risk of infection
immediate adverse effects
What are advantages of IM injections ?
faster systemic effect and faster local effect
What are the parenteral routes of adminsitration ?
IV IM Subcutaneous transdermal inhaled intrathecal - reaches the CSF
What are the ways that drugs can cross cell membranes ?
passive diffusion through lipid
diffusion across aquaporins
carrier mediated
Which substances are likely to dissolve in lipid ?
non-polar
unionised
Do ionised species have a high or low lipid solubility ?
low
Drugs that are weak acids and weak bases are….
can be both ionised and unionised
What determines the ratio of ionised:unionised ?
pH
What is enterohepatic recirculation ?
drugs pass twice through enteric metabolism before getting to the tissues `
What is the route of enterohepatic recirculation ?
drugs go to the gut and the liver and are secreted as bile into the duodenum
the bile is abosorbed by enterocytes and the transported back the liver
What is an example of a drug that passes through enterohepatic recirculation ?
morphine
What are the 2 processes behind elimination ?
metabolism and excretion
What are the systems assocaited with elimination ?
kidneys
hepato-billary system
lungs
With most drugs being lipophilic what must be done to them prior to elimination ?
they must be made water soluble and hydrophilic
this happens in metabolism
What is drug metabolism ?
enzymatic modification of the drug
phase I and phase II
What is phase I reactions ?
usually oxidation
adding a fucntional group
increases pharamcological activity
What are phase II reactions ?
conjugation
adding a conjugate to make more hydrophilic and water soluble
What are the reactions of aspirin in metabolism ?
- Aspirin is oxidised to salicylic acid
2. Salicylic acid is conjugated to gluconoride
Why does aspirin need to be metabolised ?
it is a prodrug - retaina activity until in right tissue
What are typical phase I reactions ?
oxidation
reduction
hydrolysis
What happens in phase I reactions ?
adding a functional group like OH
decreases lipid solubility
increases pharamcoligical activity
What are the phase I reactions catalysed by ?
group of enzymes called cytochromes P450s
What are the cytochrome P450 enzymes ?
superfamility of haem cofactor containing enzymes
Why do the cytochomes P450s have haem factors ?
allows enzyme to carry out redox cyclically and add fucntional groups
Where are CYPs usually expressed ?
in the intestine and the liver- hepatocytes and enterocytes
hepatocytes
always in the ER
What is the most expressed CYP enzyme ?
CYP 3A
What are the routes of ethanol metabolism ?
- ethanol to acetaldehyde by alcohol dehydrogenase
- acetaldehyde to acetae by aldehyde dehydrogenase
- small amount of metabolism by CYP2E1
Where does ethanol metabolism occur ?
liver
What is aldehyde dehydrogenase inhibited by ?
metronidazole
when taking metronidazole dont drink as it can inhibit aldehyde dehydrogenase - stop metabolism at acetaldheyde which is toxic
What are phase II reactions ?
conjugation
fucntional group is a point of attachment for conjugates decreases lipid solubility and makes a pharmacoligically inactive metabolite
What is the most common form of conjugation ?
glucoronidation
What is glucoronidation mediated by ?
UDP -glucoronyltransferases
have a broad substrate specificity
Why are glucoronides excreted rapidly ?
polar
pharmacolgically inactive
What are the routes in paracetamol metabolism ?
paracetamol can be conjugated with gluccoronide or sulfates
however some cna be metabolsied by CYP2E1 to NAPQI and then made into a glucoronide with glucathione S transferase and the mercapturic acid
What is NAPQI ?
a hepatotoxin
What happens in paracetamol overdose ?
conjugates depleted and system saturated
paracetamol forced to take CYP450 route and amke NAPQI leading to hepatic necrosis
What is the problem with alcohol and paracetamol overdose ?
CYP2E1 increases in alcohol metbaolism forcing more paracetamol down thia route and making NAPQI
What are the fluids that an excrete ?
urine bile lung milk sweat
How is penicillin cleared from the blood ?
rapidly
How is diazepam cleared from the blood ?
slowly
Are metabolites or parent compounds excreted faster ?
metbaolites
What is the limiting factor in glomerular filtration ?
molecular weight
must be less than 20000
plasma conc of the drug
What is not filtered in glomerular filtration ?
plasma proteins
plasma protein bound drugs
How are lipid soluble drugs excreted ?
lipid soluble drugs filtered through the glomerulus secreted into distal portion metabolism to more polar compounds secreted back to tubule excretion in urine
How are water soluble drugs excreted by the kidneys ?
they are secreted unchanged
How does the nephron enable the drug to be secreted ?
the nephron reabsorbs water concentrating the drug so that it can be passed out the urine
80% of renal blood flow goes where ?
peritubular capilalreis of the PCT
How are drugs transported from the peritubular capillareis to the tubular lumen ?
2 systems for acids and alkalis
transport against an electrochemical gradient
many drugs share the same transporter- leading to competition
PPB drugs not limited
Which drugs use the acid system ?
penicllin and furosemide
Which drugs use the base system ?
amiloride and cimetidine
Why are lipid soluble drugs slowly excreted ?
high tubular permeability
Why do water soluble drugs get excreted quickly ?
low tubular permeability
What does the extent of tubular reabsorption depend on ?
pH of tubular fluid
Drug lipid solubility
What happens to drugs in an alkaline fluid ?
weak acids become ionised and reasbsorption is diminished
weak bases become unionised and reabsorption increases
For weak bases when is the greatest ionisation ?
in an acidic pH
For weak acids when is the greatest ionisation ?
in alkaline pH
What does pH partition impact on ?
the rate at which drugs permeate membranes and their distribution in compartments
Where do weak acids accumulate ?
in compartments of alkaline ph
How can we rapidly excrete a weak base ?
in an acidic urine
How can we rapidly excrete a weak acid ?
in an alkaline urine
How can we eliminate volataile gases ?
exhalaton
What is clearance ?
measure of the ability of eliminating organs to remove a compound from the body
How can we work out the total body clearance ?
Addition of the organ clearances
How can clearance be defined ?
volume of plasma cleared per unit of time
How can we work out clearance with Ke ?
CL= Ek x Vd
What are the units of elimination constant ?
1/t
hr^-1
How can we work out the Ek graphically ?
slope of the log transformed graph
If the slop of the log graph is linear what does this mean ?
0 order kinetics
constant metabolism regardless of dose
What is half life ?
time it takes for a concentration of a drug to reach 50% of its current value
How can we work out half time ?
0.693/Ke
or graphically
How long does it take for a compound to reach its steady state ?
5 half lives
How many half lives does it take to remove a drug ?
6/7 half lives
What is the average intake of food additives ?
8g
What does exposure to chemicals do ?
can induce or inhibit drug metabolising enzymes
What can induction lead to ?
increased synthesis of Phase I and II reactions
increased metabolism and reduced pharmacological effectiveness
may need to increase dose
can be complicated in multi drug therapy if you remove the inducer
What can act as inducers ?
smoking
ethanol
some drugs
What can inhibition lead to ?
inhibit CYP system
reduced metabolism and increased pharmacological effect
basis of many drug-drug interactions
What can act as inhibitors ?
ethanol acutely
grapefruit juice components can inhibit CYP3A4
What is an adverse drug reaction ?
harmful or seriously unpleasant reactions at the dose intended for therapeutic effect
What must drug safety take into account ?
severity of the ADR
disease
therapetci alternatives
perception of the risk- is it bad or not ?
What is the time sequence of an ADR ?
most adverse reactions happen in a short period and some can show up in offspring
What is a side effect ?
unavoidable consequence of the drug administration due to the pharmacology of the drug
mild and expected and dependent on dose
What are secondary adverse effects ?
indirect causation - taking a drug can cause an increased risk of something else
Glucocorticoids can reduce immunity and then lead to increased risk of opportunistic infections
How can age affect ADRs ?
elderly more likely to have ADRs due to increased medications and lower phase I metabolism
Why dont newborns excrete drugs well ?
low GFR
How does sex influence ADRs ?
females have different levels of growth hormine nad CYP expression
How does medical history influence ADRs ?
if youve had an ADR to one drug more likely to have an ADR to another drug
How can ethnicity affect ADRs ?
intrinsic - pharmacokinetic and pharmacodynamic- japanese acetylate fast
or can express different receptors- pharmacodynamic
extrisnsic- alcohol, diet and smoking
What is a type A adverse reaction ?
heightened response based on what we expected at a conc
What is an example of a type A adverse reactions ?
beta blockers reduce HR
however can lead to bradycardia
What are parasympathetolytics ?
muscarinic antagonists that decrease parasympathetic activation
What are type B ADRs ?
bizarre effects
unpredictable for pharmacology of the drug
What happened in the Northwick park clinical trial ?
phase I clinical trial of leukaemia treatment led to cytokine response- indiscriminate immune response
What are type C ADRs ?
Chronic effects
occur as a result of chronic treatment of the drug
What is an example of a type C ADR ?
iatrogenic cushings syndrome by a tumour due to chronic glucocorticoid therapy
What are type D adverse reactions ?
occur remote of treatment- in children of treated patients
What are type E adverse reactions ?
withdrawal effects
What is adrenal atrophy ?
exogenous glucocorticoids act in the HPA axis in a negative feedback system for a long period of time
leads to adrenal atrophy
termination of treatment means the adrenal gland produce cortisol- leads to addisons disease.
Modification can take the form of ?
potentiatiob- increase
attenuation- decrease
Give an example of pharmacodynamic interactions ?
ethanol inceases the sedative effect of antihistamine drugs
Give an example of pharmacokinetic reactions ?
one drug interferes with anothers shape, metabolism or excretion
some drugs inhibit CYP450 and interfere with drug metabolism
What does it mean if a drug is a weak acid ?
proton donor
What doe sit man if a drug is a weak base ?
proton acceptor
What is pKa a measure of ?
the strength of an acid/base
How does the degree of ionisation change ?
the pH of the solution
What happens when the pKa of the drug equals the pH of sthe solution ?
50% of the drug is ionised
What happens to an acid and a base if you increase the acidity ?
increasing the acidity means the acid drug wil go from ionised to neutral
the base will get ionised
What happens to an acid and a base if you increase the basicity ?
the base will go from ionised to neutral
the acid will get ionised
What is the significance of ionised species ?
low solubility - cant pass through lipid bilayer
What is pH partitioning ?
acidic drugs accumulate in basic fluid compartments and vice versa
What happens to aspirin in the stomach ?
aspirin is a weak acid
stomach has pH of 2
aspirin is neutral unionised and can pass through lipid bilayer into plasma
What happens to aspirin in the plasma ?
pH is 7.4
aspirin becomes ionised
What affects the ability of a drug to get from the systemic circulation to other tissues ?
ability to cross plasma membranes
blood flow to certain tissues
extent of plasma protein binding
What is set up between the systemic circulation and the tissue ?
an equilibrium
if elimination processes remove the compund then the concentration in the tissue wil also decrease
What is drug distribution ?
reversible transfer of drug form one location in the body to another
How does drug distribution usually occur ?
by passive diffusion of an unionised drug across cell membranes until equilibrium is reached
What happens with distribution after an IV injection ?
Transfer from plasma to tissue
equilibrium
removal of compound by elimination processes from the blood means trnasfer from the blood to the tissue
What do capillaries consist of ?
basement membrane attached to endothelium
endothelium has slits
What affects the rate of distribution ?
permeability of the capillaries
amount of vasculature
What affects the extent of distribution ?
lipid solubility- ionised drugs cant enter cells easily
plasma protein binding
What are some key plasma binding proteins ?
albumin
alpha 1 acid glyocprotein
What is albumin ?
produced in the liver
binds to acidic and neutral drugs
decreased in malnutrtition and cirrhosis
What is alpha 1 acid glycoprotein ?
produced in the liver
binds to basic and neutral drugs
elevated in cancer
How do drugs bind to plasma proteins ?
reversibly
Which form of drug is pharmacologically active ?
unbound drug
What does extensive protein binding lead to ?
slows down drug action
slows down elimination
slower acting
prolonged therapeutic drugs
Why can drugs bind to tissues ?
due to tissue composition
due to cellular compartments
How can drugs bind to tissues due to composition ?
lipid soluble drugs can accumulate in fat tissue
How can drugs bind based on cellular components ?
tetracycline has high calcium affinity- accumulate in bones and teeth
chloroquine - antimalrial- afinity fro melanin so wil bind in the retina leading to ocular toxicity
What is the volume of distribution ?
measure of the extent of distribution
dilution factor between the drug in the body and the drug in the plasma
How do you work out vD for an IV dose ?
V= Dose/plasma conc at 0
How do you work out vD ?
total amount of drug in the body/ drug plasma concentration
If drugs are confined to plasma … ?
vD will be small
If drugs accumulate outside the plasma ?
vD is large
Why is Vd important ?
used to calcualte dose
How can vD be used to calculate dose ?
plasma concentration dictates the ability of a drug to reach its target organ in an effective concnetration therefore dicatates dose
What does a low Vd mean ?
confined to te plasma
What does a high vD mean ?
accumulated in the peripheral tissues
if a drug is lipid soluble and confined to body water intracellular will it be low or high vd ?
high vD
If a drug is confined to the extracellular compartment and cant enter cells will the Vd be low or high ?
low
If a drug is confned to the plasma will it have a high or low vD?
low Vd
How do you work out the concentration at t=0 ?
extrapolate backwards
How do you work out volume of distribution ?
dose/plasma conc at 0
What are the 2 ways of working out clearance ?
dose/AUC
CL= Ek x Vd
How can you work out Ek ?
Half life= ln2/Ek
ln2=0.693
How can you work out the route of administration ?
intravenous- straight line plot
Why might there be a difference in half life between 1 person on 2 ocassions ?
half life can be prolonged if the drug acts as an inhibitor of metabolism
Disease
Age
How does genetic constitution affect drug metabolism ?
genetic constitution determines if slow or fast metaboliser
Why might metabolism differ between 2 different people ?
drugs
alcohol
What are the characteristics of fast metabolisers ?
normal enzyme activity
low plasma drug concnetration
high drug metabolite concentrations
normal therapeutic effect
What are the characteristics of slow metabolisers ?
low enzyme activity
high plasma cocn of drug
low metabolite conc
exaggerated therapeutic effect
What is the effect of neonates on drug metabolism ?
low activity of CYPs
glucoronyltransferase
N-acetyltransferase
lack of conjugation activity
Why can exposure to chemicals alter drug metabolism ?
chemicals can be inhibitors or inducers of drug metabolising enzymes
How can chemicals acts as inducers ?
induce synthesis of metabolic enzymes
decreased drug effectiveness
increased dose needed
How can chemicals act as inhibitors ?
reduced rate of metabolism
increased pharmacological effect
What is the elimination constant ?
fraction of drug in the body removed per unit of time
What does an Ek of 0.2 per hour mean ?
20% of drug remaining in the body is eliminated per hour
What is the half life ?
time taken for the plasma cocnetration to reduced by one half
How can you work out half life ?
graphically
half life= ln2/Ek
What is ln2 ?
0.693
What is the therapeutic index ?
the difference between concentration needed to produce a therapeutic effect and that needed for toxicity
How to you convert from mg to micrograms ?
/1000
What is the nicotinic acetylcholine receptor an example of ?
Ligand gated ion channel
What happens to glucoronidation in paracetamol overdose ?
saturated
The IV route of adminstration is used for ?
drugs which may be easily altered by acidic pH of the stomach
