intro L1-8 Flashcards
pharmacodynamics
effect of drug on body
pharmacokinetics
effect of body on drug
pharmacokinetics factors
adsorption
distribution
metabolism
excretion
antihistimine action
cross blood-brain barrier into CNS, antagonizing H1 receptors and blocking histimine
antihistimine class
reversible competitive inhibitors, therefore can be overridden
drug-interaction factors
shape
charge distribution
hydrophobicity
ionisation of drug
conformation of target
stereochemistry of drug molecule
drug action targets
receptors
ion channels
enzymes
carrier molecules
drugs acting via physico-chemical properties
antacids
laxatives
antidotes
agonist
drug mimicking endogenous chemical messengers, eliciting a cellular response
antagonist
drug blocking chemical messengers
NSAID’s
non-steroidal anti-inflammatory drugs
Benzodiazepine action
bind to GABAa at B-2 binding site
signal receptor transduction
receptor binds agonist
altered physical/ biochemical properties of receptor
4 drug-responding receptor types
ligand-gated ion
G-protein coupled
enzyme-linked
intracellular
nicotinic ACh receptors
at skeletal muscle
antagonists used as muscle relaxants
heterotrimeric G-proteins
coupled to effectors producing 2nd messengers
Gi
inhibits adenlyl cyclase
Gq
activates phospholipase C
Gs
activates adenlyl cyclase
kinase-linked receptor
ligand-binding extracellular domain attached to intracellular by single span membrane helix
ligand binding> dimerisation> auto-phosphorylation
insulin receptorq
tyrosine kinase activity in beta sub unit increase> autophosphorylating and promoting other kinase phosphorylation
action of nuclear intracellular receptor
enters nucleus and binds to receptor for txn
CLASS II
e.g. heterodimers and lipid ligands
CLASS I intracellular receptors
in cytoplasm
e.g. homodimers and endocrine
graded dose-response curve
response of a particular system
quantal dose-response curve
drug dose for a specified response
functions of dose-response curve
allow estimation of Emax/ EC50
efficacy/ potency determination
affinity
strength w which agonist/ drug binds to receptor
tendency of ligand to form stable complex w receptor
K1
rate of receptor against association
K-1
rate of AR complex dissociation
affinity formula
K1/K-1
association rate/ complex dissociation rate
Bmax
max number of binding sites
Kd
equilibrium dissociation constant
concentration of ligand when 50% of receptors occupied
(lower=higher affin)
Kd functions
receptor identification
quantitative comparison of drug affinity
affinity factors
no./nature of bonds
level of fit
Kd
potency
amount of drug required to
produce given effect
potency factors
affinity
efficacy
receptor density
affinity of stimulus-response mechanisms used
when is Kd = EC50
if occupation and bio effect is linear
receptor property meaning only fractional occupancy is required for max effect
receptors can amplify signal duration and intensity
efficacy
ability of an agonist to activate a receptor
efficacy determination
max effect agonist can produce regardless of dose
nature of receptor-effector system
full agonist
high efficacy
max response w partial occupancy
partial agonist
max response not available even with full occupancy
inverse agonist
higher affinity for AR state than AR*
positive allosteric modulators
not active alone
high affin/ efficacy of endogenous agonist
negative allosteric modulators
not active alone
low affin/ efficacy of endogenous agonist
receptor desensitization
effect reduction with continual/ repeated administration
factors of receptor desensitization
conformational changes in receptor
receptor internalization
mediator depletion
altered drug metabolism
other physio responses
types of antagonist
chemical
physiological
pharmacological
chemical antagonist
binding of 2 agents rendering inactivity of drug
cholating agent
physiological antagonist
2 agents with opposite effects cancelling each other out
pharmacological antagonist
receptor binding blocking action
types of pharmacological antagonist
competitive
irreversible
non-competitive
competitive pharmacological
binds and prevents
overcome w ^ agonist conc
right parallel shifyt
common
irreversible pharmacological
covalent irreversible binding
parallel right shift and decreasing asymptote
less common
non-competitive pharmacological
allosteric blocking downstream effects
decreasing slope and max dose-response curve
dose ratio formulae
(agonist + antagonist EC50)/ agonist EC50
Schild equation
dose ratio -1 = antagonist conc/ antagonist dissociation constant
pA2 values
describe receptor antagonist activity
pA2 formula
-logKb
*only if linear relationship and schild plot =1
therapeutic window index
defines dose range between therapeutic and toxic effects
types of drug movement
bulk flow (e.g. blood stream/ lymphatics.)
barrier diffusion (e.g. blood-brain barrier gastrointestinal mucosa…)
drug administration routes (quickest first)
IV
oral
dermal
IV event
rapid action
high dose control
drug poorly absorbed otherwise
types of injection
IV
Intramuscular
subcutaneous
what does rate of injection diffusion depend on
tissue diffusion
blood flow removal
stomach conditions for drugs
low pH
pH partitioning as drugs ionize
small intestine conditions for drugs
large sa
v permeable
large blood supply
enterocytes have metablic enzymes/ transporters for uptake and efflux
enterohepatic recirculation
moves through gut
blood absorption
hepatic portal vein entrance
liver transport
gall bladder transport
sublingual GI routes
network of capillaries under tongue, drug bypasses 1st pass metabolism straight into bloodstream
rectal GI route
local effects
avoids 2/3 1st pass metabolism
:(unreliable
examples when rectal GI should be used
opioid withdrawal
travel sickness
status epilepticus in children
parenteral routes
inhalation
topical drugs
cornea
nasal mucosa
vaginal
transdermal
inhalation GI route
skips 1st pass
rapid action
factors affecting drug absorption
metabolism
pKa
drug molecule size
membrane permeability
skin hydration
lipid solubility
stratum corneum reservoir
ionized form of drug vs unionized
not lipid-soluble
vs lipid-soluble
oral absorption factors
gastric motility
food splanchnic blood flow
particle size
capsules
Cmax
max conc of drug after dosing
Tmax
time taken to reach Cmax
bioavailability
fraction of drug administered absorbed and available to have effect
factors of drug distribution
perfusion
cell membrane crossing
protein binding ability
albumin
binds mostly acidic and some basic drugs
AAG
A1 acid glycoprotein
binds basic drugs
^ inflam effects
bioavailiability factors
free drug available
affinity
protein conc
Vd
volume of fluid required to contain total amount of drug in body Q at same conc present in plasma
Vd formulae
Q/Cp
why do drugs need to be metabolized
lipophilic drugs not eliminated by kidney and therefore need further metabolism to more polar/ water-soluble products prior to excretion
metabolism phase 1
enzymatic reactions exposing/introducing functional groups (e.g. hydroxyl/ amino/ sulphydryl/ carboxyl)
decreasing lipid solubility and ^ pharmcological activity
hydroxylation
conversion of hydrogen to hydroxyl
deamination
conversion of an amino group to a carbonyl group
dehydrogenisation
conversion of a hydroxyl group to a carbonyl group
xenobiotic metabolism behaviour
undergo oxidation
CYP450
embedded inSER
combine w pink compound to produce pink compound
variations in P450
species differences
genetic polymorphisms
drugs
environmental factors
butrylcholinesterase
hydrolyzes suxamethonium, overactivating cholinergic receptors on muscles, causing paralysis
alcohol dehydrogenase
hepatocyte cytoplasm oxidation of ethanol to acetaldehyde
requires NAD+
aspirin esterase
aspirin hydrolysis to salicylate
found in plasma
metabolism phase 2
conjugation occurs in liver/ kidney/ lung
further decrease in lipid solubility
functionalisation
reactive group introduction
products more reactive/ toxic
total clearance
vol of plasma/ blood cleared of drug per unit time to achieve overall elimination of drug from body
Kel
elimination rate constant
fraction of drug eliminated per unit time at any point
Kel formula
total clearance / volume of distribution
glucaronidation
UDP-glucaronyl transferase (broad substrate specificity mediation)
glucaronides pharamcologically inactive and excreted
therapeutic paracetamol metabolism
conjugation w sulphate and glucoronic acid
minor proportion metabolized by CYP450 to toxic metabolite
paracetamol overdose
saturated conjugation pathways and toxic metabolite reacts w liver proteions not depleted glutathione
tissue damage occurs and hepatic necrosis
exogenous drug metabolism factors
drugs
smoking/ alcohol
environmental
endogenous drug metabolism factors
genetics
age
disease
fast metabolizer genetic constitution
normal enzyme activity
decreasing plasma conc
^metabolite conc
normal therapeutic response
slow metabolizer genetic constitution
decreasing enzyme activity
^ plasma conc
decreasing metabolite conc
exaggerated therapeutic response
pharmacogenomic factors
decreasing CYP w age
half-life variability
drug induction
examples?
^ synthesis of enzymes
^ metabolism of inducing agent
e.g. smoking/ ethanol
3 processes of renal excretion
glomerular filtration
tubular reabsorption
tubular secretion
water-soluble drug excretion
unchanged passed through kidneys
lipid-soluble excretion
glomerular filtration, tubular reabsorption, metabolism to more polar, urine excretion
do lipid solubility and pH affect glomerular filtration?
no
entry rate factors
molecular weight
conc of free drug in plasma
2 drug carrier systems to tubular lumen against echem gradient
acidic drugs
organic bases (most effective)
lipid-soluble drug effect on tubular reabsorption
^tubular permeability and slow excretion
water-soluble effect on tubular reabsorption
decreasing tubular permeability and decreasing urine concentration
tubular reabsorption factors
drug lipid-solubility
tubular fluid pH > affects ionization
what happens when solution pH = drug pKa
50% drug ionized
pH partitioning
acidic drugs accumulating in basic fluid compartments and vice versa
weak acid ionization max
at alkaline pH
* therefore more rapidly excreted in opposing pH urine
weak alkaline ionization max
at acid pH
* therefore more rapidly excreted in opposing pH urine
pharmacokinetic parameters
bioavailability
distribution volume
elimination half-life
clearance
one-compartment model
simplified model demonstrating human as single, well-stirred compartment
kinetic order
relates plasma conc of a drug and rate of elimination from the body
1st order
rate of drug decrease dependent on plasma conc
rate-limiting factor= drug concentration
2 comppartment model
drugs only enter body tissues via plasma (peripheral/ central comp)
0 order
drug decrease independent of plasma conc
constant rate due to limiting factor
Vd
volume of distribution
used to calculate drug dose / loading
Vd formula
dose/ C0
Vd effect on plasma concentration
inverse
4 phases of uk drug development
target discovery
lead identification
lead optimization
clinical candidate
high throughput screening
global protein profiling, protein-protein interaction
structure activity relationships
predicting biological activity from molecular structures
chemoproteomics
selectivity/ drug affinity profiling
GLP
Good lab practice
managerial quality control system
FDA modernisation act 2.0
no longer requires all drugs to be tested on animals before human trials
2 regulation authorities in UK
MHRA
European medicines agency
drug manufacturing authorization stages
product identification]
product maufacture
pre clinical data
clinical results
therapeutic trial
ethically designed experiment addressingrecisely-framed questions
trial question framework
treatment
prevention
diagnostic
QOL
factors affecting reliability
bias
controls
blinding
placebo effect causes
natural remission
regression to mean
classical conditioning
‘nocebo effect’ neurochemistry
clinical trial endpoint measures
clinical measures (liver/ kidney function, blood/urine chemistry/ eye testing)
PK measures (e.g. Cmax, Tmax, bioavailability)
PD measures (e.g. target affinity/ biomarkers)
phase 1 trials
establishes:
PK/PD properties of drug
toxicological properties
* roughly 1 year
phase 2 trials
establishes:
- pharmacodynamics
- clinical effectiveness
- dose ranging
phase 3 trials
establishes:
efficacy
safety
comparison to other therapeutic alternatives
