pharmacology Flashcards
pharmacology defn
study of drug action on animals, organs, tiss or cells
* mechs of how drugs work
how do drugs work (general)
mimic or block endogenous signalling mols (pharmacons)
common pharmacons for exploitation
- horms - water soluble, lipophilic, peptide
- cytokines = small peptides, paracrine/autocrine, e.g. interferons
- growth factors - IGF, EPO
- NTs, e.g. Ach, dopamine
- pheromones = aas, peptides, prots, FAs
exogenous
grows or originates from outside org
exogenously derived pharmacons
drugs usually organic + cyclic, e.g. paracetamol, morphine
specific vs non-specific effects
specific = related chem struct bc binds specific target
non = related physiochemical characs
typical drug targets (binding sites)
- enzs
- ion channs
- mRNA, DNA
- receptors
3 examples chems used as drugs
NSAIDS
beta-blockers
sulphonamides
antibiotics
chem bonds involved drug action
- covalent bonds
- ion-ion
- ion-dipole
- H bond
- dipole-dipole
- van der Waals
decr strength order
features of chem bonds
overall strength = how tightly binds = affinity
geometry = how well shape matches = specificity
pharmacology process
- identify disease
- identify target
- synth selective ligand (small mol if poss bc easier to give)
- assess function
pharmacokinetics
mech of action + movement of drugs thru bod
1. absorp
2. distrib
3. metab
4. elimination
drugs have reach target at sufficient conc to prod desired response
ideal drug properties
- few off target effects (causing something in non target tiss)
- high Ti (therapeutic index)
therapeutic index
LD50/EC50
= dose that kills 1/2 subjects/effective dose
== range of doses at which drug effective w/o unacceptable adverse events
4 types prot drugs typically bind to
- receptors = agonist/antagonist
- ion channs = block/modulate (change probability open)
- transporters = inhibitor/false substrate
- enzs = inhibit/false substrate/pro-drug to prod drug
agonist vs antagonist
- binds receptor cause conformational change => response in target cell
- binds receptor but initiates no response + occupies receptor = ag no bind = usually inhibitory
== has action vs blocks action
receptor
prots embedded lipid bilayer
* usually for endogenous horms/NTs
* interact w ligands = pharmacon = ag/antag
* each recogs small no. mols w structural sim
receptor subtypes for cannabinoids
agonists
1. CB1 = central
2. CB2 = peripheral, anti-inflamm
slightly diff shape
receptor subtypes histamine
antagonists in gut
1. H1 => sm musc contract
2. H2 => parietal cell acid secr
mol that binds receptor
== drug == ligand
receptor + drug => drug-receptor complex
high vs low affinity ligand
high = low conc ligand required b4 all receptor sites occupied
typical drug mechs of action
usually evoke 3 processes:
1. reception of signal
2. transduction
3. response
transduction of signal
- initial = shape change in receptor
- multistep pathway = 2nd messenger pathway = amplify signal + more opps coord + multiple cellular responses
- -> end-pt target
2nd messengers
mols that relay signal from receptor -> response
* often prots, also cyclic AMP + Ca2+
common end pt targets
- Ca2+
- enz => altered cell metab
- structural prot => alter cell shape + movement
- transcription factor => alter gene expression = diff type/amount prots w/in cell
signal amplification
cascade effect = small amt ligand can have large effect
* often involves kinase + phosphatase reactions
affinity vs efficacy
how well it binds vs how much action has (how well works)
types receptors
- cell surface = hydrophilic signal mol
- intracellular = small hydrophobic signal mol
effect of agonist receptors
DIRECT: ion chann opening/closing
TRANSDUCTION MECHS:
1. enz activation/inhib
2. ion chann modulation
3. DNA transcription
drug targets
- receptors
- transporters
- ion channs
- enzs
types mem receptors
- ion channs
- enz-linked
- metabotropic/GPCR
metabotropic receptors
== G-prot coupled receptors
single polypep w 7 transmembrane domains (α-helices)
* ligand binds extracellular domain or w/in transmem domain
types metabotropic receptor
- ion chann
- enz
ion chann GPCR
receptor -> G prot (excit/inhib) -> ion chann => change conc ion => depol/hyperpol
e.g. muscarinic Ach receptor
enz GPCR
receptor -> G prot (excit/inhib) -> enz -> 2nd messenger -> enzs/Ca2+ mobilisation => cellular effects
e.g. α + β adrenoreceptors
G prot activated enzs
- ATP + adenylate cyclase -> cAMP
- GTP + guanylate cyclase -> cGMP
- PIP2 + phospholipase C -> DAG/IP3
middle = G prot, 3rd = enz
G prot full name
guanosine nucleotide binding prot
how activate G prot
- GTP binding
- phosphorylation
GTP binding to G prots
- inactive G prot bound GDP + signal in
- GDP exchanged for GTP
- => active G prot bound GTP for signal out
- GTP hydrolysed to GDP by G prot => inactive again
phosphorylation of G prot
- inactive G prot + signal in
- phosphrylation by kinase enz
- => active prot w P bound + signal out
- then dephosphorylation by phosphatase enz -> inactive
GPCR in relation asthma
- noradrenaline + β2 receptor w G prot coupled
- => incr cAMP
- => decr myosin kinase = less phosphorylation myosin -> phos myosin
myosin = bronchodil, myosin-P = bronchoconstr
adrenoreceptors
- α = bvs incr bp + bronchoconstr
- β1 = incr HR
- β2 = bronchodil
noradrenaline structural activity relationship
no. OH grps:
0 = no activity
1 = indirect activity
2 = partial activity
3 = full activity
potency incr, α + β, no selectivity
isoprenaline activity
no activity at α, just β1 + β2
salbutamol
no activity at α, just β2 selective agonist
terbutaline activity
no activity at α, just β2 selective agonist
kinase-linked receptor
ligand-binding domain = α subunit
kinase domain = β subunit
inc insulin receptor (= tyrosine kinase domain)
tyrosine kinase receptor
ligand binds, tyrosine kinase domain phosphorylates, then intracellular prots bind only to phosphorylated shape => activated
ionotropic receptors
== ligand-gated ion channs, e.g. nicotinic Ach
cell surface receptors
antagonist/agonist reversible or no
agonist always reversible, antagonists can be either
* α-bungarotoxin = irreversible, blocks musc endplate nicotinic (= nicotinic AcetylCholine Receptor, nAChR) = stop contractions
* d-tubocurarine = reversible block nAChR = no contractions
structure nAChR
5 subunits: 2α, 1β, 1γ/δ
* each subunit 4 transmem (TM) domains
* ACh binds to α-subunits
GABAA receptor
= ionotropic receptor
* GABA binds + activates = Cl- thru = inhib K+/Na+ thru
* has inverse agonists to do opp
* alcohol binding site => modify behaviour of agonist = allosteric modulator
inverse agonist
bind same agonist site + cause opp effect vs just blocking site to agonist
allosteric modulator
binds allosteric site + modifies activity of agonist
examples intracellular receptors
hydrocortisone, steroid horms, oestrogen, progesterone, thyroxine
intracellular receptor structure
- transcription activating domain
- DNA binding domain
- hormone binding domain = ligand binding domain
horm-receptor complex regs transcription target genes
* slow response
inactive vs active intracellular receptor
inactive form bound inhib prots block DNA binding site, then ligand binds => inhib prot detach => DNA binding site exposed
transporters
move ions + chems against conc/electrochem grad
* requires E = ATP hydrolysis (AT) or use ion grad in co-transport
* drugs can block, e.g. digoxin blocks Na+/K+ ATPase
how inhibit ion channs (transporter prots)
- block = no thru
- modulators = incr/decr opening probability
ion chann blockers
- Ca chann blockers stop signalling musc cells, e.g. verapamil for hypertension
- Na chann blockers stop conductance, e.g. lidocaine local anaesthetic
- K+ chann blockers, e.g. sulphonylureas = back up anti-diabetics
local anaesthetics
quickly reduce pain = decr need general anaesthesia
* polymodal pain control
* keep mem polarised = no fire a pot, no conduct, no pain
2 drugs that inhibit enzs + function enz targets
- captopril competitive reversible angiotensin-converting enz => incr Na+ excr + bp decr + vasodil
- aspirin non-competitive irreversible for cyclooxygenase (shld convert arachidonic acid -> prostaglandins) = relieve pain, reduce fever, anti-inflamm, bc prostaglandins cause
false substrate
= drug action at enz => abnormal metabolite proded
pro-drug
given, binds enz => active drug proded
Michaelis-Menten curve
binding of drug to receptor = like enz reaction
high vs low affinity curve
efficacy graph
naloxone (blue) has no efficacy (antagonist)
morphine (red) has plenty efficacy (agonist)
efficacy vs conc on log curve
full vs partial agonist
of any given receptor
* partial = efficacy low, affinity high
partial agonist = partial antagonist if add full agonist later as fills receptors, blocking
effect competitive antagonist
log graph shifts right = need higher conc same effect
* reversible antagonist = high enough conc agonist will displace, e.g. naloxone
non-competitive antagonist
binds allosteric site = receptor site change = switches off = can’t bind
* no amount agonist will reverse
e.g. ketamine for NMDA receptors for glutamate
tachphylaxis
receptor desensitisation = drug slightly less effective each time = smaller peaks each time on graph
process of drugs thru sys
- absorp
- distrib
- metab
- excr
==> need adequate conc in target tiss
routes drug administration
topical (high conc 1 spot) + systemic (get everywhere)
* oral (harder in pets)
* topical - analgesics, antibiotics
* injection - insulin
* inhalation - salbutamol
dependent on drug + target area
types systemic administration
- enteral = via GI tract
- parenteral = not via GI tract (inhalation, injection)
types parenteral administration
- intravenous
- intraperitoneal
- intramuscular
- subcut
- intrathecal = epidural = bet spinal cord + vertebrae => CNS (local properties tho, e.g. pain relief)
decr speed of working
transmucosal administration
TM
tablet absorbed directly from mouth
* enteral/parenteral mash up
absorption of stuff from tablets
from SI
* microvilli = large SA compared stom
* high blood flow
* bile helps solubilise some drugs - if lipophilic
delayed gastric emptying delays absorp
oral admin gets some metab b4 becomes ‘bioavailable’
how do drugs cross gut wall
- transcellular
- paracellular (no lipophilic) = bet cells -> cap
only lipid soluble diff in passively
methods transcellular drug absorp
- passive diff = non-polar chems, down conc grad
- fac diff = polar chems, down conc grad
- AT = polar chems, no grad, need ATP
transport drugs in blood
- free in sol (if v soluble)
- bound plasma prots, e.g. albumin
- in rbcs + wbcs
–> hepatic portal vein, liver + heart
bioavailability
% of drug that reaches blood
* after absorp, liver metab etc
* IV injection gives 100%
factors affecting bioavailability
- water solubility
- lipid solubility
- degree ionisation
- molecular weight
- amount metabed
generally most important in ref oral admin
1st pass metab
how much of drug metabolised on 1st pass thru liver
effect pH on drug absorp acid drugs
v alkaline = few H+ = drug, e.g. meloxicam, loses prots = becomes charged (N- + O-) (ionised) = lipophilic -> hydrophilic
* not charged at low pH, as least ionisation = most lipophilic
= absorp best in acidic environ bc non-ionised absorb best thru mems
effect pH on absorp basic drugs
acidic = lots H+ = gains 1 = becomes charged (NHH+)
* ionised at low pH = lipophilic at high, lipophobic at low (most ionisation)
e.g. pethidine = absorp best in basic environ
pKa
pt where substance has 50% H+ bound, 50% not
Henderson-Hasselbach equ
acid drug: pH - pKa = log(ionised/nonionised)
basic drug: pH - pKa = log(nonionised/ionised)
pKa = -log(Ka)
partition coefficient
P = conc in organic solvent/conc in aqueous phase
logP vals indicate lipophilicity of uncharged version of drug
* higher = absorped easier + crosses BBB more easily
conc of unionised mols
uncharged absorbs better than charged, but diff uncharged drugs absorp diff amounts (= lipid solubility = lipophilicity)
multidrug resistance prot (MDR)
= P-glycoprot = protective transporter found in gut + BBB => removes toxins
* drug can be uncharged w good lipophilicity but actively thrown out (= decr bioavailability)
mutation in MDR gene
= absorb when shouldn’t
* ivermectin neurotoxic but removed by MDR => v effective but then toxic to collies
in collie-like dogs
drug binding
w issue
drug + prot -reversibly> drug-prot complex
* finite no. prot-binding slots
* give 2 drugs both bind albumin then not enough slots = more free = usually safe dose now toxic
* disease state can change prot content of blood, e.g. renal failure, liver disease
if drug higher % prot-bound, will have more of an effect
what binds what drugs + prots
- albumin net neg + binds acidic drugs
- lipophilic usually bind lipoprots
variation in perfusion
well perfused: heart, lungs, liver, brain
moderately: musc, skin
low: fat
negligibly: bone, teeth, tendons, ligs
why need drug metab
bc most are oral (easy give) = absorp SI = lipophilic = difficult excr as reabsorbed kidney = need break them down -> water soluble so can pee out
drug metab
PHASE 1: drug -> drug-sol
PHASE 2: drug sol -> drug-O-[conjugate]
3 things excreted in incr amounts as get more water soluble
where drug metab
kidney, gut wall, plasma, liver
* ‘microsomal enzs’ of liver acc in SER
most drugs metabed by liver, excr by kidney
phase 1 drug metab
microsomal enzs in liver add OH, COOH, NH2 etc
* cytochrome P450 (CYP) = family enzs => ox/red/hydrolysis (make drug more water soluble)
* e.g. phenobarbitol -> phenobarbital alcohol
if already water soluble then this ofc unnecessary
other phase 1 reactions
- alcohol dehydrogenation
- amine oxidation
not P450 reactions
enz inducer
slow metab, bod recogs this + upregs enz to break down more = Rometab incr
e.g. phenobarbitol
chocolate effect dog
theobromine in choc metabed -> several species by diff phase 1 enzs
* dogs eliminate diff amount metabolites in urine + faeces
* not threat to cats bc indifferent to sweet so don’t eat enough cause damage
metab codeine
-> morphine in phase 1
phase 2 metab
conjugation = sticks on big water soluble mol
* glucuronidation -> morphine, oestradiol, progest, LSD (cats don’t have = paracetamol more dangerous bc from phase 1 stays + toxic)
* sulphation
* acetylation
* glutathione-ation
via conjugation enz, some in microsomal enzs (glucurodination largely this), others in liver cytosol
energetically expensive bc losing big mols
drug excr
- most things glomerular filtration (not prot bound species)
- charged stuff = active tubular secretion
- liver secretes some metabolites directly -> SI in bile
most in kidneys, fought against by passive reabsorp
enterohepatic recirculation
liver picks up drug => water soluble species => bile -> kidney (should be lost)
* some species have gut flora = metab back to lipid soluble form => liver -> bile -> SI -> liver …. = drug lasts longer
* liver constantly metabolising leads liver damage = bad
e.g. etorphine in horses
orders of elimination
0th order clearance = over time straight line decr in drug conc as enz saturates at low conc = clears same rate regardless conc
1st order = 1 exponential decay in conc, e.g. phenobarbitol
2nd order = 2 exponential decays
C0
conc at time 0
* can be figured out by extrapolating back 0 order clearance drug
volume of distribution
w equ
estimate of extent of drug distrib
* big = high lipid solubility
* small = ionised/prot bound
V(litre) = Q(amount, kg)/conc(Kg/L)
no rep actual anatomical vol
central compartment
blood + tiss + fluids drug gains instant access to
* inc well perfused, e.g. liver, kidney, heart
* metab + excr occur from here
1st order clearance
drug disposition curve
* conc decr rapidly then more slow
* rate of fall decr w time + amount drug in bod = exponential decline
* constant fraction drug present at any time eliminated per unit time (expressed in terms 1/2 life)
* elimination mechs no saturated (are in 0 order)
plasma half life (t1/2)
time taken for conc drug in blood to halve
* eliminated by 1st order processes = constant
* independent of dose
2nd order elimination
body no act as 1 compartment => 2 phases exponential decline
* α phase-steep initial fall due distrib to peripheral compartment
* β phase-slower decline reps elimination phase
what get from pharmokinetic analysis
- half life
- true first order rate constants
- apparent vol of distrib
looking at movement drug thru bod
IV dosing
can’t give lots infrequently bc then half life shows below dose effective 90% time so ideally lots lil v often keep at working pt; compromise:
* dose
* frequency
* elimination rate
loading vs maintenance doses
loading dose
give big dose to start to get levels high then do smaller top up maintenance doses
