pharmacology Flashcards
(115 cards)
1
Q
pharmacology defn
A
study of drug action on animals, organs, tiss or cells
* mechs of how drugs work
2
Q
how do drugs work (general)
A
mimic or block endogenous signalling mols (pharmacons)
3
Q
common pharmacons for exploitation
A
- 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
4
Q
exogenous
A
grows or originates from outside org
5
Q
exogenously derived pharmacons
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drugs usually organic + cyclic, e.g. paracetamol, morphine
6
Q
specific vs non-specific effects
A
specific = related chem struct bc binds specific target
non = related physiochemical characs
7
Q
typical drug targets (binding sites)
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- enzs
- ion channs
- mRNA, DNA
- receptors
8
Q
3 examples chems used as drugs
A
NSAIDS
beta-blockers
sulphonamides
antibiotics
9
Q
chem bonds involved drug action
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- covalent bonds
- ion-ion
- ion-dipole
- H bond
- dipole-dipole
- van der Waals
decr strength order
10
Q
features of chem bonds
A
overall strength = how tightly binds = affinity
geometry = how well shape matches = specificity
11
Q
pharmacology process
A
- identify disease
- identify target
- synth selective ligand (small mol if poss bc easier to give)
- assess function
12
Q
pharmacokinetics
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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
13
Q
ideal drug properties
A
- few off target effects (causing something in non target tiss)
- high Ti (therapeutic index)
14
Q
therapeutic index
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LD50/EC50
= dose that kills 1/2 subjects/effective dose
== range of doses at which drug effective w/o unacceptable adverse events
15
Q
4 types prot drugs typically bind to
A
- receptors = agonist/antagonist
- ion channs = block/modulate (change probability open)
- transporters = inhibitor/false substrate
- enzs = inhibit/false substrate/pro-drug to prod drug
16
Q
agonist vs antagonist
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- 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
17
Q
receptor
A
prots embedded lipid bilayer
* usually for endogenous horms/NTs
* interact w ligands = pharmacon = ag/antag
* each recogs small no. mols w structural sim
18
Q
receptor subtypes for cannabinoids
A
agonists
1. CB1 = central
2. CB2 = peripheral, anti-inflamm
slightly diff shape
19
Q
receptor subtypes histamine
A
antagonists in gut
1. H1 => sm musc contract
2. H2 => parietal cell acid secr
20
Q
mol that binds receptor
A
== drug == ligand
receptor + drug => drug-receptor complex
21
Q
high vs low affinity ligand
A
high = low conc ligand required b4 all receptor sites occupied
22
Q
typical drug mechs of action
A
usually evoke 3 processes:
1. reception of signal
2. transduction
3. response
23
Q
transduction of signal
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- initial = shape change in receptor
- multistep pathway = 2nd messenger pathway = amplify signal + more opps coord + multiple cellular responses
- -> end-pt target
24
Q
2nd messengers
A
mols that relay signal from receptor -> response
* often prots, also cyclic AMP + Ca2+
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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
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signal amplification
cascade effect = small amt ligand can have large effect
* often involves kinase + phosphatase reactions
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affinity vs efficacy
how well it binds vs how much action has (how well works)
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types receptors
1. cell surface = hydrophilic signal mol
2. intracellular = small hydrophobic signal mol
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effect of agonist receptors
DIRECT: ion chann opening/closing
TRANSDUCTION MECHS:
1. enz activation/inhib
2. ion chann modulation
3. DNA transcription
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drug targets
* receptors
* transporters
* ion channs
* enzs
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types mem receptors
1. ion channs
2. enz-linked
3. metabotropic/GPCR
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metabotropic receptors
| == G-prot coupled receptors
single polypep w 7 transmembrane domains (α-helices)
* ligand binds extracellular domain or w/in transmem domain
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types metabotropic receptor
1. ion chann
2. enz
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ion chann GPCR
receptor -> G prot (excit/inhib) -> ion chann => change conc ion => depol/hyperpol
| e.g. muscarinic Ach receptor
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enz GPCR
receptor -> G prot (excit/inhib) -> enz -> 2nd messenger -> enzs/Ca2+ mobilisation => cellular effects
| e.g. α + β adrenoreceptors
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G prot activated enzs
1. ATP + adenylate cyclase -> cAMP
2. GTP + guanylate cyclase -> cGMP
3. PIP2 + phospholipase C -> DAG/IP3
| middle = G prot, 3rd = enz
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G prot full name
guanosine nucleotide binding prot
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how activate G prot
1. GTP binding
2. phosphorylation
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GTP binding to G prots
1. inactive G prot bound GDP + signal in
2. GDP exchanged for GTP
3. => active G prot bound GTP for signal out
4. GTP hydrolysed to GDP by G prot => inactive again
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phosphorylation of G prot
1. inactive G prot + signal in
2. phosphrylation by kinase enz
3. => active prot w P bound + signal out
4. then dephosphorylation by phosphatase enz -> inactive
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GPCR in relation asthma
1. noradrenaline + β2 receptor w G prot coupled
2. => incr cAMP
3. => decr myosin kinase = less phosphorylation myosin -> phos myosin
myosin = bronchodil, myosin-P = bronchoconstr
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adrenoreceptors
1. α = bvs incr bp + bronchoconstr
2. β1 = incr HR
3. β2 = bronchodil
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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
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isoprenaline activity
no activity at α, just β1 + β2
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salbutamol
no activity at α, just β2 selective agonist
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terbutaline activity
no activity at α, just β2 selective agonist
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kinase-linked receptor
ligand-binding domain = α subunit
kinase domain = β subunit
| inc insulin receptor (= tyrosine kinase domain)
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tyrosine kinase receptor
ligand binds, tyrosine kinase domain phosphorylates, then intracellular prots bind only to phosphorylated shape => activated
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ionotropic receptors
== ligand-gated ion channs, e.g. nicotinic Ach
| cell surface receptors
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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
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structure nAChR
5 subunits: 2α, 1β, 1γ/δ
* each subunit 4 transmem (TM) domains
* ACh binds to α-subunits
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GABA`A` 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
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inverse agonist
bind same agonist site + cause opp effect vs just blocking site to agonist
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allosteric modulator
binds allosteric site + modifies activity of agonist
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examples intracellular receptors
hydrocortisone, steroid horms, oestrogen, progesterone, thyroxine
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intracellular receptor structure
1. transcription activating domain
2. DNA binding domain
3. hormone binding domain = ligand binding domain
horm-receptor complex regs transcription target genes
* slow response
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inactive vs active intracellular receptor
inactive form bound inhib prots block DNA binding site, then ligand binds => inhib prot detach => DNA binding site exposed
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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
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how inhibit ion channs (transporter prots)
1. block = no thru
2. modulators = incr/decr opening probability
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ion chann blockers
1. Ca chann blockers stop signalling musc cells, e.g. verapamil for hypertension
2. Na chann blockers stop conductance, e.g. lidocaine local anaesthetic
3. K+ chann blockers, e.g. sulphonylureas = back up anti-diabetics
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local anaesthetics
quickly reduce pain = decr need general anaesthesia
* polymodal pain control
* keep mem polarised = no fire a pot, no conduct, no pain
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2 drugs that inhibit enzs + function enz targets
1. captopril competitive reversible angiotensin-converting enz => incr Na+ excr + bp decr + vasodil
2. aspirin non-competitive irreversible for cyclooxygenase (shld convert arachidonic acid -> prostaglandins) = relieve pain, reduce fever, anti-inflamm, bc prostaglandins cause
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false substrate
= drug action at enz => abnormal metabolite proded
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pro-drug
given, binds enz => active drug proded
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Michaelis-Menten curve
binding of drug to receptor = like enz reaction
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high vs low affinity curve
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efficacy graph
naloxone (blue) has no efficacy (antagonist)
morphine (red) has plenty efficacy (agonist)
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efficacy vs conc on log curve
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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
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effect competitive antagonist
log graph shifts right = need higher conc same effect
* reversible antagonist = high enough conc agonist will displace, e.g. naloxone
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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
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tachphylaxis
receptor desensitisation = drug slightly less effective each time = smaller peaks each time on graph
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process of drugs thru sys
1. absorp
2. distrib
3. metab
4. excr
==> need adequate conc in target tiss
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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
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types systemic administration
1. enteral = via GI tract
2. parenteral = not via GI tract (inhalation, injection)
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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
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transmucosal administration
| TM
tablet absorbed directly from mouth
* enteral/parenteral mash up
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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
## Footnote
oral admin gets some metab b4 becomes 'bioavailable'
79
how do drugs cross gut wall
1. transcellular
2. paracellular (no lipophilic) = bet cells -> cap
| only lipid soluble diff in passively
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methods transcellular drug absorp
1. passive diff = non-polar chems, down conc grad
2. fac diff = polar chems, down conc grad
3. AT = polar chems, no grad, need ATP
81
transport drugs in blood
1. free in sol (if v soluble)
2. bound plasma prots, e.g. albumin
3. in rbcs + wbcs
--> hepatic portal vein, liver + heart
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bioavailability
% of drug that reaches blood
* after absorp, liver metab etc
* IV injection gives 100%
83
factors affecting bioavailability
1. water solubility
2. lipid solubility
3. degree ionisation
4. molecular weight
5. amount metabed
| generally most important in ref oral admin
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1st pass metab
how much of drug metabolised on 1st pass thru liver
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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
86
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
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pKa
pt where substance has 50% H+ bound, 50% not
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Henderson-Hasselbach equ
acid drug: pH - pKa = log(ionised/nonionised)
basic drug: pH - pKa = log(nonionised/ionised)
| pKa = -log(Ka)
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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
## Footnote
uncharged absorbs better than charged, but diff uncharged drugs absorp diff amounts (= lipid solubility = lipophilicity)
90
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)
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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
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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
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what binds what drugs + prots
* albumin net neg + binds acidic drugs
* lipophilic usually bind lipoprots
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variation in perfusion
well perfused: heart, lungs, liver, brain
moderately: musc, skin
low: fat
negligibly: bone, teeth, tendons, ligs
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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
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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
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where drug metab
kidney, gut wall, plasma, **liver**
* 'microsomal enzs' of liver acc in SER
| most drugs metabed by liver, excr by kidney
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phase 1 drug metab
microsomal enzs in liver add OH, COOH, NH2 etc
* cytochrome P`450` (CYP) = family enzs => ox/red/hydrolysis (make drug more water soluble)
* e.g. phenobarbitol -> phenobarbital alcohol
| if already water soluble then this ofc unnecessary
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other phase 1 reactions
* alcohol dehydrogenation
* amine oxidation
not P450 reactions
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enz inducer
slow metab, bod recogs this + upregs enz to break down more = Rometab incr
| e.g. phenobarbitol
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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
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metab codeine
-> morphine in phase 1
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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
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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
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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
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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
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C`0`
conc at time 0
* can be figured out by extrapolating back 0 order clearance drug
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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
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central compartment
blood + tiss + fluids drug gains instant access to
* inc well perfused, e.g. liver, kidney, heart
* metab + excr occur from here
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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)
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plasma half life (t`1/2`)
time taken for conc drug in blood to halve
* eliminated by 1st order processes = constant
* independent of dose
112
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
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what get from pharmokinetic analysis
* half life
* true first order rate constants
* apparent vol of distrib
| looking at movement drug thru bod
114
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
114
loading dose
give big dose to start to get levels high then do smaller top up maintenance doses
