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NSF > pharmacology > Flashcards

pharmacology Flashcards

1
Q

pharmacology defn

A

study of drug action on animals, organs, tiss or cells
* mechs of how drugs work

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2
Q

how do drugs work (general)

A

mimic or block endogenous signalling mols (pharmacons)

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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
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4
Q

exogenous

A

grows or originates from outside org

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5
Q

exogenously derived pharmacons

A

drugs usually organic + cyclic, e.g. paracetamol, morphine

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6
Q

specific vs non-specific effects

A

specific = related chem struct bc binds specific target
non = related physiochemical characs

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7
Q

typical drug targets (binding sites)

A
  • enzs
  • ion channs
  • mRNA, DNA
  • receptors
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8
Q

3 examples chems used as drugs

A

NSAIDS
beta-blockers
sulphonamides
antibiotics

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9
Q

chem bonds involved drug action

A
  1. covalent bonds
  2. ion-ion
  3. ion-dipole
  4. H bond
  5. dipole-dipole
  6. van der Waals

decr strength order

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10
Q

features of chem bonds

A

overall strength = how tightly binds = affinity
geometry = how well shape matches = specificity

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11
Q

pharmacology process

A
  1. identify disease
  2. identify target
  3. synth selective ligand (small mol if poss bc easier to give)
  4. assess function
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12
Q

pharmacokinetics

A

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

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13
Q

ideal drug properties

A
  • few off target effects (causing something in non target tiss)
  • high Ti (therapeutic index)
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14
Q

therapeutic index

A

LD50/EC50

= dose that kills 1/2 subjects/effective dose

== range of doses at which drug effective w/o unacceptable adverse events

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15
Q

4 types prot drugs typically bind to

A
  1. receptors = agonist/antagonist
  2. ion channs = block/modulate (change probability open)
  3. transporters = inhibitor/false substrate
  4. enzs = inhibit/false substrate/pro-drug to prod drug
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16
Q

agonist vs antagonist

A
  1. binds receptor cause conformational change => response in target cell
  2. binds receptor but initiates no response + occupies receptor = ag no bind = usually inhibitory

== has action vs blocks action

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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

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18
Q

receptor subtypes for cannabinoids

A

agonists
1. CB1 = central
2. CB2 = peripheral, anti-inflamm

slightly diff shape

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19
Q

receptor subtypes histamine

A

antagonists in gut
1. H1 => sm musc contract
2. H2 => parietal cell acid secr

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20
Q

mol that binds receptor

A

== drug == ligand

receptor + drug => drug-receptor complex

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21
Q

high vs low affinity ligand

A

high = low conc ligand required b4 all receptor sites occupied

Kd = pt where 50% bound
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22
Q

typical drug mechs of action

A

usually evoke 3 processes:
1. reception of signal
2. transduction
3. response

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23
Q

transduction of signal

A
  1. initial = shape change in receptor
  2. multistep pathway = 2nd messenger pathway = amplify signal + more opps coord + multiple cellular responses
  3. -> end-pt target
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24
Q

2nd messengers

A

mols that relay signal from receptor -> response
* often prots, also cyclic AMP + Ca2+

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25
Q

common end pt targets

A
  • 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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26
Q

signal amplification

A

cascade effect = small amt ligand can have large effect
* often involves kinase + phosphatase reactions

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27
Q

affinity vs efficacy

A

how well it binds vs how much action has (how well works)

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28
Q

types receptors

A
  1. cell surface = hydrophilic signal mol
  2. intracellular = small hydrophobic signal mol
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29
Q

effect of agonist receptors

A

DIRECT: ion chann opening/closing

TRANSDUCTION MECHS:
1. enz activation/inhib
2. ion chann modulation
3. DNA transcription

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30
Q

drug targets

A
  • receptors
  • transporters
  • ion channs
  • enzs
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31
Q

types mem receptors

A
  1. ion channs
  2. enz-linked
  3. metabotropic/GPCR
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32
Q

metabotropic receptors

== G-prot coupled receptors

A

single polypep w 7 transmembrane domains (α-helices)
* ligand binds extracellular domain or w/in transmem domain

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33
Q

types metabotropic receptor

A
  1. ion chann
  2. enz
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34
Q

ion chann GPCR

A

receptor -> G prot (excit/inhib) -> ion chann => change conc ion => depol/hyperpol

e.g. muscarinic Ach receptor

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35
Q

enz GPCR

A

receptor -> G prot (excit/inhib) -> enz -> 2nd messenger -> enzs/Ca2+ mobilisation => cellular effects

e.g. α + β adrenoreceptors

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36
Q

G prot activated enzs

A
  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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37
Q

G prot full name

A

guanosine nucleotide binding prot

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38
Q

how activate G prot

A
  1. GTP binding
  2. phosphorylation
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39
Q

GTP binding to G prots

A
  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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40
Q

phosphorylation of G prot

A
  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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41
Q

GPCR in relation asthma

A
  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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42
Q

adrenoreceptors

A
  1. α = bvs incr bp + bronchoconstr
  2. β1 = incr HR
  3. β2 = bronchodil
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43
Q

noradrenaline structural activity relationship

A

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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44
Q

isoprenaline activity

A

no activity at α, just β1 + β2

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45
Q

salbutamol

A

no activity at α, just β2 selective agonist

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46
Q

terbutaline activity

A

no activity at α, just β2 selective agonist

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47
Q

kinase-linked receptor

A

ligand-binding domain = α subunit
kinase domain = β subunit

inc insulin receptor (= tyrosine kinase domain)

48
Q

tyrosine kinase receptor

A

ligand binds, tyrosine kinase domain phosphorylates, then intracellular prots bind only to phosphorylated shape => activated

49
Q

ionotropic receptors

A

== ligand-gated ion channs, e.g. nicotinic Ach

cell surface receptors

50
Q

antagonist/agonist reversible or no

A

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

51
Q

structure nAChR

A

5 subunits: 2α, 1β, 1γ/δ
* each subunit 4 transmem (TM) domains
* ACh binds to α-subunits

52
Q

GABAA receptor

A

= 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

53
Q

inverse agonist

A

bind same agonist site + cause opp effect vs just blocking site to agonist

54
Q

allosteric modulator

A

binds allosteric site + modifies activity of agonist

55
Q

examples intracellular receptors

A

hydrocortisone, steroid horms, oestrogen, progesterone, thyroxine

56
Q

intracellular receptor structure

A
  1. transcription activating domain
  2. DNA binding domain
  3. hormone binding domain = ligand binding domain

horm-receptor complex regs transcription target genes
* slow response

57
Q

inactive vs active intracellular receptor

A

inactive form bound inhib prots block DNA binding site, then ligand binds => inhib prot detach => DNA binding site exposed

58
Q

transporters

A

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

59
Q

how inhibit ion channs (transporter prots)

A
  1. block = no thru
  2. modulators = incr/decr opening probability
60
Q

ion chann blockers

A
  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
61
Q

local anaesthetics

A

quickly reduce pain = decr need general anaesthesia
* polymodal pain control
* keep mem polarised = no fire a pot, no conduct, no pain

62
Q

2 drugs that inhibit enzs + function enz targets

A
  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
63
Q

false substrate

A

= drug action at enz => abnormal metabolite proded

64
Q

pro-drug

A

given, binds enz => active drug proded

65
Q

Michaelis-Menten curve

A

binding of drug to receptor = like enz reaction

kd = dissociation constant = conc that give 50% binding
66
Q

high vs low affinity curve

A
naloxone = morphine antagonist = higher affinity (lower kd)
67
Q

efficacy graph

A

naloxone (blue) has no efficacy (antagonist)
morphine (red) has plenty efficacy (agonist)

EC50 = conc that gives 50% effect
68
Q

efficacy vs conc on log curve

A
69
Q

full vs partial agonist

A

of any given receptor
* partial = efficacy low, affinity high

partial agonist = partial antagonist if add full agonist later as fills receptors, blocking

70
Q

effect competitive antagonist

A

log graph shifts right = need higher conc same effect
* reversible antagonist = high enough conc agonist will displace, e.g. naloxone

71
Q

non-competitive antagonist

A

binds allosteric site = receptor site change = switches off = can’t bind
* no amount agonist will reverse

e.g. ketamine for NMDA receptors for glutamate

72
Q

tachphylaxis

A

receptor desensitisation = drug slightly less effective each time = smaller peaks each time on graph

73
Q

process of drugs thru sys

A
  1. absorp
  2. distrib
  3. metab
  4. excr

==> need adequate conc in target tiss

74
Q

routes drug administration

A

topical (high conc 1 spot) + systemic (get everywhere)
* oral (harder in pets)
* topical - analgesics, antibiotics
* injection - insulin
* inhalation - salbutamol

dependent on drug + target area

75
Q

types systemic administration

A
  1. enteral = via GI tract
  2. parenteral = not via GI tract (inhalation, injection)
76
Q

types parenteral administration

A
  • intravenous
  • intraperitoneal
  • intramuscular
  • subcut
  • intrathecal = epidural = bet spinal cord + vertebrae => CNS (local properties tho, e.g. pain relief)

decr speed of working

77
Q

transmucosal administration

TM

A

tablet absorbed directly from mouth
* enteral/parenteral mash up

78
Q

absorption of stuff from tablets

A

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’

79
Q

how do drugs cross gut wall

A
  1. transcellular
  2. paracellular (no lipophilic) = bet cells -> cap

only lipid soluble diff in passively

80
Q

methods transcellular drug absorp

A
  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
Q

transport drugs in blood

A
  1. free in sol (if v soluble)
  2. bound plasma prots, e.g. albumin
  3. in rbcs + wbcs

–> hepatic portal vein, liver + heart

82
Q

bioavailability

A

% of drug that reaches blood
* after absorp, liver metab etc
* IV injection gives 100%

83
Q

factors affecting bioavailability

A
  1. water solubility
  2. lipid solubility
  3. degree ionisation
  4. molecular weight
  5. amount metabed

generally most important in ref oral admin

84
Q

1st pass metab

A

how much of drug metabolised on 1st pass thru liver

85
Q

effect pH on drug absorp acid drugs

A

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
Q

effect pH on absorp basic drugs

A

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

87
Q

pKa

A

pt where substance has 50% H+ bound, 50% not

88
Q

Henderson-Hasselbach equ

A

acid drug: pH - pKa = log(ionised/nonionised)

basic drug: pH - pKa = log(nonionised/ionised)

pKa = -log(Ka)

89
Q

partition coefficient

A

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)

90
Q

multidrug resistance prot (MDR)

A

= P-glycoprot = protective transporter found in gut + BBB => removes toxins
* drug can be uncharged w good lipophilicity but actively thrown out (= decr bioavailability)

91
Q

mutation in MDR gene

A

= absorb when shouldn’t
* ivermectin neurotoxic but removed by MDR => v effective but then toxic to collies

in collie-like dogs

92
Q

drug binding

w issue

A

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

93
Q

what binds what drugs + prots

A
  • albumin net neg + binds acidic drugs
  • lipophilic usually bind lipoprots
94
Q

variation in perfusion

A

well perfused: heart, lungs, liver, brain
moderately: musc, skin
low: fat
negligibly: bone, teeth, tendons, ligs

95
Q

why need drug metab

A

bc most are oral (easy give) = absorp SI = lipophilic = difficult excr as reabsorbed kidney = need break them down -> water soluble so can pee out

96
Q

drug metab

A

PHASE 1: drug -> drug-sol
PHASE 2: drug sol -> drug-O-[conjugate]

3 things excreted in incr amounts as get more water soluble

97
Q

where drug metab

A

kidney, gut wall, plasma, liver
* ‘microsomal enzs’ of liver acc in SER

most drugs metabed by liver, excr by kidney

98
Q

phase 1 drug metab

A

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

99
Q

other phase 1 reactions

A
  • alcohol dehydrogenation
  • amine oxidation
    not P450 reactions
100
Q

enz inducer

A

slow metab, bod recogs this + upregs enz to break down more = Rometab incr

e.g. phenobarbitol

101
Q

chocolate effect dog

A

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

102
Q

metab codeine

A

-> morphine in phase 1

103
Q

phase 2 metab

A

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

104
Q

drug excr

A
  • 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

105
Q

enterohepatic recirculation

A

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

106
Q

orders of elimination

A

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

107
Q

C0

A

conc at time 0
* can be figured out by extrapolating back 0 order clearance drug

108
Q

volume of distribution

w equ

A

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

109
Q

central compartment

A

blood + tiss + fluids drug gains instant access to
* inc well perfused, e.g. liver, kidney, heart
* metab + excr occur from here

110
Q

1st order clearance

A

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)

111
Q

plasma half life (t1/2)

A

time taken for conc drug in blood to halve
* eliminated by 1st order processes = constant
* independent of dose

112
Q

2nd order elimination

A

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

113
Q

what get from pharmokinetic analysis

A
  • half life
  • true first order rate constants
  • apparent vol of distrib

looking at movement drug thru bod

114
Q

IV dosing

A

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
Q

loading dose

A

give big dose to start to get levels high then do smaller top up maintenance doses

NSF (22 decks)

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