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Phase 2a pre clinical > pharmacology > Flashcards

pharmacology Flashcards

1
Q

physiochemical

A

react with each other

  • adsorption
  • chelation
  • precipitation
  • neutralisation

e.g. paracetamol overdose treated with activated charcoal as it sticks to the paracetamol

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2
Q

pharmacodynamics

A

the effect a drug has on the body

effects of drugs and mechanism of their action

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3
Q

types of drug interactions

A

summative= addition of drugs together is the same as just one of the drugs at the same dose

synergistic= two drugs together and overall effect is greater than the individual effect of one at the same dose ( 1+1>2)

antagonism= drugs oppose each other (morphine and naloxone)

potentiation= two drugs and only one makes the other more powerful

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4
Q

pharmacodynamic mechanisms

A

receptor based
signal transduction
physiological systems

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5
Q

Receptors and drug interaction

A

agonists
partial agonists
antagonists (competitive and non-competitive)

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6
Q

physiological systems

A

different drugs that effect different receptors but in same physiological system

Ca channel antagonist and beta blocker

ACE I and NSAID

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7
Q

pharmacokinetics

A

what the body does to a drug

absorption
distribution
metabolism
excretion

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8
Q

absorption

A

motility=decrease in motility will decrease absorption

acidity= balance between ionised and unionised particles of a drug. Ionised particles can’t pass through membranes but unionised can. Changing acidity changes balance between these particles

solubility

complex formation

direct action on enterocytes

bioavailability

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9
Q

distribution

A

protein binding- wont have clinical effect

travel to other tissues- such as fatty tissue

travel to effect site

if two drugs are highly protein bound, the clinical effect of both drugs will increase as less of the drug will bind so more drugs are free in the blood

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10
Q

metabolism

A

CYP450

inhibition

induction

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11
Q

CYP450 (metabolism)

A

haemoproteins

metabolise many substrates - endo/exogenous

class 1,2,3 are most important

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12
Q

inhibition (metabolism)

A

enzyme inhibitors

e.g. metronidazole slows down CYP450 pathway

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13
Q

induction (metabolism)

A

enzyme induction can cause a drug interaction

e.g. morphine- CYP450- morpine6glucuride (becomes more potent)

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14
Q

excretion

A

renal:

  • ph dependant
  • weak bases= cleared faster if urine is acidic
  • weak acids= cleared faster if urine is basic

biliary (minor)

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15
Q

drug interactions

A

protein binding

enzyme induction and inhibition

acute kidney injury

grapefruit juice

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16
Q

risk factors- patient

A

polypharmacy

old age

genetics

hepatic disease

renal disease

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17
Q

risk factors- drug

A

narrow therapeutic index

steep dose/response curve

saturable metabolism

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18
Q

how to avoid interactions

A

prescribe rationally

BNF

ward pharmacist

product information leaflet

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19
Q

drug definition

A

a medicine or other substance that has a physiological effect when ingested or otherwise introduced into the body

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20
Q

drugability

A

the ability of a protein target to bind to small molecules with high affinity

sometimes called ligandability

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21
Q

types of drug targets

A

receptors
enzymes
transporters
ion channels

mainly proteins

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22
Q

receptor definition

A

component of a cell that interacts with a specific ligand and initiates a change of biochemical events, leading to observed effects

ligands can be exogenous (drugs) or endogenous (hormones, neurotransmitters)

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23
Q

types of receptors

A

ligand-gated ion channels, e.g. nicotinic ACh receptor

G protein coupled receptor, e.g. beta-adrenoceptors

kinase linked receptors, e.g. receptors for growth factors

cytosolic/nuclear receptors, e.g. steroid receptors

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24
Q

ligand gated ion channels

A

outside the cell is the receptor

ligand binds to it and a constitutional change occurs, opening the channel

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25
Q

G protein coupled receptor

A

largest and most diverse, make up about 4% of genes

ligands include light energy, peptides, lipids, sugars, proteins

act as a molecular switch

interact with PLC or adenylyl cyclase

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26
Q

kinase linked receptors

A

interaction with ligand causes conformational change in phosphorylation state

initiates signalling cascade

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27
Q

nuclear receptors

A

present in cytoplasm

ligand binds to receptor activating receptor

this then binds to DNA and modifies gene transcription

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28
Q

agonist

A

compound that binds to a receptor and activates it

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29
Q

antagonist

A

reduces the effect of an agonist

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30
Q

ligand

A

molecule that binds to another molecule

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31
Q

agonist response curve

A

as agonist conc. increases so does the response

until response reaches 100% and then it will plateau

when plotted as a log(agonist) there is a sigmoid curve

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32
Q

potency

A

EC50- concentration that gives half the maximal response

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33
Q

full agonists

A

drugs that have full efficacy at receptor

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34
Q

partial agonists

A

drugs bind and activate receptor but only have partial efficacy relative to a full agonist

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35
Q

efficacy

A

maximum response achievable from a dose

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36
Q

intrinsic activity

A

= maximum efficacy for partial agonist ÷ efficacy of full agonist

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37
Q

antagonists and receptors

A

they do not activate receptors

reverse affects of agonists

competitive shift curve to right
non-competitive shift curve right and down

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38
Q

cholinergic receptors

A

muscarinic- mAChR

nicotinic- nAChR

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39
Q

muscarinic

A

agonist=muscarine

antagonist= atropine

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40
Q

nicotinic

A

agonist=nicotine

antagonist= curare

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41
Q

histamine H2 receptors

A

agonist= histamine:

  • contracts ileum
  • acid secretion from parietal cells

antagonist= mepyramine:

  • reverse contraction of ileum
  • no affect on acid secretion
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42
Q

factors governing drug action

A

receptor related= affinity and efficacy

tissue related= receptor number and signal amplification

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43
Q

affinity

A

described how well a ligand binds to a receptor

a property shown by both agonists and antagonists

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44
Q

influence of receptor number

A

the number of receptors influences the response of agonists and antagonists

as you increase antagonist conc. the number of receptor available for agonists decreases

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45
Q

receptor reserve

A

spare receptors

holds for a full agonist in a given tissue

no receptor reserve for partial agonists

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46
Q

signal transduction

A

transmission of a molecular signal from a cells exterior to its interior

signalling cascade that passes through many different pathways

different pathways can be interfered with to affect the response

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47
Q

signal amplification

A

changes in signal transduction can amplify the response even when the receptor and agonist are the same

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48
Q

allosteric modulation

A

substances that indirectly influence/modulate the effects of a primary ligand (which directly activates or deactivates the function of a target protein)

allosteric ligand affects signalling cascade causing a modified response

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49
Q

inverse agonism

A

agent binds to same receptor as agonist but induces a pharmacological response opposite of that agonist

causes down regulation of response rather than an antagonist preventing agonistic effect

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50
Q

tolerance

A

reduction in a drug effect over time

continuously, repeatedly high concentrations

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51
Q

desensitiastion

A

uncoupled
internalised
degraded

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52
Q

specificity

A

no compound is every truly specific

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53
Q

selectivity

A

better term to describe drug activity, over specificity

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54
Q

enzyme inhibitor

A

molecule that binds to an enzyme and decreases its activity

prevents substrate from entering active site so prevents the enzyme from catalysing the reaction

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55
Q

types of enzyme inhibitor

A

irreversible inhibitor:
-usually reacts with enzyme and changes it chemically

reversible inhibitor:

  • binds non-covalently and different types of inhibition are produced
  • depends on whether inhibitor binds to enzyme, enzyme-substrate complex or both
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56
Q

statins

A

HMG-CoA reductase inhibitors

block rate limiting step in cholesterol pathway

class of lipid lowering medications, reducing CVD

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57
Q

parkinson’s treatment

A

L-DOPA: produced from the amino acid L-tyrosine, as a precursor for neurotransmitter biosynthesis

peripheral COMT inhibitor: prevents LDOPA breakdown, generating more for CNS pathway

central dopamine receptor agonists: agonise dopamine receptors, not enzyme inhibitors

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58
Q

drug and ion transport

A

passive:

  • symporter (Na/K/Cl, NaCl)
  • channels (Na,Ca,K,Cl)

active:
-ATPases (Na/K, K/H)

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59
Q

protein ports

A

uniporters: use energy from ATP to pull molecules in
symporters: use movement in of one molecule to pull in another molecule against a conc. gradient
antiporters: one substance moves against its gradient, using energy from a second substance moving down its gradient

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60
Q

example of symporters

A

Na/K/Cl cotransporter

moves ions in same direction

functions in organs that secrete fluids

causes ion loss in urine

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61
Q

ion channels

A

epithelial sodium- heart failure

voltage gated calcium or sodium- nerve, arrhythmia

metabolic potassium- diabetes

receptor activated chloride- epilepsy

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62
Q

voltage gated calcium channels

A

found in membranes of excitable cells

at resting potential they are closed, and opened when the membrane is depolarised

calcium ions enter cell resulting in activation of calcium sensitive potassium channels, muscular contraction and excitation of neurones

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63
Q

voltage gated calcium inhibition

A

amlodipine is a calcium channel blocker, inhibiting movement of calcium into vascular smooth muscle cells and cardiac muscle cells

causes vasodilation and reduction in peripheral vascular resistance- lowering BP

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64
Q

epithelial sodium channel

A

apical membrane bound ion channel, only permeable to sodium ions

causes reabsorption of sodium ions at collecting ducts of kidneys (also in colon, lung and sweat glands)

blocked by high affinity diuretic amiloride and thaizide

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65
Q

Proton pump

A

H+/K+ ATPase= proton pump of stomach

heterodimeric protein (2 genes)

responsible for acidification of stomach

proton-pump inhibitors= most potent blockers

omeprazole is 1st in class, irreversible inhibition with a drug half life of one hour- but works for 2-3 days

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66
Q

irreversible enzyme inhibitors

A

omeprazole- PPI

aspirin- COX inhibitor

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67
Q

xenobiotic metabolism

A

xenobiotics are compounds foreign to an organisms normal biochemistry

rate of metabolism determines duration and intensity of a drugs pharmacologic action

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68
Q

cytochrome P450

A

membrane associated proteins- either in inner membrane of mitochondria or in endoplasmic reticulum

major enzymes involved in drug metabolism (75%)

drugs undergo deactivation by them either directly or by facilitated excretion from the body

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69
Q

adherence

A

the extent to which the patients actions match agreed recommendations

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70
Q

6 ways to improve adherence

A

improve communication between patient and doctor

increase patient involvement in the care of their condition

understand the patient’s perspective by asking questions

provide information when prescribing new drugs

regularly assess their adherence

review their medicines at agreed intervals

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71
Q

allergic reactions to drugs

A

interaction of drug with patient (initial exposure may not be medical, e.g. penicillin in dairy)

subsequent re-exposure

target organs of allergy= skin, resp tract, GI tract, blood and blood vessels

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72
Q

hypersensitivity reactions

A

type 1= IgE mediated

type 2= IgG mediated cytotoxicity

type 3= immune complex deposition

type 4= T cell mediated

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73
Q

type 1 hypersensitivity

A

prior exposure so IgE antibodies formed

IgE becomes attached to mast cells or leukocytes, expressed as cell surface receptors

re-exposure causes mast cell degranulation and release of pharmacologically active substances

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74
Q

anaphylaxis

A

occurs within minutes and lasts for a couple hours

vasodilation

increased vascular permeability

bronchoconstriction

urticaria

angio-oedema

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75
Q

type 2 reaction

A

drug or metabolite combines with protein

body treats it as foreign and forms IgG andIgM antibodies

antibodies combine with antigen and complement activation damages cells

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76
Q

type 3 reaction

A

antigen and antibody form large complexes and activate complement

small blood vessels are damaged attracting leukocytes to the site- releasing pharmacologically active substances

leads to inflammatory response

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77
Q

type 4 reaction

A

antigen specific receptors develop on T lymphocytes

subsequent administration leads to local or tissue allergic reaction

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78
Q

non-immune anaphylaxis

A

due to direct mast cell degranulation

some drugs recognised to cause this

no prior exposure

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79
Q

main features of anaphylaxis

A

exposure to drug, immediate rapid onset

rash, swelling of lips and face, wheeze, hypotension (anaphylactic shock) and cardiac arrest

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80
Q

management of anaphylaxis

A

stop drug infusion

basic life support

adrenaline IM

high oxygen

IV fluid, antihistamine and hydrocortison

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81
Q

adrenaline

A

causes vasoconstriction to increase peripheral resistance, increasing BP and coronary perfusion (alpha 1 adrenoceptors)

stimulation of beta 1 adrenoceptors causes positive ionotropic and chronotropic affects on the heart

reduces oedema and bronchodilates ( beta 2 adrenoceptors)

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82
Q

risk factors for hypersensitivity

A

medicine factors= protein or polysaccharide based macro molecules

host factors= females>males and immunosuppression

83
Q

adverse drug reactions (ADRs)

A

unwanted or harmful reaction following administration of a drug under normal conditions of use and is suspected to be related to the drug

can be mild (nausea or itching rash) or severe (respiratory depression or anaphylaxis)

84
Q

side effects

A

unintended effect of a drug related to its pharmacological properties and can include unexpected benefits of treatment

85
Q

rawlins thompson ADR classification

A

type A- augmented, predictable, dose dependent, common

type B- bizarre, idiosyncratic, not predictable or dose dependent

type c- chronic

type d- delayed, e.g. malignancies after immunosuppression

type e- end of treatment, occur after abrupt drug withdrawal

type f- failure of therapy

86
Q

DoTS classification of ADRs

A

Dose relatedness (toxic, collateral)

Timing

patient Susceptibility

87
Q

risk factors of ADRs

A

patient risk: Elderly, neonates, polypharmacy, gender, genetic predisposition, allergies, hepatic or renal impairment

drug risk: steep dose-response curve, low therapeutic index

prescriber risk: limit time and lack of supervision

88
Q

causes of ADRs

A 
pharmaceutical variation
receptor abnormality
abnormalities in metabolism
immunological
drug-drug interactions
89
Q

ADR type A

A

extension of primary effect
(bradycardia and propranolol)

or secondary effect (bronchospasm with propranolol)

90
Q

ADR type B

A

can’t be readily reversed
less common
life threatening
idiosyncrasy or allergy

91
Q

idiosyncrasy

A

inherent abnormal response to drug

may be due to abnormal receptor activity or enzyme deficiency (x-linked)

92
Q

ADR type C

A

steroids and osteoporosis

analgesis nephropathy

steroids and iatrogenic cushing’s disease

93
Q

ADR type D

A

teratogenesis- drugs taken in first trimester (thalidomide)

carcinogenesis (cyclophosphamide and bladder cancer)

94
Q

ADR type E

A

withdrawal seizures when stopping anticonvulsants

withdrawal syndrome when stopping opioids

95
Q

suspecting an ADR

A

symptoms after drug is started
symptoms after dosage increase
symptoms disappear when drug is stopped
symptoms reappear when drug is restarted

96
Q

common drugs to cause ADRs

A 
antibiotics
anti-neoplastics
CVS drugs
hypoglycaemics
NSAIDS
CNS drugs
97
Q

most common system affected by ADRs

A 
GI
renal
haemorrhagic
metabolic
endocrine
dermatologic
98
Q

common ADRs

A 
confusion
nausea
diarrhoea 
constipation
hypotension
99
Q

avoiding ADRs

A

drug interactions
inappropriate medication
unnecessary medication

all can be avoided ^

100
Q

yellow card scheme

A

collects spontaneous reports
collects suspected adverse reactions
voluntary

101
Q

strengths of the yellow card

A

early warning system for identification of unrecognised reactions

provides info on factors which predispose patients to ADRs

safety monitoring of a product throughout its lifespan

102
Q

weaknesses of the yellow card

A

cannot provide estimates of risk as true number of cases is underestimated

relies on ADRs being recognised and reported

103
Q

what is the black triangle

A

indicated medicine is undergoing additional monitoring

104
Q

what is a serious reaction

A

fatal
life threatening
disabling or incapacitating
results in or prolongs hospitalisation

105
Q

information to include on a yellow card

A

suspected drugs
suspected reactions
patient details
reporter details

any useful information

106
Q

drug targets

A

approved small molecule drug target is <400 proteins

G protein receptors
nuclear hormone receptors
ion channels
kinases

107
Q

medical plants

A

poppy- morphine
deadly nightshade- atropine
periwinkle- vincristine

108
Q

organic chemistry

A

produces most prescribed drugs

chloroform, phenol, isoflurane

109
Q

inorganic elements/compounds

A

many drugs use inorganic elements e.g. platinum based anti-cancer agents

110
Q

magic bullets

A

selective poisoning of microbe through metabolic pathway absent in humans

111
Q

sulphonamide nucleus

A

unreactive and rigid

e.g. acetazolamide for glaucoma

112
Q

bacteria moulds and fungi

A

use compounds derived from these

e.g. penicillin

113
Q

receptor approach

A

noradrenaline -> propanolol

histamine -> histamine H2 receptor antagonist

114
Q

stereoisomers

A

have same molecular formula but differ in 3D orientations of their atoms

115
Q

monoclonal antibodies

A

single specificity mouse CD3 antibody which induces cytokine release

116
Q

tumour necrosis factor alpha

A

cytotoxic factor released by activated macrophages

it stimulates acute phase proteins and mediates endotoxin poisoning, septic shock and chronic inflammation

117
Q

three approaches to neutralisation of TNFalpha

A

Chimeric antibody- infliximab

Fusion protein- etanercept

human antibody- adalimumab

118
Q

infliximab

A

initially for crohn’s disease

rheumatoid arthritis

inhibits lymphocyte proliferation

119
Q

fusion protein (etanercept)

A

dimeric fusion of TNF II receptor

rheumatoid arthritis and plaque psoriasis

120
Q

human antibody (suffix -umab)

A

fully humanised TNF alpha antibody

inhibits lymphocyte proliferation, down-regulates inflammatory reactions associated with autoimmune disease

121
Q

animal sources of drugs

A

endocrine hormones- insulin, thyroxine, steroids

122
Q

insulin

A

originally extracted from cow/pig pancreas

2 peptide chains joined by disulphide bridges both derived from a single sequence

recombinant human insulin= human gene inserted into bacteria DNA

123
Q

shorter acting insulin

A

switch lysin and proline residues

faster onset, shorter duration of action

inject before a meal

124
Q

long acting insulin

A

slow release, lower risk of nocturnal hypoglycaemia

125
Q

recombinant proteins in clinical use

A

insulin
erthypoietin
growth hormone
interleukin 2

126
Q

steroids

A

work through nuclear hormone receptors

127
Q

clinical uses of glucocorticoids

A 
skin- eczema, psoriasis
lung- asthma, COPD
GI- inflammatory bowel disease
MSK- inflammatory arthritis
CNS- multiple sclerosis
128
Q

adverse effects of glucocorticoids

A 
hypertension
fluid retention
osteoporosis 
muscle wasting
peptic ulcer
Cushing's syndrome
129
Q

development of methotrexate

A
  • folic acid worsens leukaemia
  • structural analogues of folic acid developed
  • methotrexate inhibits enzyme dihydrofolate reductase, has a high affinity for folate
130
Q

high-throughout screening

A

used in drug discovery
uses robotics, data processing and sensitive detectors
rapidly identifies active compounds, antibodies or genes that modulate particular bimolecular pathways
provides starting points for drug design

131
Q

rational drug design

A

finds new medications based on knowledge of biological target
most commonly a small organic molecule that activates or inhibits the function of a biomolecule

132
Q

druggability

A

the ability of a protein target to bind to small molecules with high affinity

aka ligandability

133
Q

use of cholinergic and adrenergic pharmacology

A 
control BP
control HR
anaesthetic agents
regulate airway tone
control GI function
134
Q

parasympathetic nervous system

A

cranial nerves carry signals to the body

sacral outflow innervates the pelvis

short postsynaptic nerve fibres reach the targets and release ACh which acts on muscarinic receptors

135
Q

sympathetic nervous system

A

regulates fight and flight

nerve fibres originate in spinal cord and then send out long nerve fibres to blood vessels and muscles

they release noradrenaline which activates adrenergic receptors

136
Q

2 main neurotransmitters

A

acetylcholine

noradrenaline

137
Q

NANC system

A

non-adrenergic, non-cholinergic autonomic nervous system

releases and uses other neurotransmitters

138
Q

cholinergic pharmacology

A

nicotine stimulates all autonomic ganglia in both symp and parasymp

separate nicotinic receptors where ACh is a neurotransmitter

muscarine activates muscarinic receptors of para system

139
Q

muscarinic receptors

A

M1- in brain
M2- in heart (activation slows heart)
M3- glandular and smooth muscle
M4/5- in CNS

140
Q

muscarinic agonists and antagonists

A

agonist= pilocarpine

stimulates salivation, contracts iris smooth muscle, slows heart

antagonists= atropine
hyoscine

141
Q

muscarinic antagonists/anticholinergic uses

A

dry secretions
bradycardia
treatment of bronchoconstriction

142
Q

anti-cholinergic side effects

A

in the brain it worsens memory and causes confusion

peripherally it causes constipation, dries mouth, blurs vision, worsens glaucoma

143
Q

cholinergic side effects

A

cause muscle paralysis and twitching
salivation
confusion

144
Q

catecholamines

A

noradrenaline- sympathetic fibre ends, manage shock in ICU
adrenaline- released from adrenal glads, manage anaphylaxis
dopamine- precursor for both above

145
Q

outcomes of signalling depends on:

A

receptor
the cell it’s on
which G protein

146
Q

alpha agonists

A

alpha 1 activation causes vasoconstriction in skin and splanchnic beds

treat septic shock

adrenaline raises BP and cardiac work

147
Q

alpha 1 and 2 are not the same

A

alpha 1 raise BP

alpha 2 lowers BP

148
Q

alpha blockers

A

opposite effect to agonists

149
Q

beta agonists

A

beta 1 increases HR and chronotropic effects

beta 2 helps with muscle relaxation - asthma

beta 3 can reduce over active bladder symptoms

150
Q

beta blockers

A

propranolol blocks 1 and 2, slowing HR, reduce tremor but can cause wheeze

lowers BP by reducing cardiac work

uses= angina, high BP, anxiety, arrhythmias

side effects= tiredness, bronchoconstriction, cardiac depression

151
Q

naturally occurring opioids

A

from the opium poppy

morphine
codeine

152
Q

simple chemical modifications to opioids

A

diamorphine- heroin
oxycodone
dihydrocodeine

153
Q

synthetic opioids

A

pethidine
fentanyl
alfentanil
remifentanil

154
Q

opioid synthetic partial agonist

A

buprenorhine

155
Q

opioid antagonist

A

naloxone

156
Q

routes of opioid administration

A
  • trans dermal patches
  • epidural
  • patient controlled analgesia IV
  • parenteral (IM, IV, sub-cutaneous)
  • oral
157
Q

opioid pharmacodynamics

A
  • opioid drugs use existing pain modulation system
  • natural endorphins and G protein coupled receptors
  • inhibit the release of pain transmitters at spinal cord and midbrain
  • modulate pain perception in higher centres: euphoria
  • not designed for sustained use as it leads to tolerance and addiction
158
Q

opioid receptors

A

Mu (micro symbol )opioid receptors
delta and kappa opioid receptors
nociceptin opioid like receptors
MOP,KOP,DOP,NOP

currently all drugs used are mu (micro symbol) agonists

159
Q

opioid tolerance and dependence

A

tolerance- down regulation of receptors with prolonged use so higher doses required

dependence- craving, euphoria

withdrawal- starts within 24 hours, lasts 72 hours

160
Q

opioid side effects

A 
respiratory depression
sedation
nausea
constipation
itching
endocrine effects
161
Q

opioid induced respiratory depression

A

naloxone IV (400 micrograms/ml) titrate to effect- dilute 1ml to 10ml of saline

162
Q

opioid use in chronic pain

A

for non-cancer patients it starts to lose effectiveness relatively quickly

addiction is likely and leads to manipulative behaviour

163
Q

opioid pharmacogenetics

A
  • codeine needs to metabolised by CYP2D6 to work
  • this activity is decreased in 10-15% of caucasian people and is absent in a further 10% of people
  • therefore codeine effect is reduced or absent in these people
  • it is overactive in 5% of caucasians so the risk of respiratory depression is higher
164
Q

opioid metabolism

A

morphine is metabolised into morphine-6-glucuronide which is more potent than morphine and is renally excreted

in renal failure it builds up and causes respiratory depression

165
Q

tramadol

A
  • weak opioid agonist slightly stronger than codeine
  • metabolised by CYP2D6 to o-desmethyl tramadol and is now activated
  • secondary affect in analgesia as a serotonin re-uptake inhibitor
166
Q

pharmacokinetics

A

action of drugs in the body

absorption
distribution
metabolism
excretion

167
Q

absorption

A

process of transfer from the site of administration into general systemic circulation

168
Q

routes of administration

A 
oral
IV
Intra-arterial
IM
SC
inhalation
topical
sublingual
rectal
169
Q

passage across membranes

A

passive diffusion through lipid layer
diffusion through pores or ion channels
carrier mediated processes
pinocytosis

170
Q

passive diffusion

A

need to be lipid soluble to cross the bilayer- steroids

rate of diffusion is proportional to conc. gradient, the area and permeability of the membrane

171
Q

ion channels and pore diffusion

A

occurs down conc. gradient

restricted to small water soluble molecules e.g. lithium

172
Q

active diffusion- carrier mediated

A

uses ATP
against conc. gradient
ATP-binding cassette family (ABC)

173
Q

facilitated diffusion

A

carrier aids passive movement down conc. gradient

can use electrochemical gradient of solute to transport another molecule to move against conc. gradient

300+ members of solute carrier super family

174
Q

pinocytosis

A

carrier mediated entry
involves uptake of endogenous macromolecules
e.g. amphotericin can be taken into liposome

175
Q

drug ionisation

A

basic property of drugs that are weak acids (aspirin) or weak bases (propanolol)

ionisable groups are needed for mechanism of action for ligand-receptor interaction

PKa of drug= dissociation/ionisation constant, and is pH at which half of substance is ionised

pH affects ionisation- weak acids are best absorbed in stomach and weak bases are best absorbed in intestine

176
Q

oral absorption

A

this route is easiest and most convenient for many drugs

large surface area and high blood flow of small intestine can give rapids and complete absorption

177
Q

factors that affect oral absorption

A

drug structure
drug formation
gastric emptying
first pass metabolism

178
Q

drug structure

A
  • needs to be lipid soluble to be absorbed in gut
  • polarised tend to only be partially absorbed- passing into faeces
  • some drugs unstable at low pH or in presence of digestive enzymes
179
Q

drug formulation

A

capsule or tablet must dissolve to be absorbed
must do so rapidly
some dissolve slowly or have an acids resistant coating

180
Q

gastric emptying

A

determines how soon a drug taken orally is delivered to small intestine

can be slowed by food or drugs
and faster by gastric surgery

181
Q

first pass metabolism

A

drugs have to pass 4 major metabolic barriers to reach circulation:

  • intestinal lumen
  • intestinal wall
  • liver
  • lungs
182
Q

absorption routes: order of time until effect

A
  • IV (30-60s)
  • intraosseous
  • endotracheal (2-3 min)
  • inhalation
  • sublingual (2-5 min)
  • IM (10-20min )
  • SC (15-30 min)
  • rectal (5-30 min)
  • ingestion (30-90min)
  • transdermal
183
Q

transcutaneous

A

slow and continuous absorption is useful with transdermal patches

effective barrier to water soluble compounds so needs to be lipid soluble

184
Q

intradermal

A

avoids barrier or stratum corneum
mainly limited by blood flow
use for local affect or to deliberately limit absorption

185
Q

intramuscular

A

good blood supply and water solubility means enhanced removal of drug from injection site

186
Q

intranasal

A

good surface area

used for local (decongestants) or system (desmopressin) effect

187
Q

inhalational

A

large surface area and blood flow but limited by risks to damage to alveoli

volatile drugs only

asthma drugs are non volatile so given as aerosol

188
Q

distribution

A

process by which a drugs is transferred reversible from general circulation to the tissues
once equilibrium is reached across a cell membrane, any process that reduces the conc. on one side causes movement to restore equilibrium

189
Q

protein binding

A

drugs bind to plasma or tissue proteins
can be reversible or irreversible
most common reversible= albumin
drugs that bind irreversibly cannot re-enter circulation so it is equivalent to elimination

190
Q

drug distribution in the brain

A

lipid soluble pass from blood to brain
water soluble enter slowly due to blood-brain barrier
efflux transporters return some drugs to circulation
the brain does little metabolising so drugs are removed by diffusion into plasma, active transport in choroids plexus or elimination in CSF

191
Q

drug distribution on foetus

A

crosses placenta (lipid soluble more readily)

large molecules such as heparin do not cross placenta

foetal liver has low level of metabolising enzymes so relies on maternal elimination

192
Q

elimination

A

removal of drugs from the body

may involve metabolism and/or excretion

193
Q

metabolism

A

necessary for elimination of lipid soluble drugs
converted into water soluble products that are removed in urine
it produces one or more new compounds which show differences to parents drug

194
Q

phase 1 metabolism reactions

A

involve transformation of drug to more polar metabolite
done by unmasking or adding a functional group e.g.-OH or -SH
oxidations are most common reactions catalysed by important enzymes called CYP450

195
Q

other phase 1 reactions

A

not all require CYP450
some are metabolised in plasma, lung or gut
ethanol is metabolised by alcohol dehydrogenase
monoamine oxidase inactives noradrenaline

196
Q

phase 2 metabolism reactions

A

conjugation
involves formation of covalent blond between the drug or its phase 1 metabolite and endogenous substrate
resulting products are less active and readily excreted by the kidneys

197
Q

urine excretion

A

total excretion= glomerular filtration+tubular secretion-reabsorption

198
Q

faecal excretion

A

high molecular weight molecules taken up into hepatocytes and eliminated into bile
bile passes into gut and some may be reabsorbed and enter hepatic portal vein

199
Q

reaction kinetics

A

drug via IV is rapidly distributed

taking repeat plasma samples, the fall in plasma conc. can be measured

200
Q

first order kinetics

A

decline in plasma conc. is exponential as a constant fraction is eliminated per unit time
dC/dT= -kC where k= rate reaction constant

201
Q

zero order kinetics

A

change in conc. per time is a fixed amount, independent of concentration

dC/dT= -k

202
Q

half life calculations

A

time taken for a conc. to reduce by half
units of rate constant are hard to use practically so usually use half life

half life = 0.693/k

203
Q

bioavailability calcultions

A

fraction of administered drug that reaches the systemic circulation unaltered (F)

IV drugs F=1

oral drugs have F<1 if they are incompletely absorbed or undergo first pass metabolism

if oral bioavailability is 0.1 it’s does needs to be 10x IV dose

Phase 2a pre clinical (6 decks)

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