Pharmacology and prescribing Flashcards

Question

what is the effect/action of benzodiazapene transquilisers?

Answer 1

bind to a region of the GABA(a) receptor-chloride channel complex (ligand gated channel) that is distinct from the GABA binding site and facilitates the opening of the channel by GABA

Answer 2

- vasodilation | - inhibit opening of L-type calcium channels

Answer 3

used in treating diabetes; act on ATP-gated potassium channels of pancreatic beta cells, which enhances insulin secretion

Answer 4

G protein and other intermediaries

Answer 5

reduces the insertion of neuronal calcium channels into the plasma membrane

Answer 6

- direct: ion channel opening/closing | - transduction mechanisms: enzyme activation/inhibition, ion channel modulation, DNA transcription

Answer 7

- no effect | - endogenous mediators blocked

Answer 8

permeation blocked

Answer 9

increased or decreased opening probability

Answer 10

normal reaction inhibited

Answer 11

abnormal metabolite produced

Answer 12

active drug produced

Answer 13

transport blocked

Answer 14

abnormal compound accumulated

Answer 15

captopril, acting on ACE

Answer 16

aspirin, acting on cyclo-oxygenase

Answer 17

drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway

Answer 18

- fluorouracil, anticancer drug - replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate, thus blocking DNA synthesis and preventing cell division

Answer 19

drugs may require enzymatic degradation to convert them from an inactive form to an active form

Answer 20

enalapril is converted by esterases to enalaprilat, which inhibits ACE

Answer 21

- enzymatic conversion of the drug molecule to a reactive metabolite

Answer 22

- ATP-binding cassette transporters | - hydrolysis of ATP provides energy for transport of substances against their electrochemical gradient

Answer 23

multi-drug resistance transporters | - eject cytotoxic drugs from cancer and microbial cells, conferring resistance to these therapeutic agents

Answer 24

- symports: transport of organic molecules is coupled to the transport of ions in the same direction - antiports: transport of organic molecules is coupled to the transport of ions in the opposite direction

Answer 25

- ligand-gated ion channels - G protein coupled receptors (metabotropic receptors or 7 transmembrane receptors) - kinase-linked and related receptors - nuclear receptors

Answer 26

function: influx of ions -> hyperpolarisation/depolarisation -> cellular effects time scale: milliseconds examples: nicotinic ACh receptor

Answer 27

function: binding of ligand to receptor leads to increase/decrease in second messenger production or ion influx. Second messengers lead to Ca2+ release, protein phosphorylation or other. ion influx -> change in excitability -> cellular effects time scale: seconds example: muscarinic ACh receptor

Answer 28

function: binding of ligand to receptor/enzyme -> protein phosphorylation -> gene transcription -> protein synthesis -> cellular effects time scale: hours example: cytokine receptors

Answer 29

function: binding of ligand to receptor within the nucleus -> gene transcription -> protein synthesis -> cellular effects time scale: hours example: oestrogen receptor

Answer 30

- generally occur in several molecular varieties/subtypes - similar architecture - significant differences in their sequences and pharmacological properties

Answer 31

skeletal NMJ

Answer 32

receptors that have a large intracellular domain between transmembrane domains 3 and 4 containing multiple cystein residues

Answer 33

- GABA - glycine receptors - 5-HT receptors - nicotinic ACh receptor

Answer 34

- nicotinic ACh receptors - ionotropic glutamate receptors - purinergic P2X receptors

Answer 35

- pentameric assembly of different subunits (2 x alpha) - alpha, beta, gamma and delta subunits, each of molecular weight 40-58 kDa - subunits show marked sequence homology, each containing four membrane-spanning alpha-helices - two ACh binding sites, each at the interface between one of two alpha subunits and its neighbour - each subunit spans the membrane four time, so there are 20 membrane-spanning helices surrounding a central pore

Answer 36

both binding sites must bind ACh molecules

Answer 37

- at interface between one of two alpha subunits and its neighbour - on the extracellular N-terminal region of the two alpha subunits

Answer 38

- one of the transmembrane helices (M2) from each of the five subunits forms the ion channel - five M2 helices that form the pore are sharply kinked inwards halfway through the membrane, forming a constriction

Answer 39

- conformation change occurs in the extracelllar part of the receptor - twists the alpha subunits, causing the kinked M2 segments to swivel out of the way - this opens the channel

Answer 40

series of anionic residues, making the channel selectively permeable to cations - primarily Na+ and K+, sometimes Ca2+

Answer 41

- membrane - ion channel - direct - nicotinic ACh receptor, GABA(a) receptor - oligomeric assembly of subunits surrounding the central pore

Answer 42

- membrane - channel/enzyme - G protein or arrestin - muscarinic ACh receptors, adrenoreceptors

Answer 43

- membrane - protein kinases - direct - insulin, growth factors, cytokines - single transmembrane helix linking extracellular receptor domain to intracellular kinase domain

Answer 44

- intracellular - gene transcription - via DNA - steroid receptors - monomeric structure with receptor and DNA binding domain

Answer 45

tetrameric | - pore is built from loops rather than transmembrane helices

Answer 46

trimeric | - each subunit has only two transmembrane domains

Answer 47

binding of one agonist molecule to one site increasing the affinity of binding at the other site

Answer 48

- muscarinic AChRs - adrenoceptors - dopamine receptors - 5-HT receptors - opioid receptors - peptide receptors - purine receptors

Answer 49

beta adrenoceptor, which was cloned in 1986

Answer 50

- single polypeptide chain, usually of 350-400 residues - can be up to 1100 residues - 7 transmembrane alpha helices - extracellular N-terminal domain of varying length, and an intracellular C-terminal domain

Answer 51

A: rhodopsin family B: secretin/glucagon receptor family C: metabotropic glutamate receptor/calcium sensor family

Answer 52

- largest group - receptors for most amine neurotransmitters, many neuropeptides, purines, prostanoids, cannabinoids - short extracellular (N-terminal) tail - ligand binds to transmembrane helices (amines) or to extracellular loops (peptides)

Answer 53

- receptors for peptide hormones, including secretin, glucagon, calcitonin - intermediate extracellular tail incorporating ligand-binding domain

Answer 54

- small group - metabotropic glutamate receptors, GABA(b) receptors, Ca2+ sensing receptors - long extracellular tail incorporating ligand-binding domain

Answer 55

includes many receptors for pheromones but no pharmalogical receptors

Answer 56

third cytoplasmic loop - experiments show that deletion/modification of this section results in receptors that will still bind ligands but cannot associate with G proteins/produce responses

Answer 57

phosphorylation of serine and threonine residues on the C-terminal tail and other intracellular domains by intracellular kinases

Answer 58

buried in the cleft between the alpha helical segments within the membrane - similar to the slot occupied by retinal in the rhodopsin molecule

Answer 59

e. g. substance P | - bind more superficially to the extracellular loops

Answer 60

- four types identified - many proteases e.g. thrombin, can activate PARs by snipping off the end of the extracellular N-terminal tail of the receptor to expose 5 or 6 N-terminal residues that bind to receptor domains in the extracellular loops

Answer 61

- activated by a protease released from mast cells - expressed on sensory neurons - may play a role in inflammatory pain

Answer 62

only once | - because cleavage cannot be reversed, so continuous resynthesis of receptor protein is necessary

Answer 63

- further proteolytic cleavage that frees the tethered ligand - by desensitisation involving phosphorylation - receptor is internalised and degraded, then replaced

Answer 64

- family of membrane-resident proteins - function is to recognise activated GPCRs and passes on the message to effector systems that generate a cellular response - interact with guanine nucleotides, GTP and GDP

Answer 65

three: alpha, beta and gamma

Answer 66

- guanine nucleotides bind to the alpha subunit, which has enzymatic (GTPase) activity, catalysing the conversion of GTP to GDP - beta and gamma subunits remain together as a complex

Answer 67

anchored to the membrane through a fatty acid chain | - coupled to the G protein through a reaction known as prenylation

Answer 68

they are freely diffusable in the plane of the membrane, so a single pool of G protein in a cell can interact with several receptors and effectors

Answer 69

alpha-beta-gamma trimer - may or may not be precoupled to the receptor - GDP occupies the site on the alpha subunit

Answer 70

- when activated by an agonist molecule, there is a conformational change involving the cytoplasmic domain of the receptor - high affinity interaction of the trimer and the receptor within 50 ms - bound GDP dissociates and is replaced with GTP - this causes dissociation of the trimer, releasing alpha GTP and beta-gamma subunits

Answer 71

- alphaGTP | - beta-gamma

Answer 72

diffuse in the membrane and can associate with various enzymes and ion channels, causing activation of the target

Answer 73

- amplification: a single complex can activate several G protein molecules, and each can remain associated with the effector enzyme for long enough to produce many molecules of product (often second messenger)

Answer 74

second messenger

Answer 75

when the hydrolysis of GTP to GDP occurs through the GTPase activity of the alpha subunit - resulting alphaGDP dissociates from the effector, then reunites with beta-gamma

Answer 76

- regulators of G protein signalling proteins - possess a conserved sequence that binds specifically to alpha subunits to increase their GTPase activity, thus hastening the hydrolysis of GTP and inactivating the complex - inhibitory effect on G protein signalling

Answer 77

~ 20 cellular proteins

Answer 78

binding of the target protein by alpha subunit and/or RGS proteins

Answer 79

``` Ga(s) Ga(i) Ga(o) Ga(q) Ga(12) ```

Answer 80

associated receptors - many amine and other receptors - e.g. catecholamines, histamine, serotonin functions - stimulates adenylyl cyclase, increasing cAMP formation activated by cholera toxin, which blocks GTPase activity, thus preventing inactivation

Answer 81

associated receptors - amine and other receptors (e.g. catecholamines, histamine, serotonin) - opioid/cannabinoid receptors functions - inhibits adenylyl cyclase, decreasing cAMP formation blocked by pertussis toxin, which prevents dissociation of the alpha-beta-gamma complex

Answer 82

associated receptors - amine and other receptors (e.g. catecholamines, histamine, serotonin) - opioid/cannabinoid receptors functions - ? - limited effects of alpha subunit (effects mainly due to beta-gamma subunits) blocked by pertussis toxin occurs mainly in nervous system

Answer 83

associated receptors - amide, peptide and prostanoid receptors functions - activates phospholipase C, increasing production of second messengers of inositol triphosphate and diacylglycerol

Answer 84

associated receptors - all GPCRs functions - activate K+ channels - inhibit voltage-gated calcium channels - activate GPCR kinases - activate mitogen-activated protein kinase cascade - interact with some forms of adenylyl cyclase and phospholipase Cbeta

Answer 85

more than 20

Answer 86

Gs and Gi, respectively

Answer 87

- catalyse a conjugation reaction (ADP ribosylation) on the alpha subunit of G proteins - cholera toxin acts only on Gs and causes persistent activation - pertussis toxin specifically blocks Gi and Go by preventing dissociation of the G protein trimer - symptoms of cholera, e.g. excessive secretion of fluid from the GI epithelium are due to uncontrolled activation of adenylyl cyclase

Answer 88

- adenylyl cyclase: responsible for cAMP formation - phospholipase C: responsible for inositol phosphate and diacylglycerol formation - ion channels, particularly Ca2+ and K+ - Rho A/Rho kinase, a system that regulates the activity of many signalling pathways controlling cell growth and proliferaton, smooth muscle contraction etc - mitogen activated protein kinase, a system that controls many cell functions, e.g. cell division

Answer 89

cyclic 3',5' adenosine monophosphate | - nucleotide synthesised synthesised within the cell from ATP by adenylyl cyclase

Answer 90

- produced continuously and inactivated by hydrolysis to 5'-AMP by phosphodiesterases

Answer 91

- drugs, hormones and neurotransmitters | - change concentration of cAMPs

Answer 92

10 different molecular isoforms

Answer 93

activation of protein kinases, esp. protein kinase A

Answer 94

increased activity of voltage-gated calcium channels - phosphorylation of these channels increases the amount of Ca2+ entering the cell during the action potential, thus increasing the force of contraction of the heart

Answer 95

- phosphorylates (and inactivates) myosin light chain kinase, which is required for contraction - accounts for smooth muscle relaxation produced by many drugs that increase cAMP production in smooth muscle

Answer 96

- certain types of mAChR (e.g. M2 receptor of cardiac muscle) - a2 adrenoceptors in smooth muscle - opioid receptors

Answer 97

11 - some (e.g. PDE3 and PDE4) are cAMP selective - others (e.g. PDE5) are cGMP selective

Answer 98

methylxanthines (e.g. theophylline and caffeine)

Answer 99

- rolipram (asthma) | - PDE4 is expressed in inflammatory cells

Answer 100

- milrinone, used for heart failure | - PDE5 is expressed in heart muscle

Answer 101

- sildenafil (Viagra) | - enhances the vasodilator effects of NO and drugs that release NO, whose effects are mediated by cGMP

Answer 102

- increased lipolysis - reduced glycogen synthesis - increased glycogen breakdown

Answer 103

protein kinase phosphorylates/activates lipase

Answer 104

protein kinase phosphorylates/inactivates glycogen synthase

Answer 105

protein kinase phosphorylates/activates phosphorylase kinase -> activated phosphorylase b -> conversion of glycogen to glucose-1-phosphate

Answer 106

- phosphatidylinositol (4,5) bisphosphate - member of the membrane phospholipid class of phosphoinositides - additional phosphate groups attached to the inositol ring

Answer 107

- membrane bound enzyme, phospholipase Cbeta | - splits it into diacylglycerol and inositol (1,4,5) triphosphate

Answer 108

diacylglycerol | inositol (1,4,5) triphosphate

Answer 109

- DAG is phosphorylated to form phosphatidic acid | - IP3 is dephosphorylated and then recoupled with phosphatdic acid to form PIP2

Answer 110

- water-soluble mediator that's released into the cytosol and acts on a ligand-gated calcium channel present on the membrane of the endoplasmic reticulum - controls the release of Ca2+ from intracellular stores

Answer 111

inositol (1,3,4,5) tetraphosphate | - role is unclear but it may play a role in controlling gene expression

Answer 112

- activates protein kinase C, which catalyses the phosphorylation of intracellular proteins - highly lipophilic, remains within the membrane - binds to a specific site on the PKC molecule, causing it to migrate from the cytosol to the cell membrane (activation)

Answer 113

- at least 10 - distinct cellular distributions and phosphorylate different proteins - several activated by DAG and raised intracellular Ca2+

Answer 114

- DAG and raised Ca2+ levels - phorbol esters - arachidonic acid (generated by action of phospholipase A2 on membrane phospholipids)

Answer 115

highly irritant, tumour promoting compounds produced by certain plants

Answer 116

different functional proteins - ion channels - receptors - enzymes - transcription factors - cytoskeletal proteins

Answer 117

- control ion channel function directly by mechanisms not involving second messengers - done by beta-gamma subunits of Gi and Go proteins - controls K+ and Ca2+ channels

Answer 118

in cardiac muscle: mAChRs enhance K+ permeability which hyperpolarises the cells and inhibits electrical permeability in neurons: many inhibitory drugs reduce excitability by opening G protein-activated inwardly rectifying K+ channels or by inhibiting voltage activated N and P/Q type Ca2+ channels

Answer 119

- activated by certain GPCRs which couple to G proteins of the G12/13 type - free Galpha subunit interacts with a guanosine nucleotide exchange factor, which facilitates GDP-GTP exchange at another GTPase, Rho

Answer 120

Rho-GDP (resting form) is inactive | when GDP-GTP exchange occurs, Rho is activated, which activates Rho kinase

Answer 121

- phosphorylates many substrate proteins - controls cellular functions, e.g. smooth muscle contraction/proliferation, angiogenesis and synaptic remodelling - enhances hypoxia-induced pulmonary artery vasoconstriction, which is importnat in pathogenesis of pulmonary hypertension

Answer 122

- involves several signal transduction pathways that are activated by cytokines and growth factors acting on kinase-linked receptors and by ligands activating GPCRs - coupling of GPCRs to familes of MAP kinases can involve alpha and beta-gamma subunits and Src and arrestins (GPCR desensitisation) - controls processes involved in gene expression, cell division, apoptosis and tissue regeneration

Answer 123

restricted to the receptors activated by the desensitising agonist

Answer 124

affects other GPCRs

Answer 125

- receptor phosphorylation | - receptor internalisaton (endocytosis)

Answer 126

- residues (serine and threonine) mainly in the C terminal cytoplasmic tail can be phosphorylated by specific membrane-bound GPCR kinases and PKA/C

Answer 127

- on receptor activation, GRK2 and GRK3 are recruited to the plasma membrane by binding to free G protein beta-gamma subunits - GRKs then phosphorylate the receptors in their activated state

Answer 128

- phosphorylated receptor serves as a binding site for arrestins - arrestins are intracellular proteins that block the interaction between the receptor and G protein, leading to selective homologous desensitisation

Answer 129

- intracellular protein which blocks the interaction between the receptor and G proteins - produces homologous desensitisation of GPCRs - arrestin binding targets the receptor for endocytosis in clathrin-coated pits

Answer 130

- dephosphorylated and reinserted into the plasma membrane (resensitisation) - trafficked to lysosomes for degradation (inactivation)

Answer 131

- impaired coupling between the activated receptor and the G protein; agonist effect is reduced - leads to homologous or heterologous desensitisation - receptors phosphorylated by second messenger kinases are probably not internalised and are reactivated by dephosphorylation by phosphatases when the agonist is removed

Answer 132

2 subtypes of the GPCR, encoded by different genes | - functional receptor consists of a heterodimer of the two

Answer 133

- some are functional as monomers | - most can exist as homomeric or heteromeric oligomers

Answer 134

receptors -> guanylyl cyclase and G proteins G proteins -> adenylyl cyclase, phospholipase C and ion channels

Answer 135

produces cGMP

Answer 136

produces cAMP

Answer 137

produces IP3 and DAG

Answer 138

- activates protein kinase G | - ion channels

Answer 139

affects contractile proteins and ion channels

Answer 140

- activates protein kinase A | - ion channels

Answer 141

- activates enzymes, transport proteins etc | - ion channels

Answer 142

increased [Ca2+], leads to: - activated enzymes, transport proteins etc - activated contractile proteins - activated ion channels

Answer 143

activates arachidonic acid and protein kinase C

Answer 144

eicosanoids - released as local hormones - affect ion channels

Answer 145

activates enzymes, transport proteins etc, contractile proteins and ion channels

Answer 146

initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarization

Answer 147

- opening potassium channels, leading to membrane hyperpolarisation - inhibiting calcium channels, thus reducing neurotransmitter release

Answer 148

phospholipase A2 (controlled by G proteins)

Answer 149

- GPCRs may be spontaneously active in the absence of any agonist - seen in beta adrenoceptor, where mutations in the third intracellular loop/overexpression of the receptor, results in constitutive activation - native GPCRs can show constitutive activity when expressed in vitro - histamine H3 receptor shows constitutive activity in vivo

Answer 150

receptor activation -> RAF1 -> MEK1 -> ERK1/2 -> altered gene expression receptor activation -> ASK1 -> MKK4/7 + MKK3/6 -> JNK1-3 + p38 (respectively) -> altered gene expression

Answer 151

GRK acts on two Ps on receptor -> binding of ARR ERK is activated by: - binding of Src at the plasma membrane then binding of ERK to Src - direct activation after internalisation of the receptor/arrestin complex; JNK3 can also be activated like this

Answer 152

1. on prolonged agonist activation of the GPCR, selective GRKs are recruited to the plasma membrane and phosphorylate the receptor 2. arrestin binds and trafficks the GPCR to clathrin-coated pits for internalisation into endosomes in a dynamin-dependent process 3. GPCR is dephosphorylated by a phosphatase (PP2A) 4. either recycled and reinserted to the plasma membrane or trafficked to lysosomes for degradation

Answer 153

ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor

Answer 154

receptor activity-modifying-proteins - family of membrane proteins that associate with some GPCRs and alter their functional characteristics - discovered in 1998 when the functionally active receptor for the neuropeptide calcitonin gene-related peptide consisted of a complex of a GPCR that by itself lacked activity, with another membrane protein RAMP1 - when CRLR was coupled with RAMP2, it was activated by adrenomedulin

Answer 155

- one gene, through alternative splicing, RNA editing etc, can give rise to more than one receptor protein - one GPCR protein can associate with others, or with proteins e.g. RAMPs, to produce more than one type of functional receptor - different agonists may affect the receptor in different ways and elicit qualitatively different responses - the signal transduction pathway does not invariably require G proteins, and shows cross-talk with tyrosine kinase-linked receptors

Answer 156

- protein mediators: growth factors and cytokines | - hormones: insulin and leptin (at level of gene transcription)

Answer 157

- large proteins - single chain of up to 1000 residues with single membrane-spanning helical region - links a large extracellular ligand-binding domain to an intracellular domain of variable size and function - over 100 have been cloned

Answer 158

controlling cell division, growth, differentiation, inflammation, tissue repair, apoptosis and immune responses

Answer 159

- receptor tyrosine kinases - receptor serine/threonine kinases - cytokine receptors

Answer 160

- receptors for many growth factors, e.g. epidermal growth factor and nerve growth factor - TLRs - insulin receptor (more complex, dimeric structure)

Answer 161

- smaller class than RTKs - phosphorylate serine and/or threonine residues rather than tyrosine - example: transforming growth factor

Answer 162

- lack intrinsic enzyme activity - when occupied, they activate various tyrosine kinases, such as Jak (the Janus kinase) - ligands include cytokines such as interferons and CSFs

Answer 163

by kinases and phosphatases, respectively | - enzymes which are subject to regulation dependent on their phosphorylation status

Answer 164

in many cases, dimerisation occurs - association of two intracellular kinase domains allows a mutual autophosphorylation of intracellular tyrosine residues to occur

Answer 165

serve as high-affinity docking sites for other intracellular proteins that form the next stage in the signal transduction cascade

Answer 166

Ras/Raf/mitogen-activated protein (MAP) kinase pathway

Answer 167

1. growth factor binds to receptor domain which is lined to an intracellular tyrosine kinase domain through a transmembrane alpha helix 2. conformation change and dimerisation occurs 3. tyrosine autophosphorylation occurs. SH2-domain protein (Grb2) binds to intracellular tyrosine kinase domain 4. phosphorylation of Grb2 5. activation of Ras GDP/GTP exchange 6. activation of Raf, which phosphorylates Mek 7. Mek phosphoryaltes MAP kinase 8. MAP kinase phosphorylates various transcription factors, which leads to gene transcription

Answer 168

Jak/Stat pathway

Answer 169

1. cytokine binds to receptor, which is linked via a transmembrane alpha helix to an intracellular Jak domain 2. dimerisation and conformational change; activation of Jak 3. phosphorylation of receptor and Jak 4. binding and phosphorylation of SH2-domain protein 5. dimerisation of Stat 6. gene transcription

Answer 170

Src homology proteins; first identified in the Src oncogene product - highly conserved sequence of about 100 amino acids - form a recognition site for the phosphotyrosine residues of the receptor - individual SH2 domain proteins bind selectively to particular receptors, so the pattern of events triggered is specific

Answer 171

- varies according to the receptor involved - many SH2 domain proteins are enzymes - some growth factors activate a specific subtype of phospholipase C (PLCgamma), causing phospholipid breakdown, IP3 formation and Ca2+ release - may couple phosphotyrosine-containing-proteins with other functional proteins - end result is to activate or inhibit, by phosphorylation, transcription factors that migrate to the nucleus and suppress/induce expression of genes

Answer 172

- family of transcription factors - SH2-domain proteins that bind to phosphotyrosine groups on the receptor-Jak complex - are phosphorylated themselves - when activated, Stat migrates to the nucleus and activates gene expression

Answer 173

phosphatidylinositol-3-kinase - enzyme family activated by GPCRs and RTKs - attach a phosphate group to position 3 of PIP2 to form PIP3 - protein kinases, esp. PKB, have recognition sites for PIP3 and are thus activated, controlling apoptosis, differentiation, proliferation and trafficking, and NO synthase activation in the endothelium

Answer 174

binding of natriuretic peptides - activated by dimerisation - similar to RTKs

Answer 175

Ca2+/calmodulin-dependent kinase

Answer 176

- enzymes - receptors - ion channels - transporters - transcription factors - contractile proteins - secretory mechanisms

Answer 177

- physiological responses - immune response - apoptosis - malignant transformation - growth - differentiation

Answer 178

nuclear receptor family - receptors for hormones/substances present in the cytoplasm of cells and translocate into the nucleus after binding with ligand - includes orphan receptors (receptors with no known well-defined ligands)

Answer 179

- receptors for steroid hormones e.g. oestrogen and clucocorticoids - thyroid hormone T3 - fat soluble vitamins D and A (retinoic acid)

Answer 180

- retinoid X receptor (first to be described in the 1990s) | - cloned on the basis of its similarity with the vitamin A receptor

Answer 181

vitamin A derivative 9-cis-retinoic acid

Answer 182

those which have found binding partners

Answer 183

- in cytosol and then translocate to nucleus | - in nuclear compartment

Answer 184

- heterogenous N terminal domain harbours the AF1 (activation function 1) site - core DNA binding domain with 'zinc fingers' - hinge region - ligand-binding domain, AF2 co-activator domain and HSP binding - C-terminal extension

Answer 185

- displays most heterogeneity - harbours the AF1 site - AF1 site binds to other cell-specific transcription factors in a ligand independent way and modifies the binding or regulatory capacity of the receptor itself - alternative splicing of genes may yield several receptor isoforms each with different N-terminal regions

Answer 186

- highly conserved - consists of structure responsible for DNA recognition and binding - comprises two zinc fingers: cysteine rich loops in the amino acid chain held in place by zinc ions - recognise and bind to hormone response elements in genes - regulates receptor dimerisation

Answer 187

cysteine rich loops in the amino acid chain held in place by zinc ions - in the core DNA binding domain of nuclear receptors

Answer 188

hormone response elements - located in genes that are regulated by nuclear receptors - short (4/5 base pairs) sequences of DNA to which NRs bind to modify gene transcription

Answer 189

- highly flexible - allows it to dimerise with other NRs - dimerisation can produce molecular complexes with diverse configurations, able to interact differently with DNA

Answer 190

- contains the ligand-binding module | - specific to each class of receptor

Answer 191

- important in ligand-dependent activation - generally highly conserved although absent in Rev-erbAalpha and Rev-erbAbeta, which regulate metabolism as mart of a circadian rhythm

Answer 192

usually symmetrically in pairs or half-sites | - may be arranged together in different ways (e.g. simple or inverted repeats)

Answer 193

- ligand-bound receptor recruits large complexes of other proteins including co-activators/repressors to modify gene expression through its AF1 and AF2 domains

Answer 194

- enzymes involved in chromatin remodelling, e.g. histone acetylase/decetylase: regulate unravelling of DNA to allow access by polymerase enzymes

Answer 195

histone decetylase and other factors that cause the chromatin to become tightly packed, preventing further transcriptional activation

Answer 196

two main classes (I and II) and two other minor groups (III, IV)

Answer 197

endocrine steroid receptors - glucocorticoid and mineralocorticoid receptors (GR and MR) - oestrogen, progesterone and androgen receptors (ER, PR and AR)

Answer 198

- after diffusion/transportation into the cell from blood, ligands bind their NR partner with high affinity - form homodimers and translocate to the nucleus - transactivate or transrepress genes by binding to positive or negative HREs - once bound, the NR recruits other proteins to form complexes that promote transcription of multiple genes

Answer 199

in absence of their ligand, they're predominantly located in the cytoplasm, complexed with head shock and other proteins and possibly reversibly attached to the cytoskeleton/other structures

Answer 200

``` AR: testosterone ERalpha/beta: 17beta oestradiol GRalpha: cortisol, corticosterone PR: progesterone MR: aldosterone ```

Answer 201

- all natural and synthetic glucocorticoids, mineralocorticoids and sex steroids - together with their antagonists (e.g. raloxifine, 4-hydroxy-tamoxifen and mifepristone)

Answer 202

ligands are generally lipids already present to some extent within the cell - peroxisome proliferator-activated receptor (PPAR): recognises fatty acids - liver oxysterol receptor (LXR): recognises and acts as a cholesterol sensor - farnesoid receptor (FXR) - xenobiotic receptor (SXR): recognises foreign substances/drugs - constitutive androstane receptor (CAR): recognises steroid androstane and some drugs

Answer 203

CYP3A metabolises 60%

Answer 204

- induce drug metabolising enzymes when they sense foreign material - bind some prostaglandins, non steroidal drugs and the antidiabeteic thiazolidinediones and fibrates

Answer 205

almost always operate as heterodimers with the retinoid X receptor (RXR)

Answer 206

- non-permissive heterodimer: can be activated only by RXR ligand itself - permissive heterodimer: can be activated by retinoic acid itself or by its partner's ligand

Answer 207

- generally bound to co-repressor proteins - dissociate when the ligand binds and allows recruitment of coactivator proteins - leads to changes in gene transcription - tend to mediate positive feedback effects

Answer 208

- form homodimers | - can bind to HREs, which don't have an inverted repeat sequence

Answer 209

- function as monomers or dimers | - only bind to one HRE half site

Answer 210

consist of protein molecules designed to form water-filled pores that span the membrane, and can switch between open and closed states

Answer 211

electrochemical gradient for the ion, which is a function of its concentration on either side of the membrane, and of the membrane potential

Answer 212

- selectivity for particular ion species, determined by the size of the pore and nature of its lining - gating properties (the nature of the stimulus that controls the transition between open and closed states of the channel) - molecular architecture

Answer 213

- Na+, Ca2+ or K+ | - or non-selective and permeable to all three

Answer 214

responds to changes in the local environment instead - TRPV1 channel on sensory nerves mediates pain-producing effect of chilli pepper ingredient capsaicin - responds to extracellular protons when tissue pH falls in inflamed tissue, and to heat

Answer 215

- calcium-activated potassium channels: open and hyperpolarise the cell when Ca2+ increases - calcium-activated chloride channels - ATP-sensitive potassium channels: open when intracellular ATP concentration falls because the cell is short of nutrients - arachidonic-acid sensitive potassium channels - DAG sensitive calcium channels

Answer 216

expressed in excitable and non-excitable cells - epithelial secretion of electrolytes and water - sensory transduction - regulation of neuronal and cardiac excitability - regulation of vascular tone

Answer 217

- many nerve and muscle cells | - insulin-secreting cells

Answer 218

- IP3 and ryanodine receptors - class of ligand-gated calcium channels that are present on the endoplasmic or sarcoplasmic reticulum rather than the plasma membrane - control the relase of Ca2+ from intracellular stores

Answer 219

- from lysosomal stores | - by nicotinic acid adenine dinucleotide phosphate activating two pore domain calcium channels

Answer 220

- located in the plasma membrane - open when intracellular Ca2+ stores are depleted; through interaction of a Ca2+ sensor protein in the ER membrane with a dedicated Ca2+ channel in the plasma membrane - opening of channels allows cytosolic free Ca2+ conc to remain elevated even when intracellular stores are low

Answer 221

6T1P 2T1P 4T2P

Answer 222

voltage gated K+ channels, TRP channels

Answer 223

inward-rectifying K+ channels, acid-sensing ion channels, epithelial Na+ channel, degenerins

Answer 224

resting K+ channels

Answer 225

- ligands that bind directly to various sites on the channel protein - mediators and drugs that act indirectly, mainly by activation of GPCRs - intracellular signals, particularly Ca2+ and ATP/GTP

Answer 226

altered gating: GPCR ligands -> phosphorylation of channel channel block (extracellular side): tetrodotoxin, saxitoxin, conotoxins block of inactivation: veratridine, batrachotoxin, scorpion toxins, DDT, pyrethroids channel block: local anaesthetics, antiepileptic drugs, antidysrythmic drugs

Answer 227

short term regulation: desensitisation | long term regulation: increase or decrease of receptor expression

Answer 228

- autoantibodies directed against receptor proteins | - mutations in genes encoding receptors, ion channels and proteins involved in signal transduction

Answer 229

tyrosine -> dopa -> dopamine -> noradrenaline -> adrenaline | - final step only occurs in the adrenal medulla

Answer 230

1860s: muscarine was shown to mimic the actions of nervous activation and atropine to oppose these actions 1905: Langley showed nicotine activated the NMJ and curare opposed this activation 1920s: vagal nerve stimulation slowed the heart and released a transferrable chemical that could slow (frog) hearts

Answer 231

- peripheral ANS divides into sympathetic and parasympathetic branches (opposing effects) - ANS conveys all outputs from the CNS to the body, except for skeletal muscular control - regulatory roles in vascular, airway and visceral smooth muscle, exocrine secretions, control of heart rate, energy metabolism in the liver, links to immune system

Answer 232

somatic nervous system: neurone comes from the CNS to innervate muscle ANS: two nerves in series, the pre- and post-ganglionic fibres - parasympathetic ganglia are near their targets with short post-ganglionic nerves - sympathetic ganglia are near the spinal cord with longer post-ganglionic fibres

Answer 233

- constricts pupil - stimulates tear glands - strong stimulation of salivary flow - slows heart rate - constricts bronchi - stimulates digestive juice secretion - stimulates intestinal motility - contracts bladder - stimulates erection

Answer 234

- dilates pupil - tear glands maintain eye moisture - inhibition of excess salivary secretion - accelerates heart rate and constricts arterioles - dilates bronchi - inhibits stomach motility and secretion - inhibits pancreas and adrenals - inhibits intestinal motility - relaxes bladder - stimulates ejaculation

Answer 235

preganglionic neuron: cholinergic, ACh released at autonomic ganglion, acts on nicotinic receptor of postganglionic neuron postganglionic neuron: adrenergic, norepinephrine (NE) released at target tissue which has adrenergic alpha or beta receptors

Answer 236

preganglionic neuron: cholinergic, ACh released at autonomic ganglion, acts on nicotinic receptor of postganglionic neuron postganglionic neuron: cholinergic, ACh released at target tissue which has cholinergic receptors (muscarinic)

Answer 237

III (oculomotor), VII (facial), IX (glossopharyngeal) and X (vagus)

Answer 238

gut, bladder, heart

Answer 239

sweat glands, blood vessels

Answer 240

bronchial smooth muscle

Answer 241

ACh to stimulate muscarine receptors

Answer 242

non-adrenergic, non-cholinergic autonomic receptors | - used by enteric nervous system, parasympathetic and sympathetic system

Answer 243

parasympathetic: NO and vasoactive intestinal peptide sympathetic: ATP and neuropeptide Y

Answer 244

all autonomic ganglia via specific ganglionic nicotinic receptors, activating both parasympathetic and sympathetic nervous systems

Answer 245

- from poisonous mushroom - activates muscarinic receptors of the parasympathetic nervous system - amenable to drug targeting

Answer 246

M1-5, GPCRs

Answer 247

mainly in the brain

Answer 248

- mainly in the heart | - activation slows the heart, so we can block these

Answer 249

atropine for life-threatening bradycardias and cardiac arrest

Answer 250

- glandular and smooth muscle | - causes bronchoconstriction, sweating, salivary gland secretion

Answer 251

mainly in the CNS

Answer 252

pilocarpine - stimulates salvation: useful after radiotherapy, or in Sjorgren's syndrome (PNS) - contracts iris smooth muscle: used to treat glaucoma by facilitating drainage of aqueous humour (PNS)

Answer 253

slow the heart

Answer 254

in palliative are, to antagonise parasympathetic driven secretions

Answer 255

deadly nightshade

Answer 256

- prevent bradycardia and BP drop, dry secretions perioperatively - treat bradycardias induced by excessive doses of beat blockers - treat bradycardia in cardiac arrest

Answer 257

- in the airway, drugs block the M3 receptor (called anti-cholinergics or anti-muscarinics) - short acting: ipratropium bromide (atrovent) - long acting: LAMAs e.g. tiotropium, glycopyrrhonium

Answer 258

- selectivity by drug delivery mechanisms (inhalers) | - receptor selectivity (e.g. tiotropium relatively selective for M3 receptors)

Answer 259

- treating overactive bladders (e.g. solifenacin) - short acting ones open up the pupil to allow eye examination - act on parasympathetic fibres in intestinal colic and spasm: IBS (mebeverine) and palliative care (hyoscine)

Answer 260

- ACh signalling involved in memory: anticholinergics worsen memory, and acetylcholinesterase inhibitor may treat dementia - anti-emetic actions (e.g. hyoscine for travel sickness)

Answer 261

worsen memory | - acetylcholinesterase inhibitors may treat dementia

Answer 262

the posionous mushroom Amanita muscaria

Answer 263

nicotinic-like effects, including: - stimulation of all autonomic ganglia - stimulation of voluntary muscle - secretion of adrenaline from the adrenal medulla - initial rise in BP due to stimulation of sympathetic ganglia and consequent vasoconstriction - secondary rise in BP due to secretion of adrenaline

Answer 264

transient fall in BP due to arteriolar vasodilation and slowing of the heart: muscarinic effects that are abolished by atropine

Answer 265

release NO, which relaxes smooth muscle to cause generalised vasodilation

Answer 266

to those of ACh releaesd at postganglionic parasympathetic nerve endings exceptions: - ACh causing generalised vasodilation even though most blood vessels have no parasympathetic innervation - ACh evokes secretion from sweat glands, which are innervated by cholinergic fibres of the sympathetic nervous system

Answer 267

to those of ACh acting on autonomic ganglia of the sympathetic and parasympathetic systems, the motor endplate of voluntary muscle and the secretory cells of the adrenal medulla

Answer 268

muscle, ganglionic and CNS types

Answer 269

- pentameric | - five subunits are similar in structure

Answer 270

``` oral (po) intravenous (iv) rectal (pr) subcutaneous (sc) intramuscular (im) intranasal (in) topical (top) sublingual (sl) inhaled (inh) nebulised (neb) ```

Answer 271

``` mainly intramuscular (im) rotavirus is administered orally (po) ```

Answer 272

- 5 in 1 vaccine (diphtheria, tetanus, whooping cough (pertussis), polio and haemophilus influenza type b) - pneumococcal vaccine - rotavirus vaccine - Men B vaccine

Answer 273

orally (po), per-rectum (pr), intravenous (iv)

Answer 274

- five subunits that form the receptor-channel complex are similar in structure - so far 17 different members have been identified and cloned, designated alpha (10 types), beta (4 types), gamma, delta and e (one of each)

Answer 275

each possess 4 membrane spanning helical domains | - one of these helices (M2) from each subunit defines the central pore

Answer 276

both alpha and beta subunits, the exception being the homomeric (alpha7)5 subtype found in the bran

Answer 277

- interface between the extracelluar domain of each of the alpha subunits and its neighbour

Answer 278

(α1)2β1δε

Answer 279

(α3)2(β4)3

Answer 280

(α4)2(β2)3 | (α7)5

Answer 281

(α1)2β1δε: skeletal NMJ, mainly postsynaptic (α3)2(β4)3: autonomic ganglia, mainly postsynaptic (α4)2(β2)3: many brain regions; pre- and postsynaptic (α7)5: many brain regions; pre- and postsynaptic

Answer 282

(α1)2β1δε: excitatory; increased cation permeability, mainly Na+ and K+ (α3)2(β4)3: excitatory; increased cation permeability, mainly Na+ and K+ (α4)2(β2)3: pre and postsynaptic excitation; increased cation permeability, mainly Na+ and K+ (α7)5: pre and postsynaptic excitation; increased cation permeability; produces large Ca2+ entry, evoking transmitter release

Answer 283

(α1)2β1δε: acetylcholine, carbachol, succinylcholine (α3)2(β4)3: acetylcholine, carbachol, nicotine, epibatidine, dimethylphenylpiperazinium (α4)2(β2)3: nicotine, epibatidine, acetylcholine, cytosine, varenicline (α7)5: epibatidine, dimethylphenylpiperazinium, varenicline

Answer 284

(α1)2β1δε: tubocurarine, pancuronium, atracurium, vecuronium, alpha-bungarotoxin, alpha-conotoxin (α3)2(β4)3: mecamylamine, trimetaphan, hexamethonium, alpha-conotoxin (α4)2(β2)3: mecamylamine, methylaconitine (α7)5: alpha-bungarotoxin, alpha-conotoxin, methylaconitine

Answer 285

- odd numbered muscarinic receptors (M1, M3 and M5) couple with Gq to activate the IP3 pathway - even numbered receptors (M2 and M4) open potassium channels causing membrane hyperpolarisation and acting through Gi to inhibit adenylyl cylcase and reduce intracellular cAMP - both groups activate the MAP kinase pathway

Answer 286

- autonomic ganglia (including intramural ganglia in stomach) - glands: salivary, lacrimal, etc - cerebral cortex

Answer 287

heart: atria CNS: widely distributed

Answer 288

exocrine glands: gastric (acid-secreting parietal cells), salivary etc smooth muscle: GI tract, eye, airways, bladder blood vessels: endothelium

Answer 289

CNS: very localised expression in substantia nigra | salivary glands and iris/ciliary muscle

Answer 290

- increased IP3, DAG depolarisation - excitation (slow epsp) - decreased K+ conductance

Answer 291

- decreased cAMP - inhibition - decreased Ca2+ conductance - increased K+ conductance

Answer 292

- increased IP3 - stimulation - increased [Ca2+]

Answer 293

- decreased cAMP | - inhibition

Answer 294

- increased IP3 | - excitation

Answer 295

- CNS excitation - improved cognition? - gastric secretion

Answer 296

- cardiac inhibition - neural inhibition - central muscarinic effects

Answer 297

- gastric, salivary secretion - GI smooth muscle contraction - ocular accommodation - vasodilation

Answer 298

enhanced locomotion

Answer 299

- acetylcholine - carbachol - oxotremorine - pilocarpine - bethanechol

Answer 300

M1: McNA343 M3: Cavimeline

Answer 301

- atropine - dicycloverine - tolterodine - oxybutynin - ipratropium

Answer 302

M1: Pirenzepine and Mamba toxin MT7 M2: Gallamine M3: Darifenacin M4: Mamba toxin MT3

Answer 303

- selective M3 agonist | - used to improve salivary and lacrimal secretion in Sjogren's syndrome

Answer 304

an autoimmune disorder characterised by dryness of the mouth and eyes

Answer 305

peptic ulcer disease

Answer 306

urinary incontinence in adults with detrusor muscle instability

Answer 307

was used as a neuromuscular blocking drug

Answer 308

atropine and hyoscine

Answer 309

1. choline is taken up into the nerve terminal by a specific transporter 2. free choline within the nerve terminal is acetylated by a cytosolic enzyme, choline acetyltransferase (CAT), which transfers the acetyl group from acetyl-CoA

Answer 310

- normally 10 micromol/l in immediate vicinity of - cholinergic nerve terminals: 1 mmol/l - more than 50% of hydrolysed released ACh is recaptured by the nerve terminals

Answer 311

choline transport, which is determined by the extracellular choline concentration and is linked to the rate at which ACh is released

Answer 312

- acts postsynaptically on a nicotinic ACh receptor controlling a cation channel - acts presynaptically on a nicotinic receptor that acts to facilitate ACh release during sustained synaptic activity

Answer 313

choline and acetate

Answer 314

anticholinesterases e.g. neostigmine

Answer 315

- amount of free ACh and rate of leakage of ACh via the choline carrier is increased

Answer 316

choline carrier, which is coupled with ACh leaving

Answer 317

hemicholinium

Answer 318

presynaptic toxins, e.g. botulinum

Answer 319

recycling of ACh via presynaptic nicotinic ACh receptor

Answer 320

non-depolarising blocking agents, e.g. tubocurarine

Answer 321

depolarising blocking agents, e.g. suxamethonium

Answer 322

100 mmol/l

Answer 323

Ca2+ entry into the nerve terminal

Answer 324

the large electrochemical gradient for protons that exists between acidic intracellular organelles and the cytosol - blocked selectively by the experimental drug vesamicol

Answer 325

300 synaptic vesicles (around 3 million ACh molecules) supplying a single muscle fibre

Answer 326

around 2 ms, and are quickly hydrolysed after dissociating so they can't combine with a second receptor

Answer 327

- ACh acts on presynaptic receptors and stimulates activity - at postganglionic parasympathetic nerve endings, inhibitory M2 receptors participate in autoinhibition of ACh release - noradrenaline inhibits the release of ACh - at the NMJ, presynaptic nAChRs facilitate ACh release

Answer 328

- causes a large increase in its permeability to cations, particularly to Na+ and K+, and to a lesser extent Ca2+ - inflow of Na+ depolarises the postsynaptic membrane

Answer 329

endplate potential in skeletal muscle fibre | fast excitatory postsynaptic potential at the ganglionic synapse

Answer 330

- blocks postsynaptic ACh receptors - reduces the amplitude of the fast epsp until it no longer initiates an action potential - cell is still capable of responding when stimulated electrically

Answer 331

most ganglion cells are supplied by several presynaptic axons, and require simultaneous activity in more than one to make the postganglionic cell fire

Answer 332

only one nerve fibre

Answer 333

- lasts 2-5 s - this mainly reflects a M2 receptor mediated increase in K+ conductance, but other transmitter, e.g. dopamine and adenosine also contribute

Answer 334

- lasts for 10s | - produced by ACh acting on M1 receptors, which close K+ channels

Answer 335

- lasts for 1-2 min - may be mediated by a peptide co-transmitter, which may be substance P in some ganglia, and a gonadotrophin-releasing hormone-like peptide in others

Answer 336

- at cholinergic synapses when the excitatory nAChRs are persistently activated - results from a decrease in the electrical excitability of the postsynaptic cell

Answer 337

voltage-sensitive sodium channels become inactivated (refractory) and are no longer able to open in response to a brief depolarising stimulus

Answer 338

1. activation of nAChRs, causing a depolarisation of the cell, which initiates action potential discharge 2. after a few seconds, this discharge ceases and the transmission is blocked

Answer 339

- after nicotine has acted for several minutes, the cell partially repolarises and its electrical excitability returns - transmission remains blocked - occurs at the NMJ if repeated doses of depolarising drug suxamethonium are used

Answer 340

phase II block

Answer 341

much slower, synaptic structures are less defined | - ACh functions as a modulator rather than as a direct transmitter

Answer 342

- inhibition of choline uptake - inhibition of ACh release - block of postsynaptic receptors or ion channels - persistent postsynaptic depolarisation

Answer 343

- muscarinic agonists - muscarinic antagonists - ganglion-stimulating drugs - ganglion-blocking drugs - neuromuscular-blocking drugs - anticholinesterases and other drugs that enhance cholinergic transmission

Answer 344

bethanechol, pilocarpine and cevimeline

Answer 345

treatment of bladder and GI hypotonia

Answer 346

Sjogren's syndrome (to increase salivary and lacrimal secretion)

Answer 347

- acetylcholine - carbachol - methacholine - bethanechol - muscarine - pilocarpine - oxotremorine - cevimeline

Answer 348

- cardiac slowing and decrease in in cardiac output - due to reduced heart rate and a decreased force of contraction of the atria - generalised vasodilation (mediated by NO) - sharp fall in arterial pressure

Answer 349

paracetamol binding to activated charcol

Answer 350

effect of a drug on the body

Answer 351

effect of the body on a drug

Answer 352

- receptors - enzymes - carrier molecules (transporters) - ion channels

Answer 353

a chemical applied to a physiological system that affects its function in a specific way

Answer 354

a component of a cell whose function is to recognise and respond to endogenous chemical signals - interacts with a specific ligand (exogenous or endogenous) and initiates a change of biochemical events leading to the ligand observed effects

Answer 355

macromolecules with which drugs interact to produce their effects

Answer 356

agonists: activate the receptors antagonists: combine at the same site without causing activation, and block the effect of agonists on that receptor

Answer 357

- drugs must act selectively on particular cells and tissues | - must show a high degree of binding site specificity

Answer 358

proteins that function as drug targets show a high degree of ligand specificity; they bind only molecules of a certain precise type

Answer 359

qualitative: receptors, enzymes, selectivity quantitative: dose response, potency, therapeutic efficacy, tolerance

Answer 360

time course of drug concentration: drug passage across membranes, order of reaction, plasma half life and steady-state concentration; therapeutic drug monitoring individual processes: absorption, distribution, metabolism, elimination drug dosage: dosing schedules chronic pharmacology: consequences of prolonged drug administration and drug discontinuation syndromes

Answer 361

- pharmacogenomics: variability due to inherited influences - variability due to environmental and host influences - drug interactions: outside the body, at site of absorption, during distribution, directly on receptors, during metabolism, during excretion

Answer 362

variability due to inherited influences

Answer 363

- enzyme inhibition - inhibition or induction of transporter processes that carry substances into, across and out of cells - incorporation into larger molecules - altering metabolic processes unique to microorganisms, or by showing quantitative differences in affecting a process common to both humans and microbes

Answer 364

- direct chemical interaction | - osmosis

Answer 365

when tissues are continuously exposed to an agonist, the number of receptors decreases

Answer 366

loss of efficacy with frequently repeated doses | - can be caused by down-regulation

Answer 367

prolonged contact with an antagonist leads to formation of new receptors

Answer 368

- drugs that activate receptors - they resemble the natural transmitter or hormone - value in clinical practice often rests on their greater capacity to resist degradation and to act for longer than the endogenous ligands they mimic

Answer 369

- blockers of receptors - sufficiently similar to the natural agonist to be recognised by the receptor and to occupy it without activating a response - block the natural agonist from exerting its effect

Answer 370

drugs that have no activating effect whatsoever on the receptor

Answer 371

absorption, distribution, metabolism and excretion

Answer 372

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

Answer 373

light energy, peptides, lipids sugars and proteins

Answer 374

- treats breast cancer | - acts as a selective estrogen receptor (SERM), or as a partial agonist of the estrogen receptors

Answer 375

the concentration that gives half the maximal response

Answer 376

ability of a drug-receptor complex to produce a maximum functional response

Answer 377

binding to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor

Answer 378

muscarine and atropine

Answer 379

nicotine and curare

Answer 380

- amino acids: 481 - protein: 56 kDa - allergic conditions - GPCR

Answer 381

- amino acids: 359 - protein: 40 kDa - gastric acid secretion

Answer 382

- amino acids: 445 - protein: 49 kDa - mostly CNS disorders (e.g. narcolepsy, ADHD, Alzheimers, schizophrenia) - role in obesity, pain and rhinitis - GPCR

Answer 383

- amino acids: 390 - protein: 44 kDa - immune system and inflammatory conditions (e.g. rhinitis, pruritis and asthma) - inflammatory pain - GPCR

Answer 384

histamine and mepyramine

Answer 385

- contraction of ileum | - acid secretion from parietal cells

Answer 386

- reversed contraction of ileum | - no effect on acid secretion

Answer 387

affinity and efficacy

Answer 388

receptor number and signal amplification

Answer 389

describes how well a ligand binds to the receptor | - shown by agonists and antagonists

Answer 390

describes how well a ligand activates the receptor | - shown by agonists but not antagonists

Answer 391

when a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist

Answer 392

- reduction in agonist effect over time | - continuously, repeatedly high concentrations

Answer 393

a molecule that binds to an enzyme and decreases (normally) its activity - prevents the substance from entering the enzyme's active site and prevents it from catalysing its reaction

Answer 394

- irreversible inhibitors: usually react with the enzyme and change it chemically (e.g. via covalent bond formation) - reversible inhibitors: bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex or both

Answer 395

streptokinase: a clot buster

Answer 396

- HMG-CoA reductase inhibitors | - class of lipid-lowering medications that reduce the levels of bad cholesterol

Answer 397

- block the rate limiting step in the cholesterol pathway | - reduce cardiovascular disease and mortality in those at high risk

Answer 398

3-hydroxy-3-methyglytaryl-CoA (HMG-CoA) -> mevalonic acid - catalysed by HMG-CoA reductase

Answer 399

3-hydroxy-3-methylglutaryl-CoA

Answer 400

- RAAS increases blood pressure by inceasing the amount of salt and water the body retains - inhibition of ACE reduces the conversion of angiotensin I to angiotensin II

Answer 401

stimulates: - sympathetic activity - tubular Na+ Cl- reabsorption and K+ excretion; water retention - aldosterone secretion - arteriolar vasoconstriction; increase in BP - ADH secretion -> H2O absorption in collecting duct

Answer 402

- water and salt retention - increased effective circulating volume - increased perfusion of the juxtaglomerular apparatus - increase BP - eventually inhibits renin production by kidney (negative feedback)

Answer 403

- liver | - renin converts it to angiotensin I

Answer 404

surface of pulmonary and renal endothelium

Answer 405

captopril (1st gen) and enalaprilat (2nd gen)

Answer 406

- hypokinesia (decreased motor movement) - tremor at rest - muscle rigidity, motor inertia - cognitive impairment - degenerative disease of the basal ganglia - early degeneration of dopaminergic neurons in the nigrostriatal pathway leading to autonomic dysfunction and dementia

Answer 407

amino acid L-Tyrosine

Answer 408

1. L-DOPA crosses the BBB 2. DOPA decarboxylase acts on L-DOPA to produce dopamine 3. dopamine acts on D1 and D2 receptors

Answer 409

blocks DDC in the periphery, which generates more for the CNS pathway - leads to improved Parkinsonoid symptoms

Answer 410

- carbidopa - co careldopa - benserzide

Answer 411

L-DOPA -> 3-methyl DOPA catalysed by COMT: catechol-O-methyl transferase

Answer 412

prevents breakdown of L-DOPA, generating more for the CNS pathway - leads to improved Parkinsonoid symptoms

Answer 413

- tolcapone | - entacapone

Answer 414

``` function within the CNS to prevent dopamine breakdown by COMT and thus keep dopamine levels up - improved Parkinsonoid symptoms ```

Answer 415

3,4-Dihydroxyphenylacetic acid

Answer 416

mono amine oxidase B (MAO-B)

Answer 417

prevent dopamine breakdown and increases availability | - improved parkinsonoid symptoms

Answer 418

selegiline and rasagiline

Answer 419

antagonise dopamine receptors (not enzyme inhibitors) | - improved Parkinsonoid symptoms

Answer 420

- bromocryptine - pergolide - pramipexole - ropinirole - rotigotine

Answer 421

when molecules move across a cell membrane

Answer 422

- uniporters: use energy from ATP to pull molecules in - symptorters: use the movement in of one molecule to pull in another molecule against a concentration gradient - antiporter: one substance moves against its gradient, using energy from the second substance moving down its gradient

Answer 423

- loop diuretic - used for hypertension and edema - inhibits luminal NKCC co-transporter in the thick ascending limb of the loop of Henle - binds to the NKCC - causes sodium, chloride and potassium loss in urine

Answer 424

epithelial (sodium): heart failure voltage-gated (calcium, sodium): nerve, arrhythmia metabolic (potassium): diabetes receptor activated (chloride): epilepsy

Answer 425

- an apical membrane-bound heterotrimeric ion channel selectively permeable to Na+ ions - causes reabsorption of Na+ ions at the collecting ducts of the kidneys nephrons

Answer 426

- blocked by the high affinity diuretic amiloride (often used with Thaizide) - Thaizide targets Na+Cl- cotransporter that reabsorbs Na and Cl from tubular fluid - used as an anti-hypertensive

Answer 427

at physiologic or resting membrane potential, VDCCs are normally closed

Answer 428

a momentary change in electrical potential on the surface of a cell, that occurs when it is stimulated, resulting in the transmission of an electrical impulse

Answer 429

amlodipine

Answer 430

an angioselective calcium channel blocker that inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells

Answer 431

- inhibit contraction of cardiac muscle and vascular smooth muscle cells - causes vasodilation and a reduced peripheral vascular resistance -> lowered BP - prevents excessive constriction in the coronary arteries

Answer 432

two sets of three proteins: alpha, beta and gamma; all need to be activated

Answer 433

close, open and inactivated

Answer 434

lidocaine (anaesthetic) blocks transmission of the action potential which allows the activation gates to open - blocks signalling in the heart, thus reducing arrhythmia

Answer 435

regulate insulin in pancreas: beta islets of Langerhans 1. increased glucose goes through glucose transporter and is metabolised to produce ATP 2. ATP closes ATP dependent K+ channels 3. this leads to membrane depolarisation, which triggers calcium influx 4. calcium influx stimulates exocytosis

Answer 436

- repaglinide - nateglinide - sulfonylureal - lower blood glucose levels by blocking K+ channels to stimulate insulin secretion; treats type II diabetes

Answer 437

GABA A receptor (gamma aminobutyric acid): major inhibitory neurotransmitter in the CNS - opens Cl- channel and induces hyperpolarisation

Answer 438

barbituates, e.g. phenobarbitone

Answer 439

- GABA site - barbituate site - benzodiazepine site - steroid site - picrotoxin site

Answer 440

- Digoxin was first isolated in 1930 from the foxglove plant, Digitalis Ianata

Answer 441

- used for AF, atrial flutter and heart failure - inhibition causes an increase in intracellular Na, resulting in decreased activity of the Na/Ca exchanger and increases intracellular Ca - lengthens the cardiac action potential, which leads to a decrease in heart rate

Answer 442

- block the proton pump in the stomach (acidifies the stomach and activates pepsin) - most potent inhibitors of acid secretion

Answer 443

omeprazole (1st in class) - irreversible inhibition - half life 1hour, works for 2-3 days - metabolised at acid pH by enteric coated granules

Answer 444

irreversible inhibitors of cholinesterase

Answer 445

insecticides (Diazinon) and nerve gases (Sarin)

Answer 446

muscarinic: salivation, defecation, urination, bradycardia, hypotension nicotinic: twitching, severe weakness, paralysis, diaphragm CNS: confusion, loss of reflexes, convulsions, coma

Answer 447

compounds foreign to an organism's normal biochemistry, such as any drug or poison

Answer 448

primarily membrane associated proteins located either in the inner membrane of mitochondria or in the ER of cells

Answer 449

- drug metabolism - deactivation and bioactivation of drugs - metabolism of endogenous and exogenous chemicals

Answer 450

``` 2A6 2C19 2C8 2C9 3A4 2D6 1A2 2E1 2B6 ```

Answer 451

- coumarin - methimazole - phenobarbitone

Answer 452

- mephenytoin - tranylcypromine - phenobarbitone

Answer 453

- taxol - quercetin - phenobarbitone

Answer 454

- S-warfarin - phenytoin - tolutamide - sulphapheazole - rifampicin

Answer 455

- nifedipine - cyclosporine - erythromycine - terfenadine - ketoconazole - rifampicin

Answer 456

- debrisoquine - metoprolol - dextromethorphan - quinidine

Answer 457

- caffeine - phenacetin - theophylline - furafylline - omeprazole

Answer 458

- chlorzoxazone - disulfiram - ethanol - isoniazid

Answer 459

- ifosphamide | - orphenadrine

Answer 460

caffeine, theophylline, phenacetin, clomipramine, clozapine, thioridazine

Answer 461

omeprazole, nicotine, cimetidine, ciprofloxacin

Answer 462

phenobarbital, fluvoxamine, venlafaxine, ticlodipine

Answer 463

- CYP450 inducer | - warfarin

Answer 464

- CYP450 inhibitor - Ca2+ channel blockers - cyclosporin - tacrolimus - carbemazepine - midazolam - terfenadine

Answer 465

- CYP450 inhibitor - clozapine - haloperidol - NSAIDs - warfarin - phenytoin

Answer 466

- increases anti-platelet activity - anti-coagulants - aspirin - NSAIDs

Answer 467

- anti-coagulants - aspirin - NSAIDs

Answer 468

- strong inhibitor of platelet aggregation - warfarin - aspirin - NSAIDs

Answer 469

- CYP450 inducer - warfarin - digoxin - cyclosporine - phenytoin - antiretrovirals

Answer 470

- receptor level antagonist - MAOIs - CNS stimulants

Answer 471

- inhibits thromboxane synthetase | - anticoagulants

Answer 472

CYP3A4: increases bioavailability

Answer 473

- pH dependent - weak bases: cleared faster if urine acidic - weak acids: cleared faster if urine alkali

Answer 474

aspirin, ibuprofen, ampicillin, paracetamol, phenobarbital, warfarin, theophylline, phenytoin, levodopa

Answer 475

amphetamine, atropine, hydralazine, propranolol, amiloride, chlorpheniramine, diazepam, reserpine, salbutamol

Answer 476

a receptor occupied by a low-efficacy agonist is inaccessible to a subsequent dose of a high efficacy agonist

Answer 477

some drugs, in addition to blocking access of the natural agonist to the receptor, are capable of some activation

Answer 478

beta-adrenoceptor antagonists pinodolol and oxprenolol have partial agonist activity - this is called intrinsic sympathomimetic activity

Answer 479

propanolol

Answer 480

- some substances binding to the same receptor are specifically opposed to those of the agonist - e.g. benzodiazepines acting on the benzodiazepine receptor in the CNS produces sedation, anxiolysis, muscle relaxation and controls convulsions; beta-carbolines, also binding to this receptor, cause stimulation, increased muscle tone and convulsions - modulate effects of GABA

Answer 481

an agonist and antagonist compete to occupy the receptor according to the law of mass action

Answer 482

concentration of a radioligand that occupies half of a particular receptor population - measures the affinity of a drug for a receptor/the strength of the ligand-receptor interaction

Answer 483

maximum receptor number/saturation

Answer 484

high affinity binding occurs at low drug concentrations; vice versa

Answer 485

half of Bmax is used to extrapolate Kd on the x axis

Answer 486

the ability of a drug to produce a response

Answer 487

- the dose range over which a response is produced - dose of drug that produces 50% of the maximum response (ED50) - maximum response itself is a crude measure of efficacy

Answer 488

- competetive (reversible, surmountable) | - non-competetive (irreversible, insurmountable)

Answer 489

by increasing the dose of the agonist (i.e. the block is surmountable)

Answer 490

competetive agonist: shifts to the right - maximum response remains unchanged - degree of rightward shift is related to the affinity of the antagonist and the dose used - the higher the affinity of the antagonist, the greater the right shift non-competitive antagonist: the binding site may be the same as the agonist but it's reversible so cannot be displaced nor overcome - depresses the maximum response

Answer 491

where subtypes of receptors occur, a single ligand may have agonist and antagonist properties

Answer 492

a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist

Answer 493

a second/another drug overcomes the pharmacological effect, by a different physiological mechanism - produces counteracting effects to another substance using a mechanism that doesn't involve binding to the same receptor

Answer 494

occurs with organophosphorus insecticides and chemical warfare agents which combine covalently with the active site of acetylcholinesterase - recovery of cholinesterase activity depends on formation of new enzyme

Answer 495

- modification of drug structure - selective delivery (drug targeting) - stereoselectivity

Answer 496

- bulk flow (i.e. in the bloodstream, lymphatics or CSF) | - diffusion (i.e. molecule by molecule, over short distances)

Answer 497

- diffusion coefficient is inversely proportional to the square root of molecular weight - rate of diffusion of a substance depends mainly on its molecular size

Answer 498

movement between compartments, involving penetration of non-aqueous diffusion barriers

Answer 499

CNS and placenta have tight junctions between endothelial cells, and is encased in an impermeable layer of periendothelial cells (pericytes) - prevents potentially harmful molecules from penetrating to brain or fetus

Answer 500

- diffusing directly through the lipid - combination with a solute carrier (SLC) or other membrane transporter - diffusing through aquaporins that traverse the lipid - by pinocytosis

Answer 501

mercurial reagents such as para-chloromercurobenzene sulfonate

Answer 502

- important in transfer of gases e.g. CO2 - pores are too small in diameter (0.4nm) to allow most drug molecules (more than 1nm usually) to pass through - drug distribution not notably abnormal in patients with genetic diseases affecting aquaporins

Answer 503

- involves invagination of part of the cell membrane and the trapping within the cell of a small vesicle containing extracellular constituents - vesicle contents released within cell or extruded from other side - transport of some macromolecules, e.g. insulin across the BBB - not for small molecules

Answer 504

the transport flux of material through the membrane per unit driving force per unit membrane thickness

Answer 505

- solubility in the membrane: can be expressed as a partition coefficient for substance distributed between the membrane phase and aqueous environment - diffusivity: measure of the mobility of molecules within the lipid, expressed as a diffusion coefficient

Answer 506

- lipid soluble drug is subject to a much larger transmembrane concentration gradient than a lipid insoluble drug - diffuses more rapidly, even though the aqueous concentration gradient is same in both cases

Answer 507

- exist in both unionised and ionised forms, the ratio of both varying with pH - ionised species, BH+ or A-, has very low lipid solubility and can't permeate membranes - lipid solubility of the uncharged species depends on chemical nature of the drug

Answer 508

- gastric juice is acidic, plasma neutral and urine alkaline - ionisation of weak acid, e.g. aspirin, is greatest at alkaline pH - ionisation of weak base, e.g. pethidine, is greatest at acid pH

Answer 509

pKa of the drug and pH of the compartment

Answer 510

- ionised species is assumed to not permeate membrane at all, while the unionised species does - acidic drug is concentrated in the compartment with high pH, vice versa - can produce high concentration gradients if theres a large pH difference between compartments

Answer 511

- assuming total impermeability of the charged species is not realistic, and even a small permeability will change the concentration gradient - body compartments rarely approach equilibrium

Answer 512

difference between the large SA of the villi and microvilli in the ileum compared to the smaller SA in the stomach

Answer 513

- promoted by drugs that accelerate gastric emptying (e.g. metoclopramide) - retarded by drugs that slow gastric emptying (e.g. propantheline)

Answer 514

chloroquine, desmethylimipramine, amphetamine, atropine, histamine, propanolol, chlorpromazine, mepyramine, dopamine, noradrenaline, morphine, ergometrine, trimethoprim, chlordiazepoxide, diazepam

Answer 515

levodopa, penicillins, probenecid, aspirin, methotrexate, warfarin, sulphamethoxazole, chlorothiazide, phenobarbital, thiopental, phenytoin, ascorbic acid

Answer 516

- free-base trapping of some antimalarial drug (e.g. chloroquine) in the acidic environment in the food vacuole of the malaria parasite contributes to disruption of the haemoglobin digestion pathway underlying their toxic effect) - urinary acidification accelerates excretion of weak bases and retards that of weak acids; vice versa for urinary alkalinisation - increasing plasma pH causes weakly acidic drugs to be extracted from the CNS into the plasma - reducing plasma pH causes weakly acidic drugs to become concentrated in the CNS, increasing their neurotoxicity

Answer 517

- solute carrier (SLC) transporters: facilitate passive movement of solutes down their electrochemical gradient - ATP-binding cassette (ABC) transporters: active pumps fuelled by ATP

Answer 518

- organic cation transporters (OCT) | - organic anion transporters (OAT)

Answer 519

- translocate dopamine, choline and drugs including vecuronium, quinine and procainamide - uniporters: bind one solute molecule at a time and transport it down its gradienet

Answer 520

- present in proximal renal tubules - concentrates drugs e.g. cisplatin in cells, leading to selective nephrotoxicity - related drugs e.g. carboplatin and oxaliplatin aren't transported by OCT2 and are less nephrotoxic - competition with cimetidine for OCT2 offers protection against cisplatin nephrotoxicity

Answer 521

- influences activity of OCT2 but not OCT1 - not affected by less nephrotoxic drugs carboplatin and oxaliplatin - cisplatin accumulates in cells expressing OCT2 and causes cell death

Answer 522

cimetidine competes with cisplatin for OCT2 and thus protects against cisplatin-induced apoptosis

Answer 523

- BBB - GI tract - renal tubule - biliary tract - placenta

Answer 524

- belong to the ABC transporter superfamily | - responsible for multidrug resistance in cancer cells

Answer 525

- renal tubular brush border membranes - bile canaliculi - astrocyte foot processes in brain microvessels - GI tract

Answer 526

SCL drug carriers

Answer 527

polymorphic variation in the genes coding SLCs and P-gp

Answer 528

metformin (used to treat diabetes)

Answer 529

single nucleotide polymorphisms of OCT1

Answer 530

- binding to plasma proteins | - partition into body fat and other tissues

Answer 531

unbound to plasma proteins; free in aqueous solution

Answer 532

albumin - binds many acidic drugs (warfarin, NSAIDs, sulfonamides) - binds some basic drugs (tricyclic antidepressants and chlorpromazine)

Answer 533

- concentration of free drug - affinity for the binding sites - concentration of protein

Answer 534

- 2 | - 0.6 mmol/l

Answer 535

[DS]/([D] + [DS])

Answer 536

because they occupy, at therapeutic plasma concentration, only a tiny fraction of available sites

Answer 537

occupy about 50% of protein binding sites at therapeutic concentrations, so can displace other drugs or bilirubin (premature babies)

Answer 538

- low fat:water partition coefficient | - low blood supply

Answer 539

- thiopental accumulates in body fat due to its high fat:water partition coefficient - chloroquine accumulates in the retina (ocular toxicity) due to its high affinity for melanin - tetracyclines accumulate slowly in bones and teeth due to their high affinity for calcium - high concentrations of amiodarone accumulate in the liver and lung during chronic use, causing hepatitis and interstitial pulmonary fibrosis

Answer 540

- urine - faeces - milk, sweat - expired air

Answer 541

passage of a drug from its site of administration into the plasma

Answer 542

- oral - sublingual - rectal - application to other epithelial surfaces (e.g. skin, cornea, vagina and nasal muscoa) - inhalation - injection (subcutaneous, intramuscular, intravenous, intrathecal and intravitreal)

Answer 543

- small intestine

Answer 544

- passive transfer at a rate determined by the ionisation and lipid solubility of the drug molecules - in some cases, carrier-mediated transport is used (e.g. levodopa and fluorouracil)

Answer 545

75% of a drug given orally is absorbed in 1-3 hours

Answer 546

- gut content (e.g. fed vs fasted) - GI motility - splanchnic blood flow - particle size and formulation - physicochemical factors, including some drug interactions

Answer 547

hypovolaemia or heart failure

Answer 548

- therapeutic drugs are formulated to produce desired absorption characteristics - capsules may be designed to remain intact for some hours after ingestion to delay absorption - tablets may have a resistant coating to give same effect - mixture of slow and fast release particles may be included to produce rapid but sustained absorption - modified release preparations allow less frequent dosing

Answer 549

- very poorly absorbed - administered orally - eradicates toxin-forming Clostridium difficile from gut lumen in patients with pseudomembranous colitits

Answer 550

- formulation of 5-aminosalicylic acid in a pH dependent acrylic coat - degrades in terminal ileum and proximal colon - treats inflammatory bowel disease

Answer 551

- prodrug - dimer of two molecules of 5-aminosalicylic acid - cleaved by colonic bacteria in the distal bowel - treats distal colitis

Answer 552

the fraction (F) of an orally administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and metabolic degradation

Answer 553

by determining the plasma drug concentration versus time curves in a group of subjects following oral and IV administration

Answer 554

areas under plasma concentration time curves

Answer 555

AUCoral / AUCintravenous

Answer 556

- drug preparation - variations in enzyme activity of gut wall/liver - change in gastric pH - intestinal motility

Answer 557

AUC(0-infinity), Cmax and Tmax must be between 80-125% | - implies that if one formulation of a drug is substituted for another, no clinically untoward consequences will ensue

Answer 558

- when a rapid response is required - drug is unstable at gastric pH - is rapidly metabolised by the liver

Answer 559

- glyceryl trinitrate | - buprenorphine

Answer 560

pass directly into the systemic circulation without entering the portal system, so escape first-pass metabolism by enzymes in the gut wall and liver

Answer 561

- for drugs that are required to produce a local or systemic effect - absorption following rectal administration is often unreliable - useful for patients vomiting or unable to take meds by mouth - may be used to administer diazepam to children in status epilepticus

Answer 562

- when a local effect on the skin is required - absorption may occur and lead to systemic effects - local rub on gels of NSAIDs e.g. ibuprofen

Answer 563

- organophosphate insecticides need to penetrate an insects cuticle to work - absorbed through skin, accidentally poison some farmers

Answer 564

- drug is incorporated in a stick-on patch applied to the skin - oestrogen/testosterone for HRT; fentanyl for breakthrough intermittent pain - produce a steady rate of drug delivery and avoid presystemic metabolism

Answer 565

- absorption takes place through mucosa overlying nasal-associated lymphoid tissue (similar to Peyer's patches, which are also permeable) - e.g. ADH, GTRH, calcitonin

Answer 566

- absorption through the epithelium of the conjunctival sac - desirable local effects within the eye achieved without causing systemic side effects - some systemic absorption occurs and can lead to unwanted side effects

Answer 567

- volatile and gaseous anaesthetics - lung is the route of administration and elimination - rapid exchange from the large SA and blood flow makes it possible to achieve rapid adjustments of plasma concentration

Answer 568

- IV injection is the fastest and most certain route of drug administration - bolus injection rapidly produces a high concentration of drug, first in the right heart and pulmonary vessels, then in the systemic circulation - administration by steady IV infusion avoids the uncertainties of absorption from over sites, and high peak plasma concentration

Answer 569

- diffusion through the tissue | - removal by local blood flow

Answer 570

- increased by increased blood flow and by hyaluronidase | - reduced in patients with circulatory failure (shock), where tissue perfusion is reduced

Answer 571

to produce a local effect or to prolong systemic action - addition of adrenaline to local anaesthetic reduces its absorption into general circulation and prolongs the effect - formulation of insulin with protamine and zinc produces a long acting form - when injected as an aqueous suspension, procaine penicillin is slowly absorbed and exerts a prolonged action - esterification of steroid hormones and antipsychotic drugs increases their solubility in oil - subcutaneous implantation of drug may produce slow and continuous absorption of steroid hormones

Answer 572

- injection of a drug into the subarachnoid space via lumbar puncture needle - methotrexate is administered this way to treat childhood leukaemias to prevent relapse in the CNS

Answer 573

route of administration of a drug where the substance is delivered into the eye - e.g. ranibizumab (monoclonal antibody fragment that binds to VEGF) to treat wet age-related macular degeneration

Answer 574

- plasma water (5%) - interstitial water (16%) - intracellular water (35%) - transcellular water (2%) - fat (20%)

Answer 575

- blood plasma - interstitial fluid - lymph (1.2%)

Answer 576

the sum of the fluid contents of all cells in the body

Answer 577

cerebrospinal, intraocular, peritoneal, pleural and synovial fluids, and digestive secretions, and potentially fetus

Answer 578

- permeability across tissue barriers - binding within compartments - pH partition - fat:water partition

Answer 579

- inflammation can disrupt integrity, allowing normally impermeant substances to enter the brain - penicillin can be given intravenously to treat bacterial meningitis

Answer 580

- in some parts of the CNS, including the chemoreceptor trigger zone - domperidone (antiemetic dopamine-receptor antagonist) can access the chemoreceptor trigger zone; prevents nausea caused by dopamine agonists e.g. apomorphine for Parkinsons

Answer 581

several peptides, including bradykinin and enkephalins | - improve penetration of anticancer drugs during brain tumour treatment

Answer 582

extreme stress renders the BBB permeable to drugs e.g. pyridostigmine, which normally acts peripherally

Answer 583

the volume that would contain the total body content of the drug (Q) at a concentration equal to that present in the plasma (Cp) Vd = Q/Cp

Answer 584

0.05 l/kg body weight

Answer 585

- molecules that are too large to cross the capillary wall easily; lipid-insoluble drugs e.g. heparin - retention in the plasma after a single dose reflects strong binding to plasma protein - following repeated dosing, equilibration occurs and measured Vd increases

Answer 586

0.2 l/kg body weight

Answer 587

0.2 l/kg; vecuronium, gentamicin, carbenicillin

Answer 588

- cannot easily enter cells due to low lipid solubility - don't traverse BBB or placenta easily - many macromolecular antibodies e.g. monoclonal antibodies, access receptors on cell surfaces but don't enter cells

Answer 589

- morphine, tricyclic antidepressants, haloperidol - drugs accumulate outside the plasma compartment - not efficiently removed from body by haemodialysis

Answer 590

reach all compartments and may accumulate in fat

Answer 591

- a drug may alter the distribution of the other by competing for a common binding site on plasma albumin/tissue protein - increases concentration of free drug, followed by increased elimination - leads to a new steady state where total drug concentration in plasma is reduced but free drug concentration is similar to before

Answer 592

- toxicity from the transient increase in conc of free drug before new steady state is reached - if dose is being adjusted to measurements of total plasma conc, the target therapeutic conc range will be altered by co-administration of a displacing drug - when the displacing drug additionally reduces elimination of the first, so that the free conc is increased acutely and chronically at the new steady state, severe toxicity may occur

Answer 593

sulfonamides and chloral hydrate: trichloracetic acid, a metabolite of chloral hydrate, binds very strongly to plasma albumin

Answer 594

- bilirubin metabolism is undeveloped in the premature liver - unbound bilirubin can cross the immature BBB and cause kernicterus - causes a distressing and permanent disturbance of movement (choreoathetosis), characterised by inoluntary writhing and twisting in the child

Answer 595

staining of the basal ganglia by bilirubin

Answer 596

- caused by kernicterus | - distressing and permanent disturbance of movement characterised by involuntary writhing and twisting movements

Answer 597

- salicylates displace methotrexate from binding sites and reduce its secretion into the nephron by competition with the OAT - quinidine, verapamil and amiodarone displace digoxin from tissue-binding sites while reducing its renal excretion

Answer 598

- prodrugs - biologically erodible nanoparticles - antibody-drug conjugates - packaging in liposomes - coated implantable devises

Answer 599

irreversible loss of drug from the body - metabolism: anabolism and catabolism - excretion: elimination from the body of drug or drug metabolites

Answer 600

kidneys, hepatobiliary system and the lungs

Answer 601

rifampicin (uncharged drug in healthy individuals) and digoxin (normally excreted in urine, but faecally for patients with renal failure)

Answer 602

highly volatile or gaseous agents (e.g. general anaesthetics)

Answer 603

- more than one stereoisomer | - affects overall metabolism

Answer 604

- phase 1 and 2 | - both decrease lipid solubility, and thus increase renal elimination

Answer 605

- catabolic - e.g. oxidation, reduction or hydrolysis - products are often more chemically reactive and sometimes more toxic/carcinogenic than the parent drug

Answer 606

- functionalisation: introduce a reactive group, e.g. hydroxyl, into the molecule - this reactive group serves as the point of attack for the conjugating system to attach a substituent e.g. glucuronide

Answer 607

in the liver

Answer 608

- hepatic drug-metabolising enzymes, including CYP enzymes, are embedded in the smooth ER - often called microsomal enzymes

Answer 609

- because on homogenisation and differential centrifugation, the ER is broken into very small fragments that sediment only after prolonged high-speed centrifugation in the microsomal fraction

Answer 610

oxidation, hydroxylation, dealkylation, deamination, hydrolysis

Answer 611

- haem proteins, comprising a large family of related but distinct enzymes - CYP followed by defining set of numbers and a letter

Answer 612

- amino acid sequence - sensitivity to inhibitors and inducing agents - specificity of reactions that catalyse

Answer 613

74; CYP1, 2 and 3 are involved in drug metabolism in the liver

Answer 614

``` CYP1A2 CYP2B6 CYP2C8 CYP2C19 CYP2C9 CYP2D6 CYP2E1 CYP3A4,5,7 ```

Answer 615

caffeine, paracetamol, tacrine, theophylline

Answer 616

cyclophosphamide, methadone

Answer 617

paclitaxel, repaglinide

Answer 618

omeprazole, phenytoin

Answer 619

ibuprofen, tolbutamide, warfarin

Answer 620

codeine, debrisoquine, S-metoprolol

Answer 621

alcohol, paracetamol

Answer 622

ciclosporin, nifedipine, indinavir, simvastatin

Answer 623

- drug (substrate, DH) - P450 enzyme - molecular oxygen - NADPH - NADPH-450 reductase

Answer 624

addition of one atom of oxygen (from molecular oxygen) to the drug to form a hydroxylated product (DOH) - other atom of oxygen is converted to water

Answer 625

1. P450 containing ferric iron (Fe3+) combines with a molecule of drug (DH) 2. receives an electron from NADPH-P450 reductase, which reduces the iron o Fe2+ 3. combines with molecular oxygen, a proton and a second electron (either from NADPH-P450 reductase or cytochrome b5) to form an Fe2+OOH-DH complex 4. this complex combines with another proton to yield water and a ferric oxene (FeO)3+ -DH complex 5. (FeO)3+ extracts a hydrogen atom from DH, with the formation of a pair of short-lived free radicals, liberation from the complex of oxidised drug (DOH) and regeneration of P450

Answer 626

UDP-alpha-glucuronide -> drug-gluconide catalysed by glucuronyl transfer

Answer 627

- genetic polymorphisms | - environmental factors (enzyme inhibitors and inducers are present in the diet and environment)

Answer 628

- component of grapefruit juice inhibits drug metabolism - brussel sprouts and cigarette smoke induce P450 enzymes - components of the herbal medicine St John's wort induce CYP450 isoenzymes and P-gp

Answer 629

- plasma (e.g. hydrolysis of suxamethonium by plasma cholinesterase) - lung (e.g. prostanoids) - gut (e.g. tyramine, salbutamol) - ethanol is metabolised by alcohol dehydrogenase as well as CYP2E1 - xanthine oxidase inactivates 6-mercaptopurine - monoamine oxidase inactivates amines

Answer 630

- hydrolysis (e.g. of aspirin) occurs in plasma and many tissues - ester and amide bonds are susceptible to hydrolytic cleavage - reduction is less common in phase 1, but warfarin is inactivated by reduction of a ketone to a hydroxyl group by CYP2A6

Answer 631

synthetic (anabolic) and involve conjugation (attachment of a substituent group) which usually results in inactive products

Answer 632

mainly in the liver

Answer 633

glucuronyl, sulfate, methyl or acetyl

Answer 634

via its sulfhydryl group, e.g. in the detoxification of paracetamol

Answer 635

- formation of a high-energy phosphate (donor) compound, UDPGPA, from which glucuronic acid is transferred to an electron-rich atom (N,O or S) or the substrate - this forms an amide, ester or thiol bond - UDP-glucuronyl transferase has broad substrate specificity

Answer 636

uridine diphosphate glucuronic acid

Answer 637

acetyl-CoA and S-adenosyl methionine, respectively

Answer 638

their components differ in pharmacological effects and their metabolism, which may follow distinct pathways

Answer 639

sotalol, warfarin and cyclophosphamide

Answer 640

drugs such as ketoconazole, which forms a tight complex with the Fe3+ form of the haem iron of CYP3A4, causing reversible non-competitive inhibition

Answer 641

require oxidation by a P450 enzymes | - an oxidation product binds covalently to the enzyme, which then destroys itself

Answer 642

oral contraceptive gestodene (CYP3A4) | anthelmintic drug diethylcarbamazine (CYP2E1)

Answer 643

drugs: rifampicin, ethanol and carbamazepine | carcinogenic chemicals: benzpyrene, 3-MC

Answer 644

because several phase 1 metabolites are toxic or carcinogenic e.g. paracetamol

Answer 645

administering phenobarbital to premature babies to induce glucuronyl transferase, which increases bilirubin conjugation and reducing the risk of kernicterus

Answer 646

- some drugs are extracted so efficiently by the liver or gut wall that the amount reaching the systemic circulation is much less than the amount absorbed - reduces bioavailability, even when a drug is well absorbed

Answer 647

- much larger dose of the drug is needed when it's taken by mouth than when given parenterally - marked individual variations occur, in the activities of drug metabolising enzymes and due to variation in hepatic blood flow

Answer 648

- azathioprine (immunosuppressant drug) is metabolised to mercaptopurine - enalapril (ACE inhibitor) is hydrolysed to its active form analaprilat

Answer 649

aspirin inhibits platelet function and has anti-inflammatory activity; when hydrolysed to salicylic acid, it has anti-inflammatory but not antiplatelet activity

Answer 650

benzodiazepines

Answer 651

- bladder toxicity of cyclophosphamide, caused by its toxic metabolite acrolein - methanol and ethylene are toxic via metabolites formed by alcohol dehydrogenase

Answer 652

aspirin, gluceryl trinitrate, isosorbide dinatrate, levodopa, lidocaine, metoprolol, morphine, propanolol, salbutamol and verapamil

Answer 653

- azathioprine - cortisone - prednisone - enalapril - zidovudine

Answer 654

``` azathioprine -> mercaptopurine cortisone -> hydrocortisone prednisone -> prednisolone enalapril -> enalaprilat zidovudine -> zidovudine triphosphate ```

Answer 655

cyclophosphamide -> phosphoramide mustard -> acrolein

Answer 656

diazepam -> nordiazepam -> oxazepam

Answer 657

morphine -> morphine 6-glucuronide

Answer 658

halothane -> trifluoroacetic acid methoxyflurane -> fluoride paracetamol -> N-Acetyl-p-benzoquinoneimine

Answer 659

because the inducing agent is often a substrate for the induced enzymes, there is a slow tolerance development

Answer 660

- graft rejection due to loss of effectiveness of immunosuppressive treatment - seizures due to loss of anticonvulsant effectiveness - unwanted pregnancy from loss of contraceptive action - thrombosis or bleeding

Answer 661

greatly accelerate hepatic drug metabolism, which can increase the toxicity of drugs with toxic metabolites - important cause of drug-drug interaction

Answer 662

slows metabolism and increases the number of drugs inactivated by the enzyme

Answer 663

``` phenobarbital - warfarin rifampicin - oral contraceptives griseofulvin - corticosteroids phenytoin - ciclosporin ethanol and carbamazepine ```

Answer 664

allopurinol - mercaptopurin, azathioprine chloramphenicol - phenytoin cimetidine - amiodarone, phenytoin, pethidine ciprofloxacin - theophylline corticosteroids - tricyclic antidepressants, cyclophosphamide disulfiram - warfarin erythromycin - ciclosporin, theophylline MAO inhibitors - pethidine ritonavir - saquinavir

Answer 665

``` phenylbutazone metronidazole sulfinpyrazone trimethoprim-sulfamethoxazole disulfiram ```

Answer 666

cimetidine | omeprazole

Answer 667

amiodarone

Answer 668

S: active R: less active

Answer 669

- hydrophilic drug conjugates are concentrated in bile and delivered to the intestine, where they can be hydrolysed - this regenerates active drug; free drug can be reabsorbed by the liver and the cycle repeated

Answer 670

the volume of plasma containing the amount of substance that is removed from the body by the kidneys in unit time

Answer 671

CLren = (Cu x Vu)/Cp - CLren = renal clearance - Cp = plasma concentration - Cu = urinary concentration - Vu = rate of flow of urine

Answer 672

1. glomerular filtration 2. active tubular secretion 3. passive reabsorption (diffusion from the concentrated tubular fluid back across tubular epithelium)

Answer 673

``` p-Aminohippuric acid furosemide glucuronic acid conjugates glycine conjugates indometacin methotrexate penicillin probenecid sulfate conjugates thiazide diuretics uric acid ```

Answer 674

``` amiloride dopamine histamine mepacrine morphine pethidine quaternary ammonium compounds quinine serotonin triamterene ```

Answer 675

- binding to albumin, because it's almost completely impermeant - only free drug would be filtered - e.g. warfarin is 98% bound to albumin, so only 2% of it is filtered - most drugs cross the barrier freely

Answer 676

- OAT transports drugs against an electrochemical gradient and reduce the plasma concentration nearly to 0 - OCT facilitates transport down the electrochemical gradient

Answer 677

100-75%: furosemide, gentamicin, methotrexate, atenolol, digoxin 75-50%: benzylpenicillin, cimetidine, oxytetracycline, neostigmine 50%: propanthelin, tubocurarine

Answer 678

- altered protein binding and hence filtration - inhibiting tubular secretion - altering urine flow and/or urine pH

Answer 679

passively reabsorbed by diffusion across the tubule, so are not efficiently excreted in the urine

Answer 680

- timolol, carteolol: beta-adrenoceptor antagonist - acetazolamide, dorzolamide: carbonic anhydrase inhibitor - clonidine, apraclonidine: alpha2-adrenoceptor agonist - latanoprost: prostaglanding analogue - pilocarpine: muscarinic agonist - ecothiophate: anticholinesterase

Answer 681

- generally contracts in direct response to muscarinic agonists, in contrast to the indirect effect via NO on vascular smooth muscle - peristatic activity of the GI tract is increased, which can cause colicky pain - bladder and bronchial smooth muscle contract

Answer 682

- stimulate exocrine glands - increases all of these things - combined effect of bronchial secretion and constriction can interfere with breathing

Answer 683

- parasympathetic nerves supply constrictor pupillae muscle and the ciliary muscle - contraction of ciliary muscle due to mAChRs pulls the ciliary body forward and inward, relaxing the tension on the suspensory ligament and reducing the lens's focal length - constrictor pupillae adjusts the pupil in response to changes in light intensity and in regulating intraocular pressure

Answer 684

- abnormally raised intraocular pressure leads to glaucoma - drainage of aqueous humour becomes impeded when the pupil is dilated because folding of the iris tissue occludes the drainage angle, causing the intraocular pressure to rise - activation of the constrictor pupillae muscle by muscarinic agonists lowers the intraocular pressure - increased tension in the ciliary muscle may improve drainage by realigning the connective tissue trabeculae

Answer 685

- M1 receptors in brain are activated - tremor, hypothermia and increased locomotor activity - improved cognition

Answer 686

- competitive antagonists whose chemical structures usually contain ester and basic groups in the same relationship as ACh - bulky aromatic group in place of the acetyl group

Answer 687

- atropine and hyoscine (scopolamine) - alkaloids found in solanaceous plants - deadly nightshade (Atropa belladonna) contains mainly atropine - thorn apple (Datura stramonium) contains mainly hyoscine - tertiary ammounium compounds that are lipid-soluble and absorbable from the gut/conjunctival sac, and can penetrate the BBB

Answer 688

- peripheral actions similar to atropine - cannot cross BBB - lack central actions - hyoscine butylbromide, propantheline, ipratropium (bronchodilator)

Answer 689

cyclopentolate and tropicamide; developed for opthalamic use and administered as eye drops

Answer 690

- oxybutyrin, tolterodine and darifenacin - act on bladder to prevent micturition - used for treating urinary incontinence - effects: dry mouth, constipation and blurred vision

Answer 691

- pilocarpine eye drops cause constriction of the pupils and are used for glaucoma - pilocarpine/cevimeline, selective M3 agonist, can be used to increase salivation and lacrimal secretion in patients with dry mouth or dry eyes - bethanechol or distigmine are seldom used as stimulant laxatives or to stimulate bladder emptying

Answer 692

- salivary, lacrimal, bronchial and sweat glands are inhibited by very low doses of atropine, producing dry mouth and skin - slightly reduced gastric secretion - inhibited mucociliary clearance in the bronchi

Answer 693

- atropine causes tachycardia through block of cardiac mAChRs - no effect on sympathetic system, only inhibition of tonic parasympathetic tone - at very low doses, atropine causes a paradoxical bradycardia, possibly due to a central action - arterial BP and response of heart to exercise are unaffected

Answer 694

- pupil is dilated and becomes unresponsive to light - relaxation of the ciliary muscle causes paralysis of accomodation (cyloplegia), so near vision is impaired - intraocular pressure may rise

Answer 695

- GI motility is inhibited by atropine

Answer 696

- bronchial, biliary and urinary tract smooth muscle are all relaxed by atropine - reduces incontinence due to bladder overactivity

Answer 697

- atropine produces mainly excitatory effects on the CNS - at low doses, there is agitation and disorientation, and in poison, there is hyperactivity, increase in body temp, loss of sweating - affect the extrapyramidal system, reducing involuntary movement and rigidity in Parkinsons patients

Answer 698

most nAChR agonists act on either neuronal (ganglionic and CNS) nACh receptors or on striated muscle (motor endplate) receptors, but not, apart from nicotine and ACh, on both

Answer 699

- nicotine: stimulates then blocks autonomic ganglia; stimulates CNS - lobeline: stimulates autonomic ganglia and sensory nerve terminals - epibatidine: stimulates autonomic ganglia and CNS - varenicline: stimulates CNS and autonomic ganglia - suxamethonium and decamethonium: depolarisation block at NMJ

Answer 700

- by interference with ACh release at the NMJ - by prolonged depolarisation - by interference with the postsynaptic action of ACh

Answer 701

- hexamethonium and trimetaphan: transmission block at autonomic ganglia - tubocurarine, pancuronium, atracurium and vecuronium: transmission block at NMJ

Answer 702

- treatment of sinus bradychardia by atropine | - to dilate the pupil by tropicamide or cyclopentolate

Answer 703

- prevention of motion sickness by hyoscine | - treatmetn of Parkinsonism by benzhexol, benztropine

Answer 704

- asthma and COPD treatment by ipratropium or tiotropium by inhalation - to dry secretions by atropine or hyoscine

Answer 705

- to facilitate endoscopy and GI radiology by relaxing smooth muscle by hyoscine - as an antispasmodic in IBS or colonic diverticular disease by dicycloverine

Answer 706

- both sympathetic and parasympathetic ganglia are stimulated - tachycardia and increased BP - variable effects on GI motility and secretions - increased bronchial, salivary and sweat secretions

Answer 707

- block all autonomic and enteric ganglia - hypotension and loss of CV reflexes - inhibition of secretions - GI paralysis - impaired micturition

Answer 708

- by acting presynaptically to inhibit ACh synthesis or release - by acting postsynaptically

Answer 709

- act as competitive antagonists at he ACh receptors of the endplate - block facilitatory presynaptic autoreceptors, thus inhibiting release of ACh during repetitive stimulation of the motor nerve

Answer 710

``` tubocurarine pancuronium vecuronium atracurium mivacurium suzamethonium ```

Answer 711

tubocurarine: slow (>5min) and long (1-2 h) pancuronium: intermediate (2-3min) and long (1-2h) vecuronium: intermediate and intermediate (30-40min) atracurium: intermediate and intermediate (<30 min) mivacurium: fast (2min) and short (15min) suxamethonium: fast and short (10min)

Answer 712

- hypertension (ganglion block and histamine release) | - bronchoconstriction (histamine release)

Answer 713

- slight tachycardia | - hypertension

Answer 714

transient hypotension (histamine release)

Answer 715

- bradycardia (muscarinic agonist effect) - cardiac dysrhythmias (increased plasma K+ conc) - raised intraocular pressure - postop muscle pain

Answer 716

cholinesterase inhibitor, neostigmine | - rapid postop recovery of muscle strength is needed to reduce risk of complications

Answer 717

mainly in anaesthesia to produce muscle relaxation - given intravenously - most non-depolarising blocking agents are metabolised by the liver

Answer 718

- anticholinesterase drugs are effective in overcoming the blocking action of competitive, non-depolarising agents. this is because ACh is protected from hydrolysis and can diffuse further into the cleft, increasing its chance of it finding an unoccupied receptor before hydrolysation - depolarisation block is unaffected/increased by anticholinesterase drugs - fasciulations seen with suxamethonium as a prelude to paralysis don't occur with competitive drugs - tetanic fade is increased by non-depolarising blocking drugs, compared with normal muscle. does not occur with depolarisation block

Answer 719

failure of muscle tension to be maintained during a brief period of nerve stimulation at a frequency high enough to produce a fused tetanus

Answer 720

- bradycardia - potassium release - increased intraocular pressure - prolonged paralysis - malignant hyperthermia

Answer 721

hydrolysed by plasma cholinesterase

Answer 722

- genetic variations of plasma cholinesterase with reduced activity/absence of the enzyme - anticholinesterase drugs e.g. organophosphates and competing substrates - neonates may have low plasma cholinesterase activity and show prolonged paralysis with suxamethonium

Answer 723

- rare inherited condition due to a mutation of the ryanodine receptor - intense muscle spasm and dramatic rise in body temp when certain drugs are administered - 65% mortality rate - treated by dantrolene

Answer 724

- hemicholinium (blocks transport of choline into the nerve terminal) - vesamicol (blocks ACh transport into synaptic vesicles)

Answer 725

- Mg2+ and aminoglycoside antibiotics e.g. streptomycin and neomycin (inhibit Ca2+ entry) - botulinum toxin and beta-bungarotoxin (inhibit ACh release)

Answer 726

- blepharospasm, torsion dystonia and spasmodic torticollis - spasticity - urinary incontinence - squint - hyperhidrosis - sialorrhoea - headache prophylaxis - forehead wrinkles

Answer 727

progressive parasympathetic and motor paralysis, dry mouth, blurred vision, difficulty in swallowing and progressive respiratory paralysis

Answer 728

compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side chain

Answer 729

- noradrenaline: a transmitter released by sympathetic nerve terminals - adrenaline: a hormone secreted by the adrenal medulla - dopamine: the metabolic precursor of noradrenaline and adrenaline, and also a transmitter/neuromodulator in the CNS - isoprenaline: a synthetic derivative of noradrenaline, not present in the body

Answer 730

alpha: noradrenaline > adrenaline > isoprenaline beta: isoprenaline > adrenaline > noradrenaline

Answer 731

alpha 1 and alpha 2: alpha1A, alpha1B, alpha1D and alpha2A, alpha2B, alpha2C beta 1, 2 and 3 - GPCRs

Answer 732

CVS and lower urinary tract

Answer 733

neuronal, acting to inhibit transmitter release in the brain and at autonomic nerve terminals in the periphery

Answer 734

alpha1: coupled to phospholipase C and produce effects mainly by the release of intracellular Ca2+ alpha2: negatively coupled to adenylyl cyclase and reduce cAMP formation and inhibit Ca2+ channels and activate K+ channels

Answer 735

all three stimulate adenylyl cyclase

Answer 736

heart; responsible for positive inotropic and chronotropic effects of catecholamines

Answer 737

vasoconstriction, relaxation of GI smooth muscle, salivary secretion and hepatic glycogenolysis

Answer 738

inhibition of transmitter release, platelet aggregation, vascular smooth muscle constriction, insulin release

Answer 739

increased cardiac rate and force

Answer 740

bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis, muscle tremor

Answer 741

lipolysis and thermogenesis, bladder detrusor muscle relaxation

Answer 742

1: tyrosine -> DOPA 2: DOPA -> dopamine 3: dopamine -> noradrenaline 4: noradrenaline -> adrenaline 1: tyrosine hydroxylase 2: DOPA decarboxylase 3: dopamine beta-hydroxylase 4: phenylethanolamine N-methyltransferase

Answer 743

postganglionic sympathetic neurons whose cell bodies are situated in sympathetic ganglia - long axons ending in a series of varicosities along the branching terminal network

Answer 744

- sites of synthesis and release of noradrenaline and co-released mediators - mediators include ATP and neuropeptide Y

Answer 745

NA > A >> ISO

Answer 746

A > NA >> ISO

Answer 747

ISO > NA > A

Answer 748

ISO > A > NA

Answer 749

ISO > NA = A

Answer 750

agonists: phenylephrine and methoxamine antagonists: prazosin and doxazocin

Answer 751

agonists: clonidine antagonists: yohimbine and idazoxan

Answer 752

agonists: dobutamine and xamoterol antagonists: atenolol and metoprolol

Answer 753

agonists: salbutamol, terbutaline, salmeterol, formoterol and clenbuterol antagonists: butoxamine

Answer 754

mirabegron

Answer 755

- noradrenaline: moment-to-moment regulation of the rate of synthesis - alpha-methyltyrosine

Answer 756

- copper chelating agents and disulfiram inhibit it

Answer 757

- located in the adrenal medulla - adrenal medulla contains a population of adrenaline-releasing (A) cells separate from the smaller population of noradrenaline releasing cell (N) - production of PNMT is induced by action of steroid hormones secreted by the adrenal cortex

Answer 758

vesicles in nerve terminals or chromaffin cells

Answer 759

- very high (0.3-1 mol/l) | - maintained by vesicular monoamine transporter (VMAT)

Answer 760

- noradrenaline - ATP (4/NA molecule) - chromogranin A - DBH reversible complex is formed within the vesicle to reduce the osmolarity of the vesicle contents and to reduce the tendency of NA to leak out of the vesicles in the nerve terminal

Answer 761

- neuronal (NET) - extraneuronal (EMT) - vesicular (VMAT)

Answer 762

NET: 0.3 EMT: 250 VMAT: -0.2

Answer 763

NET: NA > A > ISO EMT: A > NA > ISO VMAT: NA = A = ISO

Answer 764

NET: neuronal membrane EMT: non-neuronal cell membrane VMAT: synaptic vesicle membrane

Answer 765

tyramine methylnoradrenaline adrenergic neuron-blocking drugs amphetamine

Answer 766

noradrenaline dopamine 5-hydroxytryptamine histamine

Answer 767

dopamine 5-hydroxytryptamine guanethidine MPP

Answer 768

cocaine tricyclic antidepressants phenoxybenzamine amphetamine

Answer 769

normetanephrine steroid hormones phenoxybenzamine

Answer 770

reserpine | tetrabenazine

Answer 771

- presynaptic alpha2 receptor inhibits Ca2+ influx in response to membrane depolarisation by action of betagamma subunits of the G protein on the voltage-dependent Ca2+ channels

Answer 772

75% released by sympathetic neurons is recaptured and repackaged into vesicles 25% is captured by non-neuronal cells in the vicinity, limiting its local spread

Answer 773

NET: act as cotransporters of Na+, Cl- and the amine, using the electrochemical gradient for Na+ as a driving force VMAT: driven by proton gradient between the cytosol and the vesicle contents

Answer 774

two intracellular enzymes: monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)

Answer 775

- two isoforms: MAO-A and MAO-B - bound to the surface membrane of mitochondria - abundant in noradrenergic nerve terminals and also in the liver, intestinal epithelium and other tissues

Answer 776

- converts catecholamines to their corresponding aldehydes - aldehydes are rapidly metabolised by aldehyde dehydrogenase to the corresponding carboxylic acid (3,4-dihydroxyphenylglycol formed from noradrenaline) in the periphery - oxidises other monoamines, e.g. dopamine and 5-HT

Answer 777

- various drugs that are used for their effects on the CNS, where three amines have transmitter functions

Answer 778

absent from noradrenergic neurons but present in the adrenal medulla and other cells/tissues

Answer 779

- methylation of one of the catechol hydroxyl groups by COMT to give a methoxy derivative

Answer 780

3-methoxy-4-hydroxyphenylglycol (MHPG)

Answer 781

partly conjugated to sulfate or glucuronide derivatives, which are excreted in the urine - most converted to vanillylmandelic acid and excreted in the urine in this form

Answer 782

- noradrenaline is removed by NET - adrenaline more dependent on EMT - isoprenaline is not a substrate for NET, and is removed by a combination of EMT and COMT

Answer 783

due to MAO in nerve terminals

Answer 784

- normally by Ca2+ mediated exocytosis from varicosites on the terminal network - non-exocytotic release occurs in response to indirectly acting sympathomimetic drugs (e.g. amphetamine) which displace noradrenaline from vesicles - noradrenaline escapes via the NET transporter (reverse transport)

Answer 785

mainly by reuptake of noradrenaline into nerve terminals via the NET transporter; NET is blocked by tricyclic antidepressent drugs and cocaine

Answer 786

autoinhibitory feedback mediated by alpha2 receptors

Answer 787

main action: alpha/beta agonist uses/function: hypotension in intensive care, transmitter at postganglionic sympathetic neurons unwanted effects: hypertension, vasoconstriction, tachycarida, ventricular dysrhythmias pharmacokinetic aspects: poorly absorbed by mouth, rapid removal by tissues, metabolised by MAO and COMT, plasma t1/2: 2 min

Answer 788

main action: alpha/beta agonist uses/function: asthma, anaphylactic shock, cardiac arrest, anaesthetic solutions, adrenal medulla unwanted effects: hypertension, vasoconstriction, tachycarida, ventricular dysrhythmias pharmacokinetic aspects: poorly absorbed by mouth, rapid removal by tissues, metabolised by MAO and COMT, plasma t1/2: 2 min

Answer 789

1. drug discovery 2. preclinical development 3. clinical development

Answer 790

candidate molecules are chosen on the basis of their pharmacological properties

Answer 791

a wide range of non-human studies (e.g. toxicity testing, pharmacokinetic analysis and formulation) are performed

Answer 792

selected compound is tested for efficacy, side effects and potential dangers in volunteers and patients

Answer 793

- target selection - lead finding - lead optimisation - pharmacological profiling

Answer 794

- drug targets are mostly functional proteins - identification of targets comes from biological intelligence - 100s to 1000s potential drug targets have yet to be exploited therapeutically - conventional, biological wisdom, drawing on a rich knowledge of disease mechanisms and chemical signalling pathways and genomic data is the basis on which novel targets are chosen

Answer 795

- when the biochemical target has been decided and the feasibility of the project has been assessed, the next step is to find lead compounds - cloning of the target protein - assay system developed, to measure the functional activity of the target protein

Answer 796

- assay system measures the functional activity of the target protein - could be cell-free enzyme assay, membrane-based binding assay or cellular response assay - must be engineered to run automatically, in a miniaturised multiwell plate format for speed and economy - robotically controlled assay facilities are often used

Answer 797

- large compound libraries are maintained by large companies, with a growing collection of a million or more synthetic compounds - these compounds in the library are routinely screened whenever a new assay is set up - X-ray crystallography etc is used to produce 3D structure of a target protein to generate possible lead structures and reduce the number of compounds to be screened - aim is to identify appropriate lead compounds with pharmacological activity that are modifiable

Answer 798

- turn out to be molecules with features undesirable in a drug, e.g. too high a molecular weight, excessive polarity and groups associated with toxicity - computational prescreening of compound libraries are used to eliminate such compounds - used as a basis for preparing sets of homologues by combinatorial chemistry to establish critical structural features

Answer 799

- penicillin - streptomycin - other antibiotics - vinca alkaloids - paclitaxel - ciclosporin - sirolimus (rapamycin)

Answer 800

- fungal and plant sources have been used in anti-infective, anticancer and immunosuppressant drugs - fungi and microorganisms are ubiquitous, highly diverse and easy to collect and grow in the lab - compounds from plants, animals or marine organisms are troublesome to produce commercially

Answer 801

they are complex molecules that are difficult to synthesise/modify by conventional synthetic chemistry - lead optimisation may difficult - commercial production expensive

Answer 802

- to increase potency of the compound on its target and to optimise it with respect to other characteristics, e.g. selectivity and pharmacokinetic properties - to identify one or more drug candidates suitable for further development

Answer 803

- broader range of assays on different test systems - studies to measure the activity and time course of the compounds in vivo - checking for unwanted effects in animals, evidence of genotoxicity and oral absorption

Answer 804

2-5 years 100 projects only about one project in five succeeds in generating a drug candidate

Answer 805

- lead optimisation is often very difficult - compounds produce the desired effects on the target molecule and have no other defects, but fail to produce the expected effects in animal models of the disease, implying that the target is not good

Answer 806

- pharmacokinetics - short-term toxicology - formulation - synthesis scale-up

Answer 807

to satisfy all requirements that have to be met before a new compound is deemed ready to be tested for the first time in humans

Answer 808

1. safety pharmacology: testing to check that the drug doesn't produce any obviously hazardous acute effects 2. preliminary toxicological testing to eliminate genotoxicity and to determine maximum non-toxic dose. - animals are checked for weight loss/gross changes, and examined post mortem to look for histological and biochemical evidence for tissue damage 3. ADME studies in animals, to link the pharmacological and toxological effects to plasma concentration and drug exposure 4. chemical and pharmaceutical development to assess the feasibility of large-scale synthesis and purification, assess the stability of the compound and to develop a formulation suitable for clinical studies

Answer 809

Good Laboratory Practice: covers record keeping procedures, data analysis, instrument calibration and staff training

Answer 810

to eliminate human error as far as possible and to ensure reliability of data - labs are regularly monitored for compliance to GLP standards

Answer 811

- 'inestigator brochure' submitted alongside specific study protocols to regulatory authorities - European Medicines Evaluation Agency - US Food and Drugs Administration

Answer 812

1.5 years | 20 compounds

Answer 813

phase I, II and III

Answer 814

- pharmacokinetics - tolerability - side effects in healthy volunteers 10 compounds involved

Answer 815

- small scale trials in patients to assess efficacy and dosage - long term toxicology studies 5 compounds involved

Answer 816

- large-scale controlled clinical trials 2 compounds involved

Answer 817

- performed on a small group (20-80) of volunteers - to check for signs of dangerous effects, tolerability, pharmacokinetic properties - pharmacodynamic effects in volunteers (proof-of-concept studies)

Answer 818

- performed on groups of patients (100-300) - determine pharmacodynamic effect in patients, and if confirmed, to establish the dose regimen to be used in phase III - cover several distinct clinical disorders to identify possible therapeutic indications for the new compound and the dose required

Answer 819

- definitive double-blind, randomised trials - performed as multicentre trials on thousands of patients - aimed at comparing the new drug with commonly used alternatives - expensive, difficult to organise and take years to complete

Answer 820

covers every detail of the patient group, data collection methods, recording of information, statistical analysis and documentation

Answer 821

clinical and economic benefits of a new drug

Answer 822

- drug submitted to relevant regulatory authority for licensing - required dossier is a massive and detailed compilation of preclinical and clinical data - takes a year or more

Answer 823

- 2/3 of submissions gain marketing approval | - only 11.5% of compounds entering phase I are eventually approved

Answer 824

- obligatory postmarketing surveillance designed to detect any rare or long-term adverse effect resulting from use of the drug in a clinical setting in thousands of patients - may lead to limiting use of the drug to particular patient groups, or withdrawl of the drug

Answer 825

therapeutic agents produced by biotechnology rather than conventional synthetic chemistry

Answer 826

- have fewer toxicological problems than synthetic drugs | - more problems with production, quality control, immunogenicity and drug delivery

Answer 827

- high-risk business, with only one drug descovery in 50 reaching its goal - takes 12 years on average - very expensive

Answer 828

20 years in most countries

Pharmacology and prescribing Flashcards

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