Block 12 Pharmacology DONE Flashcards
azathioprine is an (a____)
antagonist
azathioprine antagonises
purine metabolism
azathioprine inhibits
purine synthesis
because azathioprine inhibits purine synthesis it also inhibits…
DNA and RNA synthesis and so cell proliferation
azathioprine is used to treat
autoimmune diseases, transplant recipients
azathioprine MOA (2 steps)
- incorporates thiopurine analogues into DNA structure
2. causes chain termination and cytotoxicity
azathioprine’s most severe side effect is
bone marrow suppression
azathioprine should not be given in conjunction with
purine analogues, e.g. allopurinol
people with the enzyme _____ are most at risk of bone marrow deficiency side effect of azathioprine
TPMT (thiopurine s-methyltransferase)
(azathioprine) genetic polymorphisms of TPMT (thiopurine s-methyltransferase) can lead to
excessive drug toxicity
to avoid excessive azathioprine drug toxicity due to genetic polymorphisms of TPMT we can do an…
assay of serum TPMT
in long-term azathioprine treatment we must do…
blood tests and monitoring for signs of myelosuppression
diclofenac class
NSAID, COX inhibitor
diclofenac has an ______ effect (2)
analgesic and anti-pyretic
diclofenac’s analgesic effect is due to
inhibition of COX-1 and COX-2 enzymes
diclofenac’s anti-pyretic effect is due to (4 steps)
- effects hypothalamus
- peripheral dilation
- increased cutaneous blood flow
- heat dissipation
diclofenac is prescribed for (3 examples)
pain, dysmenorrhea, ocular inflammation
diclofenac is the least favoured non-COX specific NSAID because it…
targets COX-2 more than others
a better choice than diclofenac if we want a non-cos specific NSAID is…
naproxen
celecoxib class
NSAID, COX-2 specific inhibitor
celecoxib inhibits
COX-2
by inhibiting COX-2 celecoxib reduces
production of prostaglandins
celecoxib MOA (1 step)
- uses its polar sulfonamide side chain to bind to hydrophilic side region close to active COX-2 binding site
celecoxib only targets COX-2 so does not give _______ effects
anti-platelet
as celecoxib does not give anti-platelet effects it is not a substitute for…
aspirin for cardiovascular prophylaxis
celecoxib’s inhibition of prostaglandin synthesis can cause…. due to….
sodium and water retention in ascending loop of henle due to increased fluid reabsorption
in collecting duct, PGE2 (prostaglandin) inhibits..
water reabsorption by counteracting antidiuretic hormone
celecoxib is used to treat (3)
rheumatoid arthritis, osteoarthritis, familial adenomatous polyposis (FAP)
celecoxib is used sparingly due to it’s possible effects on the…
cardiovascular system
cyclophosphamide class
alkylating agent
cyclophosphamide is an _________ and ________ agent
antineoplastic, antiimmunosuppressive
cyclophosphamide is activated by the
cytochrome P450 isoforms (CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, 2C19) in the liver
cyclophosphamide is used to treat (3)
multiple cancers including myelomas and leukaemias
cyclophosphamide has 3 MOAs, give them (3)
- attaches alkyl group to DNA bases, so DNA is fragmented by repair enzymes, stopping DNA synthesis and RNA transcription
- cross-linking of DNA to prevent DNA transcription
- induction of DNA mispairing leading to mutations
alkylating agents are not specific to a certain part of the….
cell cycle so induce cell death
vitamin d class
coenzyme
vitamin d itself has little
biological activity
vitamin d is metabolised to
1,25-dihydroxycholecalciferol
1,25-dihydroxycholecalciferol is
hormonally active
vitamin d to 1,25-dihydroxycholecalciferol is 2 steps, the first step is in the
liver
the first step of vitamin d to 1,25-dihydroxycholecalciferol (in the liver) is…
cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by 25-hydroxylase
vitamin d to 1,25-dihydroxycholecalciferol is 2 steps, the second step is in the
kidney
the second step of vitamin d to 1,25-dihydroxycholecalciferol( in the kidney) is…
25-hydroxycholecalciferol is metabolised to 1,25-dihydroxycholecalciferol,
due to action of 1-hydroxylase
25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol are
hydrophobic
as 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol are hydrophobic, they are transported in the blood bound to
vitamin-D binding protein
25-hydroxycholecalciferol half life
several weeks
1,25-dihydroxycholecalciferol half life
few hours
1,25- dihydroxycholecalciferol has a much ______ ______ for the vitamin D receptor than 25- hydroxycholecalciferol.
higher affinity
ciclosporin class
immunosuppressant, cyclophilin binder
ciclosporin use
prophylaxis of graft rejection in organ and tissue transplantation
ciclosporin MOA (4 steps)
- binds to cyclophilin
- inhibits calcineurin
- stops transcription of IL-2
- reversible inhibits immunocompetent lymphocytes in G0 or G1 phase of cell cycle
ciclosporin preferentially inhibits…
T-lymphocytes, T-1 helper and T1-suppressor
ciclosporin’s main target is
T1-helper lymphocyte
aurothiomalate class
gold based anti-inflammatory, cytokine inhibitor
MOA of sodium aurothiomalate
unknown, free thiols play a role
aurothiomalate is given as an
IM injection
aurothiomalate benefit is not expected till…
300-500mg given
important to avoid ______ _____ of aurothiomalate as….
complete relapse, as second gold course not effective
aurothiomalate is not
widely used
aurothiomalate has been superceded by
other DMARDs
chloroquine class
anti-inflammatory, DNA/RNA synthesis inhibitor
chloroquine is more widely known as an
anti-malarial
chloroquine MOA for malaria (2 steps)
- inhibit parasitic enzyme heme polymerase
2. toxic build up of heme in parasite
chloroquine MOA for rheumatoid arthritis
unknown, reduces levels of inflammatory agents (IL-6, IL-1b, TNF-alpha) by blocking release or reducing transcription
methotrexate class
folate antagonist, anti-metabolite
anti-metabolites are…
synthetic versions of purine or pyrimidines
purines/pyrimidines are the
building blocks of DNA
anti-metabolites prevent purines or pyrimidines becoming incorporated into DNA during…
S phase (of cell cycle)
methotrexate inhibits
folic acid reductase
folic acid reductase converts
folic acid to tetrahydrofolic acid
tetrahydrofolic acid is needed for
purine and pyrimidine synthesis
methotrexate MOA (4 steps)
- inhibits folic acid reductase
- lack of tetrahydrofolic acid
- purines/pyrimidines can’t be made
- DNA synthesis stops
methotrexate affects the
most rapidly dividing cells
methotrexate uses
low dose for RA
sulfasalazine class
immunomodulatory, anti-inflammatory
sulfasalazine uses
ulcerative colitis, RA
sulfasalazine MOA
unknown
sulfasalazine is broken down into
5-aminosalicyclic acid (5-ASA) and sulfapyridine (SP)
in ulcerative colitis, sulfasalazine action is mainly via
5-ASA
sulfasalazine has been replaced to an extent by
mesalazine
mesalazine is better than sulfasalazine as it has
same active metabolite, no sulphur, better tolerated
calcitonin is a
hormone
calcitonin is produced by the
thyroid gland
calcitonin is important in
control of calcium conc in blood
calcitonin _____ action of parathyroid hormone
antagonises
calcitonin antagonises the action of
parathyroid hormone
calcitonin MOA (7 steps)
- binds to calcitonin receptor (osteoclasts)
- activates cAMP and calcium signalling
- more production of vitamin D producing enzymes
- greater calcium retention
- more bone density
- more bone mass
- reduction in plasma calcium
calcitonin also promotes
renal excretion of Ca, Na, Mg, K, phosphate ions by decreasing tubular reabsorption
calcitonin is not
commonly used as treatment
prednisolone class
glucocorticoid receptor agonist, corticosteroid
prednisone is derived from
cortisone
prednisone is metabolised in the (organ)
liver
prednisone is metabolised in the liver to (thing)
active form, prednisolone
prednisolone can cross
cell membrane
prednisolone MOA (3 steps)
- binds to corticosteroid receptor
- changes DNA transcription
- reduced inflammatory proteins
prednisolone specific example
reduction of phospholipase A2 reduces arachidonic acid production
raloxifene class
selective estrogen receptor modulator
raloxifene effect on bone and lipid metabolism
oestrogen-like (promotes)
raloxifene effect on breast and uterine tissue
antagonises oestrogen (inhibits)
raloxifene in bone (4 steps)
- binds to oestrogen receptors
- reduces bone resorption
- increases bone mineral density
- slows rate of bone loss
raloxifene antagonises the effects of oestrogen on mammary and uterine tissue by (1 step)
- prevents transcription of genes with oestrogen response
raloxifene use
less common as post-menopausal symptoms being treated with hormones decreases
alendronic acid class
nitrogen-containing, second generation bisphosphonate
alendronic acid used to treat
corticosteroid-induced osteoporosis, Paget’s disease, prevent osteoporosis in post-menopausal women
nitrogen containing bisphosphonates inhibit
farnesyl pyrophosphate (FPP) synthase
nitrogen containing bisphosphonates inhibit farnesyl pyrophosphate (FPP) synthase by acting as
analogues of isoprenoid diphosphate lipids
inhibition of FPP (by nitrogen containing bisphosphonates) in osteoclasts prevents
post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins, such as Rac and Rho
alendronic acid basically ruins
osteoclast activity, reducing bone resorption
in post-menopausal women alendronic acid causes
net gain in bone mass
digoxin class
cardiac glycoside, sodium-potassium ATPas inhibitor
digoxin uses
congestive heart failure, supraventricular arrhythmias, AF
digoxin MOA (4 steps)
- inhibits Na-K-ATPase pump
- increase in intracellular sodium
- sodium-calcium exchanger (NCX) extrudes sodium and brings in calcium
- more Ca promotes contractile proteins, myosin and actin
digoxin also acts on the
electrical activity of heart
digoxin MOA on electrical activity of heart (4 steps)
- increases slope of phase 4 depolarisation
- shortens action potential duration
- decreases maximal diastolic potential
digoxin is a 3rd line treatment for
AF
digoxin is rarely involved in
heart failure
betaxolol class
beta-adrenergic receptor
betaxolol is a
competitive antagonist
betaxolol competitively antagonises
beta-1 selective adrenergic receptor
beta-1 blockers are mainly in the
heart
beta-1 blockers bind
epinephrine, norepinephrine
activation of beta-1 blockers leads to
G activation and cAMP signalling
cAMP signalling results in a
reduction in heart rate, cardiac output, blood pressure
betaxolol (beta-1 blockers) are routinely prescribed in patients with
ischaemic heart disease
betaxolol can also competitively block (2 steps)
- release of renin (can cause vasoconstriction)
2. beta(2)-adrenergic responses in bronchial and vascular smooth muscles, causing bronchospasm
betaxolol is less commonly used than
bisoprolol
diazepam class
benzodiazepine, GABA receptor agonist
benzodiazepines (diazepam) bind non-specifically to
benzodiazepine receptors
benzodiazepine receptors mediate (5)
sleep, muscle relaxation, anticonvulsant activity, motor co-ordination, memory
diazepam causes GABA to bind to its receptor and open the chloride channel. causing
hyperpolarisation preventing further cell excitation
diazepam is still used for
anxiety, muscle relaxant
propofol class
anaesthetic, GABA receptor modulator
propofol is given
IV
propofol used for
induction and maintenance of general anaesthesia
propofol MOA (1 step)
- makes GABA bind more to GABA-A receptors
propofol IV produces
hypnosis rapidly, in 40 secs
recovery from propofol-induced anaesthesia is generally
rapid and has less frequent side effects than thiopental, methohexital and etomidate
lamotrigine class
anti-convulsant, sodium channel inhibitor
lamotrigine uses
epilepsy, bipolar disorder
lamotrigine MOA
unknown, could be inhibition of Na/Ca channels, stabilises neuronal membranes, modulates release of glutamate and aspartate
carbamazepine class
anti-convulsant, sodium channel inhibitor
carbamazepine is used to control
grand mal, psychomotor or focal seizures
carbamazepine MOA
unknown, inhibits repetitive firing by blocking Na channels
carbamazepine pain relief MOA
blocks synaptic transmission in trigeminal nucleus
response to carbamazepine is
variable, may be resistant due to RALBP1
carbamazepine is less commonly used as
anti-epileptic
carbamazepine is still commonly used as a
mood stabiliser in bipolar, trigeminal neuralgia
phenytoin class
anticonvulsant, sodium channel inhibitor
phenytoin is an anticonvulsant that lacks the _____ effect of ______
sedation, phenobarbital
phenytoin MOA
unclear, but in motor cortex to prevent spread of seizure
phenytoin is not used a lot as it has a lot of
adverse effects and interactions with other drugs
phenytoin rarely used as chronic therapy as there are better
anti-epileptic drugs
phenytoin is still first line in
status epilepticus
sodium valproate class
anti-convulsant, sodium channel inhibitor, GABA receptor agonist
sodium valproate is a
fatty acid
sodium valproate use
epilepsy, mood stabiliser
sodium valproate possible MOA (3)
- increase GABA levels by inhibiting enzymes that catabolise GABA
- alter properties of voltage dependent Na channels
- histone deacetylase inhibitor
sodium valproate therapeutic range in epilepsy
50-100mcg/mL of total valproate
donepezil class
reversible acetyl cholinesterase inhibitor
donepezil is relatively specific for
brain acetylcholinesterase
donepezil leads to an increase in
aceylcholine at cholinergic synapses, enhancing cholinergic function
donepezil use
dementia, alzheimer’s
suxamethonium class
depolarising nicotinic cholinergic receptor antagonist
suxamethonium MOA (5 steps)
- mimics acetylcholine at NMJ
- hydrolysed slower than acetylcholine
- prolonged depolarisation
- desensitisation
- muscle relaxation
suxamethonium cannot be
reversed
suxamethonium recovery is
spontaneous
suxamethonium use
after general anaesthetic as muscle relaxation can be preceded by painful muscle fasciculations
anticholinesterases such as neostigmine given alongside suxamethonium can potentiate
NMJ block
levodopa class
dopamine replacement therapy
levodopa is a natural form of
dihydroxyphenylalanine
levodopa is an immediate precursor of
dopamine
levodopa can be taken
orally
levodopa can readily cross
blood brain barrier
levodopa within the brain is taken up by
dopaminergic neurons and converted to dopamine
levodopa use
replace dopamine lost in Parkinson’s
bromocriptine class
dopamine agonist
bromocriptine mesylate is an
ergot alkaloid derivative
bromocriptine stimulates
dopamine activity
bromocriptine stimulates dopamine activity through the
D2 receptor
bromocriptine MOA
- binds D2 receptor
- Gi signalling cascade
- inhibits adenyl cyclase
- reduction in cAMPL
- blockage of calcium release
bromocriptine improves
muscle activity and coordination
bromocriptine uses
Parkinson’s, hyperprolactinaemia, acromegaly, pulmonary fibrosis
bromocriptine is less commonly used due to concerns about
fibrotic reactions
in Parkinson’s, it is more common to use _____ or ______ than bromocriptine
pramipexole, ropinirole
gabapentin class
anticonvulsant, GABA analogue
gabapentin increases
synaptic conc of GABA
gabapentin is (3)
- high lipid solubility
- not metabolised by liver
- no protein binding
gabapentin MOA (2)
- reduce mono-amine neurotransmitters
2. reduces axon excitability
gabapentin use
epilepsy, neuropathic pain, adjunct in chronic pain
selegiline class
dopamine therapy, monoamine oxidase B inhibitor
selegiline uses
Parkinson’s, depression
selegiline MOA (3 steps)
- irreversibly inhibit monoamine oxidase type B
- inhibits deamination of dopamine in brain
- enhances dopaminergic activity
selegiline at higher doses can also inhibit
monoamine oxidase type A (depression treatment)
isoflurane class
general anaesthetic, neuronal ion channel modulator
isoflurane induces
muscle relaxation
isoflurane reduces
pain sensitivity
isoflurane MOA (5 steps)
- reduces gap junction channel opening times
- increases gap junction channel closing times
- activates calcium dependent ATPase in sarcoplasmic reticulum
- increases fluidity of lipid membrane
- binds to the GABA, glutamate, glycine receptors
atracurium class
competitive cholinergic receptor antagonist, non-depolarising skeletal muscle relaxant
atracurium MOA (3 steps)
- antagonises neurostransmitter action of acetylcholine
- by binding competitively with cholinergic receptors on motor end plate
- muscle relaxation
repeat doses of atracurium can be administered at
regular intervals with predictable results
action of atracurium is reversed by
acetylcholinesterase inhibitors, e.g. neostigmine, edrophonium, pyridostigmine
repeated administration of maintenance doses of Atracurium has no cumulative effect on the duration of neuromuscular block if
recovery is allowed to begin prior to repeat dosing
memantine class
NMDA receptor antagonist
memantine use
dementia
memantine MOA (4 steps)
- binds to NDMA receptor-operated cation channels
- increased glutamate in brain of dementia patients usually allows Mg2+ to bind to NDMA channels so lots of Ca2+ comes in so neuronal degeneration
- memantine binds better than Mg2+ so stops lots of Ca2+
- protects against elevated gutamata
fentanyl class
opioid analgesic, opioid receptor agonist
fentanyl interacts with
opioid mu, kappa, and delta opioid receptors
opioid receptors are coupled with
G-protein receptors
opioid receptors function as
regulators of synaptic transmission
fentanyl MOA (3 steps)
- binds to opioid receptor
- stimulates exchange of GTP for GDP on G-protein complex
- inhibition of adenylate cyclase and so less cAMP
- decreased nociceptive neurotransmitter release
- fentanyl converted to morphine
- closure of N-type voltage calcium channels, opening of calcium-dependent potassium channels
- hypopolarisation, reduced excitability
fentanyl use
IV analgesic, epidural, spinals (regional anaesthesia), transdermal patches (chronic pain)
