Pharmacology Flashcards
1
Q
Which drugs are alkylating agents?
A
Cyclophosphomide
Ifosfomide
Temozolamide
Mitomycin C (also tumour antibiotic)
2
Q
How do alkylating agents work?
A
Transfer an alkyl group (CH3+) to guanine base on DNA in N7 position of purine ring.
Can be monofunctional (one DNA strand) - prevents effective DNA replication (NO crosslinking)
Bifunctional - majority- 2 seperate DNA strands to form a covalent crosslink (inter and intra stand crosslinks)
3
Q
Describe the MOA of cyclophosphamide
A
Prodrug -> metabolised by p450 -> 4-hydroxycyclophosphamide which is in equilibrium with aldophosphamide
Aldophosphamide -> phosphoramide mustard (active) + acrolein (urotoxic)
Aldophosphamide deactivated by aldehyde dehydrogenase (levels high in GI and haem so less toxic)
4
Q
where does cyclophosphamide work in the cell cycle?
A
Non specific
5
Q
How can you give cyclophosphamide?
A
Oral or IV
GOod oral bioavailability 75%
6
Q
WHat is the distribution of cyclosphosphamide?
A
Throughout body including brain and CSF, 60% phosphoramide musturd bound to plasma proteins
7
Q
How is cyclophosphamide excreted?
A
Urine
8
Q
Would you dose reduce cyclophosphamide in renal/liver impairment?
A
If CrCl <20 75% dose, if <10 50% dose
Liver: risk of decreased activation and increased risk of veno-occlusive disease
9
Q
When might you use ifosphamide?
A
Sarcomas, germ cell tumours, VIP, paediatric tumours
10
Q
What is the MOA of ifosfamide?
A
Activated by cytochrome p450 enzymes -> 4-hydroxyifosfamide which is in equilibrium with aldoiphosphamide -> ifosfamide musturd (active) + acrolein
11
Q
What causes neurotoxicity with ifosfamide?
A
Chloroethyl side chain oxidation (occurs more than cyclosphosphamide) -> accumulation of chloroaldehyde which is neurotoxic
12
Q
What is excretion of ifosfamide?
A
Urinary 50-70%
13
Q
Would you dose reduce in liver/renal impairment with ifosfamide?
A
CrCl <60 give 70% dose. Cr CL <45 don’t give.
Not recommended if bili >ULN or ALT/ALP >2.5x
14
Q
What type of drug is temozolamide?
A
Alkylating agent Trazine analogue (similar to decarbazine)
15
Q
Are alkylating agents cell cycle specific?
A
No
16
Q
Describe the MOA of temozolamide?
A
Spontaneously decomposes to MTIC at physiological pH
Precise mechanism unclear- drug methylates guanine residues in DNA and inhibits DNA, RNA and protein synthesis.
does NOT cross link DNA strands.
17
Q
What is the bioavailabiliy of TMZ and does it cross blood brain barrier?
A
Oral - 100% bioavailable
Lipophylic so crosses BBB
18
Q
How is TMZ metabolised and excreted?
A
Metabolism: non enzymatic hydrolysis
Urine
19
Q
Do you need to dose reduce TMZ in renal/liver impairment?
A
no, caution if severe
20
Q
What are mechanisms of resistance to alkylating agents?
A
Glutathione inactivates all alkylating agents ( increase these levels)
Glutathione-S transferase catylases the conjugation of glutathione with alkylating agents (increased levels)
Induction of DNA repair- O6 alkylguanine-DNA alkyltransferase enzyme (MGMT) removes alkyl group from O6 guanine. MGMT levels assoc with resistance in glioma
21
Q
What are the side effects of alkylating agents?
A
Myelosuppression ( cyclophosphamide plt sparing due to high ADH in megakaryocytes), nadir 8-16 days, recovery by D20. Prolonged with nitrosureas + mitomycin
Alopecia - as lipophilic- mostly with cyclo/ifosfamide
GI toxicity - less emetogenic than platinium
CNS toxicity - mainly ifosfamide
GONADAL- testicular failure (depletion of germ cells) dose dependent, may be reversable. Ovarian failure.
Haemorrhagic cystitis
IP + fibrosis
22
Q
Which classes of chemotherapy drugs cause alopecia?
A
Alkylating agents, taxanes, vincristine and anthracyclines
23
Q
Describe the CNS toxicity caused by ifosfamide, its treatment and the risk factors?
A
Accumulation of neurotoxin chloroaldehyde
From mild confusion -> somnolence, seizure, coma
Ifosfamide induced encephalopathy - onset 2-48hrs post dose, resolves on stopping drug over 1-3 days
Methylene blue - used as treatment
Risk factors: low albumin, alcohol excess, renal failure.
24
Q
How do you treat haemorrhagic cystitis?
A
Irritation of bladder mucosa by urinary metabolites (cyclophosphamide and ifosfamide) -> acrolein, phospharamide musturd and chloroacetaldehyde irritate bladder Always adminster: Mesna - detoxifies metaolites Hydration Close observation
25
How do antimetabolites work?
structually similar to metabolites so mistaken by the cell and processed - interfere with production of nucleic acids/DNA/RNA -> block purine/pyramidine synthesis
26
Which part of the cell cycle do antimetabolites work in?
G1/S phase
27
What is 5FU?
Antimetabolite
| Pyramidine
28
What is the mechanism of action of 5FU?
Inert drug
5-FU -> F-dUMP which competes with natural dUMP for catalytic side of thymidylate synthase that produces dTMP
F-dUMP forms a complex with TS and acts as a suicide inhibitor -> causes decrease in dTMP & dTTP levels and dUMP and dUTP accumulate.
(principle MOA)
Also get FUTP misincorperation in RNA and FDUTP misincorporation into DNA>
29
How is 5FU given?
Oral absorption unreliable
IV pharmacokinetics vary depending on duration of infusion
- bolus vs continuous
Half life short- ? increased duration of exposure improves survival
30
How are the side effects different whether you give 5FU as a bolus or continuous infusion?
Bolus - neutropenia, mucositis and diarrhoea
| Infusion- hand-food syndrome, (diarrhoea and mucositis but worse with bolus)
31
How is 5FU excreted?
Biliary secretion- stool
| <10% renal
32
How do you dose reduce 5FU in liver or renal impairment?
Renal - nil
| Liver- moderate impairment reduce by 1/3, severe reduce by 1/2
33
What is the MOA of capecitabine?
Absorbed GI tract as pro-drug
Undergoes 3 step metabolsim
Capectabine -> via hepatic carboxylesterase -> 5'DFCR (5′-deoxy-5-fluorocytidine)-> via cytidine deaminase -> 5'DFUR -> thymidine phosphorylase -> 5-FU
Thymdine phosphorylase is preferentially expressed in tumour tissue providing a degree of targeting for generation of 5-FU in tumour.
34
How is capecitabine excreted?
Mainly as metabolites - renal
35
How would you dose reduce capecitabine if renal/liver impairment
CrCL 30-50 75% dose
CrCl <30 C/I
Bili >3x, ALT/AST >2/5x omit
36
What are the main side effects of cap/5FU?
```
DIarrhoea
PPE
pancytopenia
Cardiac- ECG changes/chest pain
Increase in liver enzymes
N+V
```
37
What is DPD deficiency?
Dihydropyrimidine dehydrogenase usually degrades thymine and uracil
Widely present in liver
AR, mutation DYPD gene on chromosome 1p21
If severe notice in childhood- seizures, microcephaly etc.
Different penetrances so often unknown
Severe reaction to fluropyrimidines
38
What is gemcitabine?
Antimetabolite
| Pyramidine
39
What is the mechanism of action of gemcitabine?
2,2-diflurodeoxycyitidine (dFdC) - actively transported across cell membrane by nucleoside transporters as lipophilic
dFdc -> via deoxycytidine kinase -> dFdC monophosphate -> via deoxycytidylate kinase -> dFdC diphosphate (inhibits ribonucleotide reductase) -> via dFdC trisphosphate (inhibits DNA synthesis via misincorperation)
Phosphorylated
Deoxycytidine kinase is rate limiting enzyme
Incorperated into DNA/RA causing cell death
40
How is gemcitabine metabolised?
Extensive metabolism and deamination to dFdU in liver, plasma, tissues by cytidine deaminase
41
How is gemcitabine given?
Not oral - as poor availability, extensive deamination in GI tract
IV infusion if <70 mins then not extensively distirbuted (half life 30-90mins), if longer than more widely distibuted (half life 4-10hrs)
FOr lung cancer given over 30 mins
42
Does gemcitabine cross BBB?
No
43
What drugs interact with capecitabine?
Warfarin
| Phenytoin
44
What drugs can rescue against effects of 5FU?
Thymidine (only if continious infustion)- rescues TS effects
| Vistonuridine
45
What are the mechanisms of resistance of 5FU?
Increased expression of thymidylate synthase.
• Decreased levels of reduced folate substrate 5, 10-
methylenetetrahydrofolate for TS reaction.
• Decreased incorporation of 5-FU into RNA/DNA.
Increased activity of DNA repair enzymes, uracil glycosylase, and
dUTPase.
• Increased salvage of physiologic nucleosides including thymidine.
• Increased expression of dihydropyrimidine dehydrogenase.
• Decreased expression of mismatch repair enzymes (hMLH1, hMSH2).
• Alterations in TS with decreased binding affinity of enzyme for FdUMP.
46
Which part of the cell cycle is gemcitabine specific for?
S phase
47
How is gemcitabine excreted?
Renal
48
Would you dose reduce gemcitabine in liver/renal impairment?
If CrCl<30 consider dose reduction
| If bili >27 then dose reduce
49
What are the side effects of gemcitabine?
```
Myelosuppression (DOSE LIMITING)- neutropenia> thrombocytopenia
Mild N+V
Flu like symtpoms
Transient hepatic dysfunction (ALT, bili)
Pneumonitis
Oedema
Mild proteinutia/haematuria
Rarely HUS/TTP
Maculopapular rash
Alopecia is rare
```
50
What are the mechanisms of resistance of gemcitabine?
Descreased activation via decreased deoxyctidine kinase
Increased breakdown via cytidine deaminase
Decreased nucleoside transport of drug into cell
Increased expression of competing nucleotide dCTP via expression of dCTP synthetase
51
What is methotrexate used for?
Lymphoma
Leukaemia
Gestational trophoblastic disease
Antimetabolite- antifolate
52
What is the mechanism of action for methotrexate?
Enters cell via RFC (reduced folate carrier)
Undergoes intracellular polyglutamation using folylpolyglutamyl synthetase (FPGS) -> MTXPG (adds 5-7 glutamyl groups) -> competitive inhibitor of DHFR -> no thymine is made -> inhibits dna/rna synthesis
Thymineless cell
Tumour cells have higher levels of FPGS than normal cells so are more susceptible
53
What breaks down MTXPG?
Gamma-glutamyl hydrolase
54
How is methotrexate given?
Usually IV as oral bioavailability is only 40%- metabolism by intestine and deglutamation and 1st pass hydroxylation by liver
55
What is the distribution of MTX?
Wide
Third space accumulation which prolong drug exposure and toxicity.
If given intrathecally- can diffuse back into plasma causing toxicity
56
How is MTX excreted? What reduces the excretion
Renal- probably active proximal tubular secretion (distal tubular reabsorption may occur)
- reduced by weak organic acids eg NSAIDs, penicillin, PPIs
57
Would you dose reduce MTX in renal impairment?
Yes
58
How should you monitor a patient after giving high dose MTX?
Serum levels at 24hr & 48hrs
24-36hrs give leucovorin/folinic acid rescue
High volumes IVF
59
What side effects can MTX have?
```
Nephrotoxicity
Bone marrow suppression
Mucositis
Hepatotoxicity- transient transaminitis, cirrhosis with prolonged oral dosing.
Neurotoxicity
Pneumonitis
```
60
What causes nephrotoxicity with MTX and how would you avoid and treat it?
Rapid drug excretion into urine at rate >solubility -> precipitation. Accumulation in renal cortex.
Amelioration
- IV fluids - aim UO >100mls/hr
- Urinary alkalinasation - Na bicarb- aim pH >7
- Avoid nephrotoxins
- avoid those that reduce renal excretion - weak acids - NSAIDs, penicillins, cipro, PPIs
Rescue Glucarpidase (costs £80,000) - not useful after 96hrs
61
How does folinic acid rescue work for methotrexate
5-formyl derivative of tetrahydrofolic acid
Converted to other reduced folic acid derivatives
Does NOT require action of dihydrofolate reductase
62
What is pemetrexed and what is it used for?
Antimetabolite- antifolate
| NSCLC, mesothelioma
63
What are the resistance mechanisms of MTX?
Increased expression of DHFR or alterations in its binding affinity with MTX
Decreased carrier mediated transport with RFC/FRP
Decreased active FRGS or increase gamma-glutamyl hydrolase
64
What is mechanism of action of pemetrexed?
Transported into cell via RFC
Metabolised to higher polyglutamate form FPGS
Pentaglutamate form is 60x more potent and predominantly remains intracellular with prolonged cellular retention
INHIBITS TS -> causes accumulation of dUMP and incorperation of dUTP into DNA -> inhibition of funtion
INHIBITS DIHYDROFOLATE REDUCTASE -> depletion of reduce folates and critical one carbon carriers for cellular metabolism
INHIBITS GART & AICART which prevents de novo purine biosynthesis
65
How is pemetrexed excreted?
Renal 90%
| NSAIDs, aspiring may inhibit renal excretion
66
What needs to be given before starting pemetrexed?
Vit B12
| Folic acid- on regular low dose 400mcg
67
What side effects can you get with pemetrexed? When would you worry about increased toxicity?
```
Myelosuppression
Skin rash- hand-ffot syndrome
Mucositis
Diarrhoea
Transient elevation of serum transaminases
Fatigue
```
Wide vol of distribution so caution for 3rd space accumulation
68
What are the mechanisms of resistance to pemetrexed?
Increased expression of TS
Alteration in binding affinity of TS
Decreased transport of drug into cell via decreased RFC/FRP
69
What is trifluradine-tipiracil?
Anti-metabolite
Anti-folate
Used in mets colorectal and gastric cancer
70
How does trifluradine-tipiracil work?
Trifluridine taken into cell -> phosphorylated by thymidylate kinase -> TF-TMP which inhibits TS and accumulation of dUMP
Also TF-TMP can undergo further phosphorylation to TF-TTP -> misincorperated into DNA
Tipiracil inhibits the metabolism of trifluridine by inhibiting thymidine phosphorylase
71
What are the side effects of trifluradine-tipiracil?
```
Pancytopenia
Fatigue
DIarrhoea
Vomiting
Pyrexia
```
72
How is trifluridine-tipiracil excreted?
Renal
73
What anti-tumour antibiotics do you know?
Anthracyclines- doxorubicin, epiprubicin
Mitomycin (also alkylating agent)
Bleomycin
74
What are the main biological reactions caused by anthracyclines?
Topo-2 inhibition
DNA intercalation
Helicase inhibition
One and two electron reduction of anthracycline molecule with production of ROS
75
What is bleomycin used for?
Testicular cancer
Hodgkins lymphoma (ABVD)
SCC skin
76
What is the MOA for bleomycin?
Small molecule that contains a DNA binding and iron binding region at opposite ends.
Iron is necessary as cofactor for free-radical generation - reduction oxygen by Fe ions chelated by bleomycin -> ROS
Binds to DNA by intercalation of bithiazole moety between base pairs of DNA
DNA-bleomycin-Fe complex -> undergo oxidation to bleomycin-Fe which releases superoxide/hydroxyl radicals -> cause SSB/DSBs DNA
77
How is bleomycin inactivated?
By bleomycin hydrolase (present throughout the body except skin/lungs)
78
WHat is the volume of distribution of bleomycin?
Rapidly absorbed - 30mins
Half life 2hrs
WIde vol. distirbution, <10% protein bound.
Accumulates in skin and lung nodes
79
How is bleomycin excreted?
Renal
80
What should you monitor when giving bleomycin?
Pulmonary function tests
| CXR
81
What are the side effects of bleomycin?
```
Fever
Rash, pigmentation of skin
Alopecia
Raynauds
Hypersensitivity (premedicate with acetaminophen)
Pulmonary
```
82
Is bleomycin cell cycle specific?
Yes
| G2 phase
83
What types of pulmonary toxicity do you get with bleomycin and what are the possible mechanisms that cause it?
Hypersensitivity pneumonintis, bronchiolitis obliterans, acute interstitial pneumonitis, pul. fibrosis
Occurs in up to 10%
May involve:
- oxidative damage
- bleomycin hydrolase deficiency - degraded bleomycin, present in all tissues except lung/skin
- stimulates alveolar macrophages to secrete inflammatory cytokines
- genetic susceptibility
84
What are the mechanisms of resistance to bleomycin?
Increased expression of DNA repair enzymes
| Altered drug uptake
85
What are the uses of doxorubicin?
Breast cancer, lymphoma, sarcoma, ovarian, lung bladder, thyroid, gastric, wilms tumour
86
What is the MOA of doxorubicin?
Multiple mechanisms
1. Intercalates into DNA resulting in inhibition of DNA synthesis and function
2. Inhibits transcription through inhibiting DNA- dependent RNA polymerase
3. inhibits topoisomerase II be forming cleavable complex with DNA and topoisomerase II to create uncompensated DNA helix torsional tension and SSB/DSBs.
4. Formation of cytotoxic ROS
87
How is doxorubicin given? Does it cross the BBB?
IV, not absorbed orally
Wide distribution
Does NOT cross BBB
75% plasma protein bound
88
How is doxorubicin metabolised?
Extensively in liver to active hydroxylated metabolite doxorubincinol then reduced by NAPH-dependnet aldo-keto reductases - one electron reduction, two electron reduction & deglycosidation
89
HOw is doxorubicin excreted?
Biliary - stool
| <10% renal
90
What drugs does doxorubicin interact with?
Dexamethasone, 5FU and heparin will lead to precipitate if given together
Increased risk of haemorrhagic cysitis and cardiotoxicity if given with cyclophosphamide
91
What should you monitor with anthracyclines?
Cardiac function - ECHO/MUGA
| Liver function
92
What are the side effects/risks with anthracyclines?
```
STRONG VESICANT
cardiotoxic
Skin toxicity- sensitive to sunlight
Hyperpigmentation
Alopecia
N+V
Mucositis
Diarhhoea
Red/orange urine
```
93
What are the mechanisms of resistance to anthracyclines?
ELevated p170 levels -> drug efflux
Decreased expression of topoisomerase II
Increased expression of glutathione
94
What is the function of topoisomerase?
Help to unwind and untangle DNA for repair/replication
T1 create SSB
T2 create DSB
95
What is the function of topoisomerase?
Nuclear enzymes that help to unwind and untangle (break, rewind and rejoin) DNA for repair/replication
T1 create SSB allow uncoiling supercoiled DNA
T2 catalyses both SSB & DSBs
96
What is calyx and how is it different to normal drug?
```
Liposomal doxorubicin
Liposomal encapsulation leads to longer half life and possible preferential accumulation in tumour
Increased half life 45-90hrs
Reduced N+V and alopecia
Reduced cardiotoxicity
```
97
What is the MOA of mitomycin
Acts as an alkylating agent.
Cross link DNA
Activated by NADH cytochrome p450 reducatase to ROS, seimquinone and hydroquininone species which target DNA.
PREFERENTIAL ACTION IS HYPOXIC TUMOUR CELLS
98
How is mitomycin given and does it cross the BBB?
IV, not absorbed oral
| WIdely distributed but does NOT cross BBB
99
How is mitomycin metabolised and excreted?
Extensively by p450 enzymes in liver
| Bile -> faeces
100
What are the side effects of mitomycin?
```
STRONG VESICANT
myelosuppression - DOSE LIMITING
N+V
Mucositis
Anorexia
Fatigue
HUS
Pneumonitis
Heparo0venous disease
Chemical cystitis
```
101
What are the resistance mechanisms to mitomycin?
Elevated p170 levels -> drug efflux
Increased activity of DNA repair enzymes
Increased expression of glutathione and glutathione detoxifying enzymes
102
Which drugs are tubulin binding agents?
Vinca alkaloids: vincristine, vinblastine, vinorelbine, eribulin
Taxanes: paclitaxel, docetaxel
VDA: combrestatin
Antibody drug conjugates: Trastuzumab- emtandine (T-DM1)
103
What are microtubules?
```
Components of cytoskeleton
Essential in all eukaryotic cells for:
- development
- maintenence of cell shape
- transport of vesicles, mitochondria
- cell signalling
- cell division
- MITOSIS
Made of alpha and beta-tubulin
```
104
What part of the cell cycle are tubulin binding agents specific to?
G2/M phase
105
How do microtubules work?
Treadmilling- allows motion. Net growth at one end, net shortening at other end. Flow from +ve to -ve, length unchanged.
Dynamic instability
- + end switches between phases of growth and shortening
- relatively long periods of slow lengthening
- then rapid periods of shortening
- rate of DI increases in mitosis x 100. Formation and attachment of mitotic spindles to chromosomes
106
How are microtubules regulated?
Microtubule assoc proteins (MAPs) - MAP4 is a tau protein
Epigenetic alerations
Variable expression of tubulin isotu[es
Tubulin mutations
107
What are the advantages and disadvantages of targeting microtubules?
Advantages:
- tubulin essential for rapidly dividing cells
- >1 binding site thus can overcome cross resistance
- anti-angiogenic and anti-vascular effects
Disadvantages:
- not tumour selective and overexpression does not drive cancer
- needs apoptotic mechanisms eg p53 to be active
- susceptible to mechanisms of resistance eg MDR
108
What is the MOA of the vinca alkaloids?
High affinity for microtubule ends (low affinity for sides)
- increase tubulin autoaffinity-> leads to spiral aggregates
- Destabilising agent: causes depolymerisation, suppress treadmilling an dynamic instability, inhibits mitotic progression and causes cell death by apoptosis.
109
How are the vica alkaloids metabolised and excreted?
Cytochrome p450
| excreted in bile -> stools
110
Do vinca alkaloids cross BBB?
No
111
What are the side effects of vincristine and vinorelbine?
```
VESICANT
CONSTIPATION- start laxatives
NEUROPATHY- dose limiting
Hair loss
Fatal IT
SIADH
```
Vinorelbine + myelotoxicity
112
What are the mechanisms of resistance to vinca alkaloids?
P170 drug efflux
| Mutations in alpha and beta tubulin proteins with decreased affinity for drug
113
How do taxanes work?
Microtubule stabilising agents, active M phase
Bind beta subunit of tubulin interiorly
- induce stabilisation
- increase polymerisation
- suppression of microtubule dynamics
- cell cycle arrest in G2/M and ultimately apoptosis
- sensitivity/resistance to taxanes is dependent on beta-tubulin isoforms
114
What is the metabolism, VOD for paclitaxel? Does it cross the BBB.
Wide VOD, distributes to 3rd spaces
90-95% protein bound
Metabolism p450 enzymes liver -> excretion faeces
Does NOT cross BBB
115
What are the side effects of paclitaxel and docetaxel?
```
Hypersensitivity
Myelotoxicity
Neurotoxicity
Myalgia
Oedema
Alopexia
Moderate nausea + vomting
Arrythmia
Lower back muscles can contract - occasionally muscle rupture-> high CK
```
Docetaxel
++ myelotoxicity
-- neuro toxicity
116
What is difference between weekly and 3 weekly paclitaxel?
Weekly ? antiangiogenic effect- watch for MI
| Weekly - more anaemia + neuropathy, less neutropenia
117
What is the VD and excretion of docetaxel?
VD 1-2l
Hepatic excretion
95% protein bound
118
What are the side effects of cabazitaxel?
Hypersensitivity
Neutropenia- dose limiting
Less neuropathy than other taxanes
119
How is cabazitaxel excreted and would you dose reduce in renal/liver impairment?
Metabolism by p450 and Hepatic excretion
Large VD
AST/ALT >1.5 C/I
Use with caution in renal impairment
120
What are the mechanisms of resistance to taxanes?
Alterations in the tubulin binding affinity
| P-glycoprotein efflux pump (EXCEPT cabazitaxel which is a poor substrate for pump so may be useful in MDR disease)
121
What is the MOA of eribulin?
Halichondrin B analogue (non competitive inhibitor of vinca)
Suppress microtubule growth
Inhibits polymerisation inducing cell cycle arrest and apoptosis
Unique tubulin interaction as inhibits MT growth without shortening by sequestering tubulin in non-productive aggregates.
- binds to caps
- included aggregates that compete with soluble tubulin
122
How is eribulin distributed and eliminated?
Extensively distributed
| ELimination hepatobiliary- dose reduce in liver impairment
123
What does eribulin interact with?
Drugs that prolong QTc so monitor ECG
124
What are the mechanisms of resistance to eribulin?
Appears less susceptible to p-glycoprotein pump
| Maintains activity in various taxane resistant tumours
125
Name some drugs that inhibit topoisomerase I and II?
I: irinotecan
II: etoposide, anthracyclines
126
How does topoisomerase I work?
Main function is to maintain 3D conformity of DNA removing torsional stresses.
1. Causes a transient enzyme bridge with DNA SSB (topo-1 cleavable complex, TOP1ccs) through which the strand can pass.
2. Topo-1 reseals the cleaved strand
TOP1ccs is stabilised by the binding of camptothecins. Once stabilised the complex leaded to arrest of DNA replication fork and formation of SSBs.
127
How does irinotecan work?
Semisynthetic derivative of camptothecin
Converted to active metabolite SN-38 by carboxylesterases in liver.
SN-38 binds to and stabilised by topoisomerase I -DNA complex and prevents re-ligation of DNA after it has been cleaved -> causes DSB
Colorectal tumours have high levels of topoisomerase I
128
Is irinotecan cell cycle specific
Non specific
129
What can cause worse toxicity in a patient on irinotecan?
UGT1A1 def
SN-38 metabolised by glucocuronidation (UGT1A1) to SN-38 glucuronide
Reduced metabolism
significantly higher risk of diarrhoea and neutropenia x 4
130
How is irinotecan excreted? should you dose reduce in hepatic dysfunction?
64% faecal, 28% urine
| Reduce dose in gilberts or any elevation of bilirubin
131
What are the side effects caused by irinotecan?
Cholinergic syndrome
- N+V, salivation, facial flushing, diarrhoea (early onset), abdo cramps,
- managed atropine
Late onset diarrhoea - 7-10 days
- delayed mucosal cytotoxicity
- cholera like diarrhoea
- persistnet explosive watery stools
- early loperamide
Neutropenia
Hepatotoxicity
anorexia
132
What are the mechanisms of resistance to irinotecan?
Decreased expression or mutations of topoisomerase I
P170 drug efflux
Decreased carboxylesterase enzyme so decreased activity of SN-38
133
How does topoisomerase II inhibitors work?
Topo II: Mediates ATP- dependent induction of nicks in both strands of DNA duplex allowing relaxation of superhelical DNA during DNA replication and transcription
Exists in alpha and beta isoforms.
Alpha isoforms
- interfere with enzyme function by stabilising a reaction intermediate in which DNA strands are cut and covalently linked to protein tyrosine residues forming a cleavable complex
- high levels of TOP2-DNA covalent complexes
- Stabilisation of this complex blocks transcription and replication
Non-intercalating- directly bind to enzyme: etoposide
Intercalating:doxorubicin, mitoxantrone
134
Is etoposide cell cycle specific?
Yes Late S and G2 phase
135
How is etoposide given and is it protein bound?
IV
Oral availability 50% of IV dose
90-95% albumin bound so low albumin might cause more toxicity
Enters CSF poorly
136
How is etoposide excreted?
44% faeces
- bili 26-51, AST 60-180 - give 50% dose
54% urine
- CrCl 15-50ml/min : 75% dose
137
What are the side effects of etoposide?
Myelosuppression- mainly leukopenia - 5-15days
N+V, mucositis, diarrhoea
Alopecia
Hypersensitivity
2nd cancer risk - mixed lineage leukaemia after 2-3 yrs
138
What are the mechanisms of resistance for etoposide?
P170 efflux- cross resistance to vinca alkaloids, anthracycline, taxanes
Decreased expression of topoisomerase II, decreased binding affinity for it
ENhanced DNA repair
139
What is the MOA of cisplatin?
Intracellular
Aquation- Cl- ion is displaced for H2O
H2O ligand is displaced so platinum ion can bind to bases.
PREFERENCE FOR GUANINE- N7 position
Crosslinks to another guanine by displacment of another Cl- ion.
Intra-strand links - poorly repaired
Inter-strand links- repaired more efficiently
140
What are the side effects of cisplatin?
High doses it is a vesicant
Highly emetogenic - use NK receptor blocker
Nephrotoxicity- 28-38%
Neurotoxicity
Ototoxicity
Myelosuppression
Electrolyte disturbance - hypo ca, K, Mg, Na
Arterial and venous thromboembolism (all platiniums, reduced with carbo). Small increased risk of MI/CVA
141
Describe the issues with nephrotoxicity with cisplatin?
Renal impairment can be progressive
Thrombotic microangiopathy- occurs when given with bleomycin
Hypomagnaesaemia- due to urinary magnesium wasting. Occurs in 50% cases.
Anaemia- renal tubular injury results in epo deficiency
Fanconi like syndrome- increased urinary excretion of glucose, AA. Lactate and pyruvate in urine.
Increase pro inflammatory cytokines
Vasoconstriction in renal microvasculature
142
What does cisplatin interact with?
```
Nephrotoxics
cisplatin reduces phenytoin dose
reduces renal clearance of etoposide
methotrexate
ifosfamide
bleomycin
should be given AFTER paclitaxel - prevents delayed excretion and toxicity (carbo as well)
```
143
How is carboplatin different in its MOA from cisplatin?
Less potent cisplatin
Binds to guanine and adenine preferentially
aquation occurs at a slower rate 4:1 compaired to cisplatin.
Clearance proportional to GFR
2-6hrs in pts with normal GFR, up to 18hrs with abnormal GFR
144
What are the difference in side effects for carbo to cisplatin?
```
Less nephrotoxic
Less emetogenic
Peripheral neuropathy uncommon
Trade off is more myelosuppressive
Reactions
```
Adminster AFTER PACLITAXEL
145
Does haemodialysis clear carboplatin?
HD clears carbo at rate of 25% renal
| PD does not
146
What is the calculation for AUC?
Area under the curve on a plot of drug concentration in plasma against time
AUC measures total drug exposure over time- dependent on dose & rate of elimination
Carbo dose (mg)= target AUC (mg/ml x min) x (GFR +25)
147
What are the mechanisms of resistance to carbo/cisplatin?
Reduced accumulation due to alterations in cellular transport
Increased inactivation by thiol containing proteins eg GLUTATHIONE (main mechanism)
Enhanced DNA repair enzyme activity
Def in mismatch repair enzymes
148
What is oxaliplatin and how does it work?
```
Adds 2 bidentate groups- 1,2-diaminocyclohexane
Forms bulkier adducts
More effective at blocking replication
Forms inter- and intra strand crosslinks
Undergoes aquation like cis/carboplatin
```
149
How is oxaliplatin excreted
>50% renal - use with caution in CrCl <20
150
What is the VD of oxaliplatin?
40% sequestered in RBCs
Wide VD
Extensively protien bound.
151
What are the side effects of oxaliplatin?
Ototoxicity- rare compared to cisplatin
Nephrotoxicity - less than cisplatin
Acute neurosensory complex- during or after 1st inufsions.
- >85% pts. Discomfort swallowing cold items and throat discomfort, sensitivity touching cold items, paraesthesia & dyesthesias of hands, feet, perioral region.
Cumulative sensory neuropathies
- Dose dependent sensory, distal axonal neuropathy without motor involvement. Forms fewer adducts than cisplatin so less neurotoxic.
Hepatotoxicity - sinusoidal injury-portal htn, ascites
Rare cases of bronchiolitis obliterans pneumonia
152
Why do you get acute neurosensory complex with oxaliplatin and how can you reduce acute neurotoxicity?
Chelation of Ca by metabolite leading to hyperexcitability of peripheral nerves
Magnesium and calcium infusions before and after can help
153
What are the mechanisms of resistance to oxaliplatin?
Increased glutathione
Increase DNA repair
Non-cross resistant to cis/carboplatin in tumour cells that are deficient in MMR enzymes (MMR enzymes not required for oxaliplatin adducts due to bulkier size)
154
Name the egfr inhibitors and which generation they are from?
1st gen: erlotinib, gefitinib
2nd gen: afatinib
3rd gen: osimertinib
155
How do erlotinib and gefitinib work?
Reversible EGFR inhibition, bind to WT and mutant receptor
156
What is the difference between the EGFR TKIs and cetuximab?
EGFR TKIs are small molecules that work on the the intracellular portion of EGFR receptor
Cetuximab: chimeric human-mouse antibody - blocks extracellular receptor
157
How do afatinib work?
Irreversible eGFR inhibitors, bind to EGFR (incl WT) and HER2 & HER4
158
How does osimertinib work?
Superior to any other eGFR inhibitors. Irreversible inhibition of mutated EGFR including T790M. Does not bind to WT EGFR so less toxicity.
159
How are EGFR inhibitors metabolised and excreted?
Metabolism: liver CYP3A4 enzymes
Elimination: hepatic -> faeces
160
What are the side effects of EGFR inhibitors and how do you manage them?
Rash (75%)
- prevention: emollients, sun protection
- G1/2: topical hydrocortisone/1% clindamycin, oral abx
- G3/4: systemic abx, steroids, interrupt/reduce
Diarrhoea (50%)
- G1/2 loperamide, codeine
- G3/4 interrupt, stool sample, fluids, dose reduce
ILD
- risk 1-8% with EGFR, 10% with mTOR
- can be fatal
- usually within 1 month of starting
- stop, steroids, oxygen
Keratitis/conjunctivitis
Hepatitis
GI perforation
Hair and nail changes
161
What do EGFR inhibitors interact with?
```
Warfarin
Cigarettes
PPI
Antacids
p450 inhibitors/inducers
```
162
What are the mechanisms of resistance to EGFR inhibitors?
Mutations in ErbB tyrosine kinases leading to decreased binding affinity to afatinib
Presence of KRAS mutations
Presence of BRAF mutations
Activation/induction of alternative cellular signalling pathways such as PI3K/AKT, IGR-1R, c-MMET
Increased expression of mTORC1 signalling pathway
163
Name an ALK inhibitor
Crizotinib
| Alectinib - better
164
What is the mechanisms of action of crizotinib?
Inhibits multiple TK receptors- ALK and c-MET
Metabolism in liver by CYP3A4/A5 enzymes
Excretion in faeces
165
What are the side effects of crizotinib?
Common: visual disturbances, fatigue, GI toxicity, oedema
| Rare but serious: hepatitis, pneumonitis, QT prolongation, cytopenias
166
What do you monitor for patients on crizotinib?
Liver enzymes monthly
| QT initially on ECG
167
What drugs should be avoided with crizotinib?
PPIs
| P450 enzyme inducers/inhibitors
168
What drug is licenced in lung cancer patients with a ROS1 mutation?
Crizotinib
169
What is bevacizumab?
zumab = humanised mouse antibody
against VEGF-A
Works extracellularly
170
What are the side effects of bevacizumab?
HTN, MI, stroke, proteinuria/nephrotic syndrome
Poor wound healing (need 4-6wks off prior to op)
GI perforation (do not use if bowel involvement)
Posterior leukoencephalopathy syndrome
171
What are the mechanisms of resistance to bevacizumab??
Increased expression of pro-angiogenic factor ligands, PIGF, bFGF, hepatocyte growth factor (HGF)
Recruitment of bone marrow derived cells which circumvents the requirment of VEGF signalling.
Increased pericyte coverage of tumour vasculature which supports its integrity and reduces the need for VEGF mediated survival signalling.
Activation and enhancement of invasion and mets to provide access to normal tissue vasculature without obligate neovascularisation.
172
What are the VEGF TKIs used for
RCC
1st line: sunitinib, pazopanib
2nd line: cabozantinib (sorafenib)
GIST - sunitinib
PNET- sunitinib
173
How are all the VEGF TKIs metabolised and excreted?
Liver and excreted faeces.
Metabolised by CYP3A4 p450 enzymes
Affected by p450 drugs
174
What is the mechanism of action of sunitinib?
Multi targeted TKI
| Inhibits phosphorylation of VEGFR1-3, PDGF beta, KIT, FLT-3
175
Should you dose reduce in liver/renal impairment with sunitinib?
Renal- not needed, can take after dialysis
| Liver- mild-mod not needed, severe not evaluated
176
How should you monitor patients on sunitinib?
BP
Evidence of CCF
TFTs
177
What are the side effects of sunitinib?
```
HTN (in nearly 30%)
Hand-foot sundrome
Yellow discoluration of skin
Bleeding/epistaxis
LVF
GI symptoms
myelosuppression
Adrenal suppression/hypothyroidism
```
178
What is the dosing schedule for sunitinib?
4 weeks on, 2 weeks off
| One dose/schedule does not lead to same oral bioavailability in all
179
What is pazopanib?
Multi-targeted TKI
| Inhibits phosphorylation of VEFR1-3, PDGF alpha & beta, KIT, bFGF
180
Can you take sunitinib with food?
Yes, unaffected by food
181
Can you take pazopanib with food?
Exposure increased if tablet crushed or if taken with food.
| Take 1hr before or 2hrs after food
182
What do you need to monitor in patients on pazopanib?
```
LFTS every few weeks esp when starting
QTc
HTN
Proteinuria on urine dip
TFTs
```
183
What are the side effects of pazopanib?
```
Hepatic failure- SEVERE AND FATAL
HTN in 50%- related to plasma concentration
GI effects with elevated lipase and risk of perforation
MI/Angina/stoke
Hypothyroidism
Proteinuria
QTc prolongation
Myelosuppression
```
184
Can you give pazopanib in liver/renal failure.
Hepatic impairment- can be caused by pazopanib, not usually sunitinib
- Mild: ALT>ULN, bili 1-1.5x = normal dose
Mod: bili 1.5-3x : max dose 200mg OD
Severe: bili >3x: CI
Renal impairment: dose adjustment unnecesary
185
What is sorafenib?
Multi-targeted TKI
Inhibits phosphorylation of: b & c-RAF, KIT, FLT-3, RET, VEGFR2, PDGFbeta, KIT, VEGFR1-3
Used in RCC and HCC
186
What are the side effects of sorafenib?
```
HTN
Hand-foot skin reactions
Wound healing issues
Diarrhoea
Hypophosphataemia
MONITOR BP
```
187
Can you take sorafenib with food?
Absorption reduced by high fat food so take without food.
188
Do you dose reduce sorafenib in liver and renal impairment?
Renal: no
Liver: mild-mod not needed
189
What is cabozantinib?
Multi targeted TKI
Inhibits phosphorylation of VEGFR1-2, also MET and AXL (implicated in resistance to VEGF other TKIs)
Used 1st or 2nd line RCC
190
Can you take cabozantinib with food?
Take one hour before or 2hrs after
191
How do you monitor a patient on cabozantinib?
BP, urine protein regularly
| Monitor for GI perforation, osteonecrosis
192
What are the side effects of cabozantinib?
```
Hand-foot syndrome
diarrhoea, N+V, mucositis,
Proteinuria, HTN
Bleeding
Hepatotoxicity
Reversible PRES syndrome
Osteonecrosis of jaw
```
193
Can you give cabozantibib in renal/liver impairment
Renal impairment: mild/mod use with caution, severe not recommended
Liver impairment: mild/mod use 40mg OD< severe not recommended.
Start at 60mg OD normally
194
What is cetuximab?
Monoclonal recombinant chimeric IgG antibody against EGFR
Binds with 10x greater affinity to EGFR than normal ligands blocking it.
Used in H+N, colorectal (ONLY WHEN KRAS WT)
195
What should you monitor when a patient is on cetuximab?
Magnesium
196
What are the side effects of cetuximab?
```
90% infusion related reaction
Skin reactions - shows drug is working
ILD
Paronychia
Hypomagnaesaemia
```
197
What is denosumab and how does it work?
Fully human monoclonal antibody (igG) to RANKL
Prevents RANKL binding to RANK receptor on osteoclast surface reducing osteoclast survival and function -> less bone resorption
198
What are the side effects of denosumab?
```
Hypocalcaemia
Bone pain
Abdo pain
constipation
Cataracts
osteonecrosis of jaw
Atypical femoral fractures.
```
199
What is imatinib?
Phenylaminopyrimidine methanesulfonate compound that occupies the ATP binding site of the BCR/ABL protein and very limited number of other TKIs (PDGFR, c-KIT)
Results in inhibition of substrate phosphorylation
Induces apoptosis in BCR-ABL and Ph1 cells
200
What is imatinib used for?
CML
ALL with Ph +ve
GIST expressing c-KIT
201
What is the metabolism, excretion and interactions with imatinib?
100% oral bioavailability, extensively bound to plasma protiens
Metabolism: CYP4A enzymes
Excretion: faeces
Interactions: p450 enzyme inducers/inhibitors
202
Can you take imatinib with food?
Yes should be taken with food
203
What do you monitor if a patient is on imatinib?
ECHO/MUGA
mood for dpression
weight due to fluid retention
204
What are the side effects of imatinib?
```
N+V (irritates stomach lining)
Fluid retention
CCF- rare but serioud
DIarrhoea
Myelosuppression
Skin toxicity
depression
```
205
What are the mechanisms of resistance to imatinib?
Increased expresison of Bcr-abl tyrosine kinase
Mutations in Bcr/abl TK resulting in altered binding affinity of drug
Increased expression of P170 glycoprotein -> drug efflux
Increased expression of c-KIT
206
What is nintedanib?
Small molecule TKI to PDGF, FGFR, VEGFR
| Used in NSCLC with docetaxel initially
207
How does nintedanib work?
Low oral bioavailability of 5% due to p-glycoprotein transporting drug back out of lumen and high 1st pass metabolism in liver
Inactivated by esterases to free carboxylic acid which is then glucuronidated and excreted in bile and faeces
208
Is nintedanib effected by p450 enzymes?
NOT effected
209
What are the side effects of nintedanib?
Deranged liver enzymes
GI disturbance
Strokes/MI
Poor wound healing
210
What is olaparib?
PARP-i
| Small molecule
211
How does olaparib work?
Inhibits PARP which is key in base excision repair,
| Synthetic lethality with BRCA mutations
212
How is olaparib metabolised and what does it interact with?
Metabolism CYP3A
Interactions with those enzymes
Excretion urine and faeces
213
What are the side effects of olaparib?
```
Pancytopenia
N+V
Arthralgia
Flu like symptoms
Diarrhoea
dyspepsia
```
214
What is palbociclib
oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6
215
Should you take palbociclib with food?
Yes
216
What is the metabolism and elimination of palbociclib
Bioavailability 46%, 85% protein bound
Hepatic metabolism via CYP3A and SULTA1
ELimination faeces
Interacts with CYP3A drugs
217
What the side effects of palbociclib?
```
Neutropenia -common
fatigue
nausea
Diarrhoea
rash
infections
thrombocytopenia
Reduce dose in severe hepatic impairment and monitor in renal impairment
```
218
What is pertuzumab and how does it work?
Monoclonal recombinant humanised IgG1 antibody directed against extracellular dimerisation domain of HER2 receptor- subdomain II
Binding of pertuzumab leads to HER2 inhibition of heterodimerisation of HER2 with family members including EGFR, HER3, HER4.
Leads to inhibition of MAPK, PI3K
219
How do you monitor patients on pertuzumab and what are the common side effects?
ECHO
| Infusion reactions, fatigue, CCF
220
What is trastuzumab and how does it work?
Recombinant monoclonal antibody directed against extracellular domain of HER2 receptor- subdomain IV
221
What is transtuzumab-emtansine and how does it work?
HER2 targeted antibody drug conjugate made up of trastuzumab and a small molecule microtubule inhibitor DM1
Upon binding of HER2 receptor- kadcyla undergoes receptor mediated internalisation and lysosomal degradation leading to intracellular release of DM1 molecule.
Binding of DM1 to tubulin leads to disruption of microtubule ntwork and cell cycle arrest/apoptosis.
DM1 metabolised by CYP3A4/5
222
What are the side effects of trastuzumab-emtansine?
```
Severe hepatotoxicity
CCF
Pulmonary syndromes
Neurotoxicity and peripheral neuropathy
Fatigue
```
223
What is rituximab and how does it work?
Chimeric anti-CD20 antibody
Consists of a human IgG1-k constant regions and variable regions from murine monoclonal antibody
Targets CD20 antigen, a cell surface phosphoprotein expressed during early pre-B cell development until mature B stage but lost in plasma stage.
Binding results in inhibition of CD20 mediated signalling that leads to inhibition of cell activation and cell cycle progression
Mediates complement dependent lysis in presence of human complement and antibody dependent cellular cytotoxicity with human effector cells.
224
What are the side effects of rituximab?
Infusion reactions common
C/I if hypersensitivity to murine products
Tumour lysis syndrome
Arrythmias and cardiotoxicity
N+V
Skin reaction- including Stephens johnson
225
What is trametinib and how does it work?
Reversible inhibitor and mitogen-activated extracellular signal related kinase I (MEK1) and kinase 2 (MEK2)
Results in inhibition of downstrea, regulators of extracellular signal related kinase (ERK) pathway leading to inhibition of cellular proliferation.
226
What is the availability and metabolism of trametinib?
Oral availability 70%
Food with high fat content reduces cmax, tmax, AUC
Extensive binding to plasma proteins
metabolism: mainly via deacetylation (by hydrolytic enzymes eg carboxylesterases) or mono-oxidation in combination with glucorinidation.
227
How do you monitor patients on trametinib?
Cardiomyopathy - ECHO
| Eye exams- retinal detachment/retinal vein occlusion
228
What are the side effects of trametinib?
```
Cardiomyopathy - 10% develop median time of 63 days
Visual disturbances
Rashes
Pul toxicity
GI side effects
HTN
Lymphoedema
```
229
What is dabrafenib and how does it work?
Inhibits mutant forms of BRAF serine-threnonine kinase BRAF-V600E which results in constutive activation of microtubule-assoc protein kinase (MAPK) pathway.
Inhibits wildtype BRAF and CRAF kinases aswell
230
Describe the bindong, metabolism and elimination of dabrafenib?
```
High oral bioavailability 95%
Avoid with food with high fat content
Extensive plasma protein binding
Metabolism: CYP2C8, CYP3A4 in liver to hydroxy-dabrafenib metabolite -> carboxy metabolite
Elimination: faeces
```
231
How should you monitor somebody on dabrafenib?
Skin exams for SCC
| Glucose
232
What are the side effects of dabrafenib?
```
SCC/keratoacanthomas
Skin reactions
fever
hyperglycaemia
Arthralgia
OPthalmologic - uveitis, iritis
```
233
What are the mechanisms of resistance to BRAF/MEK
Increased expression of MAPK
| Activation of an alternative cellular signalling pathways eg FDF-R, PI3K
234
What are bisphosphonates and how do they work?
Inorganic pyrophosphate analogues
Attach to hydroxypatite binding sites on boy surfaces. When osteoclasts begin to resorb bone, the bisphosphonate realeased impairs the ability of osteoclast to form a ruffled border to adher to the bony surface so cannot continue to resorb bone.
Also reduce osteoclast progenitor development and recruitment
235
What is the excretion of bisphosphonates?
20-80% taken up by bone the rest is excreted renally.
| Half life in circulation short at 2hrs but once taken up by bone, half life is years
236
What is ipilimumab?
A fully monoclonal antibody against CTLA4 (T lymphocyte assoc antigen 4) expressed on surface of CD4 and CD8 lymphocytes.
This results in the inhibition of the interaction between CTLA4 and its target ligand CD80/CD86
237
What is pembro/nivolumab?
Anti-PD1 fully human IgG4 antibodies
PD1 (on T cell) receptor inhibits T-cells activity by interactions with its ligands PDL-1 on tumour cells, APCs, and PDL-2 on activated monocytes and dendritic cells.
This usually results in an immunosuppressive tumour environment so helps to interrupt this by blocking it.
238
What should you monitor for people on immunotherapy?
LFTs
TFTs
Cortisol
239
Describe the hypothalamic/pit pathway that produces testosterone
Hypothalamus produces GnRH -> anterior pit produces LH and FSH
FSH -> sertoli cells -> spermatogenesis, oestrogens, androgen binding protein
LH -> leydig cells -> produce androgens
240
How does testosterone change the transcription of particular genes/DNA?
Testosterone bound to SHBG extracellularly
Enters cell and coverted to DHG by 5 α-reductase
Binds to androgen receptor
AR undergoes dimerisation and phosporylation
Enters nucleus and binds to androgen response element of DNA - changes transcription of genes
Leads to increased growth, PSA and survival
241
Name some LHRH analogues and describe how they work?
Goserelin, Leuprolin, Triptorelin
Buserelin (can give intranasally or by SC injection)
Stimulate LH receptors of pituitary
Initial testosterone flare
Then leads to LH receptor downregulation
242
How quickly do you reach castrate levels of testosterone with LHRH analogues? What else might you need to give
May get testosterone flare in 1st 2-3 weeks - co treatment with an anti-androgen (eg bicalutamide/casodex) for 1 week before and 2-3 weeks after starting is advised
Reach castrate levels testosterone in 2-4 weeks
243
Name a LHRH antagonist and describe its mechanism of action?
Degaralix
Binds to LHRH receptors in pituitary - pure antagonist with reversible/complete binding.
No initial agonist action (no LG release) so no flare.
Rapid and profound testosterone suppression
? better cardiaac risks than LHRH agonists.
Given SC
244
How is zoladex/goserelin excreted?
Usually an implant- slowly released drug
Half life of 2-4hrs in blood. Poorly protein bound
Renally excreted
No dose change in liver/renal dysfunction
245
How is degarelix metabolised and excreted?
90% plasma protien bound
| Metabolism via hydrolysis and excreted in peptide fragments in faeces
246
What are the side effects of androgen suppression?
```
Hot flushes
Fatigue
Impotence/loss of libido
Loss of bone strength and muscle -> DEXA scan
Mood changes
Metabolic syndrome -> diabetes, CVD, MI, sudden death
- insulin resistance
- arterial stiffness
- increased BMI
```
247
How does prostate cancer become castrate resistant?
AR overexpression
AR mutation
Signalling crosstalk- alternative AR activation
Androgen indepedent AR activation
248
Name the anti-androgens and describe how they work?
20-30% response- usually used with LHRH agonists
Bind to and block AR
1st gen
- Bicalutamide - metabolised by p450
- Flutamide
- Cyproterone acetate - potent progestogen, moderately potent anti-androgen, weak glucocorticoid
2nd gen
- enzalutamide
Other drugs that inihibit adrenal androgen production:
- corticosteroids
- ketoconazole
- abiraterone acetate (x10 more potent than ketoconazole)
- oestrogens- diethylstilbestrol
249
What is enzalutamide and how does it work?
```
Novel AR antagonist
Three mechanisms of actioN:
- blocks testosterone binding to AR
- impedes movement of AR to nucleus
- inhibits DNA binding
Causes cell death in cancers resistant to bicalutamide
```
250
How is enzalutamide metabolised?
Extensive binding to plasma proteins
Metabolism : liver CYP2C8, CYP3A4
Interacts with those drugs - clopidogrel
Not tested in CrCl <30 or severe hepatic dysfunction
251
What are the side effects of enzalutamide?
```
Fatigue
MSK- back pain
Coronary syndromes
Diarrhoea
Hot flushes
Oedema
Seizures <1%
```
252
How does abiraterone work?
Derivative of steroidal progesterone
Inhibits androgen production from 3 sources- adrenal gland, testes and prostate tumour cells.
Blocks CYP17 : 17α-hydroxylase and 20-lyase
This prevents the conversion of cholesterol to cortisol (vis 17α- hydroxyprogesterone) or to testosterone (via DHEA)
Instead cortisol is converted to aldosterone (via progesterone)
Build up of mineralocorticoids.
253
How is abiraterone metabolised and excreted?
Rapidly hydrolysed to its active metabolite via esterases.
CYP3A4 and SULT2A1 further metabolizes abiraterone into two inactive metabolites called abiraterone sulfate and N-oxide abiraterone sulfate.
90% excreted in faeces
INTERACTS with CYP3A4 drugs
254
What are the side effects of abiraterone?
```
Fatigue
Oedema
Arthralgia
HTN
Hypokalaemia
Coronary syndromes
```
255
What is the mechanisms of resistance to abiraterone?
Upregulation of CYP17
Induction of AR and AR splice variants tha result in a ligand-independent AR transactivation
Expression of truncated androgen receptors.
256
What is the MOA of anastrazole and letrozole?
Non-steroidal aromatase inhibitors
INhibit conversion of adrenal androgens (androstenedione and testosterone) to oestrogens.
Serum oestradiol suppressed by 90% at 2 weeks and completely at 6 weeks.
257
How is anastrazole metabolised and excreted
In liver by N-dealkylation, hydroxylation and glucoronidation by cytochrome p450 enzymes
90% excreted faeces
Avoid if CrCl <20
258
How is letrozole metabolised and excreted?
In liver via CYP3A4 and CYP2A6.
Glucorinidation leads to inactive metabolites
75% renally excreted.
Manufacturer advises caution if CrCl <10
259
What are the side effects of aromatase inhibitors?
```
N+V
Hot flushes
Dry skin
Arthralgia
Headache
Oedema
Osteoporosis - DEXA monitoring
```
260
What is exemestane and how does it work?
Steroidal aromatase inhibitor
| Binds to and permanently , irreversible inactivates aromatase.
261
How is exemestane metabolised and excreted?
CYP3A4 enzymes
| Excreted in faeces
262
What is tamoxifen?
Non steroidal anti-oestrogen with weak oestrogen agonist effects.
Competes with oestrogen for binding to ERs (inside cells), when tamoxifen binds it leads to ER dimerisation and tamoxifen ER dimer is transported to nucleus where it binds to DNA sequence referred to as ER elements.
Inhibits transcriptional process and transduction pathways
Also inhibits TGF-B which inhibits TGF-a, IGF-1 - involved in proliferation
263
Is tamoxifen cell cycle specific?
Yes blocks cell at mid G1 phase.
264
How is tamoxifen metabolised and excreted?
Plasma protein bound
Metabolised by cytochrome p450 to main metabolite N-desmethyl tamoxifen- same biological activity as tamoxifen..
Excreted in faeces
265
What does tamoxifen interact with?
Cytochrome p450 (CYP2D6, CYP3A, CYP2B6, and CYP2C1)
SSRIs/SNRIs
antipsychotics
266
What are the side effects of tamoxifen?
```
Endometrial cancer
VTE
Menopausal symptoms
elevated triglycerides
Myelosuppression -rare
Pruitis
Initiation can cause a tumour flare- MSCC/bone mets worse
```
267
What are the mechanisms of resistance to tamoxifen?
Decreased ER expression/mutations leading to decreased binding affinity
Over-expression of growth factor receptors- HER, EGFR< IGF-1, TGF-beta
ESRi mutation
268
What is medroxyprogesterone acetate and how does it work?
```
Steroidal progestin (synthetic variant of progesterone)
Binds to progesterone receptors and blunts GnRH release
Anti-proliferative effect on endometrium
Used in endometrial/breast/renal cancer
```
269
What are the side effects of medroxyprogesterone acetate?
```
Loss of BMD
Bleeding irregularities
Cancer risks
VTE
CCF
```
270
What is octreotide?
Somatostatin analogue
Inhibits hormone secretions in carcinoid syndrome
Octreotide binds to somatostatin receptors highly expressed on surface of carcinoid tumours, where it inhibits the release of gastrin, VIP, secretin, motilin and serotonin.
271
How is octreotide given, metabolised and what does it interact with?
SC injection, half life 100mins (longer than somatostatin)
Metabolised by p450 enzymes
Interacts: cyclosporin, insulin, oral hypoglycaemic agents, beta blockers, bromocriptine.
272
What are the side effects of octreotide?
```
Biliary abnormalities
Nausea
Abdo pain
Constipation
Myalgia
Changes in glucose
```
273
What chemotherapy drugs are never given intrathecally and which are?
NEVER VINCA ALKALOIDS
Methotrexate, cytarabine
274
What are the safety conditions when giving intrathecal chemo?
All drugs labelled with FOR INTRATHECAL USE ONLY - should be transported seperately to IV drugs
Only >ST3 can prescribe if appropriately trained
Given in designated area
Given in normal working hours
Given AFTER IV chemo
Purpose designated intrathecal chemo chart
Register of delegated personel who have been traned to prescribe, authorise, dispense and administer intrathecal chemo.
275
What are pharmacokinetics?
The times course of a drug in the body (what a body does to the drug)
276
What are pharmacodynamics?
the time course of the effect pf a drug (what the drug does to the body)
277
What is the description of the time course of a drug in the body?
```
LADME
Liberation
Absorption
Distribution
Metabolism
Excretion
```
278
What effects rate of absorption of a drug?
Oral- absorption depends on the lipid solubility of a drug
| - non-ionised molecules are favoured as far more lipid soluble than ionised (H+) which have a shell of water molecules
279
What effects the distribution of a drug?
Lipid soluble drugs are generally rapidly distributed and protein bound.
280
What is the volume of distribution equal to?
VD: apparent volume into which the drug is distributed following IV injection (IV drugs have 100% bioavailability)
VD= dose/concentration at time
281
If you give 100mg of drug A IV and measure the concentration at Time T as 1420mcg/L. What is the volume of distribution at time T?
100mg = 100,000mcg
100,000/1429 = 70l
VD = dose/concentration at time
282
```
If the volume of distribution is :
1. 3l
2. 5l
3. 15l
4. 42l
Where does it suggest the drug has been distributed to?
```
```
3l (4%) = plasma
5l (7%) = blood
15l (21%) = extracellular fluid
42l (60%) = total body water
>42l = tissue distribution
```
Women have more fat so total body water is lower than men.
283
How do you calculate the concentration of a drug?
Concentration decreases exponentially
Plasma concentration = initial concentration x e^ - λt
λ = elimination rate constant = ln2/ t1/2
284
How many half lives doe sit take to reach a steady state?
5
285
What is clearance of a drug equal to?
Cl = λ x VD
286
If λ = 0.02 min ^-1 , what does that mean?
λ is elimination rate constant
| 2% of drug is eliminated per minute
287
How do you calculate the dosing rate of a drug?
Dosing rate = clearance x steady state plasma concentration
If giving orally the dosing rate = bioavailability x dose /dosing interval = plasma clearance x plasma concentration
288
What different concentration effect relationships do you know?
```
Complicated to model
- linear
- quadratic
- logarithmic
- Emax and sigmoid Emax
Complicated by hysteresis
```
289
What is hysteresis?
Peak effect doe not happen at peak concentration but after the peak concentration is dropping
can model this with effect compartment or indirect response model
290
Which drugs are vesicants?
Anthracyclines - tend to be the worse
Mitomycin C
Vinca alkaloids
Taxanes
291
Which drugs are irritants but NOT vesicants?
```
5-FU
Platinums
Topoisomerase inhibitors
Liposomal doxorubicin
Ifosfamide
```
292
What drug can you use in anthracycline extravasations?
Dexrazoxane
Water soluble ring close analog of the iron chelator ethylenediaminetretraacetic acid (EDTA)- like form which is a strong iron chelator and has ability to displace iron for th anthracycline
293
What are the steps for dealing with extravasation?
1. Stop and disconnect infusion, leave needle in place
2. Identify the extravasated agent
3. Try to aspirate as much as possible and record the volume remove. Avoid manual pressure over the area and remove cannula.
4. Mark with a pen or outline the area
5. notify plastics
If anthracycline, antibiotics, alkylating agents
- apply dry cold compresses
- use specific antidotes - anthracyclines - topical DMSO, dexrazosane, for mitomycine topical DMSO
If vinca alkaloids, taxanes, platinium
- apply warm compresses
- adminster hyaluronidase- increases resorption
Elevation and analgesia.
294
Where are opioid receptors found and name them?
Peripheral nerves
Spinal cord
Mutiple regions of brain
```
4 opioid receptors
Mu (70%) - u
Delta (24%)
Kappa (6%)
ORL-1 (opiod receptor like-1)
```
295
How is morphine metabolised and what receptor does it exert its effect?
35% PO bioavailability
Half life 1.5hrs
Metabolised (glucorinidation) by enzyme UGT2B7 to major metabolites morphine-3-glucuronide (60- 80% and is inactive), morphine-6-glucouronide (10-15% and is active)
M6G acts of u- receptors
296
What is diamorphine and how does it work?
Pro-drug of morphine
More soluble and more lipophilic
Half life 3 mins IV
M-6-G acts on u receptors.
297
How is oxycodone metabolised and which receptors does it act on?
CYP2D6
CYP3A4
u & k opioid receptors
298
What is fentanyl and what is its MOA?
```
Synthetic opioid
80x more potent than morphine
Transdermal preparation
- lipophilic low molecular weight
Increased absorption with pyrexia
```
Metabolism: CYP3A4 & CYP3A5 -> norfentanyl
Acts on u- opioid receptors
299
What is buprenorphine?
```
Semi-synthetic opioid
25-30 x more potent then morphine
Partial agonist
- partial Mu receptor agonist
- Kappa receptor antagonist
- weak delta receptor agonist
```
Highly lipid soluble
Safe to use in renal impairment
300
How is buprenorphine metabolised?
CYP3A4
301
What is methadone and how does it work?
Synthetic opioid
Broad receptor profile:
- Mu receptor, delta receptor, NMDA, presynaptic blocker of serotonin reuptake.
302
Describe the distribution and excretion of methadone
HIghly variable half life- 8-75hrs
Rapid distribution and slow elimination
Accumulates in fat stores, only 1% stays in plasma
Excreted unchanged by kidney or metabolised liver (CYP2B6 & CYP3A4) to inactive metabolites
Can use in renal failure
303
How does alfentanil work
Synthetic derivative of fentayl
Rapid onset and short duration of action
1/10 PRN dose but rarely used as lasts around 30 mints.
Metabolism by CYP3A4 to inactive metabolites- excreted in urine
304
How do NSAIDs work?
Inhibit COX-1 and COX-2 - produce prostaglandins and thromboxanes
305
How do corticosteroids work?
Diffuse into cell and bind to glucocorticoid receptors (usually kept inactive by hsp90)
When binds to cortisol it moves to nucleus and stimulates synthesis of proteins.
306
What are the effects of steroids?
Reduces inflammation and immunological responses
Increases liver glycogen deposition and increases gluconeogenesis
Increases bone catabolism - osteoporosis
Lifts mood/psychosis
Increases gastric acid
Suppresses adrenals
Mineralocorticoid effects - K+ excretion, Na reabsorption
HTN
307
How do tricyclic antidepressants work?
Blocks the presynaptic re-uptake of serotonin and noradrenaline in the CNS, enhancing the actiosn of the descending inhibitory pathways.
308
Name some TCAs. What are there side effects?
2 classes
- tertiary amines eg amitripyline
- secondary amines eg notrtiptyline
Side effects: anti-cholinergic- dry mouth, blurred vision, constipation, postural hypotension, heart block, arrythmias
Caution in cardiac diseas and hepatic disease
309
How does gabapentin/pregabalin work?
Chemical analogue of GABA
Reduced calcium influx of hyper-excited neurons.
Caution in renal impairment
310
How do benzodiazepines work?
GABA agonists- inhibit release of excitatory glutamate decreasing spasm in skeletal muscle
311
How does baclofen work?
Derivative of GABA
Works by activating GABAb receptors
Excreted renally
312
How does ketamine work?
NMDA receptor antagonist
- calcium channel involved in central sensitisation
- normally blocked by magnesium and inactive
- prolonged excitation unblocks channel and causes increased pain, expansion of field of pain and opioid resistance.
- Also acts on opioid receptors, monoaminergic receptor,s muscarinic receptors, voltage sensitive calcium ions.
NOT GABA
Extensive 1st pass metabolism to norketamine via CP3A4
Max blood concentration greater aft PO than injection
313
Describe the adjuvant analgesic step ladder for neuropathic pain?
1. Corticosteroids
2. TCA or anti-epileptics
3. TCA & anti-epileptic
4. NMDA receptor blocker
5. Spinal analgesia.
314
Which areas of the brain cause vomiting and what receptors do they have
Vestibular system - H1 receptors, M1 receptors (muscarinic)
CTZ in medulla: D2, NK, 5HT2 receptors
Vomiting centre in medulla: H1, NK, M1 receptors
GI tract: D2 receptors, 5HT3 receptors.
315
How does metoclopramide work and what are the side effects?
D2 receptor antagnost
5HT4 receptor antagonist
In addition to prokinetic effect on gut it also acts on CTZ
Side effects: Acute dystonia, oculogyric crisis, extrapyramidal side effects, galactorrhoea, gynaecomastia
316
How does domperidone work?
D2 receptor antagonist
Acts on receptors in CTZ and stomach
DOes not cross BBB
Side effects; Gynaecomastia, galactorrhoea, amenorrhoea
317
How does haloperidol work?
D2 receptor antagonist in CTZ
| Causes sedation and extra-pyramidal side effects
318
How does cyclizine work>
H1 and ACh antagonists - acts on inner ear and vomtiing centre.
319
What are the uses and side effects of cyclizine?
Use: vertigo and labyrinthine disorders, mechanical bowel obstruction and raised ICP
Side effects: drowsiness, caution in heart failure as anti=muscarinic effect can cause tachycardia
320
How does levomepromazine work?
Antagonist at D2, H1, M1, 5HT2 & alpha1-adrenergic receptors
Used for refractory nausea
Side effects: drowsiness, postural hypotension, antimuscarinic effects.
321
How does ondansetron work?
Blocks the amplifying effect of excess 5HT on vagal nerve fibres
5HT3 antagonist
Used specficially for highly emetogenic radiotherapy and chemotherapy (combined with NK often)
322
What are the side effects of ondansetron?
Constipation and headaches.
Reduces analgesic efficacy of tramadol
dose reduce in hepatic impairment
323
What is aprepitant and how does it work?
NK1 receptor antagonist
- G protein coupled receptors located in peripheral and central nervous system
- receptor has dominant ligand - substance P. SP is a neuropeptide which is found in high concentrations in the vomiting centre and whne activated results in vomiting reflex
- aprepitant blocks substance P
Metabolised by CYP3A4
324
What are the side effects of ondansetron?
Headache, hiccups, constipation, reduced appetite
325
How does GCSF work?
Binds to cell surface receptors on haemopoetic cells in bone marrow and stimulates neutrophil progenitor cell proliferation and differentiation
Also speeds up neutrophil maturations leading to increased number being released.
326
What are the possible side effects of GCSF?
```
Allergic reaction
splenic rupture
ARDS
Sickle cell criss
Glomerulonephritis
Alveolar haemorrhage
Capillary leak syndrome
low plts
Bone pain
Rash
Diarrrhoea/constipation
Alopecia
DONT USE IN MDS and CML
```
327
What is pegylated GCSF?
Addition of polyethelene glycol PEG moetiy to filgrastim
Long acting form - too large for renal clearance
Neutrophil mediated clearance- half life around 42hrs although dependent on neutrophil count.
Half life of GCSF 3.5hrs
328
What are pharmacodynamic drug interactions?
Where the effects of one drug change be the presence of another substance at its site of action eg folinic acid and 5FU
329
What are pharmacokinetic drug interactions?
Those which affect absorption, distribution, metabolism, elimination
330
Why are drugs metabolised?
Protein bound drug is not filtered by renal glomerulus.
Free drug readily diffuses back from tubule into blood
If relied on renal excretion along than drugs would have a very long half life so most drugs are metabolised.
331
What happens during drug metabolism
Process in which drugs converted to a more water soluble form that can be filtered by the kidneys
332
What is a phase I reaction?
Oxidation, reduction or hydrolysis.
Oxidation is most common.
CYP450 enzymes account for 90% drug metabolism.
CYP3A4 accounting for 50%.
Other enzymes involved in metabolism are xanthine oxidase- metabolises mercaptopurine and azathioprine
333
Name some CYP3A4 inducers?
```
Carbamazepine
Phenytoin
Modafinil
St Johns wort
Rifampicin
Dexamethasone
```
334
Name some CYP3A inhibitors
```
Aprepitant
Antifungals eg ketoconazole
Grapefruit juice
Clarithromycin/erythromycin
Ciprofloxacin
Lapatinib
Imatinib
Verapamil
```
335
What is a phase 2 reaction?
Coupling/conjugation with other substances. Usually to less active polar molecules that are regularly excreted by kidneys
- glucuronidation
- acetylation
- glutathione
- glycination
- sulphation
- mehtylation
336
What effects elimination of drugs?
Tends to be excreted in bile or urine
Changes in pH, tubular active transport systems
Reduced renal blood flow - methotrexate with NSAIDS
337
What is the max CrCl for carboplatin dosing?
125ml/min is cap
338
What are the risk factors for tubular necrosis while on cisplatin?
```
33% get nephrotoxicity
CrCl reduced, avoid if <40
Dose
Rate of administration
Hydration status
Low albumin
Other nephrotoxics
```
339
What dose is considered high dose methotrexate?
>1g/m2
340
Name some drugs which may cause permanent loss of fertility?
```
Cyclophosphamide
Cisplatin
Doxorubicin
Irinotecan
Ifosfamide
Gemcitabine
? etoposide
```
341
How can chemotherapy cause women to become infertile?
Affect on follicular growth and maturation within the ovary, caused by cell-cycle specific chemotherapies, or can result from death of the resting oocytes within the ovaries, caused particularly by alkylating agents. Destruction of the
oocytes results in a decreased number of steroid producing cells, and thus a fall in the oestrogen levels, and a direct impact on the normal cycling of gonadotrophins. The effect on ovary function may be temporary, or may, if
oocyte loss has occurred, be permanent.
Chemotherapy can cause a mitotic arrest of the endometrial epithelium, which will limit fertility. This would normally be temporary.
342
How can chemotherapy cause infertility in men?
Cause infertility or impotence
Affect sertoli cells- sperm made
Affect Leydig cells- reduce testosterone -> reduced sperm, impotence
If stem cell compartment of testes significantly affected it will not recover
Impotence - neurotoxicity - platinum based chemo
343
What chemo drugs do you dose reduce in liver impairment?
Anthracyclines
Taxanes
Paclitaxel 3 weekly: if bilirubin < 1.25 x ULN and ALT < 10 x ULN, proceed with full dose.
Vinca alkaloids
344
Which drugs develop resistance with p170 glycoprotein efflux pump?
anthracyclines, vinca alkaloids, etoposide and taxanes
345
How does cisplatin cause nephrotoxicity?
Proximal tubular necrosis and apoptosis
Vasoconstriction
Pro-inflammation
346
What does non-linear pharmacokinetics mean and why does this usually happen?
the clearance of a drug is not proportional to the concentration for all concentrations. This is usually due to saturation of metabolic pathways, which results in a decrease in (relative) clearance as the concentration of drug increases
Zero order kinetics (rather than 1st order)
347
What are the clinical implications of non-linear pharmacokinetics?
clinical implications of this are that above a certain dose for drugs with non-linear pharmacokinetics the concentration and hence toxicity may increase rapidly and disproportionately with dose
348
What is paclitaxel mixed with and why? What side effect does this cause?
Highly lipophilic
polyoxyethylated castor oil (Cremophor EL) in a 1 : 1 v/v mixture with dehydrated ethanol, a powerful solubilizer combo
Reactions
probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitax
349
Name 4 consequences of combining paclitaxel with a pGP inhibitor?
Pharmacokinetics – increased half-life
Pharmacokinetics – decreased clearance
Pharmacodynamics – increased efficacy
Pharmacodynamics – increased toxicity
350
Why are liposomal drugs removed from the body and what can be added to them to prevent this from happening?
Readily opsonised and caught by mononuclear phagocyte system + removed.
Add PEG - prevents binding of opsonins (stealth liposome), also increased uptake in tumour
351
Define oral bioavailability
Extent and rate at which active drug enters circulation
Assessed using AUC - conc/time curve
Oral bioavailability = AUC drug adminstered orally/ AUC drug administered IV
352
What is a therapeutic index?
toxic dose/ dose for therapeutic response
Usually TD50 / ED 50
ED Effective dose
353
What is the classical MDR phenotype and what drugs are susceptible?
p-glycoprotein pump
resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins (etoposide)
354
What is atypical MDR?
Atypical MDR is assoc with changes to topoisomerase IIa
Also non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene -> effects same drugs a pGP
355
MMR deficiency leads to resistance towards which drugs?
Capecitabine/5FU
Carboplatin/Cisplatin
Alkylating agents together with MGMT
