Session 7 Flashcards
common s/e of chemo
- bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets
- side effect of some cancer treatments
- When myelosuppression is severe, it is called myeloablation
Review relevant material from other Units regarding main features of DNA structure and replication within the cell cycle LO
- Nucleotide =
- DNA =
- Purines =
- Pyridimines =
- Nucleotide = sugar- phosphate-base
- DNA = double helix of nucleotides
- Purines = Adenine & Guanine
- Pyridimines = Cytosine & Thymine (Uracil in RNA)
What are the stages in the cell cycle?
TUMOUR GROWTH depends on?
variation in cycle 9-43hrs between cancer cells
G0 cell arrest
G1 cell contents duplicate
S1: DNA synthesis
G2:checks
- growth fraction
- duration of cell cycle
- rate of cell loss
What is the fractional cell kill hypothesis
cancer chemotherapy on tumour cell populations demonstrate first-order kinetics; i. e, the proportion of tumour cells killed is a constant percentage of the total number of cells present. In other words, chemotherapy kills a constant proportion of cells, not a constant number of cells. The number of cells killed by a particular agent or combination of drugs is proportional to one variable: the dose used. The relative sensitivity of cells is not considered, and the growth rate is assumed to be constant.
Classification of Tumours According to Chemo-sensitivity
What tumours are highly sensitive to chemo?
Lymphomas
Germ cell tumours
Small cell lung
Neuroblastoma
Wilm’s tumour (nephroblastoma ~ children)
no worries SLG (i respond well)
What tumours are modestly sensitive to chemo?
Breast
Colorectal
Bladder
Ovary
Cervix
COBs are okay
What tumours have low chemo-sensitivity?
Prostate
Renal cell
Brain tumours
Endometrial
Recognise the main cytotoxic chemotherapeutic groups and actions at their targets: Antimetabolites; DNA Alkylators / Intercalaters; Mitotic Inhibitors (spindle poisons) LO
What is the mechanism of action of Alkylating Agents
Replication impaired
Give an example of an Alkylating Agents
Platinum Compounds
Formation of platinated inter- and intrastrand adducts, leading to inhibition of DNA synthesis.
DACH platinum adducts are bulky and thought to be more effective in inhibiting DNA synthesis than platinum adducts.
What is the mechanism of Antimetabolites? Give examples
6-Mercaptopurine, 5-Fluorouracil, Methotrexate
Give examples of a spindle poison and their specific mechanism of action
Microtubule-binding agents affect microtubule dynamics in 2 ways
– Inhibit polymerization
– Stimulate polymerization & prevent depolymerization
Vinca alkaloids: Vincristine, Vinblastine
Taxanes: Paclitaxel
don’t want to give taxes back
What is the mechanism of Action on a Cellular Level Of Spindle Poisons?
Appreciate the main of factors influencing Pharmacokinetics in chemotherapy, including routes of delivery and drug resistance LO
What is the mechanism of resistance for alkylating agents?
- Decreased entry or increased exit of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylation
Appreciate the main of factors influencing Pharmacokinetics in chemotherapy, including routes of delivery and drug resistance LO
- For many types of cancer, chemotherapy regimen will consist of a number of different drugs - combination chemotherapy – usually given an acronym. A drug may be given as a single agent.
- Routes of administration:
IV pumps e.g.
Peripherally inserted central catheter
Describe the main ADRs as discussed and some of the treatment specific ADRs LO
SIDE EFFECTS OF CHEMOTHERAPY?
Chemotherapy adverse effects – those due to effect of treatment on the tumour: (3)
- Acute renal failure - often multifactorial – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
- GI perforation at site of tumour – reported in lymphoma
- Disseminated intravascular coagulopathy eg onset within a few hours of starting treatment for acute myeloid leukaemia
Vomiting
- Multifactorial but includes direct action of chemotherapy drugs on the ?
- Patterns of emesis:
- central chemoreceptor trigger zone
- – acute phase 4 - 12 hours
– delayed onset, 2 - 5 days later
– chronic phase, may persist up to 14 days
Alopecia
- When does this occur?
- Outcomes?
- Marked with which drugs?
- Minimal with which drugs?
- Help sometimes with?
- Hair thins at 2 - 3 weeks
- May be total
- May re-grow during therapy
- May be total
- doxorubicin, vinca alkaloids, cyclophosphamide
- platinums
- scalp cooling
Skin Toxicity
1. Local effects
- General
– bleomycin effects ? - What drugs cause hyperpigmentation?
- – Irritation and thrombophlebitis of veins
– extravasation - • hyperkeratosis • hyperpigmentation • ulcerated pressure sores
- busulphan, doxorubicin, cyclophosphamide, actinomycin D
Mucositis
• Gastrointestinal tract epithelial damage
• May be profound and involve whole tract
- Most commonly worst in ?
- Presents as
- oropharynx
- – sore mouth/throat
– diarrhoea
– G.I. bleed
Cardio-Toxicity
- What drugs cause Cardio-myopathy
- What drugs cause Arrhythmias
- – doxorubicin ++ (> 550 mg/m2)
– high dose cyclophosphamide
– mortality approx. 50% - – cyclophosphamide
– etoposide
Lung Toxicity
Whats drugs lead to lung toxicity & state their effect.
• Bleomycin
– pulmonary fibrosis
– beware concurrent radiotherapy
• Mitomycin C, cyclophosphamide, melphalan, chlorambucil
– pulmonary fibrosis
Haematological Toxicity of Cancer Therapy
- Most frequent dose limiting toxicity
- Most frequent cause of ?
- Different agents cause variable effects on degree and lineages
What lineages are effected the most?
1.
- death from toxicity
- – Neutrophils – platelets
Chemotherapy: cytotoxic drugs
Considered ‘dangerous’ drugs, need specialists to prescribe because:
• Narrow therapeutic indices
• Significant side effect profile
• Dose needs to be altered for the individual patient based on
– their surface area and/or body mass index
– drug handling ability (eg liver function, renal function… dependent on the metabolism and excretion routes)
– general wellbeing (performance status and comorbidity)
• Treatment phasing needs to take into account the balance between:
– growth fraction
– the ‘cell kill’ of each cycle of the chemotherapy regimen
– marrow and GI tract recovery before next cycle
– how tolerable is the regimen
– both short term organ toxicity and physical side effects and long term damage causing late effects
Appreciate the range of factors influencing pharmacokinetics in chemotherapy including
routes of delivery and drug resistance LO
Pharmacokinetics and chemotherapy
What causes variability?
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
Pharmacokinetics and chemotherapy (2)
What causes variability- further elaborate on what we mean by:
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
- Absorption
– N+V, compliance, gut problems - Distribution
– Weight loss, reduced body fat, ascites etc - Elimination
– Liver and renal dysfunction, other meds - Protein binding
– Low alb, other drugs
Appreciate the potential for harm from possible drug-drug interactions including cancer
chemotherapy and common drugs LO
Chemotherapy - important drug interactions
Other drugs may increase plasma levels of the chemotherapy drug (and therefore side effects). Give examples of some of these drugs which have this effect.
– Vincristine and itraconazole (a commonly used antifungal) leads to more neuropathy
– Capecitabine (oral 5FU) and warfarin
– Methotrexate – caution with prescribing penicillin, NSAIDs
– Capecitabine and St Johns Wort, grapefruit juice
Understand the clinical monitoring required to minimise ADR risk
Chemotherapy – monitoring during treatment
- How do we check response of the cancer to chemotherapy?
- Drug levels e.g.
- Checks for organ damage?
- – Radiological imaging
– Tumour marker blood tests
– Bone marrow/cytogenetics - Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
- – Creatinine clearance
– Echocardiogram
Awareness of the clinical trial basis for prescribing LO
How do the drugs get from bench to bedside?
Chemotherapy is the treatment of cancer with drug therapy – traditionally this applies to cytotoxic drugs. Over the years more classes of drugs have been introduced to treat
cancer e.g.
– Hormones
– Now… targeted drug therapy eg
• Monoclonal antibodies
• Drugs inhibiting angiogenesis
• Drugs targeting gene expression
• Signal Transduction inhibitors
• Drugs interfering with the apoptotic pathways
• Drugs interfering with cell cycle control
• Cytokines
Chemotherapy: the aim of treatment
The aim is variable…
- Neoadjuvant –
- Adjuvant –
- Palliative -
- Primary –
- Salvage –
- Neoadjuvant – given before surgery or radiotherapy for the primary cancer
- Adjuvant – given after surgery to excise the primary cancer, aiming to reduce relapse risk eg breast cancer
- Palliative - to treat current or anticipated symptoms without curative intent
- Primary – 1st line treatment of cancer.. In many haematological cancers this will be with curative intent, initially aiming for remissiom
- Salvage – chemotherapy for relapsed disease
Anaesthetic Techniques. These Can Be Combined.
Complete the flow diagram showing the different types of Anaesthetic techniques
Conscious sedation:
use of small amounts of anaesthetic or benzodiazepines to produce a sleepy-like state. (Maintain verbal contact but feel comfortable)
Anaesthesia From a Practical Viewpoint.
- Premedication (Hypnotic-benzodiazepine).
- Induction (usually intravenous but may be inhalational).
- Intraoperative analgesia (usually an opioid).
- Muscle paralysis-facilitate intubation/ventilation/stillness.
- Maintenance (intravenous and/or inhalational).
- Reversal of muscle paralysis and recovery which includes postoperative analgesia (opioid/NSAID/paracetamol).
- Provision for PONV.
- POINT: during anaesthesia many (interacting) pharmacological agents on board requiring excellent pharmacological knowledge and skill to manage.
Recognise the names of example inhalational and intravenous anaesthetics LO
General Anaesthetics Difficult To Classify-VAST Range Of Structures.
- Give examples of Gases-Volatiles-Delivered via lungs
- Give examples of Intravenous general anaesthetics
- (Image)
- • Propofol
• Barbiturates
• Etomidate
• Ketamine
Know the range of effects on the CNS produced during general anaesthesia
(Guedel’s signs) LO
Guedel’s signs:
Stage 1: analgesia and consciousness
Stage 2: unconscious, breathing erratic but delirium could occur, leading to an excitement phase.
Stage 3: surgical anaesthesia, with four levels describing increasing depth until breathing weak.
Stage 4: respiratory paralysis and death.
Anaesthesia is a combination of;
- Analgesia (inability to feel pain)
- Hypnosis (loss of consciousness)
- Depression of spinal reflexes
- Muscle relaxation (insensibility and immobility)
Understand how Minimum Alveolar Concentration (MAC) describes ‘volatiles’ drug potency LO
End-Point Is Concentration Dependent. For Volatiles We Use ?
MAC To Describe Potency.
MAC and Volatile Anaesthetic Potency
- What is potency ? (M&R year 1)
- Volatile anaesthetic potency is described by MAC or Minimum Alveolar Concentration. What is MAC?
- Anatomical substrate for MAC is ?
1.
- – [Alveolar] (at 1atm) at which 50% of subjects fail to move to surgical stimulus (unpremedicated breathing O2/air)
– At equilibrium [alveolar] = [spinal cord]
– MAC, MAC-BAR (Autonomic Response), MACawake
- spinal cord
Factors Affecting Induction and Recovery.
Partition coefficients (solubility)
• Blood: Gas partition (in the blood)
– Low value fast induction and recovery e.g., desflurane
• Oil: Gas partition (in fat)
– Determines potency and slow accumulation due to partition into fat (e.g, halothane)
What Affects MAC ?
• Age (High in infants lower in elderly)
• Hyperthermia (increased); hypothermia
(decreased)
- Pregnancy (increased)
- Alcoholism (increased)
- Central stimulants (increased)
- Other anaesthetics and sedatives (decreased)
- Opioids (decreased)
MAC and effects of Nitrous Oxide.
Nitrous Oxide is very often added to other volatile agents (reduced dosing)
(30-60 yr olds)
What receptors are important in anaesthetics?
GABAA Receptors
What is GABA?
Major inhibitory neurotransmitter -> LGIC (Cl- conductance)
Understand the role of the GABA receptors in anaesthesia LO
- What happens when anaesthetics potentiate GABA activity?
- With the exception of ? all anaesthetics potentiate GABAA medicated Cl- conductance to depress CNS activity.
- What other receptors can be used as a target for anaesthetics?
- • Anxiolysis (inhibits anxiety)
- Sedation (state of sleep)
- Anaesthesia
- Xe,NO2 and ketamine
- NMDA receptors probable other site
Molecular-Cellular Target.
- In the brain consciousness is ?
- ? modulate this balance.
- a balance between excitation (Glutamate) and inhibition (GABA)
- Anaesthetics
Describe how NDMA and GABAA receptors work
Systems Target: Brain Circuitry.
Explain the effect of anaesthesia on the brains circuitry
- Reticular formation (hindbrain, midbrain and thalamus) depressed. Connectivity lost.
- Reticular system often called activating system due to ability to increase arousal.
- Thalamus transmits and modifies sensory information.
- Hippocampus depressed (memory).
- Brainstem depressed (respiratory and some CVS).
- Spinal cord-depress dorsal horn (analgesia) and motor neuronal activity (MAC).
Targets: Putting it all together in a ‘whole’ human GABAA receptors activated in human brain during anaesthesia. In test tube Isoflurane potentiates benzodiazepine binding.
Recognise the names of example inhalational and intravenous anaesthetics LO
Main Intravenous Anaesthetics: (3)
- Propofol (rapid)
- Barbiturates (rapid)
- Ketamine (slower).
- Use of IV anaesthetics
- Can be used as sole anaesthetic in TIVA (Total IntraVenous Anaesthesia).
- Target sites as for inhalational.
- With exception of ? all potentiate GABA
- Systems target as for inhalational.
- induction
- Ketamine (NMDA)
How Do We Describe Intravenous Anaesthetic Potency ?
- Plasma concentration to achieve a specific end point (loss of eyelash reflex or a BIS value or/..).
- For induction in mixed anaesthesia – Bolus to end point then switch to volatile.
- TIVA uses a defined PK based algorithm to infuse at a rate to maintain set point. Pre-ceeded by a bolus.
Local and Regional Anaesthesia - which circumstances is it used?
Dentistry
Obstetrics Regional surgery (patient awake)
Post-op (wound pain)
Chronic pain management (PHN)
- Local Anaesthetics: e.g.
- Characteristics
- Lidocaine, Bupivacaine, Ropivacaine and Procaine.
- • Lipid solubility – potency (higher greater potency)
- Dissociation constant (pKa) – time of onset. Lower pKa faster onset
- Chemical link – metabolism
- Protein binding – duration (higher for longer duration)
Understand the mechanism of action for wound analgesia LO
Bupivacaine Infiltration For Wound Analgesia.
• Cocaine archetypal
- Esters-shorter acting
- Amides-longer acting
- Block is USE Dependent
- Block small myelinated (afferent) nerves in preferance hence nociceptive and symp block
- Adrenaline ↑ duration Bupivacaine an amide so more stable-longer lasting. Slow onset (pKa 8.2).
What are these results showing?
Compared to Procaine, Bupivacaine is more potent with a longer duration of action. Procaine is esterase metabolised and has a slower onset time but not much in it.
Regional Anaesthesia
- What does is anaesthetise?
- Often described as a ?
- Uses local anaesthetic and or an opioid.
- Upper extremity (e.g.,);
- Lower extremity (e.g.,) ;
- Extradural / Intrathecal / Combined (labour).
- part of the body
- block of a nerve and hence the patient remains awake
3.
- interscalene, supraclavicular, infraclavicular, axillary
- femoral, sciatic, popliteal, saphenous
Learn the main anaesthetic ADRs LO
Main Anaesthetic Side Effects (from the very common 1:10 category for GA)
- General anaesthesia:
- Local and regional
- Increased general concern re: ?
- – PONV (opioids)
– CVS
– hypotension
– POCD (increases with increasing age)
– Chest infection
- Depends on the agent used and usually result from systemic spread (Locals are Na+
channel blockers so cardiovascular toxicity)
3.allergic reactions/anaphylaxis
- Anaesthesia good example of polypharmacology.
- Anaesthesia: ?
- Vast array of agents for general; volatile or i.v.
- Main molecular targets of interest are;
- General, regional or local
- – GABA transmission.
– NMDA glutamate receptors.
– Voltage gated Na+ channels (locals).
