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Clinical Pharmacology, Therapeutics & Principles of Prescribing > Session 7 > Flashcards

Session 7 Flashcards

1
Q

common s/e of chemo

A
  • 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
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2
Q

Review relevant material from other Units regarding main features of DNA structure and replication within the cell cycle LO

  1. Nucleotide =
  2. DNA =
  3. Purines =
  4. Pyridimines =
A
  1. Nucleotide = sugar- phosphate-base
  2. DNA = double helix of nucleotides
  3. Purines = Adenine & Guanine
  4. Pyridimines = Cytosine & Thymine (Uracil in RNA)
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3
Q

What are the stages in the cell cycle?

TUMOUR GROWTH depends on?

A

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
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4
Q

What is the fractional cell kill hypothesis

A

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.

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5
Q

Classification of Tumours According to Chemo-sensitivity

What tumours are highly sensitive to chemo?

A

Lymphomas

Germ cell tumours

Small cell lung

Neuroblastoma

Wilm’s tumour (nephroblastoma ~ children)

no worries SLG (i respond well)

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6
Q

What tumours are modestly sensitive to chemo?

A

Breast

Colorectal

Bladder

Ovary

Cervix

COBs are okay

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7
Q

What tumours have low chemo-sensitivity?

A

Prostate

Renal cell

Brain tumours

Endometrial

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8
Q

Recognise the main cytotoxic chemotherapeutic groups and actions at their targets: Antimetabolites; DNA Alkylators / Intercalaters; Mitotic Inhibitors (spindle poisons) LO

A
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9
Q

What is the mechanism of action of Alkylating Agents

A

Replication impaired

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10
Q

Give an example of an Alkylating Agents

A

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.

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11
Q

What is the mechanism of Antimetabolites? Give examples

A

6-Mercaptopurine, 5-Fluorouracil, Methotrexate

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12
Q

Give examples of a spindle poison and their specific mechanism of action

A

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

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13
Q

What is the mechanism of Action on a Cellular Level Of Spindle Poisons?

​

A
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14
Q

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?

A
  1. Decreased entry or increased exit of agent
  2. Inactivation of agent in cell
  3. Enhanced repair of DNA lesions produced by alkylation
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15
Q

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:
A
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16
Q

IV pumps e.g.

A

Peripherally inserted central catheter

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17
Q

Describe the main ADRs as discussed and some of the treatment specific ADRs LO

SIDE EFFECTS OF CHEMOTHERAPY?

A
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18
Q

Chemotherapy adverse effects – those due to effect of treatment on the tumour: (3)

A
  • 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
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19
Q

Vomiting

  1. Multifactorial but includes direct action of chemotherapy drugs on the ?
  2. Patterns of emesis:
A
  1. central chemoreceptor trigger zone
  2. – acute phase 4 - 12 hours

– delayed onset, 2 - 5 days later

– chronic phase, may persist up to 14 days

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20
Q

Alopecia

  1. When does this occur?
  2. Outcomes?
  3. Marked with which drugs?
  4. Minimal with which drugs?
  5. Help sometimes with?
A
  1. Hair thins at 2 - 3 weeks
    • May be total
      - May re-grow during therapy
  3. doxorubicin, vinca alkaloids, cyclophosphamide
  4. platinums
  5. scalp cooling
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21
Q

Skin Toxicity
1. Local effects

  1. General
    – bleomycin effects ?
  2. What drugs cause hyperpigmentation?
A
  1. – Irritation and thrombophlebitis of veins
    – extravasation
  2. • hyperkeratosis • hyperpigmentation • ulcerated pressure sores
  3. busulphan, doxorubicin, cyclophosphamide, actinomycin D
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22
Q

Mucositis
• Gastrointestinal tract epithelial damage

• May be profound and involve whole tract

  1. Most commonly worst in ?
  2. Presents as
A
  1. oropharynx
  2. – sore mouth/throat
    – diarrhoea
    – G.I. bleed
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23
Q

Cardio-Toxicity

  1. What drugs cause Cardio-myopathy
  2. What drugs cause Arrhythmias
A
  1. – doxorubicin ++ (> 550 mg/m2)
    – high dose cyclophosphamide
    – mortality approx. 50%
  2. – cyclophosphamide
    – etoposide
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24
Q

Lung Toxicity

Whats drugs lead to lung toxicity & state their effect.

A

• Bleomycin
– pulmonary fibrosis
– beware concurrent radiotherapy

• Mitomycin C, cyclophosphamide, melphalan, chlorambucil
– pulmonary fibrosis

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25
Q

Haematological Toxicity of Cancer Therapy

  1. Most frequent dose limiting toxicity
  2. Most frequent cause of ?
  3. Different agents cause variable effects on degree and lineages

What lineages are effected the most?

A

1.

  1. death from toxicity
  2. – Neutrophils – platelets
26
Q

Chemotherapy: cytotoxic drugs

Considered ‘dangerous’ drugs, need specialists to prescribe because:

A

• 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

27
Q

Appreciate the range of factors influencing pharmacokinetics in chemotherapy including
routes of delivery and drug resistance LO

Pharmacokinetics and chemotherapy

What causes variability?

A
  • Abnormalities in absorption
  • Abnormalities in distribution
  • Abnormalities in elimination
  • Abnormalities in protein binding
28
Q

Pharmacokinetics and chemotherapy (2)
What causes variability- further elaborate on what we mean by:

  1. Abnormalities in absorption
  2. Abnormalities in distribution
  3. Abnormalities in elimination
  4. Abnormalities in protein binding
A
  1. Absorption
    – N+V, compliance, gut problems
  2. Distribution
    – Weight loss, reduced body fat, ascites etc
  3. Elimination
    – Liver and renal dysfunction, other meds
  4. Protein binding
    – Low alb, other drugs
29
Q

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.

A

– 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

30
Q

Understand the clinical monitoring required to minimise ADR risk

Chemotherapy – monitoring during treatment

  1. How do we check response of the cancer to chemotherapy?
  2. Drug levels e.g.
  3. Checks for organ damage?
A
  1. – Radiological imaging
    – Tumour marker blood tests
    – Bone marrow/cytogenetics
  2. Methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
  3. – Creatinine clearance
    – Echocardiogram
31
Q

Awareness of the clinical trial basis for prescribing LO

How do the drugs get from bench to bedside?

A
32
Q

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.

A

– 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

33
Q

Chemotherapy: the aim of treatment
The aim is variable…

  1. Neoadjuvant –
  2. Adjuvant –
  3. Palliative -
  4. Primary –
  5. Salvage –
A
  1. Neoadjuvant – given before surgery or radiotherapy for the primary cancer
  2. Adjuvant – given after surgery to excise the primary cancer, aiming to reduce relapse risk eg breast cancer
  3. Palliative - to treat current or anticipated symptoms without curative intent
  4. Primary – 1st line treatment of cancer.. In many haematological cancers this will be with curative intent, initially aiming for remissiom
  5. Salvage – chemotherapy for relapsed disease
34
Q

Anaesthetic Techniques. These Can Be Combined.

Complete the flow diagram showing the different types of Anaesthetic techniques

A
35
Q

Conscious sedation:

A

use of small amounts of anaesthetic or benzodiazepines to produce a sleepy-like state. (Maintain verbal contact but feel comfortable)

​

36
Q

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.
A
37
Q

Recognise the names of example inhalational and intravenous anaesthetics LO

General Anaesthetics Difficult To Classify-VAST Range Of Structures.

  1. Give examples of Gases-Volatiles-Delivered via lungs
  2. Give examples of Intravenous general anaesthetics
A
  1. (Image)
  2. • Propofol
    • Barbiturates
    • Etomidate
    • Ketamine
38
Q

Know the range of effects on the CNS produced during general anaesthesia
(Guedel’s signs) LO

Guedel’s signs:

A

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.

39
Q

Anaesthesia is a combination of;

A
  • Analgesia (inability to feel pain)
  • Hypnosis (loss of consciousness)
  • Depression of spinal reflexes
  • Muscle relaxation (insensibility and immobility)
40
Q

Understand how Minimum Alveolar Concentration (MAC) describes ‘volatiles’ drug potency LO

End-Point Is Concentration Dependent. For Volatiles We Use ?

A

MAC To Describe Potency.

​

41
Q

MAC and Volatile Anaesthetic Potency

  1. What is potency ? (M&R year 1)
  2. Volatile anaesthetic potency is described by MAC or Minimum Alveolar Concentration. What is MAC?
  3. Anatomical substrate for MAC is ?
A

1.

  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

  1. spinal cord
42
Q

Factors Affecting Induction and Recovery.

A

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)

​

43
Q

What Affects MAC ?

A

• 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)
44
Q

MAC and effects of Nitrous Oxide.

A

Nitrous Oxide is very often added to other volatile agents (reduced dosing)

(30-60 yr olds)

45
Q

What receptors are important in anaesthetics?

A

GABAA Receptors

46
Q

What is GABA?

A

Major inhibitory neurotransmitter -> LGIC (Cl- conductance)

47
Q

Understand the role of the GABA receptors in anaesthesia LO

  1. What happens when anaesthetics potentiate GABA activity?
  2. With the exception of ? all anaesthetics potentiate GABAA medicated Cl- conductance to depress CNS activity.
  3. What other receptors can be used as a target for anaesthetics?
A
  1. • Anxiolysis (inhibits anxiety)
  • Sedation (state of sleep)
  • Anaesthesia
  1. Xe,NO2 and ketamine
  2. NMDA receptors probable other site
48
Q

Molecular-Cellular Target.

  1. In the brain consciousness is ?
  2. ? modulate this balance.
A
  1. a balance between excitation (Glutamate) and inhibition (GABA)
  2. Anaesthetics
49
Q

Describe how NDMA and GABAA receptors work

A
50
Q

Systems Target: Brain Circuitry.

Explain the effect of anaesthesia on the brains circuitry

A
  • 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).
51
Q

Targets: Putting it all together in a ‘whole’ human GABAA receptors activated in human brain during anaesthesia. In test tube Isoflurane potentiates benzodiazepine binding.

A
52
Q

Recognise the names of example inhalational and intravenous anaesthetics LO

Main Intravenous Anaesthetics: (3)

A
  • Propofol (rapid)
  • Barbiturates (rapid)
  • Ketamine (slower).
53
Q
  1. Use of IV anaesthetics
  2. Can be used as sole anaesthetic in TIVA (Total IntraVenous Anaesthesia).
  3. Target sites as for inhalational.
  4. With exception of ? all potentiate GABA
  5. Systems target as for inhalational.
A
  1. induction
  2. Ketamine (NMDA)
54
Q

How Do We Describe Intravenous Anaesthetic Potency ?

A
  • 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.
55
Q

Local and Regional Anaesthesia - which circumstances is it used?

A

Dentistry

Obstetrics Regional surgery (patient awake)

Post-op (wound pain)

Chronic pain management (PHN)

56
Q
  1. Local Anaesthetics: e.g.
  2. Characteristics
A
  1. Lidocaine, Bupivacaine, Ropivacaine and Procaine.
  2. • 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)
57
Q

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).
A
58
Q

What are these results showing?

A

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.

59
Q

Regional Anaesthesia

  1. What does is anaesthetise?
  2. Often described as a ?
  3. Uses local anaesthetic and or an opioid.
  4. Upper extremity (e.g.,);
  5. Lower extremity (e.g.,) ;
  6. Extradural / Intrathecal / Combined (labour).
A
  1. part of the body
  2. block of a nerve and hence the patient remains awake

3.

  1. interscalene, supraclavicular, infraclavicular, axillary
  2. femoral, sciatic, popliteal, saphenous
60
Q

Learn the main anaesthetic ADRs LO

Main Anaesthetic Side Effects (from the very common 1:10 category for GA)

  1. General anaesthesia:
  2. Local and regional
  3. Increased general concern re: ?
A
  1. – PONV (opioids)

– CVS

– hypotension

– POCD (increases with increasing age)

– Chest infection

  1. Depends on the agent used and usually result from systemic spread (Locals are Na+
    channel blockers so cardiovascular toxicity)

3.allergic reactions/anaphylaxis

61
Q
  1. Anaesthesia good example of polypharmacology.
  2. Anaesthesia: ?
  3. Vast array of agents for general; volatile or i.v.
  4. Main molecular targets of interest are;
A
  1. General, regional or local
  2. – GABA transmission.
    – NMDA glutamate receptors.
    – Voltage gated Na+ channels (locals).

Clinical Pharmacology, Therapeutics & Principles of Prescribing (19 decks)

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