PHAR3827 Oncology and Anti-Infective Agents

Cancer Statistics

1 in 3 men and 1 in 4 women diagnosed by 75

2nd leading cause of death

69% chance of surviving 5 yrs after diagnosis (cured)

+ table

Cancer Causes

Physical carcinogens: radiation, sunlight

Chemical carcinogens: polyaromatic hydrocarbons (eg from burnt food)

Biological carcinogens: mutagens, viruses

Lifestyle: smoking, diet, obesity, sedentary, air pollution

Genetic predispositions: BRCA1/2, p53 mutation (increases risk, not a cause)

Genetic Predisposition to Cancer

BRCA1/2: codes breast cancer type 1 susceptibility protein

p53: most commonly mutated gene in cancer (>50% cancers), encodes protein that regulates DNA repair and cell cycle arrest

Traditional Cancer Classifications

Leukemia: blood, WBC overproduction

Sarcoma: supportive/connective (bone, cartilage, muscle, vessels) and soft tissues

Carcinoma: from epithelial cells (breast, liver, lung, stomach)

Blastoma: blasts (immature/precursor cells), usually children

Metastatic: spread from 1° to 2° location

Cancer Characteristics

1) Altered cellular growth

2) Altered cellular behaviour

3) Altered intercellular communication

Numerical Cancer Staging

I: tumour confined to primary organ, operable and completely resectable

II: spread to local tissue and first LN, operable and resectable but higher risk

III: extensive primary tumour with deep fixation to deeper structures and local invasion, may be inoperable + require multiple tx

IV: distance metastases, primary site may be inoperable

TNM Cancer Staging

T 1-4: tumour size and spreading

N 0-3: LN involvement

M 0-1: if metastasised to other organs

Stage 0 Tis, N0, M0: tumour in situ

Stage 1 T1-2, N0, M0: spread to submucosa or muscularis propria

Stage 2 T3-4, N0-1, M0: spread to/through outer layers

Stage 3 T1-3, N1-2, M0: spread to LN

Stage 4 Any T, Any N, M1: spread to distant organ (liver, lung, peritoneum)

Cancer Treatment Influences

Patient characteristics

Tumour characteristic

Patient preference

Risk vs benefit calculations

Age, Comorbidity, Access to care, Organ function, Concurrent meds, Adherence, frailty, Memory + cognition, Mutations Immune status, Histological subtype, Gene expression

Chemotherapy MOA

MOA: kill cells by inducing apoptosis, non-specific = dose limiting AE

C/I: pregnancy

Problems with chemotherapy

Myelosuppression

Ototoxicity

Nephrotoxicity

Pulmonary toxicity

Hepatotoxicity

Neuropathy/peripheral neuropathy

Hypomagnesaemia

Alopecia

Cardiotoxicity

N&V

Neutropenia

Mechanisms of Cancer Resistance

1) decreased drug uptake / increased efflux

2) enhanced tolerance of drug to adducts on DNA/protein

3) enhanced repair of DNA/protein adducts

4) increased drug deactivation

Adducts: Many chemotherapeutic drugs bind to DNA or proteins within cancer cells, forming adducts

CRC Epidemiology

4th most common cancer

2nd most common cause of cancer-related death

Incidence and mortality increase with age and male

↑ developed countries

CRC Risk Factors

Western dietary pattern: alcohol, red meat, less vegetables/soluble fibre

Obesity

Sedentary lifestyle

IBD (UC+CD); inflammation adjacent to epithelial cells

Changes in colonic microbiome

Genetics - family history accounts for 25%

CRC Clinical Presentation

Changes in bowel habits

Rectal bleeding

Abdominal pain and bloating

N&V, decreased appetite

Anaemia and fatigue

Unexplained weight loss

CRC Screening

FOBT: asymptomatic, non-invasive, at home, simple, free 50-74

Colonoscopy: symptomatic, family history, history of polyps/adenomas/cancer

CRC Diagnosis

Endoscopy/Colonoscopy

Imaging: CT, PET, MRI, X-ray

Blood tests: tumour markers (CEA)

Tumour pathology

CRC Pathogenesis

1) Adenoma-Carcinoma Sequence (85-90%): benign colorectal polyp (adenoma), accumulation of mutations > invasive adenocarcinoma

2) Serrated Pathway (10-15%): serrated adenoma > serrated adenocarcinoma

3) Inflammatory Pathway (<2%): persistent inflammation + genetic alterations

MSI

Loss of function of DNA mismatch repair function - deficient DNA mismatch-repair (dMMR)

MSI-high tumours: unable to repair DNA mutations = hypermutation genotype

Unstable MS = highly immunogenic

CRC Types

RIGHT: women, worse prognosis

LEFT: men, better prognosis

CRC Treatment

SYSTEMIC CHEMOTHERAPY: adjuvant + metastatic

- Fluoropyrimidine: 5FU, Capecitabine

> Folinic acid: Leucovorin

- Platinum: Oxaliplatin

- Topoisomerase inhibitor: Irinotecan

MOLECULAR TARGETED THERAPY (1 mAb + 1 MTKI):

- EGFR (Cetuximab, Panitumumab): most common, LEFT SIDED ONLY, must NOT contain mutations in EGFR pathway (KRAS, BRAF, MEK)

- VEGF (Bevacizumab, Regorafenib (MTKI)): angiogenesis

IMMUNOTHERAPY: for tumours with high mutation load, only MSI-high tumours

- PD1: Nivolumab, Pembrolizumab

CRC Systemic Chemotherapy Regimens

FOLFOX: 5FU + Leucovorin + oxaliplatin

Capeox: Capecitabine + oxaliplatin

FOLFIRI: 5FU + Leucovorin + irinotecan

FOLFIROX: 5FU + Leucovorin + irinotecan + oxaliplatin

EGFR-i + capecitabine AE

Skin toxicity - emollients, hand creams, maintain skin barrier

Oxaliplatin AE

paresthesias + neuropathies - education, support, keep drinks warm

Lung Cancer Epidemiology

3rd most common cancer

Leading cause of cancer-related death

Increased in females

Most are adenocarcinoma (epithelial derived)

Lung Cancer Clinical Presentation

Coughing blood

Persistent new/changed cough

SOB

Pain when coughing/deep breath

Chest/shoulder pain

Hoarse voice

Weight loss

Loss of appetite

Persistent chest infection

Fatigue/weakness

Lung Cancer Risk Factors

Current or former smoking

Occupational + environmental: asbestos, air pollution, radioactivity, coal

Lung Cancer Pathogenesis

Squamous cell process

MUTATIONS

- KRAS (most common): more frequent in male, smokers

- EGFR: more frequent in female, non-smoker, Asian ancestry

85% of EGFR mutations = deletions in exon 19 and point mutation in L858R in exon 21

Lung Cancer Systemic Chemotherapy

Adjuvant and metastatic settings

Platinum (carboplatin + cisplatin)

Taxanes (paclitaxel + docetaxel)

Vinca alkaloids (vinorelbine)

Anti-metabolites (gemcitabine + pemetrexed)

Topoisomerase I inhibitors: Etoposide + cisplatin - SCLC

Lung Cancer Molecular Targeted Therapy

INHIBITS EGFR (TK):

• Gefitinib

• Erlotinib

But; rapid and intrinsic drug resistance

INHIBIT SIGNALLING CAUSED BY ALK/EML4 FUSION PROTEINS: activate signalling pathways involved in cell growth, proliferation, survival

• Brigatinib

• Lorlatinib

• Alectinib (MTKI)

TARGETS ROS 1 GENE FUSIONS: drives carcinogenesis + continuous activation of downstream signalling pathways

• Lorlatinib

• Alectinib (MTKI)

Lung Cancer Immunotherapy

Works best in tumours with high mutation loads

PD1 and PDL1 --> allows T cells to mount an effective anti-tumour response

PD1:

• Nivolumab

• Pembrolizumab

• Durvalumab

PLD1: Atezolizumab

CTLA4: Ipilimumab

EGFR Resistance (Lung Cancer Immunotherpy)

New mutations in TK binding pocket (T790M)

EGFR amplification (increases receptor expression)

Upregulation of other EGFR

EGFR pathway bypass (activate alternate pathways)

T790M Gatekeeper Mutation: limits drug accessibility to kinase ATP-binding pocket + Increases ATP affinity of mutant EGFR = resistance + tumour growth

Goals of therapy for people with cancer

Curative: tumours are small, benign, isolated - Mainly surgery, radiotherapy, some chemotherapy

Adjuvant: addition after initial curative therapies to reduce recurrence - radiotherapy, chemotherapy, hormone therapy

Neoadjuvant: First step to shrink a tumour before main treatment - radiotherapy, chemotherapy, hormone therapy

Palliative: Treatment to relieve symptoms and reduce suffering

Most common non-cancer comorbidities

CVD, COPD, diabetes

Cytotoxic Chemo vs Molecular Targeted Tx

CYTOTOXIC CHEMOTHERAPY

• Targeted but low specificity

• Very low therapeutic indices

• Affects both normal and malignant cells

• Mainly IV

MOLECULAR TARGETED DRUGS (-MABS AND -IBS)

• Highly target specific, but not 100% tumour selective

• Improved therapeutic index

• Short bolus IV or oral

• Many CYP3A4 substrates/inducers/inhibitors - higher DDI risk

PK issues of chemotherapy

Mainly IV, some oral (F, 1st pass)

Poor tumour vascularisation = low conc of drug

Very few drugs cross BBB (CNS tumours)

Comorbidities: decreased liver/renal function

Renal excreted drugs require good GFR

Many chemo agents toxic to kidney (MTX, cisplatin)

Concurrent meds - ADR, DDI

Variability in metabolising enzymes

Need fro pro-drug metabolism to active drug

Dose adjustments in chemotherapy

>65 Gender

Other medications/comorbidity

Performance status - functional tolerance for withstand toxicity

Liver function - drug dependent dose reductions (25-50%)

Renal function - carboplatin definitely, others adjusted too

OBESE PTS: Still capped to 2.0m

If obese pts dosed according to ideal/actual BW: no increase in toxicity + improved outcomes

Action if person experiences toxicity

0 - none

1 - mild: monitor

2 - moderate: monitor + chemotherapy break + supportive care

3 - severe: monitor + chemotherapy break + supportive care +/- hospitalisation

4 - life-threatening: monitor + cease chemotherapy + supportive care + hospitalisation

SUPPORTIVE CARE: blood transfusions, fluids, steroids, antihistamines, anti-emetics

Cancer Chemotherapy Toxicities

Haematological Toxicity

GI Toxicity (diarrhoea + dehydration, colon complications)

Dermatological Toxicity (alopecia, nail sx)

Cutaneous Toxicity

Haematological Toxicity (Chemotherapy)

↓ Erythrocytes = anaemia, fatigue

↓ thrombocytes/platelets = high risk of bleeding

↓ WBC (granulocytes, myeloid cells) = infection, fever

↓ T and NK cells = increased infections

CAN BE LIFE THREATENING - SEND TO ED

GI Toxicity (Chemotherapy)

COLON COMPLICATIONS: ↓ villus and crypt cells = GI toxicity = diarrhoea and dehydration

- Irinotecan, F5U, capecitabine

Dehydration can be fatal - Recommend ED if diarrhoea is non-manageable

NAUSEA AND VOMITING: 5HT, substance P, CCK1 release > activates receptors > signal projects to central pattern generator/vomiting centre in medulla > direct stimulation of cells

- cisplatin, irinotecan, 5FU

Anti-emetics are useful

Dermatological Toxicity (Chemotherapy)

ALOPECIA: taxanes, vinca alkaloids, irinotecan

NAIL SYMPTOMS: 5FU, capecitabine, taxanes

Hand-foot reactions - Similar to management of dermatological conditions - Aim for preventative measures: 10% urea-containing moisturisers.

Lignocaine patches + CS may be needed

Cutaneous Toxicity (Chemotherapy)

AE of EGFR inhibitors, BRAF inhibitors, MEK inhibitors

Dose-dependent, acute (occurs within 1 week of tx)

Mon-life-threatening

Diffuse acneiform rash on face, trunk, extremities (not hand/feet)

MOA: ↑ epithelial cell motility, terminal differentiation = epidermal sloughing = inflammation

PRACTICE POINTS: Similar to management of dermatological conditions - Aim for preventative measures including moisturisers. Antibiotics + corticosteroids may be needed

BRAF inhibitors AE

photosensitivity (VEM), arthralgia, fever (DAB)

MEK inhibitors AE

interstitial lung disease, pneumonitis

VEGF Pathway Toxicities

Hypertension (80%) within 1 week > can precipitate further CV complications - stroke, MI, HF, AKI

Exacerbated in patients with CV risk factors

Early detection is important - toxicity is reversible on cessation

Cancer Immunotherapy Toxicities

Biological DMARD toxicities:

- Injection site reactions (SC)

- Infections - esp opportunistic bacteria, fungus

- Recurrence of latent infections - TB, HBV (avoid live vaccinations)

- Increased malignancy risk

Long-term Toxicity - Cushing's-like syndrome

• Glucocorticoid mediated effects: Muscle wasting, Fat redistribution, Osteoporosis, ↑ blood glucose, Opportunistic infections, skin thinning

• Mineralocorticoid-mediated effects: Weight gain, oedema, hypertension, Na+/water retention

Often managed with steroids + bDMARDs (infliximab)

CMs in Oncology

Laetrile (Vit B17): from apricot seed kernels

• Amygdalin: bitter substance in fruit pits

• Thought to kill cancer cells - hydrogen cyanide changed into cyanide

• No evidence

• Cases of cyanide poisoning

Mistletoe extract (IV)

• Mixed evidence on efficacy

• Favourable safety outcomes

Essiac Tea - whole herb

• No evidence

• Cases of harm

Fostering appropriate and safe use of CM in cancer

1) Identify intent behind using CM

2) Availability of credible information sources

3) General safety issues

4) Severity of disease

- HIGHLY CURABLE: avoid concomitant use of less proven tx

- DIFFICULT-TO-CURE: different situation

- PALLIATIVE CARE - CMs more accepted in this setting

3 Ps Interaction in CM use

PHARMACODYNAMIC: one substance alters sensitivity/ responsiveness of tissues to another

PHARMACOKINETIC: alteration to absorption, distribution, metabolism or excretion

PHYSIOCHEMICAL: two substances that are physically or chemically incompatible

Potential clinical outcomes of 3P interaction

• Increased therapeutic or AE

• Decreased therapeutic or AE

• Unique response that does not occur when either used alone

PRACTICE TIPS TO PROMOTE PATIENT SAFETY

1) Always ask patients about all their medications, including CM products encourage disclosure to their GP and Oncologist

2) Identify the intent and expectation of the patient

3) Respect patient autonomy

4) Communicate the known risks and benefits of the CMs

5) Always provide advice based on best currently available evidence and patient treatment goals

6) Document any CM product use on patient records

7) Be aware of and monitor and report any ADR

8) Ensure that you are practicing legally and ethically when providing any health information

Supportive Care

Improve QOL in serious or life-threatening disease

Helps person/family cope with illness and tx - before/through diagnosis/tx, through cure/continuing illness or death and bereavement

GOAL: prevent or treat as early as possible disease symptoms, tx SE, psychological/social/spiritual problems related to a disease or its treatment

Palliative Care

Towards end of life

GOAL: relief from pain, distressing symptoms, integrate psychosocial/spiritual care aspects, provide support that allows them to be as active as possible until death

Symptoms observed in palliative care

Pain

Fatigue

Psychosocial

Delirium, agitation, terminal restlessness*

Dyspnoea*

Respiratory tract secretions*

GIT incl N&V

Oral issues

Haematological

Medication Rationalisation

Reviewing medicines to rationalise, case or modify treatment

Deprescribing

Withdrawing medicines no longer beneficial/appropriate in palliative context and/or not desired by patient - generally medicines for long-term benefit

• Minimise burden/harms from treatment

• Medicines should provide benefit and optimise symptom relief/comfort

• Decisions align with the patient's goals/wishes

• Drug-related AE can be difficult to distinguish from end of life deterioration

Polypharmacy increases: interactions, AE, non-adherence, financial burden

COMMON MEDICINES DEPRESCRIBED

Antidiabetic

Antihypertensive

Lipid-modifying

Anticoagulants and antiplatelets

Thyroid replacement therapy

Routes of drug administration in palliative care/terminal phase of life

PATIENT CAN LONGER SWALLOW - Dispersed or crushed? Alternate formulation? Different route?

SC > IM (painful) or IV (infection risk)

Injection site: sufficient fat, lymphatic drainage, intact skin

Can insert indwelling plastic cannula (eg Intima) or butterfly needle

Syringe drivers: convenient, comfortable way to administer multiple medicines

Approaches to Palliative Care

1) Integrated care: Multimodal approach

2) Targeted care: Targets the cause

3) Tailored care: suitable to circumstances, beliefs, and preferences

Advanced Care Planning

Palliative Care

Documents in case decision-making capacity is lost

Considered alongside consultation with Enduring Guardian

Advance care directive is legally binding

Ideally explored early

Empowering, Unpleasant feelings

Patient Dignity Question

"what do I need to know about you as a person to give you the best care possible?"

grief, appearance, body image, changing relationships, intimacy issues

Discussion with adults in advanced stages - PREPARED

Prepare for the discussion

Relate to the person

Elicit preferences from person and carer/s

Provide tailored info for person and carer/s

Acknowledge emotions and concerns

Realistic hope (foster) - peaceful death, support

Encourage questions and discussion

Document

Discussion with children about ANOTHER'S illness

Up to 6

• Reinforcement: not being blamed for illness

• Reassurance: they will be safe and cared for

• Concrete descriptions of death - possibly repeat deceased will not come back

6-12

• Concerned about friend/peer acceptance

• Encourage to maintain friendships and affirming activities (sports, social)

• Encourage to think about entire relationship rather than recent - avoids guilt

• May provide simple explanation of dx/tx

• Will have misconceptions regarding causes - provide clear and accurate info

12+

• As above

• Give opportunity to discuss changed family roles and illness with parents

• May seek info independently - encourage to check reliability with parents

MEDICINAL CANNABIS

Delta-9-THC more psychoactive than CBD

• Nabiximols (Sativex)

• Cannabidiol (Epidyolex)

Indications: Seizures, others on SAS

Some Evidence: MS, epilepsy in kids/YA, Chronic non-cancer pain, N&V due to chemo, Palliative (pain, insomnia, appetite, stimulant, anxiety, depression)

No Evidence: Weight gain, appetite improvement, improved mood (cancer, AIDS, Alzheimer's)

AE: N&V, somnolence, dizziness, asthenia, fatigue, anaemia, confusion, pain, diarrhoea, headache, dyspnoea, hallucinations

Recommendations

Recommendations:

- Only use in palliative care after standard tx ineffective

- Likely to be more useful in palliative as they promote appetite and relaxation

- CBD component - may reduce convulsions, anxiety, psychotic symptoms

- Driving prohibited if THC consumed

NSW VAD eligibility

Pt has decision making capacity

1st request > 2x assessment > written declaration > final request

Adult citizen/PR of AUS, in NSW, ≥1 advanced dx that will likely cause death in 6-12 mths and causes suffering that can't be relieved

BURNOUT, MORAL DISTRESS, AND COMPASSION FATIGUE IN HEALTHCARE PROVIDERS

BURNOUT: Stressors exceed capacity

- Dissatisfaction, unhappiness

- Emotional exhaustion

- Depersonalisation: ↓ empathy

- Headache, weight loss, GI, fatigue, sleep, irritable, low morale

MORAL DISTRESS: Disconnect between required actions vs ethical values, cultural standpoints

- Aggression

- Decreased job satisfaction

- Resignation

COMPASSION FATIGUE: Gradual weakening of compassion over time

- May lead to burnout

SELF-CARE MEASURES TO PREVENT STRESS AND BURNOUT IN HEALTHCARE PROVIDERS

Education, training, skills

Self-awareness and realistic expectations

Peer and professional support

Workload and work-life balance

Prostate Cancer Risk Factors

Age

Family history

Genetics (BRCA1, BRCA2)

Ethnicity

Lifestyle and environment factors

Prostate Cancer Symptoms

Rare in early disease

• Frequent/sudden urge to urinate

• Difficulty urinating

• Blood in urine or semen

• Pain in lower back, pelvis, hips, upper thighs

• Unexplained weight loss

Prostate Cancer Screening, severity

Physical examination or DRE: size/consistency/abnormalities

• 20-25% with abnormal DRE have prostate cancer

Prostate-specific antigen (PSA) blood test - strongly associated with risk (produced by malignant and non-malignant epithelial cells)

Pathology

Gleason score: evaluates aggressiveness

• higher score = higher grade tumour = aggressive

MRI & radionuclide bone scans (bone scintigraphy)

Prostate Cancer Number Staging

1: <0.5 of ONE side of prostate gland

2: >0.5 of ONE side of prostate gland

3: broken through capsule of prostate gland

4: spread to nearby organs, LN or body parts outside pelvis

Prostate Cancer Surgical Removal

Radical prostatectomy (prostate)

TURP (inner prostate): symptom relief

Orchiectomy (testicles): control cancer growth

Prostate Cancer Brachytherapy

Implant radioactive seeds > intense irradiation of prostate

Minimal exposure to surrounding tissue

Well-tolerated

Prostate Cancer Hormonal Therapies

ANDROGEN DEPRIVATION THERAPY (ADT): Testosterone is responsible for the growth of prostate cancer... ↓ testosterone by testes

FOR Advanced Prostate Cancer

GnRH/LHRH agonists: Goserelin, Leuprorelin, Triptorelin

GnRH/LHRH antagonists: Degarelix

Anti-androgens: Bicalutamide, Enzalutamide, Cyproterone

Steroid synthesis inhibitors: Abiraterone

ANDROGEN DEPRIVATION THERAPY (ADT) AE

Osteoporosis (all except anti-androgens)

Zoledronic acid, pamidronate, denosumab:

- Increase BMD in men with osteopenia receiving ADT for non-metastatic PC

- Prevent skeletal-related events in patients with bone metastases from solid tumours

- Reduce incidence and severity of metastatic bone pain, improve QOL

- Treat hypercalcaemia of malignancy (following IV hydration)

Defining features not found in eukaryotic cells - so can be selectively targeted in bacterial cell

1) Cell wall + plasma membrane

2) No define nuclei - selectively targets bacterial nucleoid

3) No organelles - can target specific bacterial processes

4) Different biochemistry - different metabolic pathways etc

Antimicrobials agent classes + examples

Inhibition of cell wall synthesis (b-lactams, cycloserine, vancomycin)

Inhibition of metabolism (sulphonamides)

Inhibition of nucleic acid transportation and replication (quinolones)

Inhibition of protein synthesis (chloramphenicol, macrolides)

Inhibition of cell membrane function (isoniazid)

SUMMARY of mechanisms of RESISTANCE against antimicrobials

DRUG MODIFICATION

b-Lactams, chloramphenicol, aminoglycosides, isoniazid

TARGET MODIFICATION

b-Lactams, aminoglycosides, isoniazid, vancomycin, daptomycin, quinolones, sulphonamides, linezolid, macrolides, azoles

INCREASED LEVELS OF DRUG TARGET

D-cycloserine, isoniazid, azoles

DECREASED ACCUMULATION OR INCREASED EFFLUX

Chloramphenicol, aminoglycosides, Quinolones, macrolides, azoles

Empirical Therapy of Antimicrobial Therapy

Treat based on most likely organisms and susceptibility

Aim to use narrowest spectrum agent first

Directed Therapy of Antimicrobial Therapy

Treat based on culture and susceptibility test

IV to oral conversion of Antimicrobials criteria + benefits

1) Clinical improvement + Fever resolved or resolving

2) No unexplained haemodynamic instability

3) Tolerating oral intake with no concerns about malabsorption

4) Suitable ORAL antimicrobial that is same drug or same/similar spectrum

Can go home sooner

↑ time in hospital = ↑ risk of infection from resistant bacteria

Clinical Microbiology

Improves antimicrobial use

Limits results seen by a clinician + Encourages appropriate use = ensures antimicrobials are prescribed judiciously and effectively

Ethical issues in immunology and cancer

Respect for autonomy

'Best interests' vs 'respect for autonomy'

Access to treatment - cost, choice, availability [justice]

Conscientious objection

New technologies, medicines, and regulations

Steps in decision making

Identify the Facts

Moral Parameters

Legal Constraints

Human Values

Identify Options

Recognise Implications

Red Face Test

Make the Decision

Justify - The most important part in decision making

Revisit & Reflect

Principles of Bioethics

Non-Maleficence - Do No Harm

Beneficence - To do good; Best interests

Autonomy - respect for individuality, informed consent, confidentiality, respect for refusal

Justice - equity of access

Euthanasia

Painless killing of patient suffering from an incurable and painful disease or in an irreversible coma

VOLUNTARY: Competent patient makes the request

NON-VOLUNTARY: physician/guardian decides to end life on behalf of incompetent patient

Advanced directive

A living will which gives durable power of attorney to a surrogate decision-maker

Remains in effect during the incompetency of the person making it

Nembutal

Pentobarbital, pentobarbitone

Short-acting barbiturate

High doses --> death by respiratory arrest

Types of Fungal Infections

Mold: aspergillus

Yeast: candida

Risk factors for fungal infections

[essentially anything that lowers immune system]

Neutropenia

Leukemia

Immunosuppression

HIV/Aids CD4<200

GCs >0.3mg/kg/d

Central venous catheter

Mucositis

Broad spectrum antibiotics

Genetics (impaired innate/adaptive immunity)

Lung cavities

Signs and Symptoms of Fungal Infections

Fever, chills

Cough that brings up blood

Chest/joint pain

Headache

Eye symptoms

Skin lesions

Aspergillus Infection Treatment (mold)

Voriconazole IV/PO:

- loading 400mg (6mg/kg) bd

- maintenance 200mg (4mg/kg) bd

INTERACTIONS: inhibitor and substrate of CYP3A4, 2C9, 2C19

AE: hepatotoxicity, hallucinations, rash (due to photosensitivity)

METABOLISM: hepatic

- liver impairment = ↓ metabolism = ↑t1/2, toxic conc

- inflammation = ↓CYP450 = ↓CL = accumulation

- metabolic ratio lower when CRP higher

TDM: target 20-25fAUC/MIC ratio

RESISTANCE: combination amphotericin + azole, step down when no resistance shown

Alternatives: amphotericin, posaconazole

- Covers candida + aspergillus + mucorales

- DDI: CYP540 inhibitor, pgp substrate

- AE: hepatotoxicity

- susp: PPI reduces absorption, needs food/acidic enviro

- TDM for ALL susp patients and selected tab patients (altered drug exposure suspected)

Candida Infection Treatment (yeast)

Echinocandins (IV ONLY)

- caspofungin: 70mg then 50mg d (>80kg=70mg)

- anidulafungin: 200mg then 100mg d

- micafungin: 100mg d (no loading)

INTERACTIONS: few

AE: few

Alternative: Fluconazole (PO/IV)

- loading 800mg (12mg/kg)

- maintenance 400mg (6mg/kg)

INTERACTIONS: inhibits CYP3A4, 2C9, 2C19

METABOLISM: renal

- CrCl 21-50mL/min = 50% d

- CrCl <21mL/min = 25% d

Importance of loading dose for voriconazole

Loading dose administered - plasma conc close to SS achieved within first 24h

Without loading dose - accumulation occurs during bd dosing and SS achieved by day 6

Oral Thrush Treatment

CAUSE: candida albicans

AT RISK: immunodeficiency, diabetes, malignancy, HIV, prolonged CS/antibiotic use

MILD: topical

- Nystatin oral suspension 4x/d 10000 units

- Miconazole oral gel 4x/d 2.5mL

(after meal, rinse in mouth for as long as possible then spit out)

- Amphotericin lozenges 4x/d 10mg

SEVERE: systemic

- fluconazole PO 50-200mg d

Denture-wearer: soak overnight in 0.2% chlorhexidine, antifungal gel

Cryptococcus Infection Treatment

INDUCTION 2 WKS

Amphotericin B 10mg/kg ONE DOSE +

Flucytosine 25mg/kg every 6h +

Fluconazole 1200mg d

CONSOLIDATION 8 WKS

Fluconazole 800mg d

TDM: Flucytosine

- Maintain conc 2h after a dose at 30-80mg/L or trough conc at 25-50mg/L

- Prolonged conc >100 mg/L = toxicity

Pneumocystis Infection Treatment

PROPHYLAXIS: trimethoprim + sulfamethoxazole 960mg d

TREATMENT: trimethoprim + sulfamethoxazole 30mg/kg 3-4x/d for 14 days, preferably IV

ALTERNATIVE

- dapsone + trimethoprim

- clindamycin + primaquine/atovaquone/pentamidine

TARGETS FOR ANTI-CANCER AGENTS

DNA: Anthracyclines, Camptothecin, Nitrogen mustards, Cisplatin, Temozolomide

Microtubules: Taxanes (M-phase specific)

Metabolism: Methotrexate, 5-FU (S-phase specific)

Epigenetics: Azacitidine, Decitabine, Vorinostat, Romidepsin

Cell Signalling: TKI

Phases of cell cycle

G1: Cell expands, content duplicated

S Phase: Chromosomes duplicated - helicase, polymerase, ligase

G2: Growth and preparation for mitosis, Chromosomes checked for errors

M Phase (Mitosis) - PMATC: Chromosomes separated between two new nuclei

G1, S, G2 = Interphase - period between each mitosis

Methotrexate MOA and resistance

S-phase specific

(i) inhibit de novo synthesis of nucleotides for RNA and deoxynucleotides for DNA

(ii) incorporate into RNA/DNA and affect replication, transcription, translation

Anti-metabolite

MOA: DHFR inhibitor

RESISTANCE: up-regulation of DHFR gene = ↑ enzyme = insufficient MTX to inhibit all of DHFR

INDICATIONS: Acute leukaemias, breast cancer

- binds more tightly to cancer cells than normal cells because cancer cells has higher levels of polyglutamate, this allows folinic acid to "rescue" normal cells by displacing MTX

- Folinic acid doesn't need DHFR to convert into an active form; can be directly used by cells

5-FU

S-phase specific

Anti-metabolite

MOA: Irreversibly binds to thymidylate synthase > enzyme-substrate complex > blocks conversion of dUMP into dTMP

RESISTANCE: down regulation of cellular enzymes

- Capecitabine (5FU prodrug) - avoids DPD-catalysed degradation (used in breast cancer)

Main toxicity to bone marrow