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NUR3120 Pharm, 2nd half - Coggle Diagram

- - - - Ends with pam, lam
      - Types/examples
        
        Used as hypnotics: diazepam, triazolam, temazepam
        
        Used as pre-anaesthetics: diazepam, midazolam
        
        May also have anti-convulsant effects: diazepam
        
        Used as anxiolytics/sedatives: diazepam, lorazepam
      - MoA
        
        Benzodiazepines binds to benzodiazepine site of chloride channel > makes the GABA open chloride channel more easily
        (potentiates influx of Cl ions leading to hyperpolarisation --> neurons not firing, less activity)
        
        If in limbic system = alter mood
        If in reticular activating system = cause drowsiness
        If in motor cortex = relax muscles
      - Duration (onset of action shorter, most likely half life shorter)
        
        Intermediate acting (10-20hr)
        
        Used for anxiety disorders, insomnia
        
        Examples: Alprazolam, estazolam, lorazepam, temazepam
        
        Estazolam side effect: lapse in memory
        
        Long acting (1-3days)
        
        Used for chronic conditions, insomnia
        
        Examples: diazepam, flurazepam, quazepam, chlordiazepoxide, clorazepate
        
        Short acting (3-8hr)
        
        Used for surgery, insomnia
        
        Examples: Midazolam, triazolam, oxazepam
      - Adverse effects
        
        Acute toxicity/overdose = cause severe respiratory depression, especially used concurrently with alcohol
        Treatment by flumazenil benzodiazepine antagonist
        
        Drowsiness, confusion, amnesia, impaired muscle coordination (non-optimal brain function)
        
        Tolerance and dependence:
        Has abuse potential
        Dependence can develop: disturbed sleep, rebound anxiety, tremor and convulsions (withdrawal effects)
        Important to withdraw gradually
    - - Barbiturates: phenobarbital
        
        MoA: potentiate GABAvA mediated Cl currents but at a site distinct from benzodiazepines (barbiturate site)
        
        Why is barbiturates mostly replaced by benzodiazepines now?
        Barbiturates have tendency to develop tolerance and dependence + flumazenil not effective for treating barbiturate overdose
        
        Severe withdrawal symptoms
        
        Anaesthetic doses = barbiturates can directly open Cl- channels as well as Na+ channels
        
        Duration of action
        
        Short (3-8hrs) Pentobarbital/amobarbital
        Sedative and hypnotic
        
        Ultrashort (20min): Thiopental
        Induction of anesthesia
        
        Long (1-2days) phenobarbital
        Anticonvulsant
        
        Barbiturates last line for epilepsy, high abuse potential, and severe withdrawal effects = not meant for long term use
      - Buspirone
        
        MoA: serotonin 5-HTv1A receptor partial agonist, also binds to dopamine receptors
        
        Indicated for generalized anxiety disorder, but anxiolytic effects takes 1-2 weeks
        (Lacks anticonvulsant and muscle relaxant properties --> does not work on GABA receptor)
      - Zolpidem
        
        MoA: potentiates GABA allosteric mediated Cl- currents at the same site as benzodiazepines
        
        Good hypnotic effect = primarily for insomnia
        (Not as effective as anxiolytics)
      - Propranolol
        
        Class: beta-adrenergic receptor antagonist
        
        A lot of anxiety states = related to activation of adrenergic system/sympathetic nervous system
        
        Contraindications: patients with asthma/heart conditions
        
        Used for: treating performance anxiety/social phobias
        
        Reduces physical symptoms associated with adrenergic activation
- - - - Examples and duration of action
        
        Lidocaine (Xylocaine/lignocaine) Medium
        Mepivacaine (Carbocaine; isocaine) Medium
        Bupivacaine (Marcaine) Long
        Etidocaine (Duranest) Long
        Prilocaine (Citanest) Medium TAKE NOTE
        Ropivacaine (Naropin) Long
      - Method of metabolism: Hepatic enzymes (amide bond)
    - - Examples and duration of action
        
        Cocaine Medium
        Procaine (Novocaine) Short
        Tetracaine (Pontocaine) Long
        Benzocaine Surface use only (very low solubility: use as dry powder)
      - Method of metabolism: plasma/tissue non-specific esterases (ester bonds)
      - Can cause allergic reactions (Ester LA hydrolyzed to PABA derivatives)
    - - Infiltration
        
        Use: Direction injection into tissues to reach nerve branches and terminals. Used in minor surgery
        
        Drugs: Most
      - Nerve block
        
        Uses: LA injected close to nerve trunks to produce a loss of sensation peripherally. Used in surgery, dentistry, analgesia
        
        Drugs: Most
      - Surface
        
        Use: nose, mouth, bronchial (spray form), cornea, urinary tract
        
        Drugs: lidocaine, tetracaine, dibucaine, benzocaine
      - Epidural
        
        Uses: Injected into epidural space, blocking spinal roots. Used for spinal anesthesia, also for painless childbirth
        
        Drugs: Mainly lidocaine, bupivacaine
  - - - CNS and CVS issues
        Bupivacaine more cardiotoxic than most other LAs
        Cocaine blocks noradrenaline reuptake, increased noradrenaline in synapse causes vasoconstriction and hypertension
        
        Ester LAs can be hydrolyzed to PABA
        
        Prilocaine metabolised to O-toluidine = causes methaemoglobin (blood turn blue, ability to have oxygen exchange is now compromised)
        
        Treatment: IV methyleneblue/ascorbic acid: convert methaemoglobin to haemoglobin
- - - - The higher solubility in blood, the slower onset (stay in blood)
        Nitrous oxide vs halothane. NO>
        
        Absorption into blood factors
        
        Concentration of anaesthetic in inspired air
        
        Solubility of GA
        
        Blood flow through lungs
        
        Which organs/tissue will receive GA faster and how?
        Brain, livver, lungs and heart. This are highly perfused organs. Anaesthetic levels in these tissues equilibrate with those in blood quickly after administration
        
        Elimination
        
        Inhalation anaesthetics eliminated almost entirely via lungs
        
        Miniimal hepatic metabolism
        
        Factors that determine uptake also determine elimination
        
        Some metabolites can be toxic: fluorides/isoflurane and enflurane neprotoxic. Halothane is hepatotoxic
      - MoA (proposed):
        
        Enhance neurotransmission at inhibitory synapses via allosterically increasing GABA receptor sensitivity = GABA neurotransmitter is inhibitory, this reduces overall synaptic activity of brain
        
        Depress neurotransmission at excitatory synapses via blocking glutamate neurotransmitter acting on NMDA receptor thus preventing NMDA receptor activation
      - Minimum alveolar concentration (MAC) low = higher anesthetic potency
        MAC defined as minimum concentration of drug in alveolar air that will produce immobility in 50% of patients exposed to painful stimulus
        1.2-1.5x of MAC to ensure 100% patients get immobilised.
        Does not apply to nitrous oxide
        
        MAC values alter with age, conditiion, concomitant administration of other drugs, etc.
      - Examples
        
        Halothane
        
        MAC: 0.75%
        Medium rate of onset and recovery
        Little no analgesia until unconsciousness --> supplement with Nitrous oxide?
        Causes respiratory depression dose-dependently (higher the concentration, the more the breathing affected)
        Decrease BP due to depression of cardiac output bradycardia and arrhythmia may also occur leading to hypotension and dysrhythmia
        Relaxes skeletal muscle and potentiates skeletal muscle relaxants
        May lead tto halothane-associated hepatitis
        NOT COMPATIBLE WITH EPINEPHRINE
        
        Isoflurane
        
        Pungent smell
        MAC: 1.4%
        Medium rate of onset and recovery
        Similar to halothane with less hypotension and arrhythmia
        Decreases BP due mmainly to decrease in systemic vascular resistance
        
        Genetic predisposition to malignant hypertermia should not use
        
        Adverse effects including mild nausea, vomiting, tremor, dose-dependent respiratory depression and a reduction in blood pressure.
        
        Sevoflurane
        
        MAC: 2%
        More rapid rate of onset and recovery
        Metabolised in liver = release inorganic fluoride = nephrotoxic
        When exposed to CO2 absorbents in anesthetic machines, degrade to a compound that is potentially nephrotoxic
        
        Nitrous oxide
        GAS
        
        Rapid onset and recovery but lack potency
        Gives analgesia + amnesia but not complete unconsciousness or surgical anaesthesia
        Supplement primary anaesthetic
        When used alone: as analgesic agent (dentistry: entonox)
        Major concern: post-operative nausea and vomiting
        NO SIGNIFICANT EFFECTS ON BP AND RESPIRATION
    - - Examples
        
        Thiopentone (Sodium thiopental)
        
        Extremely high lipid solubility
        Enters brain easily and rapidly --> rapid onset of action (unconsciousness occurs 10-20 sec after IV)
        Single dose: redistributes to less vascularized tissues Ultrashort action
        Multiple doses depends on clearance --> slow elimination, large Volume of distribution, Vd --> goes to peripheral organs
        Active metabolite: pentobarbital --> existing liver problems, less able to metabolise
        Extensively bound to plasma protein --> only small amount of free drug excreted by glomerular filtration + reabsorption in tubules
        Less than 1% excreted unchanged
        
        MoA: potentiating action of neurotransmitter GABA on GABA receptor gated chloride channels
        
        Propofol
        
        Most common IV anaesthetic used in SG
        Induction rate is similar to thiopentone, recovery is more rapid (patients move sooner and feel better)
        Used for induction and maintenance
        Rapid onset (works within 60 seconds)
        Short duration of action (3-5min following single injection) because rapid redistribution from brain to other tissues
        Extensively used in day surgery
        Need continous low dose infusion for extended effects
        Reduces postoperative vomiting
        Significant cardiovascular effect during induction: decrease bp and negative intropic --> hypotension, NEED CAUTION with patients with heart problem/elderly
        
        Ketamine
        
        Produces state known as dissociative anaesthesia --> patient feels dissociated from environment
        Cause sedation, immobility, analgesia and amnesia
        Rapid induction: responsiveness to pain is lost
        Metabolized in liver to less active metabolite, excreted in urine and bile
        Large volume of distribution, Vd = suitable for continuous infusion without lengthening in duration of action
        Only IV anaesthetic that posses analgesic property --> hence very popular in 3rd world country as the only anaesthetic due to lack of other anaesthetic agents
        
        Side effects:
        Unpleasant psychologic reactions (hallucinations, disturbing dreams, delirium) during recovery
        = adverse reactions may be reduced with premedication of diazepam/midazolam
      - Uses
        
        Induction agent is a substance that induces unconsciousness
        
        Does not necessarily keep you asleep for very long
        
        Depress respiration = need take over ventilation of patients
        
        Used alone or to supplement effects of inhalation agents
        
        Why combine inhaled and IV GAs?
        
        Permit dosage of inhalation agent to be reduced
        
        Produce effects that cannot be achieved with inhalation alone
  - - - Sedation prior to and/or during procedures in non-intubated patients
        
        (Example: dexmedetomidine)
        Highly selective alpha 2 adrenergic receptor agonist
        Short term sedation (<24hrs)
        Little respiratory depression
        Tolerable decrease in BP and HR
        Undesirable side effects: nausea, dry mouth, hypotension, bradycardia
    - - Typically administered with GA to reduce anaesthetic requirement
        
        (Examples: NSAIDS)
        Minor surgical procedures
        Need stronger? Opoids
        Choice- based primarily on duration of action
        Metabolised in liver (except remifentanil, hydrlyzed by tissue and plasma esterases)
        Excretion: urine, bile
    - - Anxiolytics, amnesia, sedation prior to induction of anaesthesia
        
        Rapid onset
        Metabolized in liver
        Side effects compounded by concurrent usagae of other agents
        Adverse effects minimised by prolongating administration
    - - Induction of anaesthesia to relax muscles (jaw, neck, airway) to facilitate laryngoscopy and endotracheal intubation
        
        Deploraissing: succinylcholine/ non-depolarising: vecuronium
        Administered induction to relax muscles of jaw, neck, airway --> facilitate laryngoscopy and endotracheal intubation
        Aids many surgical procedures and provide additional insurance of immobility
        Barbiturates will precipitate when mixed with muscle relaxants --> should be allowed to clear from IV lion prior to injection of muscle relaxant
- - - - Works best in low disease burden as in early stages of cancer
      - Combination chemo: cancer cells mutate to become resistant to single agent. But using different drugs would make it difficult for tumour to develop resistance to combination
        
        Primary resistance: cancer does not respond to standard chemo from the very first exposure
        Acquired resistance: when tumour iniitially responds and then becomes resistant
        
        Cancer cells may mutate and develop pathways that are independent of those blocked by chemotherapy
        
        Gene amplification can lead to overproduction of proteins that are blocked by anti-cancer agent
        
        Cancer cells may develop mechanisms that inactivate the chemotherapeutic agent
        
        Cancer cells learn to repair the DNA and protein damages that are induced by chemotherapeutic drugs
        
        Resistant clones of cancer may develop
        
        DISADVANTAGES
        
        Multiple toxicitiies
        
        Reduction or holding of doses due to to toxicity wiill limit effectiveness
        
        Complicated to administer
        
        Expensive
      - Side effects of chemotherapy
        (Affects cells with high growth fraction
        Normal tissues with high growth fraction: bone marrow, hair follicles, GI mucosa, skin)
        Common side effects:
        Decreased WBC, RBC and platelets
        Alopecia
        Mucositis (inflammation and ulceration of mucous membranes lining digestive tract)
        Nausea and vomiting (stimulation of vomiting centre in CNS + stimulation of nerves in GI tract)
        REFER TO DOCS for more side effects
    - - Skipper-Schabel model
        one leukemic cell is lethal = necessary to kill ALL
        percentage of leukemic cell population of various sizes is constant for every dose
        Percentage of leukemic cecll population of any size killed by single dose of treatment of drug is proportional to dose level of drug (higher dose, higher percentage kill)
      - Gompertzian Model of Tumour growth
        Growth-growth rate of tumour cell decreases with time
        Response to chemotherapy is high during rapid growth phase (refer to doc)
      - Goldie-Coldman Hypothesis
        
        fraction of tumour will develop resistance after treatment
        
        This clone will continue to grow even though patient appears to respond
        
        Alternating combination of chemo agents early in treatment is necessary to prevent development resistant clones
    - - G1>S>G2>Mitotic phase
  - - - Bleomycin
      - Plant alkaloids
        
        Podophyllin alkaloids (S-G2 phase)
        Etoposide & teniposide
        
        Extracted from root of mayapple
        
        MoA: inhibition of topoisomerase II, blocking cells in late S-G2 phase
        DNA damage through strand breakage induced by formation of ternary complex of drug, DNA and enzyme
        
        Indications:
        Etoposide: lymphomas
        Teniposide: childhood acute lymphoblastic leukemia (ALL)
        
        Side effects:
        Major toxicities: myelosuppression, mucositis, GI tract toxicities
        
        Camptothecins ??????????
        Topotecan
        
        Vinca alkaloids (M phase)
        vinblastine
        
        MoA: inhibit microtubules (spindle) assembly causing metaphase cell arrest in M phase
        
        bind to microtubular protein tubulin in dimeric form
        drug-tubulin complex adds to forming end of microtubules to terminate assembly
        Depolymerization of microtubules occurs
        Mitotic arrest at metaphase, dissolution of mitotic spindle and interference with chromosome segregation
        
        Spindle poison (alongside taxanes)
        
        Indications: lymphomas + leukemias
        
        Side effects: alopecia, hyponatremia, myelosuppression
        
        Taxanes
        Paclitaxel & Docetaxel
        
        MoA: interfere with normal function of microtubule breakdown (interfere with disassembly) --> hyperstabilise microtubule structure
        
        resulting microtubule/paclitaxel complex does not have the ability to disassemble --> adversely affect cell function
        
        Spindle poisons alongside vinca alkaloids
        
        Indications: lung, ovarian, breast, head and neck cancers
        
        Side effects: myelosuppression
        alopecia
        neuropathy
        alergies
      - Antimetabolites (S phase)
        
        Purine analogs
        Mercaptoguanine
        
        Pyrimidine antagonists
        Fluorouracil (5FU)
        Cytarabine
        Gemcitabine
        Capecitabine
        
        Fluorouracil
        
        MoA: inhibits thymidylate synthase --> depletion of thymidylate
        
        5-FU incorporated into DNA --> inhibits RNA processing
        
        Indications: metastatic carcinomas of breast + GI tract
        hepatoma
        Carcinomas of ovary, cervix, urinary bladder, prostrate, pancreas and oropharyngeal areas
        
        Side effects: myelosuppression
        mucositis
        dermatitis
        diarrhea
        cardiac toxicity
        
        Gemcitabine
        
        MoA: gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA strands, inhibiting DNA replication and repair
        +induce cell death
        
        Gemcitabine induced cell death = apoptosis
        
        Masked termination makes germcitabine more difficult to remove from DNA strands
        
        Indications
        Pancreatic cancer
        Small cell lung cancer
        Carcinoma of bladder, breast, kidney, ovary, head and neck
        
        Side effects: Neutropenia, nausea and vomiting, fever
        
        Folic acid analogs
        Methrotrexate
        
        MoA: competitively inhibits dihydrofolate reductase (DHFR) an enzyme that catalyzes dihydrofolate(DHF) --> tetrahydrofolate (THF)
        
        prevent formation of THF --> intracellular deficiency of folate coenzymes + accumulation of toxic inhibitory substrate DHF polyglutamate
        one carbon transfer reactions for purine and thymidylate synthesis cease, interrupting DNA and RNA synthesis
        
        Indications: ALL, Burkitt's/non-Hodgkin lymphomas,
        cancers of breast
        head and neck
        ovary and bladder
        
        Side effects: bone marrow suppression (rescue with leucovorin which is also called folinic acid)
        Nephrotoxic (give sodium bicarbonate to alkalinize urine)
    - - Antibiotics
        
        Examples
        Anthracyclines: doxorubicin & daunorubicin
        Dactinomycin
        Plicamycin
        Mitomycin
        Bleomycin
        
        Types
        
        Anthracycline antibiotics
        
        MoA:
        
        Intercalating between base pairs of DNA/RNA strand --> inhibit DNA/RNA synthesis --> prevent replication of rapidly growing cancer cells
        
        Inhibits topoiosomerase II enzyme --> prevent reelaxing of supercoiled DNA
        
        Creates free oxygen radicals that damage the DNA and cell membranes
        
        Side effects:
        Cardiotoxicity (due to free radical production)
        Alopecia
        
        Dactinomycin/Actinomycin D
        
        MoA: intercalates in DNA minor grooves betwewen adjacent GC pairs --> prevent elongation by RNA polymerase and inhibits transcription
        Also inhibits topoisomerase II
      - Cisplatin (NOT COVERED LOL)
      - Alkylating agents
        
        Types
        
        alkyl sulfonates: busulfan
        
        Nitrogen mustards: cyclophosphamide
        
        nitrosoureas: carmustine
        
        Can cross blood brain barrier
        
        Other examples:
        Lormustine
        Semustine
        Streptozocin
        
        MoA: exert its effeects due to both alkylation of DNA and carbamylation of lysine residues on proteins
        
        Ethylenimines: thiotepa
        
        MOA: bind to DNA causing breaks
        
        alkylate DNA at N7 position of guanine, miscoding of DNA + cross-linking of DNA --> ring cleavage may also occur
        
        Side effects
        Myelosuppression, alopecia
        
        Indications: wide variety of hematologic and solid tumours
        thiotepa> ovarian cancer
        busulfan> chronic myeloid leukemia
        nitrosoureas> brain tumours
        streptozocin> insulin-secreting islet carcinoma of pancreas
  - - - Other drugs/substances that block the growth and spread of cancer by interfering iwth specific molecules involved in tumour growth and progression
      - Less harmful to normal cells
        Since focus on molecular and cellular changes that are specific to cancer, may be more effective than other types of treatment
        Can be for use alone or in combination with other targeted therapies
    - - Monoclonal antibodies
        
        Cetuximab (Erbitux) binds to Epidermal growth factor receptor (EGFR), blocking down-signalling events, preventing ligand receptor function
        
        Trastuzumab (Herceptin) bind to HER2 --> antibody-dependent cell mediated cytotoxicity + blockage of HER2 dimerisation
      - Small molecule inhibitors
        
        Erlotinib/Geftinib (for lung cancer), tyrosine kinase inhibitors --> ATP analogs, inhibit EGFR signalling by competiting and binding with ATP-binding pockets on intracellular kinase domain of tyrosine kinase, preventing phosphorylation
        
        Sorafenib (liver cancer) binds to inracellular VEGFR
        
        Bortezomib (multiple myeloma) binds to catalytic site of 26S proteasome, prevent degradation of pro-apoptopic factors = inducing cell death
    - - Consolidation therapy: post remission therapy, aimed at destroying any remaning leukemia in body
        Vincristine, daunorubicin, cyclophosphamide, etoposide
        
        vincristine major dose-limiting toxicity is neurotoxicitiy
      - Maintenance therapy: prevent leukemia cells from regrowing., Treatments used in this stage are often given at lower doses over a long period of time
      - Induction therapy: kill most of the leukemia cells in blood and bone marrow to restore normal blood cell production
        Vincristine, daunorubicin
      - Targeted therapies: for example, in ALL, target Philadelphia chromosome by using tyrosine kinase inhibitors to attack this particular protein (BCR-ABL form abnormal protein)
        Imatinib mesylate
        Ponatinib
      - Adverse effects:
        nausea and vomiting
        diarrhea
        edema/swelling in legs or around eye
        (rare) fluid in lungs
        Usually not severe and can be managed
    - - Types
        
        classical (cHL) 95% --> CD30 expressing Reed Sternberg cells
        
        Lymphocyte predominant (NLPHL) cells, positive for CD20 and lack CD30
      - 80% treated with first line treatment of chemo and/or radiotherapy
        20% suffer relapse --> second line treatment, consists of high dose chemo followed by autologous stem cell transplantation for those under 60
      - REFER TO DOCS, which chemotherapeutic agents used
      - NOVEL therapies (refer to docs)
        major targets: CD30 + programmed cell death protein 1 (PD1)
        CD30 antibody drug conjugate: brentuximab vedotin +
        PD-1 inhibitors: nivolumab, pembrolizumab
        
        Side effects
        (Brentuximab vedotin)
        Low blood counts
        peripheral neuropathy
        Fatigue
        Nausea
        Diarrhea
        Fever
        Upper respiratory infections
        (Anti PD-1 antibodies)
        Hypothyroidism
        Joint paint
        Skin rash
        Addison disease (adrenal insufficiency)
    - - Context
        
        Diffuse large cell lymphoma (commonest aggressive type)
        Follicular lymphoma (Commonest indolent type)
      - Treatments
        
        Alkylating agents
        
        CHOP therapy
        
        Targeted agents like rituximab: monoclonal anti-CD20 antibody, cell surface receptor primarily found on surface of immune system
        -Rituximab (Rituxan) binds to CD20 and eventually leads to cell lysis
    - - Context
        
        HL (less common): Epstein-Barr virus, history of disease in family
        NHL (more common): autoimmune disease (HIV/AIDS), human T-lymphotropic virus, immunosuppressants medications and some pesticides
        
        **CHOP is acronym for chemo regimen used in treatment of non-Hodgkin lymphoma. It consists of:
        cyclophosphamide, alkylating agent, damage CNA binding
        Hydroxydaunoorubicin (doxorubicin/adriamycin) intercalating agent which damages DNA
        Onocovin (vincristine) prevents cell by duplicating by binding to protein tubulin
        Prednisone/prednisolone which are corticosteroids
        R-CHOP: CHOP + monoclonal antibody rituximab, chimeric monoclonal antibody against protein CD20, found in surface of immune system B cells --> destroy B cells with malignant CD20
        
        Aggressive chemo, including CHOP/R-CHOP
        For people who relapse, high dose chemo then autologous stem cell transplantation