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Flashcards in Michaelis Deck (102)
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1
Q

How does glutamate cause calcium overload

A

Glutamate acts on metabotropic receptors -> Ca from ER
Activation of AMPA receptors which depolarises the cell (NA entry)
Depolarisation unblocks the NMDA Ca channels allowing entry

2
Q

Results of calcium overload

A

Increases glutamate release
Activates proteases and lipases -> membrane damage
NO synthase -> ROS, hydroxyl radicals
Increases arachidonic acid release -> enhances free radical production and inhibits glutamate uptake

3
Q

Oxidative stress

A

Mutations in SOD genes -> amyotrophic lateral sclerosis

TNFa activates superoxide dismutase catalase which converts O into O2 or H2O2

4
Q

Stroke pathogenesis

A
85 ischaemia, 15 haemorrhagic
Lack of blood causes calcium overload
Rapid loss of neurons
No ATP stops the NA+ Ca+ pump so there is overload
ROS formed
5
Q

5 treatments of stroke

A

Primary prevention- aspirin/warfarin
Recanalosation- tPA disperses clots if given in 3 hours. Plasminogen -> plasmin which breaks down clots
Neuroprotection- glutamate antagonists, ROS scavengers, protease inhibitors. Blood supply difficult.
Secondary prevention- anti thrombin therapy to those at risk. Tachycardia as risk factors
Neuro repair- IPSC therapy

6
Q

Alzheimer’s disease

Amyloid plaques

A

APP gene on chromosome 21
AB42 overproduced, forms plaques
APP -> b40 and b42 by y Secretase
Presenillin gene- affects the y Secretase complex

7
Q

Alzheimer’s disease

Tau tangles

A

Phosphorylation of tau by kinases
Dissociates from micro tubules and forms paired helical filaments -> Neurofibrillary tangles
Hyper phosphorylated tau increases amyloid deposits
Impairs axonal transport

8
Q

Results of Alzheimer’s

A

Loss of cholinergic neurons in basal forebrain
Affects ACH formation, degradation and action
Nicotinic ACH receptors reduced

9
Q

Treatment of Alzheimer’s

A

Cholinesterase inhibitors (Tacrine). Can be hepatotoxic.
Donepezil- reduce AB formation and toxicity
Memantine- blocks NMDA, stops calcium influx
ACH receptor agonists??

10
Q

Parkinson’s disease

A

Suppression of voluntary movements, ischaemia, virus.
Low dopamine in substantial nigra and corpus striatum
Loss of dopaminergic neurons
Cannot inhibit cholinergic neurons -> hyperactivity

Aggregation of a-synuclein in Lewy bodies

11
Q

Levodopa and side effects

A

Often combined with peripheral dopa decarboxylase inhibitor
5-10% crosses blood Brain barrier
Peripheral dopamine -> nausea, dyskinesia
On off effect common between rigidity and hypokinesia
Fluctuation corrected with COMT inhibitors

12
Q

Dopamine agonists

A

Bromocriptine inhibits prolactin release from pituitary
Perv oldie can cause heart valve disease
Replaced by D2/3 selective drugs

13
Q

MAO-B inhibitors

A

Selegiline-Prevent dopamine degradation

Amantadine- originally antiviral drug. Increased dopamine release. Less effective but better side effects.

14
Q

Acetylcholine antagonists

A

mACH receptors inhibit dopaminergic neurons
mACH antagonists- Atropine
Dry mouth, vision, urine retention
Only used in patients who are on dopamine antagonists for antipsychotic

15
Q

Deep brain stimulation

A

Brain pacemaker- electrodes in globus pallidus
Implanted pulse generator below clavicle
High frequency impulses override tremors

16
Q

Anxiolytics drugs

A

Antidepressants- SSRIs, TCAs and MAOIs
Benzodiazepines- acute anxiety. Combination therapy SSRI
Anti epileptics- for GAD
Antipsychotics- olazepne, more side effects
Buspirone- 5-HT1A agonist, only GAD
B-Adrenoreceptor antagonists- propranolol

17
Q

Barbituates

A

Anxiety and insomnia
Thiopental to sedate animals
Meprobamate- binds to GABA. Can cause seizures

18
Q

Benzodiazepines

A

Directly open GABA-A receptor chloride channel
Distinct from GABA binding site
Increases conduction of CL when GABA bound
Diazepam/Valium

Respiratory depression with alcohol. Can have severe withdrawal.
Rohypnol- prevent memories of event

19
Q

Monoamine theory of depression

A

Deficit of noradrenaline and serotonin

Drugs with affect monoamine transmitters affect depression

20
Q

Tricyclic antidepressant drugs

A

Non selective serotonin and noradrenaline reuptake inhibitors
Some block a2-Adrenoreceptors and increase transmitter release

Sedation, confusion, hypotension, atropine like. In overdose, coma, delirium

Contraindications- increase alcohol and anaesthetic effects. Anti hypertensive.

21
Q

SSRIs

A

Selectivity for serotonin
Fluoxetine, paroxetine
Less atropine side effects
In combination with MAOs -> serotonin syndrome, tremor, hyperthermia, collapse

22
Q

Monoamine oxidase inhibitors

A

Major depression who have not responded
Type A inhibitor- stops noradrenaline and serotonin
Type B inhibitor- stops phenylethylamine

Reversible selective- Moclobemide. Irreversible unselective- Phenelzine
Rapid sustained increase in monoamines

Increase tyramine induced BP increase (cheese)
Delayed down regulation of b-Adrenoreceptors and serotonin receptors

23
Q

Mood stabilisers- Lithium

A

Narrow window
Nausea, tremor, renal effects. Thyroid enlargement. Weight gain.
Lithium toxicity- confusion, motor impairment, coma, convulsions

24
Q

2 types of epilepsy

A

Partial- discharge locally, symptoms by Brain region

Generalised- whole brain

25
Q

Epilepsy treatments

A

Completely controlled 75%
Phenytoin, carbamazepine
Also benzodiazepines

Enhance GABA action (inhibitory neurotransmitter)
Inhibit sodium and calcium channel function

26
Q

Dopamine theory of schizophrenia

A

Amphetamine releases dopamine, can induce episode
Hallucinations side effect of L-dopa
D2 receptor agonists exacerbate symptoms
D2 receptor antagonists used for treatment

27
Q

Glutamate theory of schizophrenia

A

NMDA receptor antagonists cause symptoms
Amphetamine only positive symptoms
Reduced glutamate concentrations in patients

28
Q

Serotonin theory of schizophrenia

A

Originally based on LSD (partial 5-HT2A agonist) hallucinations
Serotonin modulates dopamine pathways (control release)
Combined with D2 antagonists

5-HT2A receptors are Gi coupled, decreases neuron excitation

29
Q

Promethazine

A
Surgical sedation
Reduces agitation and anxiety 
Can be antitussive (anti cough)
Old antipsychotic, 1/10 potency of chloropromazine
H1 and mACH antagonist
30
Q

Chloropromazine

A

Dopamine D2 antagonist
Weight gain, sedation, hepatic failure and lover disease,

Acute dystonias, Tardive dyskinesias (involuntary movements)

31
Q

Acute dystonias

A

Involuntary movement
Reversible after drugs stopped
Consequence of effects on nigrostriatal dopamine

32
Q

Tardive dyskinesia

A

Disabling movements of face, toungue, trunk, limbs
Develops after months or years of drug
Irreversible, worse after treatment stopped

33
Q

Unwanted effects of antipsychotics

A
Booking D2 receptors increases prolactin secretion
Causes breast pain, swelling
Constant side effect
Sedation
Atropine like effects
Hypotension (a-Adrenoreceptors)
Jaundice
Leukopenia
34
Q

Clozapine

A

Negative symptoms of schizophrenia
High agranulocytosis risk
Adjunct therapy

35
Q

Thiopental anaesthetic

A

Intravenous barbiturate
NA salt, lipophillic
Long lasting hangover as accumulates in fat
Only used for induction

36
Q

Etomidate anaesthetic

A

Rapidly metabolised, shorter hangover
Involuntary movement, nausea
Suppresses adrenal steroid production
Increases mortality

37
Q

Propofol

A

Very rapid metabolised
Continuous infusion
Day care surgery

38
Q

Inhalative anaesthetics

A

Blood/gas and oil/gas coefficients
May give toxic metabolites
Chloroform -> free radicals
Halothane -> Br

39
Q

Nitrous oxide

A

Analgesic

Pro longed causes methionine synthase inhibition- bone marrow depression

40
Q

Neuromuscular blockades

A

Atracurium
Blockers of ACH receptors
Cause muscle relaxation

41
Q

Action and effects of cocaine as local anesthetiser

A
Inhibition of NA influx, block channels
Higher efficacy in high pH
Euphoria
Inhibition of noradrenaline and dopamine uptake by transporters
Hypersensitivity
Cardiovascular depression, vasodilation
42
Q

Class I antiarryhythmic drugs

A

NA+ channel blockers

Bupivacaine, lidocain

43
Q

3 stages of analgesic drug administration

A

NSAIDS
Weak opiates
Opiates

44
Q

NSAIDS mechanism (paracetamol etc)

A

Non steroidal anti inflammatory drugs
COX inhibitors
Anti inflammatory effects of COX2, unwanted gastrointestinal COX1
Decrease prostaglandins which sensitise to bradykinin to cause vasodilation

45
Q

Excitotoxicity

A
Caused by the neurotransmitter glutamate
Is toxic to neurons
Causes stiff neck when given orally as taste enhancer
Agonist produces neurotoxic lesions
Induces calcium accumulation
46
Q

Anti inflammatory effects of NSAIDs

A

Reduces prostaglandins
Stops vasodilation which stops oedema
Suppress inflammation and pain

COX converts Arachidonic acid -> prostaglandin H2

47
Q

NSAIDs side effects

Gastrointestinal

A

40% mucosal damage
COX1 -> prostaglandins that protect mucosa and reduce acid
Inhibits antithrombic prostacyclin PGI2 vasodilator
But does not affect prothrombic thromboxane TXA2

Skin reactions - Stevens Johnson- severe rash, cell death, epidermis seperation

Inhibit PGE2, PG12 prostacyclin synthesis -> renal failure
Meloxicam is COX2 specific

All may prolong bleeding, overdose causes liver failure

48
Q

Aceytlsalicylic acid (aspirin)

A

Inhibits platelet aggregation
Anticoagulant- because irreversible and targets COX1 more, stops thrombosis

Tinnitus, nausea
Not used in gout- lowers urate excretion
Reye’s syndrome- associated with virus. Rash, sick, liver damage. Severe encephalopathy -> fatal 20-40%

49
Q

Paracetamol

A
Anomaly- reduces both pain and fever. Inhibits prostaglandin synthesis in CNS
Low anti inflammatory
Selective COX2? 
No inhibition of platelets
-> glucurinide or sulphate in liver

High doses -> kidney damage
Liver toxicity- n-Acetyl-p-benzoquinone imine. Cured by Acetyl cysteine

50
Q

Coxibs

A

Selective COX2 inhibitors
Celecoxib and etoricoxib
Headache, rash, oedema
Not given to patients with ulcers as need COX2

51
Q

2 types of chronic pain

A

Hyperalgesia- increased pain with mild stimulus

Allodynia- pain evoked by non-noxious stimulus

52
Q

Transmission of pain (ascending and descending)

A

From dorsal horn
Synapse in ventral and medial thalamus
Projections in the somatosensory cortex
Lesions in medial thalamus cause analgesia

Descending control transmission in dorsal horn (inhibitory)
PAG -> RVM -> dorsal horn
Stimulation of PAG causes analgesia

53
Q

4 synthetics derivatives of morphine

A

Phenylpiperidine derivatives- more potent, faster acting
Methadone- similar conformation
Benzomorphan- different binding profile and side effects
Semisynthetic thebaine derivatives- less respiratory depression

54
Q

Loperamide

A
Phenylperidine derivative
Opioid receptor agonist
Constipation
Does not enter brain
Inhibits peristalsis so used to inhibit diarrhoea
55
Q

Opioid receptor mechanism

A

Gi/Go , types OP1-4
Opening of K channel into cell (hyperpolarisation)
Inhibit Ca channel. Inhibit adenylyl cyclase and activate MAP kinase
Pure agonists euphoria on u/OP3

56
Q

Morphine action on CNS

8

A

Analgesia- Protein kinase C and NMDA (glutamate) receptor activation
Euphoria- u receptor agonists
Respiratory depression- u inhibition. Increased PCO2
Cough- inhibit coughing
Vomiting- 40%. action on medulla oblongata.
Pupillary constriction- u and k. Pinpoint poisoning.
GI tract- reduced motility, increased pressure,. Inhibited by atropine.
Histamine- histamine release, bad for athsma

57
Q

Tolerance and withdrawal from morphine

A

Within 24hrs
cAMP reduction -> compensatory increase
Tolerance of drugs acting on same receptor

Methadone to control withdrawal, long half life avoids euphoria

58
Q

Common phenylpiperidine derivatives

A

Pethidine- no sedation, anti muscarinic, convulsions

Fentanyl- rapid onset, anaesthesia, transdermal

59
Q

Common thebaine derivative

A

Buprenophine
Partial u agonist
Causes dysphoria
Less addictive

60
Q

Tramadol

A

Weak u agonist
Dizziness, GI, no respiratory depression (preferable)
Inhibits noradrenaline uptake
Serotonin antagonist??

61
Q

Opiate antagonists (reverse opiates)

A

Naloxane- inhibits all 3 receptors. No effect in normal healthy. Intravenous, rapid. Hyperalgesia in response to stress, as interferes with opioids

Naltrexone- longer duration, slow release implant

62
Q

Co analgesics (analgesic side effects)

A
Glucocorticoids
TCAs 
Anti epileptics
Class I antiarryhythmic drugs
Bisphosphonates - induce apoptosis in osteoclasts
63
Q

Viral vaccinations

A

Cowpox immunised to small pox
Live vaccines- attenuated pathogens. MMR vaccine
Dead vaccines- inactivated virus e.g. Influenza

64
Q

Antiviral chemotherapy

A

Viruses do not have own metabolism

Some enzyme can be used

65
Q

Method of HIV infection

Symptoms

A

34mil infected
Infects CD4 helper T cells
Cytotoxic T cells induce apoptosis in normal cells
These T cells are killed by - cell lysis, apoptosis, Cd8 cells
Low CD4 levels causes AIDS

Fever, pharyngitis, myalgia, headache, rash, vomiting, lymphadenopathy

66
Q

Reverse transcriptase inhibitors

3 types

A

Phosphorylated to give 5’-triphosphate derivative
Competes with triphosphate in DNA synthetis by transcriptase
Incorporation causes chain termination

Nucleoside reverse transcriptase inhibitor
AZT- 65% conc in CSF.

Nucleotide analogue reverse transcriptase inhibitor
Tenofovir- combination therapy. 2yrs +.

Non nucleoside reverse transcriptase inhibitor
Bind to catalytic site of enzyme. Most alter liver CytP450 enzymes
Nevaprine- penetrates CSF. Prevents mother to baby

67
Q

HIV fusion inhibitors

A

CCR5 receptor antagonist- maraviroc
Inhibits R5 virus’s

Enfuvirtide- binds and inhibits gp41, involved in entry pore formation

68
Q

Integrase inhibitors of HIV

A

Raltegravir- targets Integrase. Metabolised by glucurinidation.

69
Q

Protease inhibitors of HIV

A

MRNA -> poly proteins -> cleavage
Protease not present in host, stops cleavage
Ritonavir- in activase proteases, combined with reverse transcriptase inhibitors

70
Q

Highly active antiretroviral therapy

A

Reverse transcriptase inhibitors + protease inhibitors
Rapid resistance development- no proofreading of DNA
Resistance monitoring and patient adherence critical

Motioned by T cell count, virus genotyping
Treatment after anticipated exposure- decreases transmission 90%

71
Q

HIV diagnosis tests

A

ELISA - antigens from sample, antibodies added. Antibody is linked to enzyme, substrate is added to diagnose how much enzyme/antibody bound. Colour change.

Western blot- separates antigens on weight

Rapid test- immunoblot. In 30mins.

72
Q

Patient cured of HIV

A

Haematopoetic stem cell transplant with CCR5 delta32 mutation

73
Q

Herpes simplex virus

A
dsDNA
Enveloped
HSV-1 and HSV-2 cold sores and genital herpes
Regular reactivation
Mother to child transmission
74
Q

Antivirals for herpes simplex

A

Aciclovir- converted to acyclo-guanosine monophosphate
Phosphorylated 3x by kinases
Causes chain termination
36% resistant in immunocompromised
Resistance- thymidine kinase and DNA polymerase mutations

Foscarent- inhibits pyro phosphate site of DNA polymerase.
Cidofovir- acyclic nucleoside phosphonate. Lots of viruses. Used with probenecid which decreases renal clearance

75
Q

Varizella zoster virus

A

Chickenpox- can induce Reye’s syndrome with aspirin
Adults treated with aciclovir
Causes foetal varicella syndrome -> brain and eyes

Shingles- reactivation. Analgesics, aciclovir

Vaccine- live attentuated. Higher dose prevents shingles.

76
Q

Human cytomegalovirus

A

dsDNA
TORCH infection, leads to congenital abnormalities (50% transmission)
80-90% with symptoms suffer from hearing loss, vision and mental retardation
Hepatitis, retinitis, colitis, pneumonitis

Ganciclovir- 3x phosphorylated by UL97 kinase
90% resistance due to UL97 mutation

77
Q

Name the 5 types of herpes virus

A
HSV-1 
HSV-2
Varicella zoster
Epstein Barr
Cytomegalovirus
78
Q

Influenza

A

Orthomyxoviruses
-sense RNA
Lower respiratory tract

79
Q

Replication of Influenza A

A

Haemagglutinin binds to silicon acid residues
Uncoating
Synthesis of viral RNA and proteins
Liberation, antigenic drift and shift

80
Q

Influenza A adamantanes

Neuraminidase inhibitors

A

Block M2 receptors, protons cannot flow in
Amantadine and rimantadine
High resistance, 80% in children

Neuraminidase inhibitors
Stop virus binding to sialic acid
Zanamir (dry powder), tamiflu (H1N1 100% resistant)

81
Q

Influenza vaccine

A
Split vaccine (types A and B)
Yearly vaccination (antigenic drift)
82
Q

Hepatitis C virus

A

Positive sense ssRNA, enveloped
Replicates in hepatocytes
Chronic infection -> cirrhosis and cancer

83
Q

Treatment of hepatitis C

PEGylated Interferon a

A

6 genotypes, 2,3 more treatable than 4,5
Covalent attachment of PEG to interferon. Increases half life.
Stops protein synthesis, induced death, MHC expression

Ribavirin- prodrug -> RNA nucleotide analogue (A?)
Inhibits polymerases, IMP dehydrogenase

84
Q

5 things that limit efficacy of cancer therapies

A
Drug adherence- patients do not take drugs. Reduced recurrence time to 52%
Small window- limited targets
Action unknown
Complex
Adaptable populations
85
Q

Platinum drugs

A
Cisplatin
Reacts with guanine
Intra and inter DNA strand linking
Inhibits mitosis
Induces DNA repair or cell death
86
Q

Tubulin binding agents

Vinca domain

A

Destabilising
Bind to Tubulin dimers, block mitosis
Vinca alkaloids- vincristine

87
Q

Tubulin binding agents

Colchicines domain

A

Colchicine
Destabilising
Binds to dimers, stops assembly
Also used for gout

88
Q

Tubulin binding agents

Taxiod domain binders

A

Stabilise micro tubules
Prevent disassembly and therefore mitosis
Taxanes and epothilones

89
Q

Methotrexate

A

Folate antagonist
Stops thymidylate synthesis and therefore DNA synthesis
Cancer, autoimmune,
Oral, low lipid solubility
Can cause depression of bone marrow, damage to GI tract

90
Q

Topoisomerase I and II inhibitors

A

1- intercalates and stops single strand breaks, stops replication
2- etoposide forms complex with DNA and TI2 and prevents relegation after double strand break. Anthracyclins form complex with TI2 and prevent reselling.

Cancer therapy

91
Q

How are cancer cells primed for death

A

Pro apoptotic signal
BLC2, activators bind (bim, bid)
Bax and Bak, activators bind
Pores form and CytC leaks

92
Q

Apoptosis as a cancer drug target

A

TRAIL receptor activation
Caspase 8 expressed -> Bcl-2 -> caspase 3 -> apoptosis

Caspase 8 activation- interferons, retinoic acid
cFLIP (cap8 inhibitor) inhibitors- mTOR inhibitors, HDAC inhibitors
Anti Bcl-2 protein antagonist- ABT-737/199

93
Q

Adaptation of cancer populations

A

Clonal evolution- selection pressure causes mutation

Selection pressure- hypoxia, drugs, starvation

94
Q

3 types of targeted anti cancer drugs

A

Tamoxifen- anti oestrogen. Metabolised by cytP450 into active
Antibodies- tagged with biotinylated radioactive ligand
Kinase inhibitors

95
Q

Kinase inhibitor

Cetuximab and Panitumumab

A

Anti EGFR antibody
Colorectal cancer
With chemotherapy or after failed oxaliplatin

96
Q

Kinase inhibitor

Gefitinib and Erlotinib

A

EGFR tyrosine kinase inhibitors
Reversible, inhibit ATP binding site
Lung cancer with EGFR mutation
Interfere with ABC transporters

97
Q

Kinase inhibitors

Lapatinib and Afatinib

A

Dual HER2 and EGFR tyrosine kinase inhibitor
Lapatinib- competative. Interferes with ABC transporters.
Afatinib- irreversible inhibitor
Lung cancer, EGFR mutation

98
Q

Poly pharmacology

A

Interaction with multiple targets

Kinase inhibitor can increase efficacy of co administered drug

99
Q

Multi targeted kinase inhibitor

Sunitinib

A

Renal cell carcinoma and gastrointestinal stroma tumour
First cancer drug approved for 2 indications
Inhibits angiogenesis and proliferation

100
Q

Multi targeted kinase inhibitor

Imatinib

A

Inhibits bcr-abl protein (Philadelphia chromosome 22)
Targets ABL, c-KIT, PDGFR
Chronic myeloid leukaemia (22) treatment
Also GI stromal tumour

101
Q

Drug repurposing for cancer

A

Methotrexate
Aspirin
Valproic acid (epilepsy)

102
Q

Vemurafenib and resistance

A

Inhibitor of V600E mutated BRAF
50% response in metastasised melanoma

Resistance after 2-18 months