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CP > Lecture 6: how do drugs work > Flashcards

Lecture 6: how do drugs work Flashcards

1
Q

Four primary drug tagets?

A
  1. ion channels
  2. enzymes
  3. carrier molecules
  4. receptors

the only exception being DNA for which some anti-tumour drugs and antimicrobial drugs bind to

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2
Q

4 steps of neurotransmission

A
  1. synthesis
  2. release
  3. receptors
  4. inactivation
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3
Q

key sites of action of drugs in neurotransmitter:

synthesis

release

reception

A
  1. choline trnsporter (for ACh synthesis)

Choline acetyl transferase (ChAT) -for choline synthesis

  1. Vesicular ACh transporter acks ACh into vesicles

Ca 2+ causes vessicle binding to membrane

  1. Ligand gated ion channels, G-protein couples receptors, tyrosine/cytokine kinase receptors, steroid/nuclear hormone receptors
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4
Q

4 types of channels

A
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5
Q

Ligand gated ion channels features?

A
  • fast signal transmission
  • multi-subunit complexes
  • responds to specific ligands, select ions to let through
  • conduct these ions through otherwise impermeable membranes
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6
Q

nicotinic acetylcholine receptors

the receptor pore?

A
  • 5 subunits arranged around central channel
  • each subunit has 4 transmembrane domains (20 total)
  • each binding site sits between alpha subunit and adjacent subunit
  • both binding sites needed to be occupied for channel opening
  • onened by ACh binding
  • aa in TM2 determies conductivity (usually Na+ and K+)
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7
Q

Ionotropic receptors as drug targets?

A

GABAA -Benzodiazapines and barbiturates (sedation and anxiolytic effects). Muscimol (hallucinogenic mushrooms)

Glutamate - ketamine (anaesthetic) have adverse effects

Nicotinic - nicotine, pancuronium (antagonsist) used as a muscle relaxants during anaesthetic

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8
Q

GPCRs?

A
  • 7 transmembrane domains
  • intracellular C terminal interacts with G protein
  • Gαs = activates adenyl cyclase, ↑cAMP
  • Gαi = inhibits adenyl cyclase, ↓cAMP
  • Gαq = activates PLC (PIP2 —> DAG + IP3)
  • Use Muscarinic receptors M1,2,3,4,5
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9
Q

GPCR pre-synaptic receptors?

A
  • usually Gi linked
  • activation leads to inhibition of voltage sensitive Ca2+ channels
  • results in decreased neurotransmitter release
  • FEEDBACK LOOP
  • drugs can be targeted to block these decreasing release 10 fold
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10
Q

tyrosine kinase receptors

A
  • receptor functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins (autophosphorylation)
  • mediate action of growth factors, cytokines and certain hormones (eg insulin)
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11
Q

vascular endothelial growth factor receptors

A
  • essential for angiogenesis during development, pregnancy, woud healing
  • also in pathophysioloical conditions: cancer, rheumatoid arthritis, CVD
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12
Q

VEGFR2?

A
  • ligand stimulated receptor dimerisation
  • autophosphorylation of tyrosine residues in cytoplasmic domain
  • associated with SH2 domain proteins
  • work via big cascades (proliferation pathways)
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13
Q

proliferation pathways?

A
  1. receptor activation leads to PLCy activation by phosphorylation
  2. this hydrolyses PIP2 to DAG and IP3
  3. DAG activates PKC
  4. PKC activation leads to activation of ERK via Raf and MEK
  5. ERK activation leads to increased gene transcription
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14
Q

how do drugs bind to receptors? weak to strong

A
  1. Ven der waals forces
  2. hydrogen bonding
  3. ionic
  4. covalent - irreversible
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15
Q

Kd?

A

affinity constant = concentration when 50% is bound

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16
Q

affinity of drug

A

higher affinity means more binding for same conc

17
Q

affinity vs biological response

A

is NOT LINEAR and is dependent upon many factors downstream usually

18
Q

C50

A

potency- 50% of max response is observed determines this. Higher the conc at C50 the lower the potency

19
Q

efficacy?

A

ability of a drug to bind to a receptor and cause a change in the receptor’s action

positive efficacy = agonist

negative efficacy = inverse agonist

no efficacy (binds but has no effect ie. it doesn’t activate or inactivate it just stops other things binding) = antagonist

20
Q

different tyoes of antagonists

A
  1. reversible competitive
  2. irreversible

NB: sometimes irreversible can appear reversible if the % occupacy of receptor required for max effect is very low

21
Q

mechanism of neurotrans inactivation?

A

transport back

enzymatic degradation

22
Q

Serotonin (5HT) transporter

A

5HT is involved in sleep, apetite, memory, sexual behavior

reuptake determines extent and duration of receptor activation

SSRI’s such as fluoxetine block thismaking you happy

CP (19 decks)

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