Term
| We know that most drugs work via binding to macromolecules/ receptors and so what are the major types? |
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Definition
Ion channels
G protein-linked receptors
Ligand-regulated transmembrane enzymes
Cytokine receptors
Intracellular receptors
Extracellular enzymes
Transporters
Cell surface adhesion receptors |
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Term
| Ion channels work via two modes, which are? |
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Definition
| Voltage-gated and Ligand-gated (can be neurotransmitters like ACh, GABA, glutamate or intracellular mediators such as Ca2+, cAMP, cGMP) |
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Term
| Two examples of ion channel class drugs are? |
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Definition
A) Local anesthetics - there is a lipophilic ligand that crosses the membrane and binds to the cytoplasmic side of the receptor and blocks the voltage-gated Na+ channel
B) Benzodiazepines - is a allosteric ligand that binds to GABA-A receptor to enhance GABA's abilty to open the Cl- channel and thus hyperpolarize the neuron in the CNS |
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Term
| Around 60% of prescription drugs act via G protein-linked receptors, examples include? |
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Definition
A) Albuterol - a beta-2 agonist used in asthma
B) Propranolol - a beta antagonist used in hypertension
C) Bethanechol - a muscarinic agonist used for atonic bladder
D) Ipratropium - a muscarinic antagonist used for asthma |
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Term
| Around 60% of prescription drugs act via G protein-linked receptors, examples include? |
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Definition
A) Albuterol - a beta-2 agonist used in asthma
B) Propranolol - a beta antagonist used in hypertension
C) Bethanechol - a muscarinic agonist used for atonic bladder
D) Ipratropium - a muscarinic antagonist used for asthma |
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Term
| Two examples of ion channel class drugs are? |
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Definition
A) Local anesthetics - there is a lipophilic ligand that crosses the membrane and binds to the cytoplasmic side of the receptor and blocks the voltage-gated Na+ channel
B) Benzodiazepines - is a allosteric ligand that binds to GABA-A receptor to enhance GABA's abilty to open the Cl- channel and thus hyperpolarize the neuron in the CNS |
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Term
| How does acetylcholine slow the heart rate? |
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Definition
| Acetylcholine acts on the muscarinic receptor and activates Gi which in turn acts on the K+ channel to pump out K+ from the cell making it hyperpolarized. NB that Gi also decreases adenylyl cyclise signalling pathway |
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Term
| cAMP-mediated hormonal responses are? |
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Definition
A) Breakdown of glycogen in liver (mediated by beta-adrenoceptors & glucagon receptors)
B) Breakdown of TAGs in adipose tissue (mediated by beta-adrenoceptors)
C) Increased heart rate & contraction force (mediated by beta-adrenoceptors)
D) Relaxation of smooth muscle (mediated by beta-adrenoceptors) |
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Term
| What does Protein Kinase A (PKA) do and how is it able to do so many different things in different cells? |
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Definition
| PKA phosphorylates proteins and in different cells it has different substrates to phosphorylate. NB that inactive PKA has a regulatory subunit that needs to be bound to cAMP to activate the catalytic subunit |
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Term
| Gq activates Phospholipase C-beta which? |
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Definition
| Hydrolises PIP-2 into IP3 and DAG. IP3 triggers Ca2+ release from the SER and that Ca2+ inturn binds to calmodulin to regulate other enzymes like protein kinase C along with the help of DAG. |
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Term
| Ligand-regulated transmembrane enzymes span the membrane once (NB that they have an extracellular hormone-binding domain & a intracellular enzyme domain) and mediate signalling via? |
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Definition
| Insulin, Epidermal growth factor, Platelet-derived growth factor, Atrial natriuretic factor and many other growth factors |
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Term
| What are the four intracellular enzyme domains? |
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Definition
Tyrosine kinase (largest group)
Guanylyl cyclise
Serine/ threonine kinase
Tyrosine phosphatase |
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Term
| Two Receptor Tyrosine Kinases come together to form a dimer when a signalling molecule binds to it, this then? |
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Definition
| Activates the kinases (2 per receptor) which phosphorylates the tyrosine and assembles intracellular signalling complexes at the receptor tail. Ultimate response is cell proliferation (cellular growth and differenciation). NB that gain-of-function mutations at these receptors will lead to cancer (protooncogenes). Imatinib is a tyrosine kinase inhibitor and is effective against Chronic Myelogenous Leukemia |
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Term
| What are two examples of ligands/ Signalling molecules for receptor guanylyl cyclases? |
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Definition
| B-type natriuretic peptide – a hormone releases by the heart ventricles in response to volume overload. A recombinant to this peptide is Nesiritide which is used to Tx decompensated heart failure |
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Term
| Cytokine receptors respond to which peptide ligands? |
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Definition
| Growth hormone, EPO and several interferons. NB that tyrosine kinase is not intrinsic to the receptor but rather comes from the Janus kinase family (JAK) and simply non-covalently binds to the receptor |
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Term
| Intracellular receptors are? |
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Definition
Enzymes
Gene regulatory proteins
Structural proteins |
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Term
| Give 2 examples of drugs targeting intracellular enzymes |
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Definition
A) Statins – competitively inhibit HMG-CoA reductase (catalyzes the first committed step of cholesterol biosynthesis and thus depletes intracellular supply of cholesterol and thus LDL receptors are upregulated in the liver thus clearing LDL from blood)
B) Nitroglycerin – which acts to release NO from BV’s thus reducing workload in the heart and thus the O2 required this is used to Tx pts w/ angina pectoris. Endothelial cells have NO synthase, which converts arginine to NO, NO then diffuses to adjacent SM cells and enters their cytoplasm where it binds to and activates guanylyl cyclise -> cGMP -> activates cGMP-dependent protein kinase (PKG) => which is what leads ultimately to the vasodilation |
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Term
| Gene regulatory proteins/ transcription factors (steroid receptor superfamily) bind? |
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Definition
Steroid hormones
Vitamin D
Thyroid hormones |
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Term
| Structural Proteins such as tubulin are the target for antineoplastic drugs (Vinca alkaloids) via? |
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Definition
| Binding to tubulin and preventing the polymerization of the monomers into microtubules and thus arrest cell cycle at metaphase |
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Term
| ACE inhibitors are an example of drugs targeting Extracellular enzymes, True or False? |
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Definition
| True, the whole pathway is intigated by renin acting on angiotensinogen, which is produced by the liver to make Angiotensin I, this is then acted on via ACE at the lungs to make Angiotensin II which acts via two modes to increase the BP (Na+ and H2O retention & Vasoconstriction) |
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Term
| SSRIs and Digoxin are drugs that target transporters as their drug receptors, they work by? |
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Definition
A) SSRI – is a selective serotonin reuptake inhibitor
B) Digoxin inhibits the Na+ pump and thus leads to Ca2+ build up in the cytoplasm and thus increased cardiac contractility (NB that Ca2+ is pumped out as 3Na+ come in, this in turn is pumped out using an ATPase where 2K+ come in and 3Na+ go out) |
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Term
| Cell surface adhesion receptor targeting drugs like Natalizumab act via? |
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Definition
| Blocking alpha-4 integrins, which are critical for immune-cell adhesion and homing and thus this humanized monoclonal antibody is used to Tx MS |
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