Mechanisms of Drug Action (Cecilia A. Jimeno, MD) Flashcards
1
Q
Drugs are usually grouped according to what properties?
A
Pharmacodynamic properties
2
Q
Define: Pharmacodynamics
A
What the drug does to the body
It includes receptor interactions, dose-response phenomena and mechanisms of therapeutic and toxic action.
3
Q
Define: Pharmacokinetics
A
What the body does to the drug
Study of absorption, distribution, metabolism and excretion of the drug
4
Q
“Toxic effects are usually an (1) of the therapeutic effect.”
A
(1) extension
5
Q
What type of receptor does insulin interact with?
A
Tyrosine kinase receptor
6
Q
What receptive substance did John Newport Langley investigate?
A
Atropine in pilocarpine induced salivation.
7
Q
What does pilocarpine do?
A
It induces salivation in people with dry mouths.
8
Q
What term did Paul Ehrlich coin?
A
Receptor
“A drug will not work unless it is bound!”
9
Q
Describe drugs, effectors and receptors in terms of composition
A
Drug - heterogenous
Receptor - homogenous
Effectors - heterogenous (i.e. ion channels or kinases)
10
Q
“Receptors determine (1) relations between dose or concentrations of drug and pharmacologic effects.”
A
(1) quantitative
11
Q
Describe the relation between potency and quantity of a drug.
A
The more potent the drug, the less of it is needed to effect a change.
12
Q
Describe: Sigmoid Dose-response Curve
A
Saturation - total number of receptors may limit the maximal effect of a drug
13
Q
What properties of the ligand must be considered in receptor binding?
A
- Size
- Shape
- Electrical charge
14
Q
Describe the mechanism of action of paracetamol
A
Only works in brain COX
Good anti-pyretic but poor anti-inflammatory
15
Q
Describe the action of glucocorticoid
A
It is anti-inflammatory.
It can bind to mineralocorticoid receptors.
16
Q
T/F: The same drug may be both an agonist and antagonist.
A
True
This may be the case for different receptors.
17
Q
What are the two major domains of a receptor?
A
- Ligand binding domain
2. Effector domain
18
Q
What are non-protein receptors?
A
DNA receptors
Anti-microbial and anti-tumor drugs bind to these.
19
Q
Methods of identifying receptors
A
- Drug binding (radioisotope-tagged)
2. Molecular biology (gene sequencing)
20
Q
Define: Orphan Receptor
A
Receptor with a structure similar to existing receptors but for which the endogenous ligand has not yet been determined.
21
Q
Types of protein receptors
A
- Regulatory
- Enzymes
- Transport
- Structure
22
Q
What chemical signals do regulatory receptors deal with?
A
Neurotransmitters, autacoids and hormones
23
Q
What ligands does dihydrofolate reductase bind?
A
Methotrexate and alpha-glucosidase inhibitors
24
Q
What is methotrexate?
A
Anti-neoplastic drug
25
What are alpha-glucosidase inhibitors?
Anti-diabetic drugs
26
What is the receptor for colchicines?
Tubulin
27
What are colchicines?
Anti-inflammatory agents used against gout
28
What are the common receptor superfamilies?
1. Ligand-gated Ion Channels (Ionophores)
2. G-Protein Coupled Receptors (Metabotropic)
3. Enzyme-linked Receptors
4. Nuclear Receptor (in cytoplasm!)
29
What entity developed the nomenclature system for receptors?
International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification
30
Describe the mechanism of action of ligand-gated ion channels
1. Signal binds
2. Channel opens
3. Ions flow across the membrane
31
What can be said about neurotransmitters and ionophores?
Most neurotransmitters utilize ionophores.
32
What neurotransmitters use ionophores?
1. Acetylcholine
2. GABA
3. Serotonin
4. Glutamate
33
What is the result of ionophore activation?
There is increased transmembrane conductance and alteration of membrane electric potential.
34
Describe the subunits of ionophores
4 - 5 transmembrane helical subunits
35
Describe the Nicotinic Ach receptor
1. It possesses 5 subunits (2 alpha, 1 beta, 1 delta, and 1 gamma).
2. Each subunit is made up of four polypeptides.
3. Alpha-helices form the gate.
4. Curved conformation when sealed; straight conformation when open.
36
What is the result of Nicotinic Ach receptor activation?
Local excitatory postsynaptic potential resulting in depolarisation
37
What is the barbiturate receptor targeted for?
1. Inducing sleep
| 2. Used as anaesthesia for convulsions and seizures
38
What is the mechanism of action of the barbiturate receptor?
It causes hyperpolarization by allowing entry of Cl- ions. There is failure of action potential.
39
What is the mechanism of action of benzodiazepine?
Allosteric activator of GABA receptor
40
What substances bind to the barbiturate receptor?
Barbiturates and benzodiazepine
41
Enumerate four anti-seizure medications that close Na+ channels.
1. Carbamazepine
2. Phenytoin
3. Lamotrigine
4. Valproate
42
Describe the time course of action of ionophores
Rapid (milliseconds)
43
How are ionophores regulated?
1. Phosphorylation
| 2. Endocytosis
44
T/F: CNS acting drugs are examples of ionophores.
True
45
What cardiac effects does verapamil have?
1. Anti-arrythmia
| 2. Reduce BP
46
Describe the mechanism of action of verapamil
Inhibits voltage-gated Ca2+ channels in the heart and vascular smooth muscles
47
What is the largest superfamily of receptors?
G Protein Coupled Receptors (GPCRs)
48
What are other names for the GPCR?
7-transmembrane receptors or metabotropic receptors
49
GPCRs are usually utilised by what substances?
Peptide hormones
50
What are the results of GPCR activation?
1) Closing/opening of ion channels
| 2) Activation of enzymes
51
T/F: GPCRs have the C-terminal end extracellularly and N-terminal end intracellularly.
False
It's the opposite.
52
What is the secondary structure of the protein subunits in the GPCR?
Alpha helix
53
What happens to the G Protein when a ligand binds to the GPCR?
GDP on the G Protein is replaced by GTP
54
What are the 3 components of GPCR trans-membrane signalling?
1. Binding
2. Activation
3. Effector
55
Enumerate the major effector pathways of the GPCR
1. Adenylyl cyclase pathway
| 2. Phospholipase C/inositol pathway (involves ion channels and Rho A/Rho kinase)
56
What processes does cAMP regulate?
1. Cellular metabolism
2. Cell division
3. Cell differentiation
57
Enumerate the different second messengers involved in GPCR signalling
1. cAMP
2. Phosphoinositides
3. Ca2+
4. cGMP
58
Where is cGMP important?
Vascular endothelium
59
What channels does Gas open in the myocardium and skeletal muscles?
Ca2+ channels
60
What opens K+ channels in the heart and smooth muscles and closes neuronal Ca2+ channels?
Gi
61
How do opiate analgesics open K+ channels?
Through the beta-gamma G Protein complex
62
What molecule does cAMP act on?
Phosphokinase A (PKA)
63
What cleaves PIP2 into DAG and IP3?
Phospholipase C-beta (PLC-beta)
64
What is the action of IP3?
Opens Ca2+ channels
65
What is the action of DAG?
Activates phosphokinase C (PKC)
66
What is the largest family of GPCRs?
Rhodopsin family
67
T/F: Receptor tyrosine kinases are also cytokine receptors
True
68
What substances utilise receptor tyrosine kinases?
Growth factors
69
What are the first molecules to be phosphorylated by an activated RTK?
Docking proteins (Insulin receptor substrate 1 to 6)
70
What do IRS molecules activate?
Other kinases such as PI-3-K, growth factor receptor-binding protein 2, guanine nucleotide releasing factor, GTP binding protein RAS and the MAPK system.
71
What popular hormone utilises receptor tyrosine kinases?
Insulin
72
Which glucose transporter is translocated to the cell membrane by RTKs?
GLUT-4
73
In the case of insulin, what are the rapid and slow-acting effects of RTK activation?
Rapid - GLUT-4 translocation
Intermediate - Protein synthesis, lipolysis and lipogenesis
Slow - Glycogen formation
Slowest - Activation of transcription factors that enhance DNA synthesis and cell growth and division
74
What are drugs that act on RTKs?
Herceptin and Imatinib
75
What are physiological ligands for RTKs?
Insulin, PDGF, EGF, and VEGF
76
What are physiological ligands for cytokine receptors?
Interleukins and other cytokines
77
What are physiological ligands for guanylyl cyclase?
Natriuretic peptides
78
What drug acts on guanylyl cyclase?
Nesiritide?
79
What are the types of kinase-linked receptors?
1. Receptor for Tyrosine Kinase
2. Cytokine Receptors
3. Guanylyl Cyclase
80
Define: Amplification
Attachment of phosphoric group to a serene, threonine or tyrosine residue amplifies regulatory signal by providing molecular memory.
81
What functions does phosphorylation carry out?
1. Amplification
| 2. Flexible Regulation
82
Define: Flexible Regulation
Different substrate specificities of protein kinases provide branch points in signalling pathways.
83
What is the mechanism of action of transtuzumab?
It is an antibody that antagonises growth factor receptor signalling used in breast cancer treatment.
84
Describe the process of nuclear receptor activation
1. Hormone crosses plasma membrane.
2. Hormone binds to nuclear receptor in cytoplasm
3. Heat shock proteins are released.
4. Dimerization
5. Translocation
6. Complex binds to heat response element.
7. Transcriptional changes occur.
85
What ligands bind to nuclear receptors?
Steroids and thyroid hormones
86
What is the predominant structural module in nuclear receptors?
Zinc finger
87
Describe: Zinc finger configuration
Four cysteine residues coordinating with a zinc ion to enable intercalation in DNA.
88
What are the types of nuclear receptors?
1. Class 1 (homodimers)
2. Hybrid Class (RXR)
3. Class II (except RXR)
89
What are the therapeutic consequences of activating nuclear receptors?
1. Characteristic lag (minutes to hours)
| 2. Effects persist for hours/days because of downstream effect
90
What are the four types of drug-receptor interactions?
1. Agonist
2. Antagonist
3. Allosteric activator
4. Allosteric inhibitor
91
How would an increase in affinity reflect in the dose-response curve?
Leftward shift
92
T/F: Agonists possess both affinity and efficacy.
True
93
What is the reason for plateauing of the response curve?
Saturation of receptors
94
What are the two types of agonists?
1. Full
| 2. Partial
95
T/FL: Antagonists have both affinity and efficacy.
False
They only have affinity.
96
Presence of a competitive inhibitor or antagonist shifts the dose-response curve to the (1).
Right
97
Can the full effect of the agonist be achieved in the presence of an allosteric inhibitor?
No
98
What is the function of alpha-glucosidase?
Breakdown of polysaccharides in the GIT for absorption
99
Give examples of alpha-glucosidase inhibitors.
1. Acarbose
| 2. Miglitol
100
Describe: Acarbose
Pseudo tetrasaccharide compound isolated from Actinoplanes utanhesis
101
What are the neurotransmitter transporter superfamilies?
SLC1 & SLC6
102
Give examples of neurotransmitter transporters.
Norepinephrine Transporter - tricyclic antidepressant
Serotonin Transporter - fluoxetine
Dopamine Transporter - cocaine
103
What are the neurotransmitter transporters responsible for?
Reuptake of neurotransmitters
104
What are examples of non-neuronal transporters?
1. Cholesterol Transporter
2. Nucleoside Trnasporter
3. Glucose Transporter
4. Na+ H+ Antiporter
105
T/F: Antacids are an example of receptor mediated drug action.
False
They are non-receptor mediated.
106
What does Para-Amino Benzoic Acid do?
Used against fibrotic skin disorders
107
What does potassium permanganate do?
Antiseptic
108
What does mannitol do?
Osmotic diuretic
109
What does ispaghula do?
It is a dietary fiber and a laxative.
110
Define: Tachyphylaxis
There is short-term diminution of receptor response caused by continuous exposure to agonists.
111
Define: Tolerance
Drug resistance for antibiotics
112
What are the mechanisms for tachyphylaxis?
1. Intracellular proteins block G-protein access to activated receptor.
2. Agonist bound receptors may be endocytosed.
3. Depletion of essential substrate for downstream effects
113
What does arrestin do?
1. It binds to the intracellular loop of the beta-adrenoreceptor.
2. Loss of GPC
3. Endocytosis of GPCR
114
What are the fates of endocytosed receptors?
1. Reinsertion (morphine receptors)
| 2. Degradation (adrenoreceptors & EGF receptors)
115
What is responsible for nitroglycerin tolerance?
Depletion of thiol cofactors
116
Define: Drug Holiday
Taking a break from medication to reverse the effects of tolerance to medication
117
What are the mechanisms for desensitisation?
1. Downregulation
| 2. Upregulation
118
T/F: Upregulation may result if receptor is not activation for prolonged periods.
True
