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Pharmacology (MPAS) > Lecture 1: Drug receptor interaction (pharmacodynamics) > Flashcards

Lecture 1: Drug receptor interaction (pharmacodynamics) Flashcards

1
Q

What is pharmacology?

A

The study of drugs

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2
Q

What is a drug?

A

A substance used as a medicine to treat a disease

A substance used to prevent disease

A substance used to diagnose disease

A substance used with the intent of producing a change within the body

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3
Q

Pharmacodynamic processes

A

Receptor and signal transduction

The actions of the drug on the body

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4
Q

What is a receptor?

A

A protein molecule in the cell that interacts with drugs (aka ligands) and initiates a chain of events causing some form of cellular response

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5
Q

What is a ligand?

A

A substance that forms a complex with receptors including drugs, hormones and neurotransmitters

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6
Q

Location of receptors

A

Cell membrane, cytoplasm, or nucleus

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7
Q

Structure of receptors

A

Proteins

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8
Q

Function of receptors

A

Bind to ligands -> activates or inhibits post-receptor signalling (signal transduction cascade) -> triggers biological responses

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9
Q

Significance of receptors

A

Transduces a signal from outside cell to inside

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10
Q

Four receptor families

A

G protein coupled receptors

Ligand gated ion channels

Enzyme linked receptors

Intracellular receptors

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11
Q

G protein coupled receptors (GPCRs) general info

A

Biggest family of receptors (30% of drugs act on members of this family)

Most common site of drug action

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12
Q

Structure of G protein coupled receptors

A

7 transmembrane domains

External domain: ligand binding

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13
Q

What are the G protein subunits?

A

Alpha, beta, gamma

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14
Q

G protein alpha subunit iso forms?

A

Gas (stimulatory), Gai (inhibitory), Gq

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15
Q

Function of alpha subunit of G protein

A

Binds GTP and GDP

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16
Q

Function of Beta-gamma subunit of G protein

A

Inhibits alpha subunit

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17
Q

What occurs once the ligand binds to the G protein coupled receptor?

A

Ligand binds -> receptor conformation change -> receptor binds to G protein -> Cellular effectors (enzyme, protein, ion channel) -> second messenger

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18
Q

Effectors of G proteins

A

Adenyl cyclase (Gas and Gai), phospholipase C (Gaq)

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19
Q

Second messengers of G proteins

A

cAMP (Gas, Gai)

IP3, DAG (Gaq)

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20
Q

What happens when Gas is activated?

A

1) Adenyl cyclase is stimulated
2) AC converts ATP to cAMP
3) cAMP activates protein kinase A
4) PKA phosphorylates target proteins

(see figure)

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21
Q

What happens when Gai is activated?

A

Inhibits adenyl cyclase and downstream effects

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22
Q

What happens when Gaq is stimulated?

A

1) Gaq activates phospholipase C (PLC)
2) PLC hydrolyzes PIP2 (membrane phospholipid) into DAG and IP3
3) IP3 stimulates release of Ca2+ from ER
4) Ca2+ and DAG stimulate protein kinase C
5) protein kinase C phosphorylates target proteins

(see figure)

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23
Q

What does activation of GPCRs do?

A

Increases or decreases production of second messengers (depending on which G protein is activated)

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24
Q

Examples of GPCRs

A

Muscarinic receptors (M1-M5) - acetylcholine, drugs for parasympathetic nervous system

Adrenic receptors (alpha, beta receptors) - norepinephrine, epinephrine, drugs for sympathetic nervous system

Dopamine receptors (D1-D5) - Dopamine, antipsychotics

Serotonin (5-HT) receptors - serotonin, antipsychotics

Opioid receptors - endorphins, morphine, other analgesics

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25
Q

Why do ions move across a ligand-gated ion channel?

A

Asymmetrical distribution of ions

Electric potential is different across cell membrane

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26
Q

Where are Ligand gated ion channels abundant?

A

On excitable cells (neurons and muscle cells)

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27
Q

Resting membrane potential of nerve cell and smooth muscle cell

A

Nerve cell: -70 mV

smooth muscle: -50 mV

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28
Q

Structure of ligand gated ion channels?

A

Various subunits

Extracellular domain binds to ligand

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29
Q

Regulation of ligand gated ion channels

A

Ligand binding causes conformational change in the receptor

Channel opens, ion moves across membrane

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30
Q

Selectivity of LGIC

A

Different ion channels for different ions

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31
Q

Direction of movement across LGIC

A

Determined by electrochemical gradient (influx or efflux)

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32
Q

Which ions will move into the cell when their LGIC open?

A

Na+, Ca2+, Cl-

see figure

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33
Q

Which ions will move out of the cell when their LGIC open?

A

K+

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34
Q

Nicotinic acetylcholine (ACh) receptor

A

Ligand gated Na+ channel

Muscle contraction

Drugs: succinylcholine

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35
Q

Glutamate N-methyl-D-aspartate (NMDA) receptor

A

Ligand gated Ca2+ channel

Long-term potentiation (learning and memory)

Drug: memantine, ketamine

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36
Q

Gamma-Aminobutyric acid (GABA) receptor

A

Ligand gated Cl- channel

Central nervous system depression

Drugs: benzodiazepines

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37
Q

LGIC vs VGIC

A

VGIC respond to changes in electrical membrane potential

LGIC respond to ligand binding

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38
Q

LGIC and VGIC in nervous system

A

VGIC transmit signals INSIDE a neuron (electrical)

LGIC transmit signals BETWEEN neurons (chemical)

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39
Q

Similarities between Ion channels and ion pumps

A

Located in cell membrane

Transmembrane proteins

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40
Q

What happens in Ion pumps?

A

Ions move across a membrane AGAINST their concentration gradient

Uses ATP

Re-establishes ion gradients

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41
Q

What happens in Ion channels?

A

Ions move down their concentration gradients

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42
Q

Types of enzyme-linked receptors

A

Cell membrane enzyme-linked receptors

Intracellular enzyme-linked receptors

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43
Q

Type of cell membrane enzyme linked receptor

A

Tyrosine kinase receptors

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44
Q

Examples of tyrosine kinase receptors

A

Nerve growth factor (NGF) receptor

Brain derived neurotrophic factor (BDNF) receptor

Epidermal growth factor (EGF) receptor

Platelet-derived growth factor (PDGF) receptor

Insuline receptor

Cytokine receptor

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45
Q

Structure of tyrosine kinase receptors

A

Spans the membrane

Many form dimers or multi-subunit complexes

Extracellular domain binds ligand

Intracellular domain has cytosolic enzyme activity (induces tyrosine phosRphorylation)

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46
Q

Regulation and function of tyrosine kinase receptors

A

1) Binding of ligand to receptor subunits -> conformational changes
2) Form dimers
3) Kinases are converted from inactive to active forms
4) Tyrosine receptor auto-phosphorylation
5) Recruit many protein targets

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47
Q

Important biological functions controlled by tyrosine kinase receptors

A

Metabolism, growth and

differentiation

48
Q

Examples of receptor tyrosine kinases that act as growth factor receptors

A

Imatinib (Gleevec -> tyrosine kinase -> chronic myeloid leukemia

Interleukin-2 (Proleukin) -> tyrosine kinase -> cancers (malignant melanoma, renal cell cancer)

49
Q

Example of intracellular enzyme-linked receptor

A

Soluble guanylyl cyclase (GC)

In cytoplasm

50
Q

Structure of Guanylyl cyclase

A

Forms a heterodimer composed of an α- and a β-subunit

Contains a regulatory domain (RD), a coiled- coil domain (CCD) and a cyclase domain (CD)

(see figure)

51
Q

Regulation and function of guanylyl cyclase

A

1) Is activated by nitric oxide (NO) - can cross membrane
2) GC converts GTP to cGMP
3) cGMP activates protein kinase G which c uses smooth muscle vasodilation
3) Phosphodiesterase (PDE) covers cGMP to GMP

52
Q

Examples of guanylyl cyclase

A

Nitroglycerin (glyceryl trinitrate) ->  guanylyl
cyclase -> treats angina

Sildenafil (Viagra) ->protects cGMP from phosphodiesterase -> treats hypertension and erectile dysfunction

53
Q

Structure of intracellular (nuclear) receptors

A

Ligand binding domain and DNA binding domain

Usually located in the nucleus

54
Q

Regulation and function of intracellular (nuclear) receptors

A

Receptor ligands are lipid soluble

The ligand must diffuse into the cell to
interact with nuclear receptor which is cytosol or nuclear

ligand-receptor complex translocates to nucleus

Activated receptor binds to promotor region of gene -> acts as transcription factor

Regulate gene expression

55
Q

Examples of intracellular nuclear receptors

A

Steroid receptors (cortisone, estrogen, progesterone, testosterone)

Non-steroid nuclear receptors (retinoid acid, vitamin D, thyroid hormone)

56
Q

Duration of action of ion channels

A

Milliseconds

57
Q

Duration of action of G protein coupled receptors

A

Seconds to minutes

58
Q

Duration of action of enzyme-linked receptors

A

Guanylyl cyclase: seconds to minutes

Receptor tyrosine kinases: minutes to hours

59
Q

Duration of action of Intracellular nuclear receptors

A

Hours to days

60
Q

Which ion has the greatest difference between intracellular and extracellular

A

Ca2+

61
Q

Duration of effect of activated receptors (relative)

A

Intracellular (nuclear) receptors > Enzyme-linked receptors > G-protein- coupled receptors > Ligand-gated ion channels

62
Q

What is Bmax?

A

The maximal specific binding of a ligand to receptor

Indicates the total concentration of receptor sites

(see figure)

63
Q

Kd

A

Equilibrium dissociation constant between ligand and receptor

Represents the concentration of drug at which half-maximal binding (50%) is observed

64
Q

Affinity

A

The ability of the drug to bind to a receptor (the concept is not related to response)

Affinity describes the strength of binding between a ligand and its receptor – how attractive the receptor is to the drug

65
Q

What determines the affinity of a drug for its receptor?

A

Affinity is inversely proportional to Kd

(The higher Kd is, the higher the concentration of drug needs to be for half the sites to be filled, which means the sites have a lower affinity for the drug)

66
Q

Selectivity

A

The degree to which a drug acts on a given site relative to other sites.

Describes preference for one receptor over another

Refers to the affinity of a drug for the “desired” target relative to its affinity for “non-desired” targets.

67
Q

Example: The Kd of a drug for receptor A is lower than for receptor B. Which receptor does the drug have more affinity and more selectivity for?

A

More selective and more affinity for A

68
Q

Emax

A

the maximal effect induced by a drug (full agonist)

see figure

69
Q

EC50

A

the concentration of drug producing an effect that is 50 percent of the maximum

70
Q

Potency of a drug

A

a measure of the amount of drug required to produce an effect of given magnitude.

Determined by EC50

The higher EC50, the lower potency the drug has

(see figure)

71
Q

Efficacy

A

Measure of the ability of a drug to elicit a biological response by agonist

Determined by Emax (higher Emax, higher efficacy)

(see figure)

72
Q

What efficacy is most therapeutically beneficial?

A

A drug with greater efficacy

More important than potency

73
Q

What is an agonist?

A

Agents that can bind to a receptor and elicit a biologic response.

usually mimics the action on the original endogenous ligand on the receptor

74
Q

Types of agonists

A

Full agonists, partial agonists, inverse agonists

see figure

75
Q

What can block an agonist?

A

Antagonist

76
Q

What is a full agonist?

A

A drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand.

Good efficacy

77
Q

Example of a full agonist

A

phenylephrine – α1-adrenoceptor

78
Q

What is a partial agonist?

A

Have affinity for the receptor but have low efficacy

Binding site is the same with a full agonist

79
Q

What happens when a partial agonist is administered alone?

A

Activates the receptor, but less than full agonist

80
Q

What happens when a partial agonist is administered in the presence of a full agonist?

A

Partial agonist reduces the effects of the full agonist

81
Q

Example of partial agonist

A

Aripiprazole

82
Q

What is an inverse agonist?

A

Have affinity for the receptor but have negative effect (negative efficacy)

Reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists.

83
Q

What is an antagonist

A

A drug has affinity for the receptor but has no efficacy

Can bind to a receptor, but fails to produce a response

An agent that can decrease actions of agonist or endogenous ligand.

84
Q

Antagonist used alone

A

No biological response

85
Q

Partial agonist used alone

A

Biological response less than full agonist

86
Q

Partial agonist used with full agonist

A

Reduces biological response

87
Q

Antagonist used with full agonist

A

Reduces biological response

88
Q

Antagonist used with partial agonist

A

No biological response

89
Q

Mechanism of competitive antagonist

A

Bind to the same site on the receptor as the agonist

Prevent an agonist from binding to its receptor

Increasing the concentration of the agonist to the receptor will tend to overcome the inhibition.

90
Q

Dose-response curve of drug in presence of antagonist

A

Curve shifts to right (p.37 of notes)

Increase EC50 of agonist

Emax and Efficacy are the same

91
Q

Types of Irreversible antagonists

A

Orthosteric

Allosteric

92
Q

Orthosteric irreversible antagonists

A

Bind covalently or with very high affinity to the active site of the receptor -> reduces the amount of receptors available to the agonist

Example: Naloxazone

93
Q

Allosteric irreversible antagonists

A

Bind to a site other than the agonist binding site -> prevents the receptor from being activated even when the agonist is attached to the active site.

Example: Strychnine

94
Q

What happens to Efficacy? EC50? Potency? when irreversible antagonists are used

A

Emax and Efficacy: decrease

EC50, potency: less effect

95
Q

Competitive antagonist vs irreversible antagonist

A

see figure

96
Q

What is an adverse effect?

A

An undesired harmful effect resulting from a medication

97
Q

Types of adverse effects

A

Too much therapeutic effect (overdose), i.e. benzodiazepine

Poor tissue selectivity, i.e. antihistamines (become drowsy)

Poor receptor selectivity, i.e. tricyclic
antidepressant (dry mouth etc)

Drug interactions: i.e. benzodiazepine and alcohol

98
Q

How can we measure drug safety?

A

Therapeutic index

99
Q

How to determine therapeutic index (TI)?

A

TI = TD50/ED50

100
Q

What is TD50?

A

The drug dose that produces a toxic effect or adverse effect in 50% of patients taking the drug

101
Q

ED50

A

The drug dose that produces a therapeutic or desired response in 50% of patients taking the drug.

102
Q

If TI is high…

A

Therapeutic window is wide -> safety is high, less adverse effects, and vice versa

A drug with high affinity and high selectivity has a high therapeutic index.

See figure

103
Q

How is the TI determined?

A

Drug trials and accumulated clinical experience.

104
Q

Hyporeactive

A

A lower response to a drug than is usual among the population.

105
Q

Hyperreactive

A

A higher response to a drug than is usual among the population.

106
Q

Idiosyncratic

A

Individuals exhibit an unusual drug response

107
Q

Tachyphylaxis

A

an acute rapid loss of response to a
drug.

receptors are still present on the cell surface but are unresponsive to the ligand

108
Q

Tolerance

A

a decreased response to a drug when the drug is taken repeatedly.

receptors are down-regulated in the presence of continual stimulation;

or receptor undergoes endocytosis

109
Q

Receptor desensitization

A

a mechanism that reduces
the receptor response to an agonist.

Tolerance and Tachyphylaxis are examples

110
Q

What is drug development?

A

process to discover new candidates

111
Q

Clinical trials are done in…

A

Humans

112
Q

Phase 1 of clinical trial

A

in a small number (20–100) of healthy volunteers. 

Screening for safety

Find the maximum tolerated dose, is designed to prevent severe toxicity

113
Q

Phase 2 of clinical trial

A

In a modest number of patients (100–200)

Identify the therapeutic dose and study the efficacy of drugs.

114
Q

Phase 3 of clinical trial

A

In a larger numbers of patients (usually thousands)

Further establish and confirm safety and efficacy.

115
Q

Phase 4 of clinical trial

A

in a large numbers of patients (Post-marketing studies)

Monitor the safety of the new drug under actual conditions of use

Safety studies during sales.

Pharmacology (MPAS) (19 decks)

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