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Pharmacology FPP > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

What is pharmacodynamics

A

It is the study of the biochemical and physiological effects of drugs and their mechanisms of action at organ level and cellular level

Also a study of dose/effect relationship

Also it is modification of action of one drug by another drug.

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2
Q

What are the 2 states a receptor can be in

A

active (Ra) & inactive (Ri) which are in equilibrium.

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3
Q

What shifts the equilibrium of the receptor

A

Binding to a drug shifts the equilibrium to either direction

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4
Q

What’s a ligand

A

any molecule which attaches selectively to particular receptors.

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5
Q

What’s affinity

A

The strength of the reversible interaction between a drug and its receptor, as measured by the dissociation constant, is defined as the affinity of one for the other.

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6
Q

What is intrinsic activity

A

capacity of a drug to induce a functional change in the receptor.

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7
Q

What is specificity

A

A drug that interacts with a single type of receptor that is expressed on only a limited number of differentiated cells will exhibit high specificity.

the measure of a receptors ability to respond to a single ligand

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8
Q

What are agonists

A

Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds

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9
Q

What are primary agonists

A

drugs that bind to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor)

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10
Q

What’s a primary agonist

A

drugs that bind to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor)

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11
Q

Difference between selectivity and specificity

A

Selectivity is the degree to which a drug acts on a given site relative to other sites while Specificity is the measure of a receptors ability to respond to a single ligand

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12
Q

What’s an allosteric agonist

A

bind to a different region on the receptor referred to as an allosteric site.

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13
Q

What’s an allosteric agonist

A

Agonist that bind to a different region on the receptor called an allosteric site

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14
Q

What’s an antagonist

A

Drugs that block or reduce the action of an agonist are termed antagonists.

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15
Q

What is a syntopic interaction

A

competition for the same or overlapping site on the receptor

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16
Q

What are the types of agonists

A

Inverse
Partial

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17
Q

What are physical antagonists

A

Antagonists that bind to the drug and prevents its absorption

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18
Q

Example of physical antagonist

A

Charcoal binding to alkaloids to prevent absorption

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19
Q

What are chemical antagonists

A

antagonists that combines with an agonist chemically like chelating agents binds with the metals

This antagonism is the combination of agonists with antagonists, with resulting inactivation of the agonists

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20
Q

What are physiological antagonist

A

Physiological antagonist produces an action opposite to a substance but by binding to the different receptors e.g. adrenaline is a physiological antagonist of histamine because adrenaline causes bronchodilatation by binding to β2 receptors, which is opposite to bronchoconstriction caused by histamine through H1 receptors

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21
Q

What is a partial agonist

A

Agents that are only partly as effective as agonists regardless of the concentration employed.

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22
Q

What are inverse agonists

A

Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse agonists (produce effect opposite to that of agonist).

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23
Q

What is Efficacy

A

A maximal effect (Emax) an agonist can produce.

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24
Q

How is efficacy mead

A

measured with a graded dose-response curve only.

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25
Q

What is potency

A

The amount of the drug needed to produce a given effect.

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26
Q

What determines potency

A

affinity of the receptor for the drug.

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27
Q

What is EC50 and how is it gotten

A

The dose causing 50% from the maximal effect and can be obtained from graded dose-response curve.

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28
Q

What’s ED50, TD50 and LD50

A

ED50 is the dose causing an effect in 50% of the population (mean effective dose)
TD50 is the dose causing therapeutic effect in 50% of the population (mean therapeutic dose)
LD50 is the dose causing lethality in 50% of the population (mean lethal dose)

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29
Q

In what I’m what graph do you see TD50, ED50, LD50

A

quantal dose response curve

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30
Q

What is Tolerance

A

Repeated administration of a drug results in diminished effect

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31
Q

What is tachphylaxis

A

a type of tolerance which occurs very rapidly.

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32
Q

What is desensitization

A

decreased response to the agonist after its repeated injection in small doses.

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33
Q

What could be the cause of tolerance

A

1- Masking or internalization of the receptors.
2- Loss of receptors (down regulation)- decreased synthesis or increased destruction.
3- Exhaustion of mediators (depletion of catecholamine).

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34
Q

What is synergism

A

When the action of one drug is facilitated or increased by the other, they are said to be synergistic.

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35
Q

What is additive

A

The effect of the two drugs is in the same direction and simply adds up:
effect of drugs A + B = effect of drug A + effect of drug B

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36
Q

Give 5 examples of additive drug combinations

A
  1. Aspirin + paracetamol = as analgesic / antipyretic
  2. Nitrous oxide + halothane = as general anaesthetic
  3. Amlodipine + atenolol = as antihypertensive
  4. Glibenclamide + metformin = as hypoglycaemic
    5, Ephedrine + theophylline = as bronchodilator
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37
Q

What’s Supra additive

A

The effect of combination is greater than the individual effects
of the components:
effect of drug A+ B > effect of drug A+ effect of drug B
This is always the case when one component is inactive as such

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38
Q

Give 6 examples of Supra additive drugs

A

Acetylcholine + physostigmine = Inhibition of breakdown (treat antimuscarinic toxicity)

Levodopa + carbidopa/benserazide = Inhibition of peripheral metabolism (treat Parkinson’s $

Adrenaline + cocaine/desipramine = Inhibition of neuronal uptake (of adrenaline) (intranasal vasoconstriction)

(5) Sulfamethoxazole + (1) trimethoprim = Sequential blockade
(Treat bacterial infections)

Antihypertensives (enalapril+hydrochlorothiazide) = Tackling two
contributory factors

Tyramine + MAO inhibitors = Increasing releaseable CA store

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39
Q

What are the types of antagonists mists

A

Competitive and non competitive

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40
Q

Give 6 characteristics of competitive antagonist

A

•Same binding site as of agonist
•resembles chemically with agonist
•Right shift of DRC
•Surmountable antagonism by increasing agonist dose
•Inactivation of certain agonist molecules
•Response depends on concentration of both

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41
Q

Give 2 examples of competitive antagonists

A
  1. Ach – Atropine,
  2. Morphine - Naloxone
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42
Q

Give 6 characteristics of non competitive inhibitors

A

•Different binding site as of agonist.
•Not resembles chemically with agonist.
•Flattening/downward shift of DRC.
•Unsurmountable antagonism (Maximum response is suppressed).
•Inactivation of certain receptors.
•Maximum response depends on concentration of antagonist

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43
Q

Give 2 examples of non competitive antagonists

A
  1. ketamine -NMDA-glutamate receptor.
  2. Diazepam - Bicuculline
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44
Q

Give 6 examples of physiological receptors

A

•GPCR
•Ion channels
•Transmembrane enzymes
•Transmembrane, non-enzymes
•Nuclear receptors
•Intracellular enzymes

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45
Q

What are Cellular Pathways Activated by Physiological Receptors

A

Signal Transduction Pathways

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46
Q

What are the 2 major functions of the physiologic receptors

A

ligand binding and message propagation

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47
Q

What are the 2 functional domains within the receptor

A

-ligand-binding domain and
-effector domain.

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48
Q

How are the regulatory functions of a receptor exerted

A

may be exerted •directly on its cellular target(s), on effector protein(s), or may be conveyed by •intermediary cellular signaling molecules called transducers.

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49
Q

What are the functional family under ion channels

A

Ligand gated
Voltage gated

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50
Q

What are physiological ligands under ligand gated

A

GABA,
5-HT3, nicotinic cholinergic, glycine, NMDA

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51
Q

What are effectors and transducers for ion channels

A

Na, Ca?, K*, CI-

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52
Q

Example of drugs with ligand gated ion channel

A

Nicotine,
gabapentin

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53
Q

What are physiological ligands under voltage channel

A

None (activated by membrane depolarization)

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54
Q

Effectors and transducers for voltage channel

A

Na, Ca?, K*, other ions

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55
Q

Drugs with voltage gated ion channels

A

Lidocaine, verapamil

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56
Q

Drugs with voltage gated ion channels

A

Lidocaine, Verapamil

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57
Q

What are Receptors with intrinsic ion channel

A

Ligand gated ion channels.

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58
Q

Give 2 characteristics of receptors with intrinsic ion channels

A

•No intervention of G-protein or second messenger.

•Response is fastest (in milliseconds)

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59
Q

Give 5 examples of receptors with intrinsic ion channels

A

5HT3, GABA, glycine, Ach(N), NMDA

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60
Q

In the voltage activated Na channels, what open and closes it

A

Depolarization opens it, leading to an influx of ions, the depolarization closes it

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61
Q

Describe the structure of the nicotinic cholinergic receptor

A

The five receptor subunits (α2, β, γ, δ) form a cluster surrounding a central transmembrane pore.

Each subunit have a large extra cellular domain, and four trans membrane helices

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62
Q

What are the functional families under GCPR

A

β Adrenergic receptors
Muscarinic cholinergic receptors
Eicosanoid receptors

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63
Q

Physiological ligands of β Adrenergic receptors

A

Epinephrine
Norepinephrine
DA

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64
Q

Physiological ligands under Muscarinic cholinergic receptors

A

Ach

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65
Q

Physiologic ligands under Eicosanoids

A

Prostaglandin
Thromboxane
Leokotrianes

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66
Q

Physiologic ligands under Eicosanoids

A

Prostaglandin
Thromboxane
Leoktrienes

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67
Q

Transducers for β Adrenergic receptors

A

Gs:AC

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68
Q

Transducers for Muscarinic cholinergic receptors

A

Gi, Gq : AC, PLC, , ion channels

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69
Q

Transducers for Eicosanoids

A

Gs, Gi, Gq proteins

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70
Q

Example of drugs with β Adrenergic receptors

A

Dobutamime

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71
Q

Example of drugs with Muscarinic cholinergic receptors

A

Atropine

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72
Q

Example of drugs with Eicosanoids receptors

A

Montelukast
Misoprostol

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73
Q

What is GPCR

A

Large family of cell membrane receptors linked to the effector enzyme/channel/carrier proteins through one or more GTP activated proteins (G-proteins i.e. guanine nucleotide binding protein)

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74
Q

What are G proteins

A

signal transducers that convey the information that agonist is bound to the receptor from the receptor to one or more effector proteins

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75
Q

What is the G protein heterotrimer

A

a guanine nucleotide-binding ‘α’ subunit, which confers specific recognition to both receptors and effectors, and an associated dimer of β and ϒ

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76
Q

What are G protein regulated effectors

A

Adenylyl cyclase
Phopholipase C
Cyclic GMP phosphodiesterase (PDE6)
Membrane ion channels selective for Ca+ and K+

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77
Q

How does GPCR span the membrane

A

GPCRs span the plasma membrane as a bundle of seven alfa-helices.

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78
Q

The GPCR is a binding site for what

A

•Extracellular binding site for ligand.

•Cytosolic binding site for transducer G-protein.

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79
Q

How many subunits do ligand gated receptors have and what are they

A

Five
2 α, β, γ, δ

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80
Q

How many subunits do GPCR receptors have and what are they

A

3

α, β, γ,

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81
Q

What do Gs, Gi , Gq and G12/13 do respectively for α-subunits

A

•The Gs α-subunit uniformly activates adenylyl cyclase; and Ca++ channels in myocardium and skeletal muscles
•the Gi α-subunit can inhibit certain isoforms of adenylyl cyclase; and * open K+ channel in heart and muscle and close Ca+ in neurones*
•the Gq α-subunit activates all forms of phospholipase C;
•and the G12/13 α-subunits couple to guanine nucleotide exchange factors (GEFs), such as p115RhoGEF for the small GTP-binding proteins Rho and Rac.

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82
Q

What’s the Adenylyl cyclase-cAMP pathway

A

↑ cAMP (2nd messenger)
⬇️
PKA phosphorylation
⬇️
Various functions

-↑ heart contraction
-Smooth mus relaxation
-Glycogenolysis
-lipolysis
-inhibition of secretion/mediator release
- hormone secretion, among others.
- Modulation of junctional transmission
- Opens specific type of Ca++ channel - Cyclic nucleo tide gated channel (CNG) - - -heart, brain and kidney

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83
Q

What’s the Phospholipase C: IP3-DAG pathway

A

PIP2
⬇️

   IP3      +      DAG
   ⬇️.                  ⬇️                Mobilize  Ca 2+          PKc activation

Via Calmodulin and PKC

Activation of CCPK, MLCK, PKc
-contraction
-neural excitation
-cell proliferation, secretion
-transmitter release
-eicosanoid synthesis

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84
Q

Explain Resensitization and Down regulation

A

I. Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm.

  1. Agonist-activated receptors are phosphorylated by a G protein-coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, - β arrestin (β-Arr), to the receptor.

3.The receptor- β arrestin complex binds to coated pits, promoting receptor internalization.

4.Dissociation of agonist from internalized receptors reduces - β Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase.

5.Return of receptors to the plasma membrane result in the efficient resensitization of cellular responsiveness.

  1. Repeated or prolonged exposure of cells to agonists favor the delivery of internalized receptors to lysosome , promoting down regulation rather than resensitisation
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85
Q

What are the 2 types of enzyme linked receptors

A

•With intrinsic enzymatic activity.

•Without intrinsic enzymatic activity (but bind a JAK-STAT kinase on activation

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86
Q

What’s the therapeutic index

A

That’s the LD50/ ED50

The larger the the T.I( farther from 1) the easier to take

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87
Q

Examples of drugs that are competitive

A

Neostagmine-acetylcholine esterase

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88
Q

Examples of drugs that are non competitive

A

Omeprazole
Imipramine
Aspirin

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89
Q

Examples of ions channel blocking drugs

A

Niphedipine
Quinidine
Amiodarone

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90
Q

Ion channel modulators

A

Amlodipine
nateglinide
repaglinide
sulfonylureas
alprazolam
zolpidem,

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91
Q

What is phenoxybenzamine

A

An antagonist for alpha adrenoceptor

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92
Q

Drugs with high and low therapeutic index

A

Penicillin: High therapeutic index (100)
Digoxin : Low therapeutic index (0.8–2.0)

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93
Q

Factors that affect dose response relationship

A

absorption,
metabolism, and elimination of the drug;
the site of action of the drug in the body;
and the presence of other drugs or disease.

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94
Q

What’s the proportional relationship between dose Abd response

A

At low doses, relatively directly proportional
At higher doses the amount of change in response to an increase in the dose gradually decreases until a dose is reached that produces no further increase in the observed response (i.e., a plateau).

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95
Q

What kind of curve is the d/r curve

A

Sigmoid

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96
Q

What’s the d/r curve

A

Measurement of the relationship between the quantity/concentration of a substance and its overall effect on an organism.

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97
Q

How is the d/r curve plotted

A

the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa

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98
Q

How is the curve plotted

A

the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa

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99
Q

How is the curve plotted

A

the response (ordinate) is plotted against the logarithm of the drug concentration (abscissa

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100
Q

How is the scale of the drug conc determined

A

the scale of the drug concentration axis is expanded at low concentrations where the effect is rapidly changing, while compressing the scale at higher doses where the effect is changing more slowly

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101
Q

What are the salient features of the curve

A

i.Threshold
ii.Slope
iii.Emax

102
Q

When are there no no adverse effects from exposure to the chemical. ( the human body can take some toxic insult )

A

At a dose below threshold

103
Q

What thresholds are easier and more difficult to determine

A

Thresholds based on acute responses, such as death, are more easily determined, while thresholds for chemicals that cause cancer or other chronic responses are more difficult to determine.

104
Q

How do technologist determine the toxicity when the threshold is difficult to determine

A

, toxicologists look at the slope of the dose-response curve to give them information about the toxicity of a chemical.

105
Q

What does the slop say about the toxicity

A

A sharp increase in the slope of the curve can suggest increasingly higher risks of toxic responses as the dose increases, A relatively flat slope suggests that the effect of an increase in dose is minimal

106
Q

How can you define the potency of a chemical

A

The potency of a chemical is a measure of its strength as a poison compared with other chemicals

The more potent the chemical, the less it takes to kill

107
Q

What does the slope of the curve say about the potency of a drug

A

A steep curve that begins to climb even at a small dose suggests a chemical of high potency

108
Q

List 3 characteristics of DR curve

A

•i. curves are sigmoid, having between 20 and 80 % as straight lines for statistical analysis.
•ii. Drugs with a similar mechanism of action have parallel curves.
•iii. Beyond Emax, further increase in drug concentration cannot produce any increase in response

109
Q

What are the 2 types of D/R curve

A

Graded D/R curve
Quantal D/R curve

110
Q

Give 3 characters of GRADED D/R curve

A

• Measured in a single biologic unit
• Continuous scale (⬆️dose -› ⬆️effect)
• Relates dose to intensity of effect

111
Q

List 3 characteristics of QUANTAL D/R curve

A

• Population studies
• All-or-none pharmacologic effect
• Relates dose to frequency of effect or % of population showing a specific result

112
Q

How do you define the potency of a drug

A

A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity

A highly potent drug evokes a given response at a low concentration. A drug of lower potency evokes the same response only at higher concentrations.

113
Q

Example of a highly potent drug

A

Fentanyl

114
Q

Example of a drug with low potency

A

Miperidine

115
Q

How is the potency usually measured

A

Often measured at 50 % concentration or dose leve

116
Q

Is the potency of a drug clinically important

A

Relatively unimportant in clinical use of drugs.

117
Q

What is efficacy of a drug

A

Ability of the drug to produce effect. Emax is the maximal effect that can be produced by a drug.

118
Q

What determines the efficacy of a drug

A

determined mainly by the properties of the drug and its receptor-effector system

119
Q

Is the efficacy of a drug important clinically

A

Yes efficacy is an Important clinical measure

120
Q

What’s the max efficacy of a partial agonist in comparison to an agonist

A

Partial agonist have lower maximal efficacy than full agonists.

121
Q

How does the D/R curve help estimate the safety of a drug

A

Through the therapeutic index

122
Q

Example of chemical antagonists

A

dimercaprol and mercuric ion.

123
Q

What is pharmacological antagonism

A

caused by action of the agonist and antagonist at the same site.

124
Q

I’m what type of antagonism is competitive and non-competitive used.

A

Pharmacological antagonism

125
Q

What’s the effect of a competitive antagonist on the D/R curve

A

It shifts the curve to the right

E max is still attained BUT with an increase in dose of the agonist

126
Q

What’s the effect of a non competitive antagonist on a D/R curve

A

It flattens or shifts the curve downward

E max can never be attained no matter how much you increase the dose

127
Q

What’s an antagonist of epinephrine

A

Dibenamine

128
Q

What do agonists possess that antagonists don’t

A

Agonist have both affinity and efficacy (due to intrinsic activity) but antagonists only have affinity but no efficacy

129
Q

What words are pharmacodynamics gotten from

A

•Pharmakon =drug
•Dynamikos =force or power

130
Q

What does pharmcodynamics entail

A

•It involves receptor binding (including receptor sensitivity), post-receptor effects and chemical interactions

131
Q

What determines how quickly the drug initiates the effect and how long the effect lasts.

A

The strength and length of the interaction

132
Q

Give an example of a bacterial enzyme penicillin binds to to prevent cross links in the bacteria

A

Transpeptidase

133
Q

Describe the pharmacodynamics of penicillin

A

When penicillin binds to transpeptidase to stop cross links, if the penicillin is enough cross linking (to create strong cell walls) stops completely, but if the penicillin is too little, the enzyme resumes cross linking

‼️HENCE ; The bacterial killing activity of penicillin changes with the levels in the body.

134
Q

What physiological changes can affect the pharmacodynamics of a drug

A

physiologic changes due to disorders which can change receptor binding, alter the level of binding proteins or decrease receptor sensitivity

135
Q

Examples of physiological changes that affect drugs pharmacodynamic

A

genetic mutations,
malnutrition,
thyrotoxicosis.

136
Q

What are the principles of drug action

A

Drugs (except those gene based)
-Do NOT impart new functions on any system, organ or cell.
-Only alter the PACE of ongoing activity.

137
Q

What are the basic types of drug action

A

Stimulation
Depression
Irritation
Replacement
Cytotoxic action

138
Q

What is drug stimulation

A

selective enhancement of the level of activity of specialized cells,.

139
Q

Examples of stimulation by drugs

A

adrenaline on the heart,
pilocarpine on salivary glands
Picrotoxin on CNS (high dosage)

140
Q

What is drug depression

A

selective diminution of activity of specialized cells,

141
Q

Examples of depressions done by drugs

A

barbiturates on the CNS,
quinidine on the heart,
omeprazole on gastric secretion.
Ach on SA nodes

142
Q

Examples of depressions done by drugs

A

barbiturates on the CNS,
quinidine on the heart,
omeprazole on gastric secretion
Ach on SA nodes of the heart

143
Q

What is drug irritation

A

particularly applied to -nonspecialized cells (epithelium, connective tissue), a non-selective and often noxious effect.

144
Q

What does strong irritation lead to

A

Strong irritation results in inflammation,
corrosion,
necrosis, and
consequently, loss of function.

145
Q

Examples of irritation caused by drug

A

bitters on salivary and gastric secretions.

146
Q

What is drug replacement

A

use of natural metabolites, hormones or their congeners in deficiency states

147
Q

Examples of drug replacement

A

levodopa in Parkinson’s disease,
insulin in diabetes mellitus.
Iron In anemia

148
Q

What is drug cytotoxic action

A

selective cytotoxic action on cancer cells or invading organisms, attenuating them without significantly affecting the host cells

149
Q

Examples of drugs with cytotoxic action

A

cyclophosphamide,
zidovudine,
penicillin.
Chloroquine

150
Q

What are the mechanisms of drug action

A

Physical and chemical mechanics

151
Q

Example of physical mechanisms in drugs

A

-Activated charcoal binds with poisons in the stomach.
-Mannitol as an osmotic diuretic, freely filtered but not reabsorbed.
-Bulk laxatives e.g. ispaghula.

152
Q

Examples of chemical mechanisms in drugs

A

-NaHCO3 as an antacid.
-Dimercaprol, penicillamine, desferrioxamine as chelating agents.
-Pralidoxime as a choline esterase reactivator.
-Cholestyramine for sequestration of bile acids and cholesterol in the gut.

153
Q

Most drugs produce their effects by interacting with a discrete target biomolecule - usually a protein such as what

A

Carrier molecules
Ion channels
Receptor
Enzymes

154
Q

Drug-enzyme interactions may take place as what and what

A

Enzyme activator and enzyme inhibitors

155
Q

Give 3 examples of competitive enzyme inhibition

A

1.Angiotensin converting enzyme inhibitors e.g. captopril
2.Reversible anticholinesterases e.g. neostigmine, physostigmine
3.Allopurinol used in gout since it inhibits xanthine oxidase,

Atropine
Scopolamine. (Both inhibit muscarinic receptor)

156
Q

Give 4 examples of non competitive inhibitors

A

1.Irreversible anticholinesterases e.g. organophosphorus compounds (insectisides and war gases).
2.Aspirin inhibits cyclooxygenase enzyme and therefore prostaglandin synthesis.
3.Monoamine oxidase inhibitors used to treat depression e.g.
4.Proton pump inhibitors: e.g. omeprazole inhibit the H+/K+ ATPase in parietal cells of stomach.

157
Q

Examples of sodium channel drugs

A

Quinidine
Procainamide
Lidocaine
Carbamazepine

158
Q

How do sodium channel drugs work

A

local anaesthetics block the channels, (inhibit sodium influx) thus depolarization does not take place and there is no nerve conduction in that localized area. They are used respectively in cardiac arrhythmias and as local anaesthetic.

159
Q

How do sodium channel drugs work

A

local anaesthetics block the channels, thus depolarization does not take place and there is no nerve conduction in that localized area. They are used respectively in cardiac arrhythmias and as local anaesthetic.

160
Q

How do calcium channel drugs work

A

Block the voltage gated calcium channels; (prevent ca influx) useful in hypertension and arrhythmias

161
Q

Example of calcium channel drugs

A

nifedipine,
verapamil,
diltiazem
Amlodipine
Nicardipine

162
Q

How do potassium channel drugs work

A

blockade of the channels leads to a prolonged refractory period. (Prolongs duration of action potential)

163
Q

Examples of potassium channel drugs

A

amiodarone,
sulfonylureas (treats diabetes)
Dalframpidine
Dofetilide

164
Q

How do chloride channel drugs work

A

upon activation, the GABA A receptor selectively conducts Cl- through its pore, resulting in hyperpolarization of the neuron, which causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring

165
Q

Example of chloride channel drug

A

Benzodiazepines (lorazepam)

166
Q

Give 5 examples of drugs that inhibit carrier molecules

A

-Inhibition of choline carrier by hemicholinium.

-Inhibition of noradrenaline vesicular uptake by reserpine.

-Inhibition of neuronal reuptake of noradrenaline by desipramine.

-Inhibition of neuronal reuptake of serotonin by fluoxetine.

-Inhibition of weak acid (e.g. uric acid) carrier by drugs (e.g. probenecid, which prevents uric acid tubular reabsorption, thus enhancing its excretion).

167
Q

Which agents have no effect on receptors on its own

A

Antagonists

168
Q

Examples of agonists

A

acetylcholine,
adrenaline,
noradrenaline

169
Q

Examples of antagonists

A

atropine, (competitive muscarinic inhibitor)
scopolamine, (competitive muscarinic inhibitor)
phenoxybenzamine. (Alpha blocker)

170
Q

Example of an inverse agonist

A

Beta carbolines

171
Q

Explain agonist, antagonist, partial and inverse agonist in terms of affinity and intrinsic activity mathematically

A

Agonist : Affinity + IA= 1
Antagonist : Affinity + IA= -1
Partial agonists: Affinity + IA = Between 0 and 1
Inverse agonist : Affinity + IA = Between 0 and -1

172
Q

How are the functions of a receptor determined

A

determined by the interaction of lipophillic or hydrophillic domains of the peptide chain within the drug molecule.

173
Q

What induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain.)

A

Binding of polar drugs in ligand binding domain

174
Q

What are the subtypes of Ach receptors

A

Muscarinic M1, M2, M3
Nicotininic Nn,Nm

175
Q

What are the criteria used in classifying receptors

A

Pharmacological criteria
Tissue distribution
Transducer pathway
Molecular cloning

176
Q

What is pharmacological criteria of receptors with examples

A

it is the classical and oldest approach, based on potencies of selective agonist and antagonists – Muscarinic, nicotinic, alpha and beta adrenergic etc

177
Q

Explain the tissue distribution receptors

A

the relative organ or tissue distribution is the basis for designating the subtype e.g. the cardiac beta adrenergic receptor as beta 1 and bronchial as beta 2.

178
Q

Explain the ligand binding types of receptors

A

Measurement of specific binding of high affinity radio-labelled ligand to cellular fragments (usually membranes) in vitro and its selective displacement by various selective agonists/antagonists is used to delineate receptor subtype. E.g. multiple 5-HT receptors were distinguished by this approach.

179
Q

Explain the transducer pathway types of receptors

A

receptor subtype may be distinguished by the mechanism through which their activation is linked to the response, e.g. M cholinergic receptor acts through G-proteins, while N cholinergic receptor gates influx of Na+ ions.

180
Q

Explain the molecular cloning types of receptor

A

the receptor protein is cloned and its detailed amino acid sequence as well as three dimensional structure is worked out. This approach has resulted in a flood of receptor subtypes and several isoforms, even in receptors without known ligands (orphan receptors).

181
Q

What are silent receptors

A

These are sites which bind specific drugs but no pharmacological response is elicited. They are better called Drug acceptors or Sites of loss e.g. plasma proteins.

182
Q

What are spare receptors

A

A drug can produce the maximal response when even less than 1% of the receptors is occupied. The remaining unoccupied receptors are just serving as receptor reserve and are called spare receptors.

183
Q

What is receptor up regulation

A

increase in the number of receptors with subsequent increase in receptor sensitivity

184
Q

Give 2 examples of receptor up regulation

A

Depletion of noradrenaline : treatment with adrenergic antagonist (absence makes the heart fonder) - leads to super sensitivity to nore adrenaline and increase in receptor number

Administration of beta blockers increase adrenergic receptors

185
Q

What is receptor down regulation

A

reduction in the number of receptors available for activation
Reduced affinity & reduced No of receptors

186
Q

Explain what causes down regulation

A

Due to continued exposure to a drug/ agonist: It results in blunted response: desensitisation/ refractoriness/ tolerance

187
Q

Example of receptor down regulation

A

Repeated administration of adrenergic agonist leading to down regulation of beta receptors

188
Q

What are the two types of mechanisms of receptor related diseases

A

• Autoantibodies directed against receptor proteins

•Mutations in genes encoding receptors and proteins involved in signal transduction.

189
Q

Give 2 examples of receptor related diseases caused by antibodies attacking receptor proteins

A

•Myasthenia gravis , - autoantibodies that inactivate nicotinic acetylcholine receptors.
•Autoantibodies can also mimic the effects of agonists, as in many cases of thyroid hypersecretion, caused by activation of thyrotropin receptors

190
Q

Give 4 examples of receptor related diseases

A

•Myasthenia Gravis:
–Antibodies against the cholinergic nicotinic receptors at motor end plate.
•Insulin Resistant Diabetes
•Testicular feminisation
•Familial hypercholesterolemia

191
Q

What are the 4 main categories of transducer metabolism

A

1.GPCR
2.Receptors with intrinsic ion channel
3.Enzyme linked receptor
4.transcription factors (receptors for gene expression

192
Q

Which receptors are called seven-transmembrane domain receptors.

A

GPCR

193
Q

Which receptors Mediate the majority of cellular responses to external stimuli

A

GPCR

194
Q

Which receptors common pattern of structural organization

A

All GPCR

195
Q

How do GPCR span the cell

A

The molecule has 7 α-helical membrane spanning hydrophobic amino acid segments – 3 extra and 3 intracellular loops

196
Q

What ligands bing GPCR

A

light-sensitive compounds,
odours,
hormones,
neurotransmitters,
and they vary in size from small molecules to peptides to large proteins.

197
Q

What is intracellular receptor

A

Found in the cell
Receptor enters the nucleus and changes gene transcription
Coupling is indirect

198
Q

Examples of intracellular receptors

A

Steroids
Estrogen

199
Q

What’s the effector of a GCPR

A

Ion or enzyme

200
Q

What kind of coupling or transduction do each types of receptors have

A

Ion channel-Direct transduction
Enzyme linked-Direct transduction
GCPR-Indirect (via G proteins)
Intracellular-Indirect

201
Q

Examples of enzyme linked receptors

A

Insulin
Cytokines

202
Q

Types of drug receptor relationship

A

Drug receptor binding
Drug receptor interaction
Drug receptor outcome
Drug receptor regulation

203
Q

What are the 2 types of drug receptor binding

A

Reversible and irreversible

204
Q

What type of bonds do reversible ligand binding have

A

Hydrogen bond
Usually competitive

205
Q

What type of bond do irreversible ligand binding have

A

Covalent bond
Mostly non competitive

206
Q

What are the types of drug receptor interactions

A

Ligand - Drug must be a ligand
Affinity- Drug must have affinity
Intrinsic activity- Not compulsory for drug to have
Specificity- Not compulsory for drug to have

207
Q

What are voltage gated receptors

A

the rate and direction of ion movement through the pore is governed by the electrochemical gradient (as measured by its concentration on either side of the membrane as well as the membrane potential) for each ion.

208
Q

How does Ligand-binding and channel opening occur

A

on a millisecond timescale, so they are confined to excitable tissues-CNS, NMJ, autonomic ganglia.

209
Q

What receptor does Benzodiazepene work on

A

enhance stimulation of gamma-aminobutyric acid (GABA), resulting in increased chloride influx and hyperpolarization of the respective cell.

210
Q

What’s another name for enzyme linked receptor

A

Receptor tyrosine kinase

211
Q

Which receptors are metabotrophic

A

G protein

212
Q

Function of G12/13

A

regulate actin cytoskeletal remodeling in cells during during movement and migration, including cancer cell metastasis.

213
Q

Examples of ligands for GCPR

A

: adenosine,
bradykinin,
endothelin,
opioid peptides,
dopamine,
serotonin,
acetylcholine (muscarinic effects), histamine,
chemokines,
eicosanoids,
adrenaline, noradrenaline etc.

214
Q

What are the three second messenger systems

A

•Cyclic AMP
•Cyclic GMP
•Calcium and phosphoinositol second messenger system

215
Q

When are G proteins active and inactive

A

rendered inactive when reversibly bound to Guanosine diphosphate (GDP), but active when bound to Guanosine triphosphate (GTP).

216
Q

How does the inactive G protein function

A

•The inactive G protein is bound to the receptor in its inactive state.
•Once the receptor is recognized, the receptor changes in its conformation and therefore, mechanically activates the G protein, which detaches from the receptor.
•The receptor can now activate another G protein or switch back to its inactive state.

217
Q

What happens to a G protein that’s been activated by binding to an inactive receptor

A

Upon activation, the subunits of the G protein dissociate from the receptor, as well as from each other to yield Gα-GTP monomer and a tightly interacting Gβϒ dimer, which are now free to modulate the activity of other intracellular proteins.

218
Q

What’s the function of Go

A

Reduces Ca

219
Q

What’s the effector for Gs

A

Beta-receptors,
H2, D1

(Opens Ca channel)

220
Q

What’s the substrate for the Gi

A

Muscarinic M2
D2, alpha-2, 5HT1, GABA B

(Opens K channel)

221
Q

What’s the substrate for Gq

A

Alph-1, H1, M1,M3, 5HT2

222
Q

What’s the substrate for Go

A

K+ channel in
heart, sm
M2, D2, Alpha2, 5HT1, GABA B

223
Q

What ion channels are targets for G protein

A

Ca and K

224
Q

How is cAMP produced

A

G-alpha binds to andenyl cyclase to produce cAMP

225
Q

What’s the function of cAMP

A

regulates many aspects of cellular functions such as: cell division and cell differentiation, ion channels, ion transport etc. These different activities are via a common pathway i.e. activation of protein kinases by cAMP.

226
Q

What terminates cAMP activity

A

terminated by phophodiestarases, which hydrolyse it to 5-AMP.

227
Q

What forms resting G protein

A

The GTP is hydrolysed to GDP by GTPase activity of the α-subunit, therefore, there is reassociation with Gβϒ dimer to form the “resting” G-protein.

228
Q

Functions carried out by enzyme linked receptors and examples

A

metabolism, growth and differentiation

Insulin and cytokine

229
Q

Where are ligand gated receptors found

A

confined to excitable tissues-CNS, NMJ, autonomic ganglia.

230
Q

Functions of ligand gated receptors
And example

A

neurotransmission, cardiac conduction and muscle contraction

example, stimulation of nicotinic receptor by ACh results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle.

231
Q

Targets of G protein

A

Adenylate cycle
Phospholipase C
Ca and K ion channel

232
Q

Function of intracellular receptors

A

primary targets are transcription factors, which cause the transcription of DNA into RNA and translation of RNA into an array of proteins.

233
Q

What are the three major pathways of GPCR

A

•Adenylyl cyclase: cAMP pathway
•Phospholipase C: IP3-DAG pathway
•Channel regulation

234
Q

What is cAMP dependent protein kinase

A

Protein kinase A

235
Q

What is phosphate lipase C dependent protein kinase

A

Protein kinase C

236
Q

Examples of hormones that need cAMP second messenger to pass info into cells because they can’t pass through the membrane

A

Glucagon
Adrenaline

237
Q

Which is hydrophilic and lipophilic (IP3 and DAG)

A

IP3 is hydrophilic
DAG is lipophilic

238
Q

Can G proteins open or close up ion channels without second messengers

A

Yes

239
Q

What are the natural ligands for intrinsic ion channels

A

The natural ligands include acetylcholine, serotonin, aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate)

240
Q

What are the drug receptor binding forces

A

•Covalent bond: Strong and in many cases not reversible under biological conditions.
•Ionic bond: Weaker than covalent, but stronger than the others
•Hydrogen bond: Stronger than Van-der-Waals
•Van-der-Waals

241
Q

What are the receptor theories

A
  1. Occupancy theory
  2. Rate theory
  3. Stephenson’s theory
  4. Ariens’ theory
  5. The induced-fit theory
  6. Macromolecular Perturbation theory
242
Q

State the occupancy theory

A

response is proportional to the fraction of occupied receptors; maximal response occurs when all the receptors are occupied.

243
Q

State the receptor Rate theory

A

response is proportional to the rate of Drug-Receptor complex dissociation. Here, duration of receptor dissociation determines whether a molecule is agonist, partial agonist or antagonist.

244
Q

State the receptor Stephensons theory

A

response is proportional to the fraction of occupied receptor and the intrinsic activity.

245
Q

State the receptor Ariens theory

A

response is a function of affinity; maximum response can be produced without 100 % receptor occupation.

246
Q

State the receptor Induced fit theory

A

binding site is not necessarily complementary with the ligand conformation. Rather binding produces a plastic molding of both the ligand and the receptor as a dynamic process (thus nullifying the obsolete “key and lock” concept)

247
Q

State the receptor Macromolecular perturbation theory

A

when a drug-receptor interaction occurs, one of two general types of macromolecular pertubation is possible. Either a specific conformational pertubation (by agonist), which leads to a biological response Or a non-specific conformational pertubation (antagonist), leads to no biologic response.

248
Q

What are the types of drug effect

A

Desired effect
Side effect
Adverse effect

249
Q

What is side effect with example

A

Undesired, Dose dependent, predictable

Aspirin; excess bleeding
Septein; dark urine

250
Q

What is adverse effect with examples

A

Undesired, unpredictable, dose independent

Aspirin; Reye sydrome
Septrin; Steven Johnson syndrome

251
Q

Types of adverse effects

A

Type A - Augmented
Type B - Bizarre
Type C - Chronic
Type D - Delay
Type E - Ending of use
Type F - Failure of use

252
Q

Which of the types of adverse effects are dose related

A

Type A and Type C

Pharmacology FPP (4 decks)

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