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Pharmacology MT1 > Pharmacodynamics > Flashcards

Pharmacodynamics Flashcards

1
Q

Suicide substrates

A

Drug bikds covalently/irreversibly to inactivate a receptor

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2
Q

Full agonists

A

bind to and activate their targets to the maximal extent possible.

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3
Q

Partial agonists:

A

produce a submaximal response upon binding to their targets.

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4
Q

Inverse agonists:

A

cause constitutively active targets to become inactive.

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5
Q

Competitive antagonists

A

Drugs directly blocking binding site of a physiologic agonist

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6
Q

Noncompetitive (allosteric)/uncompetitive antagonists:

A

drugs that bind to other sites on the
target molecule, and prevent the conformational change required for receptor activation (or inactivation). require receptor activation by an agonist before they can bind to a separate allosteric binding site

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7
Q

Ligand-gated ion channels, states

A

Open and Closed

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8
Q

Voltage-gated ion channels (Sodium) states

A

Can be Inactivated

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9
Q

What are Gi, Gs and Gq receptors

A

Gs: activating AC and prod more cAMP
Gi: inactivating AC and prod less cAMP
Gq: activating PLC and producing IP3 and DAG

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11
Q

Name the Gαs (Gα stimulatory)-coupled receptors

A

Histamine (H2)-receptors: increases gastric acid production, causes vasodilation, and generally relaxes smooth muscles

β-Adrenoceptors: adrenaline

β1-receptors (excitatory): mediate increased contractility (cardiac muscle) and heart rate (SA node of heart), fat cell lipolysis

β2-receptors (inhibitory): mediate vasodilation and intestinal, bronchial, and uterine smooth muscle relaxation

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12
Q

Gq (and G11)-coupled receptors, example ligand

A

eg Serotonin

Histamine (H1)-receptors: - In the brain: increases wakefulness.
- In vessels: causes vasodilation and increase in permeability.

α1-Adrenoceptors: vasoconstriction, gastrointestinal relaxation, pupil dilation (mydriasis)

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13
Q

Benzodiazepines: how do they work on receptors

A

inhibit neurotransmission in the CNS by potentiating the ability of the
neurotransmitter GABA to increase the conductance of Cl- ions across neuronal membranes, preventing action potential propagation and pain perception (voltage gated ion channels)

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14
Q

Name the Gαi (G inhibitory)-coupled receptors, example ligand

A

eg: Somatostatine

α2-Adrenoceptors : inhibition of release of norepinephrine and other neurotransmitters

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15
Q

Local anesthetics: how do they work on receptors

A

(block the conductance of Na+ ions through voltage-gated Na+ channels in neurons that
transmit pain information from the periphery to the CNS

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16
Q

how does drugs work on Receptor-activated Tyrosine kinases? example ligand

A

Eg. Insulin

bind to the extracellular domain of a transmembrane
receptor causing conformational changes in the
receptor.. Activate or inhibit an enzymatic intracellular domain of the same receptor, which cause a change in IC cell signalling.

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16
Q

Intracellular nuclear receptors, how to they work, ex ligand

A

Cortisol

  • must be lipophilic to diffuse through membrane!
  • no ligand: inactive receptor
  • ligand binds: entry of receptors into nucleus to regulate gene expression (controle metabolism, hoemostasis and development of the organism)
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17
Q

Cellular Regulation of drug-receptor interactions by tachyphylaxis

A

Rep admin of same dose results in a reduced effect of the drug over time

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18
Q

Cellular Regulation of drug-receptor interactions by desensitization

A

Decr ability of a receptor to respond to stimuli by a drug or ligand

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19
Q

Cellular Regulation of drug-receptor interactions by homologous and heterologous mechanism

A

Dece response to a single/ two or more types of receptors

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20
Q

Cellular Regulation of drug-receptor interactions by inactivation

A

Loss of ability of receptor to respond to binding of drug or ligand

21
Q

Cellular Regulation of drug-receptor interactions by refractory

A

Time needed for the receptor btw effects to produce an effect

22
Q

Cellular Regulation of drug-receptor interactions by down-regulation

A

Receptors used a lot - there will be fewer of that type, by putting them in vesicles IC so they cannot be used, can be recycled if we need more. Can also synthesize more.

(leads to cellular desentisization)

23
Q

Give examples of drugs who alter the activity of enzymes

A

Acetylcholineesterase: decr ach conc
Inhibitor: neostigmine: incr ach conc

Cyclooxygenase: incr pain and inflamm
Inhibitor: Aspirin: decr pain and inflamm (NSAIDs)

24
Q

Antimetabolite action

A
  • S-phase specific drugs
  • structural analogues of essential metabolites -> interfering with DNA
    synthesis
25
Q

Nonspecific chemical or physical interactionst

A

Drugs that DO NOT act on receptors

Antacids: weak bases that partially neutralize gastric acid. NaHCO3

Osmotic agents : include both salt-containing(MgSO4) and salt-free agents(glycerin). Alter water and ion balance by changing the osmolarity in the nephron directly.

Metal-chelating agents: form complexes with cationic ions to be exreted- EDTA: Ca2+, Fe2+, Deferoxamine: Fe2+ and Fe3+

26
Q

Cumulative effect of receptor “occupancy”

A

When sufficient number of receptors bound / “occupied” on or in a cell

27
Q

what is the dissociation constant

A

At equilibrium the dissociation constant (Kd) which is induvidual for each drug, will decide how many will be in bound vs free/inactive state.

Its the ratio btw bound and free receptors at equilibrium = half of all receptors are bound, the ligand conc at this stage = max drug binding

Lower kd, fewer is bound, the drug has higher affinity

Equilibrium only works where the receptors have an active and an inactive state

28
Q

Drug-Receptor binding Curves

A

Binding two hypothetic drugs to the same receptors to see the difference in potancy and efficacy

Response to a drug is proportional to concentration of receptors bound/occupied by it. Incr dose - incr effect (until max ofc)

29
Q

What is the difference btw potent and efficacious drugs

A

(EC50)More potent drugs: BINDING - those having higher affinity for their receptors (lower Kd), the dose where 50% of max response is seen

(Emax)More efficacious drugs: EFFECT - those causing a higher proportion of receptors to be activated.
- incr dose can NOT incr the effect if if the max effect is reached

Eg drugs can have very different potency but same efficacy - different doses to reach same effect

30
Q

Partial, full and inverse agonists

A

If all bind same resceptor:

Full: can elicit max response
Partial: cannot elicit max response
Inverse: elicit opposit pharmacological response

31
Q

Receptor antagonists

A

Active site binding,

  • competitive: same spot as antagonists - prevents binding, reversible
  • non-competitive is irreversible

Allosteric binding/on other spot
- non-competitive: other spot: change Kd/potancy or prevents effect

32
Q

Non-receptor antagonists

A

INHIBIT the effect of the agonist w/o binding

Chemical antagonist: inactivate the agonist

Physiological antagonist: eg antohistamine elicit PHYSIOLOGICAL effect opposite to the one induced by the agonist - so the agonist is bound and give its effect but the effect itself is counteracted

33
Q

Describe the difference in Drug-Receptor binding Curves of competitive va non-competitive antagonists

A

Competitive: potancy changes, efficacy stays the same - it just needs a higher dose to reach max!

Non-competitive: potency stays the same, but efficacy change, sp the max effect cannot be reached.

34
Q

Quantal dose-response relationships

A

Used to determine the therapeutic index of a drug to generalize a result to a population.

  • For predicting the effects of a drug when it is administered, min dose
  • For determining population-based toxic doses and lethal doses.
35
Q

Median effective dose (ED50) what is it and what is examined

A

dose at which 50% of animals exhibit a therapeutic response to a drug

Effectiveness (therapeutic effect) is examined

36
Q

Median toxic dose (TD50) what is it and what is examined

A

dose at which 50% of animals experience a toxic
response

Toxicity (adverse effect) is examined

37
Q

Median lethal dose (LD50) what is it and what is examined

A

dose at which 50% of animals die

Lethality (lethal effect) is examined

38
Q

EC50

A

dose at which a drug elicits a half-maximal effect in an individual animal.

39
Q

Therapeutic Window

A

Range of doses (concentrations) of a drug that elicits a therapeutic response, without unacceptable adverse effects (toxicity), in a population of patients.

Eg. Small therapeutic window: plasma drug levels must be monitored closely to maintain effective dosing without exceeding the level that could produce toxicity.

40
Q

Therapeutic Index (TI)

A

​TI=TD50/ED50

Large TI: more safe! a large / “wide” therapeutic window (for example, a thousand-fold difference between the therapeutic and toxic doses)

Small TI: a small / “narrow” therapeutic window, less narrow! (for example, a twofold difference between the therapeutic and toxic doses).

41
Q

Define drug toxicity

A

Cause change in an organ or in a whole system eg. CNS

42
Q

How can genetic factors change the drug toxicity

A

Genetic differences in:

pharmacokinetics: drug metabolism, differences in the
activities of repair mechanisms
- Ex: Kidney dysfunction eg., drugs working in kidney will be more toxic

Pharmacodynamics: drug-receptor interaction will alter pharmacological response eg receptor no

43
Q

“Off-target” adverse effects: toxicity of drug

A

Caused by the drug binding to a target or receptor for which it was not intended.

44
Q

Non-covalent interactions causing incr toxicity

A
  • ROS are produced
  • toxic chemicals or ROS from normal metabolism is accumulated and will decr. decr glutathione which will Decr protection
  • change on sulfhydryl groups which are responsible for the catalytic activity of many enzymes
45
Q

Production of harmful immune response

A

Xenobiotics are drugs that are rec by the immune system as foreign substances causing an immune response

Small drugs will trigger immune resp indirectly, while larger drugs will trigger it directly

46
Q

Immune mechanisms damaging the cell

A

Hypersensitivity/allergic reactions and autoimmune reactions

47
Q

When does hypersensitivity reactions occur?

A

Prior exposure to a substance is required for each of the four types of hypersensitivities to occur

48
Q

Idiosyncratic responses

A

Rare adverse effects for which no obvious mechanism is apparent.
- Difficult to explain and often difficult to study in animal models, precisely because the
genetic variation that may be causing the adverse response is not known.

Pharmacology MT1 (2 decks)

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