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Pharacodynamics Flashcards

1
Q

What is pharmacokinetics?

A

Subfield of pharmacology dealing with the absorption, distribution, biotransformation, and excretion of drugs

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2
Q

What is pharmacodynamics?

A

What’s happening at the point the molecule binds to the receptor. Looks at the effects at the level of the receptor.

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3
Q

What is pharmacology?

A

The branch of medicine that deals with the uses, effects, and modes of actions of drugs.

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4
Q

What are drug-receptor interactions?

A

Receptor = the molecule(s) a drug (or other ligand) interacts with to imitate its biological effects. The ability to a drug to get to the receptor is the realm of pharmacokinetics. What it does when it gets there is in the realm of pharmacodynamics. Drugs don’t do new things - they alter ongoing, existing things. They don’t produce effects that are unusual - not something different. Has intrinsic activity - it does something.

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5
Q

What are agonists (‘mimetic’)

A

Drugs that bind to receptors and cause a biological response (they have ‘intrinsic activity’)

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6
Q

What do drugs do?

A

Drugs do not produce new or unique biological effects, rather, they modify the rate of ongoing cellular events (receptors are not there to mediate effects of drugs, but effects of endogenous ligands)

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7
Q

What happens when drugs bind?

A

When drugs bind, you begin to get some sort of effect. Drug receptor interactions may involve many different types of chemical bonds, but usually non covalent interactions. Noncovalent bonds = weak bonds. Drugs bind then come off (not permanent). These are readily reversible: drug associates at binding site and then rapid dissociates. Measured by the affinity of the drug (how strong is the bond, how often does it bind, how long does it stay bound), an Kd - the smaller the number, the higher the affinity. Drugs that have high affinity for receptor binds for a longer period of time.

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8
Q

What processes do drugs affect?

A

Drugs affect many ongoing processes. Drugs are promiscuous - act o various neurotransmitter systems and/or receptor subtypes. On graphs see affinity (Kd) of MDMA at receptor. Lower K values indicate low dissociation and high affinity.

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9
Q

What are principles of D-R interactions?

A

The magnate of the drug is proportional to the number of receptors occupied. A drug produces maximal effect when all receptors occupied = ‘law of mass action’ (when all receptors are occupied at any one point in time)This relationship is described by the dose-response curve.

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10
Q

What is the dose-response curve?

A

The relationship between ligand concentration and fraction binding. At a certain point, adding more drug doesn’t produce anymore binding and stops increasing any effect that you’re looking at. This is the maximal effect.

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11
Q

What are dose-response/effect curves? (2)

A

After a certain point adding more drug does not increase the observed effect Effective Dose (ED) = 100%. Ed 100 is where you achieve the maximum effect, law of mass action. Increasing the concentration doesn’t do anything further. This is because there are no more receptors available that don’t already have drug at their binding sites (but adding more drug may continue to increase other drug effects, at other receptors).

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12
Q

What is dose-response terminology?

A

Sometimes the y-axis of a dose-response curve is used to refer to the proportion of a subject population showing a response (or not). If it shifts to the right on the graph, a higher dose is needed to produce that effect, e.g. anxiety, sedation, respiratory depression.

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13
Q

What is dose-response terminology? (2)

A

ED50 (effective dose) = dose that produces response in 50% of subjects
TD50 (toxic dose) = dose that produces a given toxic effect in 50% of subjects
LD50 (lethal dose) = dose that kills 50% of subjects.

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14
Q

How do you calculate the therapeutic index (TI)?

A

TD50/ED50

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15
Q

How do you calculate the safety margin?

A

LD50-ED50

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16
Q

What is an agonist?

A

A drug that binds to a receptor and has a pharmacological effect. Bind to receptors, have high intrinsic activity. Two major characteristics: potency (which is always relative), and maximum effect.

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17
Q

What are dose-effect functions?

A

Potency is how much drug is needed to produce an effect. Efficacy is the maximum effect that can be produce by a drug. Aspirin has a different maximum effect - at some point it doesn’t matter how much aspirin you give to someone, it won’t produce an effect in pain relief.

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18
Q

Why do some analgesics have different potencies?

A

e.g. morphine, fentanyl, heroin, codeine, hydromorphine, and aspirin. In part, this reflects pharmacokinetic factors (e.g. access of drugs to brain). e.g. fentanyl gets to the brain much faster than morphine.
Another key differences is the affinity of drugs for their receptors - after it binds, how long does it stay on the receptor?

19
Q

What happens to drugs with a high affinity for their receptor?

A

Drugs with high affinity are more likely to stay bound to their receptor, and thus keep on having an effect. But affinity does not determine the maximum possible effect, because at high doses, lots of drug molecules are available to take the place of those that dissociate.

20
Q

Why do some drugs have higher efficacy than other?

A

They may act by different mechanisms (at different receptors). Even when they bind, they may not do the same thing to the receptor that other drugs will do. They may have more or less intrinsic activity at the same receptor, once bound (maximal change when bound to receptor).

21
Q

What is a summary of the first section?

A

Agonists can vary in terms of their potency to produce an
effect which is determined by their pharmacokinetic profile
(accessibility) and affinity (Kd of disssociation constant).
‣ Differences in potency can be overcome by changing the
amount (dose) of drug given
‣ Differences in efficacy (intrinsic activity) between drugs
determine the maximum effect it can produce
‣ Difference in maximum effect are not altered by varying
dose

22
Q

What are antagonists?

A

Bind to receptors (have ‘affinity’), but have no intrinsic activity. Antagonists produce their effects by blocking the action of an agonist, or an endogenous ligand (e.g. a neurotransmitter), at that same receptor. Antagonists bind to the receptor, but when they do they don’t produce an effect, but they antagonise the effects of endogenous effects like neurotransmitters (block the effects of other types of drugs).

23
Q

What are competitive antagonists?

A

Binds to same receptor site as agonist and “competes” for
available binding sites. Shifts the dose-response curve for agonist to right. Competitive antagonist effect can be overcome by increasing the dose of agonist. Compete with the other drugs for the same receptor binding sites. Act on the same receptor site in a competitive manner. Can recognise it because it causes a shift in the potency of the drug. Changes the concentration of the agonist you’d have to inject.

24
Q

What is an example of a competitive antagonist?

A

Naloxone (Narcan ©) - an opioid competitive antagonist with high
receptor affinity, used to treat heroin overdose).

25
Q

What are non-competitive antagonists?

A

Do not compete with agonist for the same receptor binding
site (e.g. may bind to another site). Shift the dose-effect curve for
agonists to the right, but also change its shape. Antagonism can not be overcome by increasing the dose of the agonist - there is a decrease in maximum effect. Essentially, non-competitive antagonists make receptors unavailable for drug action. Changes the potency, but more importantly they change the maximum effect, because they bind to different mechanisms – not competing for the same binding site. Taking out certain receptors as a potential binding site, which leads to a changing of maximum effect.

26
Q

What is reversibility?

A

Antagonists tend to form weak non-covalent interactions that are readily reversible. However, some are irreversible: they form a long-lasting bond. Recovery of function only after new receptors are synthesised. e.g. alpha-bungarotoxin (from banded krait venom). Irreversible binding to acetylcholine receptor at neuromuscular junction. Causes paralysis, respiratory failure, death (though fully conscious).

27
Q

What are partial agonists?

A

Mixed agonist/antagonist effects. Intermediate levels of intrinsic activity at a receptor,
antagonize in presence of full agonist (e.g., Buprenorphine
is an opioid partial agonist used in addiction therapies.) Do basically the same thing, just has less intrinsic activity.

28
Q

What are inverse agonists?

A

Drugs that produce a descending dose-effect curve (rather than the usual ascending curve).

29
Q

What are partial agonists? (2)

A

Drug with intermediate levels of intrinsic activity at a receptor (compared to “full agonist”). Usually behave as weak (lower efficacy) agonists. But in the presence of full agonists, they can act as competitive agonists. Doesn’t produce full maximum effect as full agonist, has lower intrinsic activity and efficacy, low maximum effect (all the same thing – intrinsic activity, efficacy, and maximum effect).

30
Q

What are inverse agonists? (2)

A

Drugs that producing a descending dose-effect curve (rather than the usual ascending curve). They are agonists, in that they produce a biological effect. Inverse, in that they produce an effect that is opposite to that of the endogenous ligand or that produced by an agonist. This is possible because some receptors have substantial endogenous activity even when ligands are not bounds. Inverse intrinsic activity, very rare drugs.

31
Q

What is an example of an inverse agonist?

A

Some beta-carboline alkaloids (e.g.DMCM) are “antibenzodiazepines” - bind to GABA-A receptors but provoke anxiety,
panic and at high doses, convulsions.

32
Q

How can drug effects change with experience?

A

With chronic (repeated or long-lasting) drug administration, the effects on the brain and behaviour can change. If a drug effect gets smaller, this is called tolerance (some effects of the drug you become tolerant to, others you don’t). If a drug effect gets bigger, this is called sensitisation (some drug effects actually increase with repeated use). Sensitisation or tolerance not to a drug, but to a drug effect.

33
Q

What are changes in the dose-response curve for tolerance and sensitisation?

A

With tolerance, more drug is required to produce the same
effect (shift to right in the dose-response curve). With sensitisation, less drug is required to produce the same
effect (shift to left in the dose-response curve). Different degrees of
tolerance to different
drug effects can make drugs more dangerous. Tolerance shift to the right - more drug is required. Sensitisation shift to the left - less drug is required. Margin of safety also shifts, as you move closer to lethal dose (tolerance).

34
Q

What is acute tolerance?

A

Tachphylaxis. Drug effect decreases rapidly - within a single session. e.g. alcohol produces greater behavioural deficits when blood alcohol content is rising vs. falling.

35
Q

What is protracted tolerance?

A

Drug effect decreases with repeated administration. Tolerance that sticks around and is semi-permanent. e.g. regular alcohol drinkers are less impaired by a given dose of alcohol than non-drinkers.

36
Q

What is cross-tolerance?

A

Drug effect decreases with repeated administration of another drug. Not only can you become tolerant to the effect of one drug, you can also become tolerance to the effects of other drugs the do similar things as the original drug. e.g. regular alcohol drinkers are less affected by barbiturates, benzodiazepines, some aesthetics.

37
Q

What are mechanisms of tolerance?

A

In many cases, tolerance reflects homeostatic adaptions (compensatory responses) of the body - trying to return to normal despite the presence of a drug.

38
Q

What is pharmacokinetic tolerance?

A

Changes can be
pharmacokinetic/metabolic, such as enzyme induction
(chronic drinkers have morealcohol dehydrogenase). Decreases in the effect of the drug e.g. because better at metabolising alcohol.

39
Q

What is pharmacodynamic tolerance?

A

Changes also occur to receptors and their corresponding signaling pathways. For example, receptors may become
fewer in number, or change their intracellular location

40
Q

What is behavioural tolerance?

A

Learning factors can also be important - compensating for behaviour caused by the effect of the drug. E.g. tachyphylaxis with alcohol - after maximum effect, get excretion phase.

41
Q

What is dependence and withdrawal?

A

A state of dependence exists when tolerance has developed, so that ceasing drug use will result in withdrawal symptoms (could be ‘physical’ or ‘psychological’ symptoms). Withdrawal symptoms are typically opposite to the acute effects of the drug. Withdrawal effects are the result of tolerance.

42
Q

What is cross-sensitisation?

A

Can occur between drugs (e.g. cocaine and amphetamine), between drugs and stress (i.e. repeated stress increases sensitivity to some drugs, and vice versa).

43
Q

Effect curves (possibilities of A and B)

A
  1. If A is a full agonist, B is a full agonist in the presence of a competitive agonist
  2. If A is a full agonist, B is a similar agonist that is less potent
  3. If A is a full agonist, B is the full agonist in the presence of a partial agonist
  4. If A is a full agonist, B is that same full agonist in some who has developed tolerance
44
Q

Effect curves (possibilities of A and C)

A
  1. If C is a full agonist, Z is a full agonist after the development of sensitisation
  2. If A is a full agonist, C is a partial agonist
  3. If A is a full agonist, C is a full agonist in the presence of a non-competitive agonist
  4. If A is a full agonist, C is a similar agonist that is less potent
  5. If A is a full agonist, C is a full agonist in the presence of an irreversible agonist/antagonist

DBB (8 decks)

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