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Flashcards in Pharmacodynamics - Sinal 1 Deck (51)
1

What is pharmacology?

What drugs are, how they work and what they do
Divided into pharmacodynamics and pharmacokinetics

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Drugs

Therapeutic agent
Any substance other than food, used in prevention, diagnosis, alleviation and treatment or cure of disease

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Pharmacy

Concerns with scientific, legal and managerial aspects of dispensing drugs

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Pharmacodynamics

Study of relationship of drug concentrations to drug effects
Biological effect is proportional to amount of drug-receptor complex

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Major classes of receptors targeted

1. Ligand-gated ion channels
2. Enzyme-linked receptors
3. G-protein coupled receptors
4. Ligand-activated transcription factors

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Agonist

A drug causing receptor to respond in same way as naturally occurring substance
Independent impact on receptor activity

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Antagonist

Drug that binds to receptor but does not produce a response
Inhibitory effect on naturally occurring substance
Impacts receptor activity only in presence of agonist (lacks efficacy)

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B

Fraction of total receptors bound

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Bmax

Maximal faction of total receptors bound

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Kd

Equilibrium dissociation constant
Drug concentration at which 1/2 of Bmax is achieved
A measure of the inherent affinity of the drug-receptor interaction
Constant and not altered by concentration of drug or receptor number

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Saturation point

Level out of B/[D] graph because all receptors are saturated

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High Kd

Low affinity

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Low Kd

High affinity

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Graded dose-response curves

Drug dose/Biological effect (%)

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Emax

Maximum response achieved by the drug

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ED50

Drug dose where 1/2 Emax is achieved
Also referred to as drug potency

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Concentration-Binding Curve

Drug concentration/fraction of receptors bound

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Quantal Dose-Response Curves

Used to describe population rather than single individual responses to drugs
Based on plotting cumulative frequency distribution of responders against the log drug dose, adding bars of histogram

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Graded phenomena

Infinite number of intermediate states
ie. vessel dilation, blood pressure change, heart rate change

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Quantal phenomena

All or none
ie. death, pregnancy, pain relief

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Potency

Amount of agonist needed to produce an effect of a given magnitude
Usually expressed as ED50: dose to achieve 50% of the maximum effect achievable with that agonist

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Efficacy

Maximum effect that can be achieved with a particular agonist
Usually expressed as Emax: maximum effect that can be achieved with that drug

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Full agonist

High/low potency, maximum efficacy

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Partial agonist

High/low potency, reduced efficacy

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Inverse agonists

Stabilize the inactive state or destabilizes the active state
Reduces constitutive receptor activation
Has an independent impact on receptor activity
Opposite effect of agonist: classified as an agonist as it has a functional impact on the receptor

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Chemical antagonism

Direct interaction of two substances in solution such that the effects of one or both is lost
ie. acid and base anticoagulant

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Physiological antagonism

Indirect interaction of two substances with opposing physiological actions
ie. Histamine vs. EN

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Pharmacological antagonism

Blockage of interaction of one substance with receptor by another substance

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Pharmacological antagonists

Bind to receptors but do not activate signal transduction mechanisms
Biological effects derived from blocking ability of agonist to bind/activate receptor

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Competitive antagonists

Bind reversibly to receptor
Inhibition can be overcome by increasing agonist concentration
Primarily affect agonist potency but can still achieve same magnitude of biological affect

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Non-competitive antagonists

Bind irreversibly to receptor or reversibly/irreversibly to allosteric site
Inhibition cannot be overcome by increasing agonist concentration
Primarily affect efficacy

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IC50

Inhibitory concentration

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Endogenous receptor ligands

Such as hormones and neurotransmitters
Mostly are agonists
Inverse agonists are rare
Antagonists are rare
Some drugs mimic effect of endogenous agonists and some block

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Epinephrine

Full agonist of cardiac beta2-adrenergic receptor to increase rate and force of heart contraction

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Agouti-related Peptide

AGRP
Endogenous inverse agonist
Reduces constitutive receptor activity of melanocortin receptor

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Kynurenic Acid

Endogenous pure antagonist
NMDA receptor antagonist
Physiological role unclear but may play a role in neurotransmission and neuropathologies

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Isoproterenol

Full agonist that mimics epinephrine at cardiac beta2 adrenergic receptor

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Buprenorphine

Partial agonist that mimics endogenous endorphins at n-opiod receptor
Safer analgesic than morphine due to less rest of respiratory depression

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Superagonists

>100% Emax
Uncommon in clinical practice

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Propranolol

Pure antagonist of epinephrine at cardiac beta2-adrenergi receptor

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Drug desensitization

Effect of drug often diminishes when given continuously or repeatedly
Receptor-mediated and non-receptor mediated mechanisms

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Receptor mediated drug desensitization

Loss of receptor function due to change in receptor conformation
Reduction of receptor number

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Non-receptor mediated drug desensitization

Reduction of receptor-coupled signalling components
Increased metabolic degradation
Physiological adaptation

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Adverse drug effects

1. Side effect
2. Toxic reaction
3. Allergic reaction

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Side effect

Dose dependent
Not directly related to desired effect of drug
Action of drug at other sites to produce undesirable effects

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Toxic reaction

Dose-dependent
Directly related to desired effect of drug
Excessive action of drug at intended target site

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Allergic reaction

Not dose-dependent
Not related to desired effect of drug
Immunologic response to drug and largely unpredictable

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Cyclosporine

Promotes survival of transplanted organs
Increased susceptibility to infection, kidney damage, rash/hives/itching/breathing difficulties

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Paracelsus

It is not the nature of the drug that determines toxicity, but rather the amount
Everything in excess is potentially toxic

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Therapeutic index

Measure of drug safety
Considers dose required for a toxic or other adverse drug effect versus that required for the desired beneficial effect
Toxic ED50/Beneficial ED50
A larger TI indicated a clinically safer drug

51

Therapeutic window

Measure of drug safety that considers the range of blood concentration of a drug that are associated with toxic, therapeutic benefit or lack of effect within a population
If drug falls between window, it fulfills clinical role