Pharmacodynamics

Name: Pharmacodynamics
Uploaded: 2022-09-02T14:00:09.000Z
Duration: 2 h 56 min 42 s

In this video, the speaker discusses pharmacodynamics and how it relates to pharmacokinetics. They explain how drugs interact with receptors in cells to produce a cellular response.

Drug Interaction with Receptors

Drugs need to bind to a receptor on a cell in order to produce a cellular response.

There are two types of receptors: extracellular and intracellular.

Extracellular receptors require second messenger systems to stimulate the cell, while intracellular receptors directly activate the cell.

Different drugs interact with different types of receptors.

Desensitization

Desensitization, also known as tachyphylaxis intolerance, can occur when a drug is used repeatedly and loses its effectiveness over time.

This can happen because the body becomes less responsive to the drug or because there are fewer available receptors for the drug to bind to.

Conclusion

Pharmacodynamics is an important concept that helps us understand how drugs interact with cells in our bodies. By understanding how drugs bind to receptors and produce cellular responses, we can better understand their effects on our bodies.

Extracellular Receptors and Ligand-Gated Ion Channels

This section explains how extracellular receptors work, specifically ligand-gated ion channels. It describes how drugs can bind to these channels and produce a cellular response.

Ligand-Gated Ion Channels

Ligand-gated ion channels are channels that allow for particular ions to flow in or out of a neuron.

A gate controls the entry of ions into the cell.

Drugs can bind onto a pocket on the channel, lifting the gate open and allowing ions to easily flow in or out of the neuron.

The type of ion that flows through the channel determines the associated cellular response.

GABA A Receptors and Lorazepam

This section discusses GABA A receptors, which are ligand-gated ion channels. It explains how lorazepam works by binding to these receptors and decreasing neuronal activity.

GABA A Receptors

GABA A receptors are ligand-gated ion channels that allow negatively charged chloride ions to flow into neurons when activated by GABA.

When chloride ions inflow into the neuron, it hyperpolarizes it and decreases action potentials.

Lorazepam

Lorazepam is a drug that binds to GABA A receptors, opening up chloride ion channels and decreasing neuronal activity.

Lorazepam is used in situations where decreased neuronal activity is desired, such as seizures.

G-Protein-Coupled Receptors

This section explains how drugs can bind to extracellular receptors via g-protein-coupled receptors (GPCRs). It describes how this process produces a cellular response.

G-Protein-Coupled Receptors

GPCRs have a receptor domain where drugs can bind onto pockets on the receptor.

When a drug binds to the receptor domain, it changes the shape of the intracellular domain and stimulates a particular G protein.

The G protein moves along the cell membrane and stimulates an enzyme called phospholipase C, which breaks down components of the cell membrane.

Extracellular Receptors

This section discusses the three types of extracellular receptors and how drugs can produce a cellular response through them.

Ligand-Gated Ion Channels

Ligand-gated ion channels are one type of extracellular receptor.

When a ligand binds to the receptor, it opens or closes an ion channel, producing a cellular response.

G-Protein Coupled Receptors

G-protein coupled receptors are another type of extracellular receptor.

When a ligand binds to the receptor, it changes the shape of the protein connected on the outside of it, activating second messenger systems to produce a cellular response.

Tyrosine Kinase Receptors

Tyrosine kinase receptors are the third type of extracellular receptor.

When insulin binds to this receptor domain, it activates tyrosine kinases that phosphorylate tyrosine residues and change their structure.

This makes it easier for specific types of proteins or second messengers to bind and activate second messenger systems that produce a cellular response.

Intracellular Receptors

This section discusses intracellular receptors and how drugs can produce a cellular response through them.

Hydrophobic Drugs

Intracellular receptors are for hydrophobic or lipid-soluble non-polar small drugs such as steroids and nitric oxide.

These drugs can easily pass across the cell membrane and bind onto an intracellular receptor.

The activated receptor then translocates into the nucleus where it stimulates transcription factors that regulate DNA transcription into RNA which is important in making proteins.

Activating Multiple Second Messengers

This section discusses the activation of multiple second messengers.

Activation of Multiple Second Messengers

Drugs can activate multiple second messengers.

Tolerance is a chronic response that occurs over time with repeated exposure to a drug.

Tolerance involves reducing the synthesis and internalizing receptor proteins, as well as increasing metabolic enzymes to break down the drug.

Increasing the dose of a drug can overcome tolerance and produce the same clinical effect.

Examples of Tolerance

Opioid abuse, alcohol abuse, cocaine, and methamphetamines are examples where tolerance plays an important role.

Drug-Receptor Interaction

In this section, the speaker explains the relationship between drug potency and receptor affinity. They introduce the concept of EC50 as a measure of potency and explain how it relates to drug concentration.

Affinity and Potency

The strength of the bond between a drug and receptor determines its affinity and potency.

EC50 is a measure of potency that represents the concentration of a drug needed to produce 50% of the maximum effect.

As EC50 increases, more drug is required to produce 50% of the max effect, meaning that potency decreases. Conversely, decreasing EC50 means higher potency.

Efficacy

Efficacy depends on two factors: how many receptors are occupied by the drug and intrinsic activity.

Full agonists bind to receptors and produce a 100% clinical response, while partial agonists may only produce 70% or 50%.

Dose Response Curves

In this section, the speaker discusses dose-response curves and how they relate to efficacy and toxicity.

Introduction to Dose Response Curves

A dose-response curve shows how much effect a drug has at different doses.

The x-axis represents dose or concentration, while the y-axis represents response or effect.

Types of Dose Response Curves

A graded dose-response curve shows individual responses at different doses for one person.

A quantal dose-response curve shows whether an individual responds or not at different doses for many people.

A sigmoidal dose-response curve shows the relationship between dose and response for many people.

Efficacy and Toxicity

The maximum efficacy of a drug is represented by the plateau of the dose-response curve.

The therapeutic index is the ratio of the toxic dose to the effective dose. A higher therapeutic index means a safer drug.

Occupancy Theory and Intrinsic Activity

This section discusses the occupancy theory and intrinsic activity between drug receptor interactions.

Occupancy Theory

Large doses of steroids have less risk of toxic side effects.

The efficacy of a drug is proportional to the number of receptors occupied by that drug.

The potency of a drug is inversely proportional to the concentration required to occupy 50% of the receptors.

Intrinsic Activity

Intrinsic activity compares drugs that bind to a particular receptor with our endogenous system.

Norepinephrine and epinephrine bind onto alpha-1 receptors on blood vessels, stimulating vasoconstriction.

A full agonist produces the same maximal effect as norepinephrine, while a partial agonist produces an effect below the maximal effect.

A drug that keeps the receptor completely inactivated reduces efficacy and maximal effect below basal activity.

Examples

Full Agonist

Full agonists mimic endogenous systems, producing maximal clinical response when binding to 100% of receptors.

Examples include norepinephrine, epinephrine, and phenylephrine.

Partial Agonist

Partial agonists like buprenorphine bind onto mu opioid receptors but produce sub-maximal clinical effects even when saturating all receptors.

Partial and Inverse Agonists

This section discusses partial and inverse agonists, their effects on receptors, and how they interact with other drugs.

Partial Agonists

Partial agonists can never reach maximum effect.

Higher concentrations of a partial agonist can block the binding of an agonist to a receptor, resulting in competitive inhibition.

Competitive inhibition occurs when a partial agonist competes with an agonist for the same active site on a receptor.

Inverse Agonists

Inverse agonists bind to receptors and decrease the effect of the drug below basal activity.

Inverse agonists shift the reaction to keep receptors in an inactive form, reducing drug-receptor interaction below basal activity.

Antihistamines can act as inverse agonists on H1H2 receptors.

Antagonists

This section discusses antagonists and their effects on receptors.

Antagonists

Antagonists bind to receptors but do not activate them, blocking other molecules from binding to that receptor.

Competitive antagonism occurs when two molecules compete for the same binding site on a receptor.

Noncompetitive antagonism occurs when an antagonist binds to a different site than the molecule it is blocking.

Summary

This section summarizes the main points of the video.

Partial agonists can never reach maximum effect and can act as competitive antagonists.

Inverse agonists bind to receptors and reduce drug-receptor interaction below basal activity.

Antagonists bind to receptors but do not activate them, blocking other molecules from binding to that receptor.

Competitive antagonism occurs when two molecules compete for the same binding site on a receptor, while noncompetitive antagonism occurs when an antagonist binds to a different site than the molecule it is blocking.

Pharmacodynamics

In this section, the speaker discusses how drugs affect the body and how they interact with receptors. They cover agonists and antagonists, dose-response curves, and non-competitive inhibitors.

Agonists and Antagonists

An antagonist blocks the receptor from being activated.

An agonist activates the receptor.

Dose-Response Curves

The potency of a drug stays the same regardless of concentration or efficacy.

The Emax is the maximum effect a drug can have at 100% response or effect.

EC50 is where half of the maximal response occurs.

Non-Competitive Inhibitors

Non-competitive inhibitors decrease efficacy but do not change potency.

Response decreases significantly because agonists cannot bind to active sites.

Emax decreases with respect to non-competitive inhibitors.

Practice Problems

This section covers practice problems related to pharmacodynamics.

GABA A Receptor Agonist Effects on Signal Transduction in Neurons

GABA A receptors are ligand-gated ion channels that allow chloride ions to enter cells when activated by an agonist.

Lorazepam vs Diazepam Anxiolytic Response Equivalence

If one milligram of lorazepam produces the same anxiolytic response as 10 milligrams of diazepam, then lorazepam is more potent than diazepam.

Understanding Drug Receptors

In this section, the speaker discusses drug receptors and how they work.

Alpha-1 Adrenergic Receptor Antagonist

An alpha-1 adrenergic receptor antagonist binds to the alpha-1 adrenergic receptor and blocks other drugs from binding to it.

This can be problematic because in certain situations, we may want to stimulate that receptor but cannot because it is blocked by the antagonist.

To stimulate the receptor, more receptors need to be available for agonists like phenylephrine or norepinephrine or epinephrine to bind to. This is done through up-regulation of receptors.

Therapeutic Index

The therapeutic index is calculated by dividing the TD50 (dose that causes a toxic effect in 50% of population) by ED50 (dose that produces a desired effect in 50% of population).

The therapeutic index for methylphenidate is 3. A larger therapeutic index means there is a lower risk of toxic side effects because there is a larger margin of error.

Safety of Drugs

Warfarin has a small therapeutic index, making it less safe than penicillin which has a large therapeutic index for most patients.

Warfarin and Therapeutic Index

In this section, the speaker discusses the therapeutic index of warfarin and how altering its bioavailability can lead to dangerous adverse effects.

Warfarin's Small Therapeutic Index

Warfarin has a small therapeutic index.

Altering warfarin's bioavailability can increase the amount of drug in circulation, leading to higher toxic effects.

If another medication increases warfarin's bioavailability from 50% to 80%, there will be more of the drug in the bloodstream, making it easier to reach toxic levels.

Drugs with a small therapeutic index have very dangerous side effects if they lead to higher concentrations of the drug.

Large Therapeutic Index

Drugs with a large therapeutic index are less likely to cause adverse effects even at high concentrations.

A larger range of dosages can be given without causing toxic effects.

Overall, it is important to be aware of a drug's therapeutic index and how altering its bioavailability can affect its toxicity.