Intro to Pharmacology

How do paritial agonists work?

**Partial agonists bind to the same targets as full agonists.*** blocks or dampens agonist-mediated responses= antagonist

Inverse Agonist Graph

Cause a decreased response with a higher dose

Inverse Agonist Example

GABAA Receptor Is constitutively active so ligands that enter and block channel act as inverse agonists

Drug Promiscuity

• Side effects due to hitting the other targets • Drugs are rarely selective

Factors that determine drug response (5)

1. Number of Receptors (drug targets) 2. Receptor Binding (DR/Rt) 3. Efficacy 4. Orthosteric/allosteric bonding 5. Duration of drug-receptor interaction

Orthosteric binding

Binding of drugs to a *common* site such that they compete for occupancy on the same receptor.

Allosteric binding

Binding of drugs to a site *different* from the common site such that they do not compete for occupancy of the same site on the receptor.

Physical/ Chemcial Nature of Drug Target Interaction

Chemical Bond: Usually: • Ionic, • Hydrogen, • Hydrophobic, • Van der Waals. Occasionally: • Covalent Usually involve non-covalent bonding

Most common Drug Targets

GPCR, Nuclear Receptor, Ligand-Gated ion channel, Voltage-gated ion channel, neurotransmitter transporters

Potency

Potency is not efficacy- can be both potent and effective, but these are not the same. potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity potency= amount of drug efficacy= maximum effect of drug

Response depends on Duration of the drug

Prolonged Exposure to Antagonists => Sensitization (=> usually produces a left shift in dose-response curve) Prolonged Exposure to Agonists => Desensitization (=> usually but not always produces a right shift in dose-response curve)

Sensitization

Prolonger exposure to antagonist, • Inhibit for a prolonged period of time, increase sensitivity of the tissue to the drug - is defined as an increased effect of drug following repeated doses (the opposite of drug tolerance) - Respond faster to the drug

Drug Efficacy

- about the most effect a drug will produce, the maximum response - dose versus response, lower dose and higher response= effective, full versus low Ceiling effect= what is the maximum that it can do!

Competitive Antagonism

A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor. Sufficient antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation= surmountable. Curve is shifted to the right because you need MORE of the drug to get a response

Agonist

An agonist is a chemical that binds to some receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance.

Irreversible Competitive Antagonism

An irreversible antagonist is a type of antagonist that binds permanently to a receptor, either by forming a covalent bond to the active site, or alternatively just by binding so tightly that the rate of dissociation is effectively zero at relevant time scales.[1] This permanently deactivates the receptor and is usually followed by rapid internalisation and recycling of the non-functional receptor protein.

Types of Drug Antagonism

Competitive, Competitive Irreversible, Non-Competitive

Dose-occupancy graph

Concentration of drug Vs. Fraction of Receptors being bound Unaffected by noncompetitive antagonists- because they are binding allosterically and not affecting the receptor site Shifted right by Competitive antagonists- harder to bind receptors, need a higher dose to bind more receptors Shifted down Irreversible competitive antagonists- because there are not as many receptors able to bind

Dose-Response Graph

Concentration of drug vs. response of patient competitive antagonists- shifts to the right, need more of the drug to cause an effect because the drug is competing noncompetitive antagonists- curve is lowered because the maximum efficacy or "ceiling" of the drug cannot be reached, receptors aren't going to respond to drug Irreversible competitve antagonist- shift curve downward because the maxiumum or "ceiling" efficacy cannot be reach, receptors aren't going to respond to drug

Modulators and potentiators

Drugs that bind allosterically typically modulate the actions of the orthosterically binding drugs. GABAA receptor where benzodiazepines & barbiturates bind to two different sites (allosteric) from the GABA binding site to enhance the effects of GABA.

Low Efficacy Drugs are not always partial Agonists

Drugs with different efficacies may or not act in the same manor/target, e.g. morphine and aspirin. **Partial agonists bind to the same targets as full agonists.***

Irreversible Competitive Antagonism (2)

Inhibition is non-surmountable Cannot wash away inhibitor Inhibitor and agonist bind orthostatically to the same spot Shifts dose-dependency curve and responsive curves downward- because response is not happening at all, **lowering the efficacy/ ceiling**

Typical Targets of Drug Action

Ligand-gated ion channels, e.g. nicotinic ACh receptors (A) - Voltage-gated ion channels, e.g. Na+, K+, Ca++, etc. channels (E) - Seven-Transmembrane Domain, G-Protein coupled receptors, e.g. muscarinic ACh receptors & adrenergic receptors (B) - Enzyme-Associated Receptors with subunits having one membrane-inserted domain, e.g. Tyrosine kinase receptors like the Insulin, receptor (C) - Enzymes - Ion Transporters and Pumps (G) - Cytoplasmic or Nuclear Receptors (D) - Neurotransmitter Transporters (F)

Noncompetitive Antagonism

Non-surmountable No covalent bonding Inhibitor cannot be washed away, Only the dose dependent curve is shifted downward because they are binding to the same spot. Response curve same because there is still binding even though there is still binding!!!

Duality of Partial Agonists

Partial agonists can act either as an agonist or as an antagonist!! They may also be considered ligands which display both agonistic and antagonistic effects - when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone

Spare Receptors

Sometimes respond at a lower dose than occupancy, curve moves to the left, this occurs when you have spare receptors, i.e. more receptors than you need to produce a response Spare receptors are receptors which exist in excess of those required to produce a full effect.

Number of receptors

There is a plateu when receptors are saturated= enters the receptor reserve space, no more response Dose dependence, rate of binding and dissociation= falling off

Partial Agonists

are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist Binding is orthosteric clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present

Antagonist

Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist.

Inverse Agonist

is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. A ligand that by binding to its target receptors reduces the fraction of them in an active conformation. Another way of saying this is that inverse agonists reduce the basal activity of the targeted receptor. Inverse because it is restricting a response instead of helping to produce one

Pharmacokinetics

is the study of drug and metabolite concentrations in the blood and body fluids.

Pharmacodynamics

is the study of drug-target (drug-tissue) interactions.

Desensitization

• Agonist, become less sensitive to it, adaptive response, wont respond to the drug • E.g. short pulse of AcTH, change in potential, continuously expose, and the response goes up and starts fading, go back to short pulses and starts to recover

Types of Drugs

• Agonists • Partial Agonists or Antagonist • Potentiators or Modulators of Activity • Antagonists • Inverse Agonists