exam 1 : Foundational Pharmacology and Medicinal Chemistry

Pioneers of modern pharmacology that created a concept of a magic bullet when he argued that a chemical could deliberately target bacteria.

Paul Ehrlich

What is pharmacology?

Figure determine how substances interact with living systems through chemical processes, which can occur when drugs bind to molecules or affect operations in the body.

What is pharmacokinetics?

deals with the absorption, distribution, and elimination of drugs (drug action)

what is pharmacodynamics?

the action of the chemical on the organism (drug effect)

What does the drug receptor refer too?

The molecular component of a cell with which the drug interacts

The concept of drug receptors can lead to what three thing

1) interaction leads to an increase or decrease in the rate of cell’s ongoing function

2) Receptor site concept offers a convenient, logical explanation for the pharmacological effects of drugs. Various kinds of macromolecules can be receptors

3) receptor location

What are the various kinds of macromolecules that can be receptors?

Lipids, nucleic acids, carbohydrates, and proteins

where can receptor locations be found?

the cell surface, embedded in cell membrane

how to study receptors

1)Isolate and purify macromolecular component and study drug “structure-activity” relationship (SAR) by the information inferred from kinetics of the drug-receptor interaction; “binding” studies

2) Determine amino acid sequence (for protein receptors); “clone” and “express” the receptor in cultured cells, which enables study of receptor function in living cells, but isolated from components of native cells in intact tissue

What type of binding occurs for drugs to receptors?

van der waals attraction, hydrogen bond, hydrophobic interaction, ionic bond, and covalent bond

van der waals attraction?

weak electrostatic forces that attract neutral molecules to each other

What is a hydrogen bond?

a special type of dipole-dipole interaction that occurs between a hydrogen atom covalently bonded to a highly electronegative atom (like oxygen, nitrogen, or fluorine) and another electronegative atom with a lone pair of electrons

What is a hydrophobic interaction?

Weak bonds that are more for lipid-soluble drugs

What is a Ionic bond?

a chemical bond formed through the complete transfer of electrons between atoms, resulting in the attraction of oppositely charged ions (cations and anions)

What is a Covalent bond?

involve atoms sharing electrons(really strong, takes long time leve body ex. aspirin)

Examples of drugs which do not specifically act through receptors are

Antacids, Osmotic diuretics and cathartics, and chelating agents which bind heavy metals

In the concept of drug receptors, things that effect drugs impact are?

The physical nature of drugs, drug size, and drug shape

Agonist:

A drug that causes a specific physiological effect due to direct interaction with a receptor

Antagonist:

A compound which is devoid of intrinsic pharmacological activity but blocks the action of a specific agonist or an endogenous substance that produces the effect

Allosteric modulator

A drug that binds to a different site on the receptor than that bound by endogenous ligands; it can modulate positively or negatively.

Addition

When two agonists that produce the same effect are administred together, they produce an effects equal in magnitude to the sum of the effects of the individual drugs

Synergism

When two agonists which produce the same effects are administered together, they produce an effect greater in magnitude than the sum of effects of the individual drugs.

Potentiation

When a drug is itself without effect, but if administered with a second drug, increases the effect of the second drug.increases the effect of the second drug. Only one receptor target.

Quantal Dose-Response:

The response is "all-or-none," such as death or the presence or absence of a seizure

Example of all-or-none pharmacological effects are?

1. dose of barbiturate to induce sleep

2. dose of carcinogen to induce tumor in rats after single injection

3. dose of drug to produce lethality in mice

logarithm of dose yields?

a sigmoid (S-shaped) curve

Graded Dose-Response:

The response is measured along a continuous scale, such as the degree of pain relief or blood pressure reduction.

Examples of graded pharmacological responses are?

drug-induced, graded changes in heart rate or degree of muscle contraction

ED50 (Effective Dose 50):

A dose in that produce a “half-maximal” response for example, a response which is 50% of the maximal attainable response for the tissues or organ

LD50 (Lethal Dose 50):

The dose that is lethal to 50% of the population.

linear plot are

intuitive scaling

semi-log plot are

compact scaling

A way to capture/characterize a large-scale data set

is through quantal, linear, and logarithmic

Tolerance:

When repeated administration of a given dose of drug produces a decreased effect, or conversely, larger doses must be administered to obtain the same effect observed with the original dose.

Tachyphylaxis:

A very rapidly developing tolerance; decreasing effect of a drug following consecutive doses given at short intervals.

The time scale is between

days to months vs. minutes to hours

Supersensitivity:

A heightened state of pharmacological responsiveness of a tissue or organ, leading to an exaggerated effect of an agonist.

Supersensitivity may be due to a compensatory increase in number of receptors called

“up-regulation”

In supersensitivity such changes can be what?

be drug- induced (as after prolonged exposure to an antagonist) or due to denervation (destruction of the neuronal input to the tissue)

Desensitization

A reduced state of pharmacological responsiveness of a receptor due to continuous presence of the agonist at that receptor.

Desensitization may be due to a decrease in receptor number or to a change in the receptor’s conformational state to an inactive “desensitized” state this term is called

“down-regulation”

Therapeutic Index:

A ratio comparing the toxic or lethal dose to the therapeutic dose; a larger therapeutic index generally indicates a safer drug.

What the therapeutic index (TI) formual

TI= LD50/ED50

Margin of safety:

a more useful expression of drug safety, which relates the lethal dose in 0.1% of subjects to the effective dose in 99.9% of subjects.

What’s the formula for the margin of safety

margin of safety = LD0.1/ED99.9

Magnitude of drug effects is proportional to what?

The number of receptors occupied by agonist.

Factors that determine receptor occupancy is

a. Drug dose or its availability at receptors
b. Affinity of receptor for drug – its tendency to combine with receptor

When KD for a drug is small,

its affinity for the receptor is high.

When KD for a drug is large,

its affinity for the receptor is low.

Ligand occupancy leads to activation of what?

receptor and functional effect

Intrinsic activity or efficacy

degree of effect obtainable for a given level of receptor occupancy. Drugs with the same efficacy elicit the same maximal response.

Potency:

used in comparing two or more drugs when specifically referring to the doses of each required to produce the same effect. (left-right)

efficacy is

independent of the slope or position of the dose-response curve. (up & down)

slope

another important parameter when 2 drugs are compared

Competitive, reversible antagonism

agonist and antagonist compete for same receptors

log dose-response curves to agonist in the presence of antagonist will

be shifted in a parallel manner to the right; no change in maximum response.

Irreversible antagonism:

agonist and antagonist compete for same receptor but once antagonist combines with receptor, combinations is irreversible.

Non-competitive (allosteric) antagonism

agonist and antagonist combine with different parts of same receptor in such a way that action of the agonist at its site does not result in a response.

Positive allosteric modulation

It can be a left-ward shift, but typically accompanied by an upward shift.

in Positive allosteric modulation Its distal binding by itself does not cause activation; it needs simultaneous

its called orthosteric binding

The fate of drugs in the body, key componets are what?

absorption, distribution, metabolism and excretion

when drug is transport in the body it needs to get through drug transport,

the cell membrane

The properties of the cell membrane contain

contains a lipid bilayer with protein embedded, the surface has polar ionized groups of molecules, inside of the membrane bilayer has hydrophobic, non-polar side chain

Factors determining diffusion of drugs across membranes are what?

concentration gradient (Fick’s law), lipid solubility of the drug(its lipid)

Many drugs are what?

weak acids or bases which are ionize to some extent in solution

Ionized (charged) forms of drugs are what?

polar and exhibit low lipid solubility

Non-ionized (uncharged) drugs are what?

not as polar and exhibit greater lipid solubility

Proportion of drugs in ionized and unionized forms is depended on what?

pH and drugs’s pKa

Weak acids are unionized at what?

low pH and ionized at high pH

Weak bases are unionized at what? high pH and ionized at low pH

high pH and ionized at low pH

What equation can be used to determine the proportion of ionized to unionized drug at a given pH

Henderson-hasselbach equation

A weak acid is defined as…

a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin

A weak bases can be defined as…

a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. For example, pyrimethamine, an antimalarial drug,

If the drug is a weak electrolyte, its degree of ionization influences what?

its lipid solubility

for acids if the ph is lower than pka what happens?

>50% non-ionized

For acids if the pH is above pka what happens?

>50% ionized

For bases if the ph is lower than pKa then what happpens

>50% ionized

for bases if the ph is above pka then what happens?

>50% non-ionized

As a result of the partitioning effect, the drug is what?

“trapped” in the urine

What happends to weak acids in alkaline urine?

They are usually excreted faster, and weak bases are usually excreted faster in acidic urine

What the normal pH of the stomach

pH 1.9-3

Whats the normal pH of the small intestine?

pH 7.5-8

Other processes which can mediate drug transport are what?

carrier-mediated membrane transport such as active transpot and facilitated transport and bulk flow through intercellular pores