Lecture 13_Drug Specificity

Question 1

(T/F) Some drugs are entirely specific.

Answer 1

FALSE. No drug is entirely specific in the sense that it acts exclusively only on one type of cell or tissue, having just the desired effect and no other. EX: Antipsychotics with adverse side effects.

Question 2

(T/F) A drugs usefulness clinically is often directly related to its specificity.

Answer 2

TRUE.

Question 3

What is poison?

Answer 3

A compound which has deleterious effects on cell function without having any therapeutic effects (cyanide).

Question 4

If a drug has no toxicity at clinical concentrations, can it still be toxic?

Answer 4

YES. Penicillin inhibits a bacterial enzyme involved in the formation of bacterial cell walls. Even though penicillin isn’t toxic at clinical concentrations, it does have a level of toxicity in patients with meningitis.

Question 5

What is methotrexate? How does it act? Can it be dangerous at high doses?

Answer 5

A drug used in cancer chemotherapy and treat severe cases of psoriasis (overgrowth of skin cells). It acts by inhibiting the rapid reproduction of epithelial cells in psoriatic plaques. However, at slightly higher doses, methotrexate also inhibits reproduction of mucosal cells in the intestine, which would lead to ulceration and diarrhea.

Question 6

(T/F) Useful drug actions are often accompanied by unwanted toxicity due to side effects while non-selective toxicity gives rise to poisoning.

Answer 6

TRUE.

Question 7

Generally, the useful, therapeutic effects of drugs may be separable from the toxic effects based on differences in…

Answer 7

• their respective mechanisms of action.
• their dose-response relationships if their mechanisms of action are similar.
• the sites at which therapeutic and toxic effects are produced.

Question 8

Attempts to increase the utility of a drug are based on improved ________ or an enhanced _______.

Answer 8

Attempts to increase the utility of a drug are based on improved pharmacodynamic specificity or an enhanced pharmacokinetic selectivity.

Question 9

Pharmacodynamic specificity vs. pharmacokinetic selectivity.

Answer 9

• Pharmacodynamic specificity: If the mechanisms of toxic and therapeutic effects differ.
• Pharmacodynamic selectivity: Distribution to the desired target site.

Question 10

For specific drug receptor interactions to occur…

Answer 10

…the drug molecule must have several points of attachment to corresponding points on the receptor molecule. The nature of these points of attachment and their relative positions and distances apart are all critical for the drug’s ability to combine with a receptor and to produce a response.

Question 11

Molecular features necessary for acetylcholine action:

Answer 11

• 1. Positively charged N
• 2. Three CH3 (methyl) groups attached to N.
• 3. Ester linkage (COO)
• 4. Spacing between N and carbonyl C.

Question 12

Describe acetylcholine features:

Answer 12

• Binds to two different kinds of receptors, muscarinic (GABA) and nicotinic (G protein coupled).
• ACh oscillates between cis (nicotinic) and trans (muscarinic) conformation (so ACh is not just one molecule, it really is a combination of two).
• The spacing between N and carbonyl C is what determines cis or tarns conformation.
• This is an example of drug and receptor specificity of a particular isomer.

Question 13

Acetylcholine has actions at muscarinic and nicotinic ACh receptors, but many other drugs act at one but not the other. Why?

Answer 13

The ACh molecule changes its shape between cis and trans forms (because it contains only single bonds that do not limit rotation), and that changes the distance between the N and the carbonyl C. While ACh can rotate to change length, ligands specific to either nicotinic or muscarinic subtypes have structures that limit intramolecular rotation.

Question 14

Do antagonists of muscarinic and nicotinic ACh receptors have the same molecular features of ACh agonists?

Answer 14

• The antagonists do have enough structural molecular features to bind to their respective receptors, but not all the features that allow them to exert a functional effect after binding.
• Atropine (muscarinic sites) and curare (nicotinic sites) have structures that limit intramolecular rotation, preserving their selective effects on these receptors.

Question 15

How can molecular selectivity of drugs binding to specific receptors help in the development of new therapeutic agents displaying fewer side effects?

Answer 15

• EX: Raclopride is highly selective antagonist at D2 and D3 (but not D1, D4, or D5) receptors. It is a potent antipsychotic used in treatment of schizophrenia. Use of this drugs leads to fewer side effects than other antipsychotics that block all dopamine receptor subtypes.
• use of specific antagonists also helps in understanding disease mechanisms. D1 receptor specific antagonists have no utility in treatment of schizophrenia, which tells us that dopamine at D1 is not important for schizo.

Question 16

What is stereospecificity?

Answer 16

• Many drugs have optically isomeric forms in which only one isomer is active, or one isomer is considerably more potent than the other.
• This is consistent when at least 3 points of attachment need to exist between a receptor and its ligand, and there exists either a center or plane of asymmetry in the drug.

Question 17

Give some examples of stereospecificity.

Answer 17

• d and I-hyoscyamine, of which only the I-form is active as a muscarinic receptor blocker.
• Morphine has d- and I-forms, of which only the I-form has analgesic activity, although both forms act as antitussives.
• Only the I-form of norepinephrine elevates blood pressure.
• d-amphetamine is a much more effective CNS stimulant than I-amphetamine.
• Only the I-form of opioids causes pain relief.

Question 18

There are varying degrees of selectivity (meaning that certain drugs share similar functions). Give an example of a high degree of selectivity and low degree.

Answer 18

• HIGH: Tetrodotoxin only binds to Na channels, blocking action potential propagation.
• LOW: R-CH2-CH2-CH2-N-(CH3)2 enables a compound to interact with receptors for histamine, ACh, and maybe catecholamines. If the R-group is large, it can also function as an antihistamine or a local anesthetic.

Question 19

How do chlorpromazine, procaine, and diphenhydramine show off degrees of selectivity?

Answer 19

• These share a number of properties: they are all good local anesthetics, H1 receptor antihistamines and myocardial antiarrythmics.
• However, unique parts of each of their molecules also give them pharmacological properties that are not shared with the other compounds.

Question 20

(T/F) Slightly changing the molecular structure of a compound wouldn’t have an effect.

Answer 20

FALSE. Slightly changing the molecular structure of a compound can change its effect on receptors, and even what receptors it binds to. A drug can go from a systemic antibacterial, to an oral anti diabetic just because of a simple change in structure.

Question 21

Pharmacokinetic selectivity: For those drugs that either do not act selectively on particular receptors, or act on receptors that are found on many cell types or tissues, selectivity can still be obtained due to:

Answer 21

• 1. Selective distribution of drug to an intended site.

- 2. Metabolic differences that make one tissue more sensitive to the effect of the drug than another.

Question 22

Different types of selectivity related to drug distribution:

Answer 22

• 1. Topical application
• 2. Intra arterial injection
• 3. Selectivity by ionization
• 4. Differential blood flow
• 5. Distribution by selective carriers
• 6. Selective concentration by excretion

Question 23

Topical application

Answer 23

egs., injection into abscess or joint cavity, or drops in the eye. Selectivity arises from the fact that any drug absorbed systemically from the site is diluted in a large volume of circulating blood. Vasoconstrictors may increase usefulness.

Question 24

Intra-arterial injection

Answer 24

Useful for antitumor agents. Dissolving chemotherapeutic in an oily carrier enables oily droplets to be trapped in capillaries of the tumor and facilitates drug uptake into tumor cells.

Question 25

Selectivity by ionization

Answer 25

Propantheline and atropine are both good muscarinic blockers but the former does not cross the blood-brain barrier because it has a quaternary N, which makes it a permanent cation.

Question 26

Differential blood flow

Answer 26

Drugs given i.v. are initially primarily distributed to tissues with high blood flow (remember VRG?). Thiopental, because it has a high Pm/b value, will rapidly cross the blood-brain barrier as it is brought to the brain.

Question 27

Distribution by selective carriers

Answer 27

Eg., CD20 is a cell-surface antigen found on 90% of B-cell lymphomas but not normally on B-cells. 131I is linked to an antibody to CD20 to radiate B-cell lymphomas.

Question 28

Selective concentration by excretion

Answer 28

Many drugs are concentrated in urine because they undergo glomerular filtration or secretion but are poorly re-absorbed (eg. thiazides used as diuretics).

Question 29

Different types of selectivity related to tissue differences.

Answer 29

• 1. Selective cellular binding
• 2. Selective uptake by tissues
• 3. Selective intracellular activation
• 4. Selective tissue vulnerability

Question 30

Selective cellular binding

Answer 30

Some drugs that are capable of acting on many different types of cells if present in high enough quantities, show selectivity at normal dosages when they bind to cellular components in certain cells. Eg. quinine has a high affinity for malarial DNA.

Question 31

Selective uptake by tissues

Answer 31

Some tissues can concentrate drugs. Eg. the thyroid concentrates iodine, so 131I is concentrated in the thyroid in the treatment of hyperthyroidism.

Question 32

Selective intracellular activation

Answer 32

Some drugs are given as pro-drugs that need to be bioactivated to function. If the tissue to be targeted has the ability to convert the precursor to the active form, that increases selectivity. Eg., Enteric sulfonamides are bioactivated by gut bacteria to free sulfathiazole which has antibacterial activity locally in the gut.

Question 33

Selective tissue vulnerability

Answer 33

A drug may be relatively nonselective in terms of the range of tissues it acts upon, yet may have therapeutic specificity if the cellular function it affects is more important in one tissue than in the rest. Eg., Cardiac glycosides such as digoxin inhibit (Na++K+)-ATPase, but the heart enzyme is more sensitive than that in skeletal muscle, liver, kidney, etc.

Question 34

Different types of individual and species differences

Answer 34

• 1. Bacteria vs. host
• 2. Insects vs. mammals
• 3. Genetic differences within species

Question 35

Bacteria vs. host

Answer 35

Differential sensitivity between bacterial and animal cells forms the basis for antibacterial therapy. Egs., (1) penicillin acts on bacteria (that have cell walls), but not on animal cells. (2) Animal cells take up folic acid but bacteria synthesize it and cannot take it up. Sulfonamides act as competitive antagonists of PABA, a precursor of folic acid.

Question 36

Insects vs. mammals

Answer 36

Malathion is an organophosphate cholinesterase inhibitor that is metabolized quickly in birds and mammals but slowly in insects, yielding relatively specific toxicity to insects.

Question 37

Genetic differences within species

Answer 37

Selective toxicity arising from genetic variations within a species can be harmful , beneficial or both. A hereditary deficiency of glucose-6-phosphate dehydrogenase renders affected individuals sensitive to primaquine-induced hemolytic anemia, but at the same time also makes them more resistant to the growth of malaria in the liver.