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Pharmacology and toxicology > week 21 p1 > Flashcards

week 21 p1 Flashcards

1
Q
  1. What is a drug
A
  • A drug is any substance that causes a change in an organism’s physiology or psychology when consumed.
    • A drug can be defined as a chemical substance of known structure, other than a nutrient of an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.
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2
Q

What is pharmaceutical drug

A

is a substance used as a medication
or in the preparation of medication
and it it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease

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3
Q

What is small molecule drug

A

Drugs like ibuprofen are called: Small molecule drugs

Small molecule drugs are defined as any organic compound with low molecular weight (less than 900 Dalton).

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4
Q
  1. What is the advantage of small drug molecule
A
  • They have a definite chemical structure
    • Most can be administered orally and they can pass through cell membranes to reach intracellular targets.
    • They can be designed to engage biological targets by various modes of action `(e.g. agonism, antagonism).
    • Their distribution can be tailored, for example, to allow for systemic exposure with or without brain penetration.
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5
Q
  1. how do drugs and targets interact?
A
  • The field of pharmacology that describe that interaction is called pharmacodynamics
    • The target for drug action Is divided into receptors, ion channel, enzymes and transporter
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6
Q

what the drug does to the body

A
  • once a drug enters into the body, it will bind a drug receptor/target at cellular level
    • This interaction will produce a signal, which in turn leads to a biological effect
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7
Q
  1. What is drug target
A
  • A target is any system that can potentially be modulated by a molecule (e.g. a drug) to produce a beneficial effect eg receptors, ion channels, transporter
  • target is a protein molecule although it could be any biological component, be it nucleic acid, carbohydrate, lipid etc.
  • drug-target interaction, the function of the target is modified, such that a change in a pathway is induced
  • The modification of that pathway will produce a beneficial effect on a disease process
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8
Q

What is effincy of drug target

A
  • targets as proteins or other biomolecules (such as DNA, RNA, heparin and peptides) to which the drug directly binds, and which are responsible for the therapeutic efficacy of the drug.
  • Biomolecules that the drug may also bind to, or be metabolized by, but which are not known to be responsible for its therapeutic effect, are not defined as targets
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9
Q

What is enzymes

A

Enzymes are proteins which act as catalysts to facilitate the conversion of substrates into products.

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10
Q

What is Drug-mediated enzyme inhibition

A

Can be done through reversible or irreversible inhibition

Enzyme induction refers to an increase in the rate of hepatic metabolism, mediated by increased transcription of mRNA encoding the genes for drug-metabolizing enzymes. This leads to a decrease in the concentrations of drugs metabolized by the same enzyme

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11
Q

What at is Reversible inhibition ( drug mediated inhibition)

A

• easily removed by dilution or dialysis.
• Drug attaches to enzymes with non-covalent interactions (hydrogen
bonds, hydrophobic interactions and ionic bonds.)
• Multiple weak bonds between the inhibitor and the active site combine to
produce strong and specific binding.

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12
Q
  1. How does Reversable inhibition work
A

. Competitive inhibition-block active sites so substrate cannot bind
. Non-competitive inhibition-can bind to the active site but reaction is low
Un-competitive inhibition -

Allosteric inhibition (a type of mixed inhibition)- cannot bind t the substrate site due tot the active site being distorted

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13
Q

What is reversible inhibition action

A

inhibition can not be reversed.

Covalently modify an enzyme

Drugs often contain reactive functional groups (e.g. aldehydes, alkenes,
phenyl sulfonates) that react with amino acid side chains
to form covalent adducts.

Inhibitors display time-dependent inhibition and their potency therefore
cannot be characterised by an IC50 value

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14
Q

How does is reversible inhibition work

A

irreversibly inhibit nerve action by forming covalent bonds to the OH group of serine on the active site of acetylcholinesterase.

eg Diisopropyl fluorophosphate, DIPF (used for the treatment of chronic glaucoma)

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15
Q

What is Enzymes - Cyclooxygenase (COX)

A

Cyclooxygenase (COX) inhibitors are non-steroidal anti- inflammatory drugs (NSAIDs), used clinically to relieve fever, pain, and inflammation

COX inhibitors can act at one or both of the isozymes,

COX-1 and COX-2 v Inhibitors differ in their relative specificities for COX-1 and COX-2
Drug like aspirin, ibuprofen, naproxen and diclofenac act on both COX1 and COX2 and are called “non-selective NSAIDs”

Drugs like celecoxib acts only on COX-2 and are called COX-2 selective NSAIDs \

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16
Q

What is Enzymes - Phosphodiesterase’s (PDEs)

A

Enzymes responsible for the inactivation of the intracellular second messengers

cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)

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17
Q

Give examples pf Phosphodiesterase (PDEs)

A

• PDE3 inhibitors: cardiotonic agents used to treat congestive heart failure (eg. milrinone, enoximone, and inamrinone)

PDE4 inhibitors: suppress the release of cytokines and other inflammatory signals to achieve an anti-inflammatory action.
(eg. roflumilast and apremilast are used to treat asthma and chronic obstructive pulmonary disease (COPD), and psoriatic arthritis respectively)

PDE5 inhibitors: PDE5 is a cGMP-selective enzyme, expressed in the smooth muscle cells lining the blood vessels of the corpus cavernosum (eg. sildenafil, tadalafil, vardenafil, and avanafil are used primarily to treat erectile dysfunction)

18
Q

What is Enzymes – Kinases

A
  • A kinase is an enzyme that catalyses the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates.
    • Protein kinases represent an important target class for treating human disorders,

Kinases are used extensively to transmit signals and regulate complex processes in cells

19
Q

How does Enzymes – Kinases work

A

• Phosphorylate proteins on serine, threonine, tyrosine, or histidine residues

• Phosphorylation can modify the function of a protein in many ways: 
• §  increase or decrease a protein's activity 
• §  stabilize it or mark it for destruction 
• §  localize it within a specific cellular  compartment  §  initiate or disrupt its interaction with other proteins
20
Q

example of Enzymes – Kinases

A
  • Activation leads to cascade
    • Activate another protein by phosphorylation
    • Keep going
    • Then causes prefiltration and tumorigenesis

If a inhibitor is used it will prevent this

21
Q

What is Ion channels

A

are pore-forming membrane proteins that allow ions to pass through the channel pore.
• Ion channels are located within the membrane of all excitable cells, and of many intracellular organelles.
• In many ion channels, passage through the pore is governed by a “gate”, which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.

22
Q

Example of drug Ion channel blockers

A

calcium channel blockers act via binding specific sites

and inducing allosteric modifications that block the calcium current

23
Q

Example of drug Ion channel openers

A

• minoxidil (used for hair loss) is a potassium channel opener
Benzodiazepine drugs bind to GABA receptor to facilate with opening of channel by inhibitory neurotransmitter

24
Q

What is Transporters

A

• The plasma membrane regulates the traffic of molecules into and out of the cell.

Ions, sugars, amino acids cannot diffuse across the phospholipid bilayer at sufficient rates to meet the cell’s needs and must be transported by integral membrane proteins

  • channels, transporters, and ATP- powered ion pumps
25
Q

Example of transporters

A
  • Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs.
    • The key transporters involved in drug absorption, excretion, and drug-drug interactions belong to the ABC (ATP binding cassette) and SLC (solute carrier) transporter families.
    • ABC transporters, including P-glycoprotein (P- gp), MRP2, and BCRP, play major roles in hepatobiliary and urinary excretion of drugs, intestinal absorption of drugs, and in blood-brain barrier (BBB) penetration of drugs.
    • SLC transporters, including members like OATP1B1, OAT1, and OCT2, play major roles in hepatic and renal uptake of drugs, as well as, urinary excretion of drugs.
26
Q

What is the reason importance of transporters goes beyond pharmacokinetics.

A

• target transporters as primary mode of action.
• For example, Serotonin-Reuptake Inhibitors (SSRIs) (e.g. Prozac) inhibit the serotonin
• transporter - a protein that in humans is encoded by the SLC6A4 gene.
• For people who have an imbalance of serotine which can lead to depression
• This transporter is a member of the sodium-neurotransmitter symporter family.
SSRIs target

27
Q

What is Nuclear receptors

A
  • Small lipophilic substances such as natural hormones diffuse through the cell membrane
    • and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell.
    • Binding causes a conformational change in the receptor
    • which, depending on the class of receptor,
    • triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression.
    They generally function as homo/heterodimers
28
Q

Importance of NR

A

• Unlike other receptors .NR can directly bind with DNA and induce transcription sigal

Are present in soluble phase of the cells

29
Q

How does Nuclear receptors – Type I

A

Type I nuclear receptors include members of subfamily 3,

such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.

30
Q

How does Nuclear receptors – Type II

A

Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor.

31
Q

How does NR work

A

• Nuclear receptors are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various other lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone.
• Unlike most intercellular messengers, the ligands can cross the plasma membrane and directly interact with nuclear receptors inside the cell, rather than having to act via cell surface receptors.
• Once activated, nuclear receptors directly regulate transcription of genes that control a wide variety of biological processes, including cell proliferation, development,
metabolism, and reproduction.

Some nuclear receptors have also been found to regulate cellular functions within the cytoplasm. For example, estrogens act through the estrogen receptor in the cytoplasm of endothelial cells to rapidly activate signaling pathways that control vascular tone and endothelial cell migration.

32
Q
  1. What is Nuclear receptors as drug targets -

Agonists

A
  • Endogenous ligands (e.g. estradiol or testosterone) bind their relative nuclear receptors leading to the upregulation of gene expression.
    • This stimulation of gene expression by the ligand is referred to as an agonist response.
    • The agonistic effects of endogenous hormones can be mimicked by certain synthetic ligands:
33
Q

Example of agonists

A
  • Ethynylestradiol (a component of the contraceptive pill) - agonist of estrogen receptor alpha and beta (nuclear receptors)
    • Environmental chemicals present in plastic products - bisphenol A.
  • Agonist ligands work by inducing a conformation of the receptor which favours coactivator binding.
34
Q

What is Nuclear receptors as drug targets -Antagonists

A

• Antagonists are drugs that bind to receptors, but do not produce a substantial
degree of receptor stimulation.

• Antagonists are typically classified as competitive or non-competitive. 

• Competitive antagonists bind reversibly to the same receptor site as the agonist. The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists. 

• Non-competitive antagonists either bind irreversibly (e.g. by covalent bonds) to the same site as the agonist, or bind to a different site which reduces the binding of the agonist by an allosteric mechanism.
35
Q

example: of antagonists

A

Mifepristone - binds to the glucocorticoid and progesterone receptors and blocks
the activity of the endogenous hormones cortisol and progesterone respectively.

36
Q

What is Inverse agonists

A

• Some nuclear receptors have a basal or constitutive activity and promote a low level of gene transcription even in the absence of agonists.

Synthetic ligands which reduce this basal level of activity of nuclear receptors are known as inverse agonists. Example - antihistamine drugs

37
Q

what is Nuclear receptors as drug targets Selective receptor modulators

A

Drugs that display an agonist response in some tissues and an antagonistic response in other tissues are called selective receptor modulators (SRMs).

38
Q

Drugs that display an agonist response in some tissues and an antagonistic response in other tissues are called selective receptor modulators (SRMs).

A
  • Non genomic responses of NR agonists
    • Some steroid-mediated responses do not fit the classical genomic model of steroid action.
    • Many steroid-induced phenomena occur too rapidly to be explained by genomic action (e.g. dimerization, translocation to the nucleus, binding to DNA responsive elements, changing gene expression, changing protein synthesis, changing phenotype….).
    • Some responses take place seconds after the cell come into contact with the steroid
39
Q

Why is this important Non genomic responses of NR agonists

A
  • Interaction of genomic and non-genomic responses mediated by steroid hormone signalling.
    • It is believed that some NRs also act via a nongenomic action, which often involves the generation of intracellular second messengers,

and various signal-transduction cascades, such as ion fluxes (often calcium), cyclic AMP modulation and protein kinase pathways.

40
Q

What is G Protein Coupled Receptors (GPCRs)

A

• G protein-coupled receptors (GPCRs) are a large group of cell surface receptors that detect molecules outside the cell
and activate cellular responses.

GPCRs are also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linkedm eceptors (GPLR),

Coupled with intracellular signal via Proteins

Receptosd for many hormones and slow transmitters

41
Q

What does GPCRs consists of

A

single polypeptide that is folded into a globular shape and embedded in a cell’s plasma membrane.

Seven alpha segments of this molecule span the entire width of the membrane and the intervening portions loop both inside and outside the cell.

The extracellular loops form part of the pockets at which signaling molecules bind to the GPCR.

42
Q

What Drugs acting on GPCRs

A
  • Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue,
    • the conducting system, and contracting myocytes.
    • These receptors primarily induce noradrenaline that is released from sympathetic adrenergic nerves.
    • they bind noradrenaline and adrenaline that circulate in the blood.
    • Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site.

Pharmacology and toxicology (9 decks)

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