Pharm Quiz 1

pharmacology

study of how drugs work and how they affect our bodies

drugs

substances that have a physiological effect when introduced into the body

medicines

types of drugs that are an approved therapeutic goods that are used to treat or prevent specific health conditions

ligands

molecules that bind to a receptor

can be endogenous or introduced into the body (drug)

small molecule drug

<500 Da

small size may allow easier absorption into the body and crossing cell membranes

• can be orally active

synthesized by chemists or purified from nature

peptide drugs

500 Da < 5000 Da

synthesized by chemists or purified from nature OR derived from living organisms

biologics

5 kDa < 150 kDa

include vaccines, blood/blood components, somatic cells, growth factors, recombinant peptides and proteins, immune modulators, monoclonal antibodies

synthesized by chemists or purified from nature OR derived from living organisms

peptides vs proteins

both made of chains of amino acids joined together by peptide bonds

peptides (<50 AA)

larger molecules (>50 AA) such as monoclonal antibodies, growth factors

large size and potential enzymatic digestion make them not suitable for oral administration, most by injection

nucleic acid-based therapies

targets components inside the cell to either correct or compensate for disease caused by genetic mutations or altered gene expression

gene therapy

• antisense oligonucleotides

• small interfering RNA

• mRNA therapies

• CRISPR/Cas9 editing

• microRNA

inclisiran

targets the mRNA encoding PCSK9 a protein involved in regulating LDL levels, used in the treatment of homozygous familial hypercholesterolemia

3 drug names

IUPAC

• International union of pure and applied chemistry

INN

• international non-proprietary name

• all lowercase

Brand or trademark

• capitalized first letter

international non-proprietary name (INN)

approved by the WHO

each name is unique and globally recognized and is aka the generic name

must end in approved “stem”, same stem used for pharmacologically related substances

pharmacodynamics

what the drug does to the body

study of the molecular, biochemical, and physiological effects of drugs on cellular systems and their mechanisms

receptor

macromolecule (protein) that mediates the actions of endogenous and exogenous ligands

formation of the drug-receptor complex leads to a biological response

binding sites

region on the receptor where a ligand binds

the site where the endogenous ligand binds is the orthosteric site

binding sites outside of the orthosteric site are called allosteric sites

agonist

a ligand that binds to a receptor and stimulates it to function

antagonist

a ligand that blocks binding of agonist ligands to a receptor preventing signaling by the receptor

can bind to but not activate a receptor, thus blocking the actions of agonists at the receptor

• if bind with high affinity but no efficacy

have an efficacy of zero

pharmacokinetics

what the body does the drug

study of absorption, distribution, metabolism, and excretion (ADME)

therapeutics

uses of drugs and the methods of their administration in the treatment of disease

drug target - what the drug binds to elicit an effect (receptor)

mechanisms of actions - how the drug works, how it modulates the function of the target

indications - what diseases or conditions the drug is used in the treatment of

contraindications - what disease or condition or patient population the drug should not be used in

routes of administration- how the drug can be given

pharmacokinetic parameters - ADME factors that affect the clinical efficacy of the drug

drug interactions - a change in a drug’s effect due to interactions with other drugs, food, or a medical condition

adverse effects or side effects

drug-drug interactions

a change in a drugs effect on the body and the body’s effect on the drug when it is taken together with another drug

• drugs can have an additive effect or opposing effects due to their mechanisms of actions

• can delay, decrease, or enhance absorption of either drug. it may change the metabolism or excretion of one or both drugs

• may increase or decrease the effects of one or both drugs

adverse event

an unexpected medical event that is generally harmful to the participant that occurs during treatment with a pharmaceutical product, but which does not necessarily have a causal relationship with the treatment

adverse effects

unintended pharmacological effects that occur when a medication is administered correctly. include any unexpected medical event that is generally harmful to the participant due to taking the treatment. known to occur in a percentage of patients determined from clinical trials

very common >10%, common >1%, uncommon >0.1%, rare >0.01%, and very rare <0.01%

side effects

unintended but predictable symptoms that can develop while taking a drug

• can happen at normal recommended doses and are unrelated to the intended purpose of the medication

• side effects are often dose-related

• side effects may be desirable, adverse, or inconsequential. adverse or negative side effect = adverse effect

  • can be due to actions at the intended target or unintended

dose response

when observing the effect of a drug in a whole animal or human (in vivo)

concentration can interact and changes over time due to ADME factors

concentration response

when observing the effect of a drug isolated cells or tissues (in vitro or ex vivo)

concentration doesn’t change because confined to known volume

drug development 3 things

unsent medical need: condition or symptom whose treatment or diagnosis is not addressed adequately by available therapy

target: specific molecules, often a protein, in the body that is closely linked to a particular disease process and can be influenced by a drug to produce a desired therapeutic outcome

lead: chemical compound that shows promise as a treatment for a disease and may lead to the development of a new drug

clinical trial phase 1

drug safety

20-100 healthy patients

drug side effects, MOA, safety

clinical trial phase 2

does it treat patient

up to several 100 with disease/condition

safety, efficacy, dosage and frequency

clinical trial phase 3

1-4 years

300-3,000 with disease/condition

benefits and risks within populations

efficacy

safety

drug affinity

physical interaction between the drug and receptor

measures how strongly a drug interacts with the receptor

governed by:

• shape complementarity: if a molecule doesn’t fit into the binding pocket less van Der Waals interactions can occur leading to decreased affinity

• strength and number of non-covalent interactions between the ligand and the receptor

specificity

case when a ligand has increased affinity for one receptor over others

governed by:

• shape complementarity

• specific interactions between the ligand and receptor

k on

forward constant of R + L = R.L. (complex)

units = 1/Ms concentration dependent rate

k off

reverse constant of R+L=R.L complex

units 1/s concentration independent rate

K(D)

binding dissociation constant

measures affinity

k off/k on = KD = [R][L]/[RL]

ligand concentration at which half of the total number of receptors are bound to ligand

units M

B max

binding max

totally density (concentration) of receptors in a sample of tissue or per cell

units = sites/cell or fmol/mg protein

saturation assays

to experimentally measure affinity

use radioactive isotope or fluorescent molecule

use increasing concentrations of radioligand and require incubation until equilibrium is reached

lower KD is higher affinity

competition binding assay

experimentally measures affinity

use a single concentration of labelled ligand and increasing concentrations of unlabelled ligand and require incubation until equilibrium is reached

IC50

concentration of drug required for 50% inhibition of labelled-ligand binding in competition binding assays

lower value is higher affinity

Ki

experimentally measuring affinity

equilibrium dissociation constant for binding of the unlabeled drug to the receptor

property of receptor and unlabelled drug

efficacy

extent to which a drug can produce a response

agonist

compound that can bind to and cause activation of a receptor, thus mimicking the actions of the endogenous ligand

can be full or partial

antagonist

compound that can bind to but not activate a receptor, thus blocking the actions of the endogenous ligand

concentration response curve

graphically describe the relationship between the concentration of a ligand applied to cells and the resulting response

for measuring efficacy

hill slope

usually 1, occurs when a ligand binds to a single binding site

>1 indicates positive cooperativity

<1 indicates negative cooperativity

Emax

maximum response of a drug compared to a reference ligand

if 100% then it is a full agonist

functional assays

demonstrate that a ligand binds to a receptor and “does something” aka outcome

can be activation (agonist response) or inhibition/modulation of an agonist response (antagonism)

used to quantitate the response

in vitro, ex vivo, or in vivo

potency

refers to the dose/concentration of a drug that is required to produce a defined response or effect

depends on both recent (affinity, efficacy) and tissue or cell parameters (e.g. receptor numbers, intracellular mediator levels, drug accessibility

experimentally measuring potency

measured and reported as the dose/concentration of a drug that produces 50% of the drugs maximal effect (ED50 or EC50)

effective dose or effective concentration

EC50

concentration of the drug to reach 50% of drugs maximal effect

half maximal effective concentration

higher number is less potent

partial agonist

produce an effect if no agonist is present but act as competitive antagonists in the presence of a full agonists

types of antagonists

competitive

non-competitive/insurmountable

physiological

competitive antagonist

competes with an agonist for the same receptor binding site (orthosteric)

surmountable: increasing the concentration of agonist can overcome competitive antagonism

efficacy of the agonist is unchanged

potency of the agonist is reduced

competitive antagonists graph

reduces agonist potency so higher EC50 but higher dose can still achieve max effect

Emax doesn’t change

physiological antagonists

does not directly compete with an agonist for the same receptor binding site

drug that counters the effects of another by binding to a different receptor and causing opposing effects

non-competitive/insurountable antagonists

alters the receptor so that an agonist can’t bind, or the receptor can’t produce an effect

insurmountable: increasing the concentration of agonist does not overcome antagonism

efficacy of agonist is reduced

potency of agonist may be reduced

three types:

• negative allosteric modulation

• orthosteric irreversible

• orthosteric pseudo-irreversible

negative allosteric modulation antagonists

allosteric antagonist binds to a receptor at a site distinct from the active site

induces a conformational change in the receptor, which decreases the affinity of the receptor for the agonist or the agonist efficacy

efficacy of the agonist is reduced

potency of the agonist may be reduced

E max is reduced

orthosteric irreversible antagonists

irreversible antagonist binds covalently to the receptors orthosteric binding site and cannot be displaced by either competing ligands or washing

permanently deactivates the receptor

efficacy of the agonist is reduced

orthosteric pseudo-irreversible antagonist

stay bound to the receptor’s orthosteric binding site for extended periods of time (hours)

slowly dissociate from their receptor over time

in the timescale of the functional assay acts in a manner similar to irreversibly antagonists

efficacy of the agonist in reduced

experimentally measuring antagonist potency

IC50: concentration of antagonist required for 50% inhibition of a fixed concentration of agonist

functional assay

increasing concentrations of antagonist are added to the assay (e.g. cells) a set concentration of agonist is then added and the agonist response measured

pA2: negative logarithm of the molar concentration of an antagonist that would produce a 2-fold shift in the concentration response curve for an agonist

IC50

concentration of antagonist required for 50% inhibition of a fixed concentration of agonist

depends on three factors:

• affinity of the antagonist to the receptor

  • the higher the affinity the lower the IC50 value

• concentration of the agonist being displaced

  • higher concentrations of the ligand will require more antagonist to reach 50% inhibition and the IC50 values will increase

• affinity (Kd) of the agonist for the receptor

  • lower the Kd value, the more concentration of the antagonist will be needed to displace the ligand and the IC50 will increase

pA2

negative logarithm of the molar concentration of an antagonist that would produce a 2-fold shift in the concentration response curve for an agonist

increasing concentrations of agonist are added to the assay, in the presence and absence of a set concentration of antagonist, the agonist response is measured

selectivity

refers to a drug’s ability to preferentially produce a particular effect and is related to the structural specific of the drug binding to receptors

relative between 2 receptors, does not equal specific

at low concentrations an agonist selective for receptor A will activate receptor A and not receptor B

at high concentrations, an agonist selective for receptor A will activate both receptor A and receptor B

agonists or antagonist drugs that are ‘selective’ for the intended receptor can still produce significant effects at other related receptors if high enough dose given

useful in clinical practice only when the ratio of the affinity of a drug at the target receptor verses other related receptors is 100x or more

• when lower, difficult to predict drug doses that will exploit the difference in subtype activity. reduces off-target side effects

atropine selective example

atropine is selective for the muscarinic Ach receptor (mAchR) over the alpha-adrenoceptors, the dopamine receptors, and the histamine receptors so less side effects compared to chlorpromazine

receptor subtypes

receptors are often named on the basis of their major endogenous agonist (e.g. adrenergic, serotonin, opioid, dopamine)

were ‘subtyped’ on the basis of their selectivity for agonists or antagonists and sequence similarity

closely related receptors have similar binding sites. this means that drugs are more likely to have off-target effects at related receptors

how to achieve selectivity

many ligands share common binding site

sequence variation between drug-binding domain of the target and other members of its protein family improves selectivity and reduces side effects

alpha 1-adrenergic receptor selectivity

alpha 1A, 1B, 1D

smooth muscle of the prostate expresses predominantly alpha1A-AR. activation of this leads to contraction of the muscle further occluding the urethra

smooth muscle of the blood vessels of older men express predominantly alpha1B-AR

benign prostatic hyperplasia

long wait for stream of urine to begin, frequent/urgent need to urinate, weak and poorly directed stream, needing to urinate many times at night (nocturia), dribbling after urination has finished or an irregular stream

prostate keeps growing through life from testosterone which can occlude the urethra

prazosin moa

non-selective alpha 1-adrenergic antagonist

prevents activation of all three alpha 1-adrenergic receptors, preventing activation of smooth muscle contraction

preventing vasoconstriction and contraction of smooth muscle of prostate

prazosin indications

benign prostatic hyperplasia

Raynaud’s disease

hypertension

prazosin contraindications

known sensitivity to quinazolines

caution for patients with hypotension

prazosin side effects

postural hypotension (alpha 1) 14%

blurred vision (alpha 1) 4%

nasal congestion (alpha 1) 4%

priapism (sustained erection) (alpha 1) <1%

tachycardia <1%

palpitations 5%

detumescence pathway

sympathetic

removing an erection

alpha-adrenergic nerve → NE → - to smooth muscle cells

or endothelin → + rho kinase → - to smooth muscle cells

erection pathway

parasympathetic

cholinergic nerve → + Ach

NANC NO → + smooth muscle

NO from endothelial cells

tamsulosin moa

alpha 1A-adrenergic selective antagonist

prevents smooth muscle contraction

binding of drug to alpha 1A-adrenoceptors in the prostate results in relaxation of prostate smooth muscle followed by improvements in urodynamics

tamsulosin indications

relief of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

tamsulosin contraindications

cataract surgery

history of orthostatic hypotension

tamsulosin side effects

Abnormal ejaculation-failure of ejaculation or retrograde ejaculation (

• off target affinity for dopamine D3-Receptor & serotonin 5HT1A-Receptor (2%)

amblyopia (poor pupil dilation) (α1-AR), dizziness (2%),

floppy iris syndrome

• serotonin 5HT1A-Receptor

postural hypotension (α1B-AR) (<1%),

priapism (<0.01%) (α1-AR)

types of protein drug targets

receptor drug targets

• ligand-gated ion channels

• G protein-coupled receptors

• catalytic receptors

• nuclear receptors

non-receptor drug targets

• voltage gated ion channels

• transporters

• enzymes

receptors vs non-receptor protein drug targets

receptors bind endogenous molecules (ligands) to induce cellular signaling

non-receptors do not bind endogenous molecules to induce cellular signaling, but instead have a unique function, e.g., enzymes catalyze reactions, transporters transport ions

transporters

non-receptor drug targets

move substances from one side of a cell membrane to the other

• inhibition of CNS transporters can control neurotransmitter levels (monoamine transporters)

• involved in absorption, distribution and elimination (pharmokinetics) of drugs

• control concentration of drugs in particular organs or compartments, which can influence drug toxicity

• responsible for development of resistance seen with some antiviral, antiviral, antibacterial and anticonvulsant drugs as they actively pump drugs out of target cells

ABC and SLC transporters