Pharmacology Flashcards
What is pharmacology?
The branch of medicine concerned with the uses, effects, and modes of action of drugs.
What are the two classes of interactions in pharmacology and their definition?
- Pharmacodynamics: The effects of the drug on the body
- Pharmacokinetics: The way the body affects the drug with time.
What are the four things that can affect the drug within the body?
Absorption, distribution, metabolism and secretion.
Who is the father of pharmacology?
Jonathan Pereira
What is a receptor?
A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific effect in the cell.
What are the four main classes of receptors based on structure and function?
- Ligand-gated ion channels (Ionotropic receptors)
- G protein-coupled receptors (metabotropic)
- Kinase-linked receptors
- Nuclear receptors
Define ligand
A substance that is bound to a protein
What is the time scale for each class of receptor?
- Ionotropic- Milliseconds
- Metabotropic- Seconds
- Kinase linked receptors- Hours
- Nuclear receptors- Hours
2 Examples of ionotropic receptors
- Nicotine
-Acetylcholine receptor
Two examples of metabotropic receptors
- Muscarinic
- Acetylcholine receptor
Example of Kinase-linked receptors
Cytokine receptors
Example of Nuclear receptors
Oestrogen receptor
What is one example of membrane-bound receptors, and in what category are they?
Nicotinic acetylcholine receptors
-Ligand-Gated Ion Channels.
What is the function of Ligand-Gated Ion channels? Is it passive? What is it driven by?
Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore that allows the regulated flow of selected ions across the plasma membrane. Ion flux is passive and driven by the electrochemical gradient for the permeant ions.
What are nicotinic acetylcholine receptors permeable to? Are they specific or non-specific, and what do they modulate?
- Permeable to Na+, K+ and Ca2+
- Non-specific cation (a positively charged ion) channels
- Modulate fast synaptic excitation.
What are glial cells?
A type of cell that provides physical and chemical support to neurons and maintain their environment.
What are agonists?
Chemicals or drugs that activate receptors and produce a response.
What are antagonists, and what do they do?
They are drugs that combine with receptors but do not activate them. They reduce the probability of the transmitter substance or agonists combining with the receptor and do reduces or blocks its action.
Define specificity
The ability of a drug to combine with one particular part of receptor.
Are drugs always specific?
Nah, no drug is truly specific but many have relatively selective action on one type of receptor.
Define affinity
The degree to which a substance tends to combine with another.
What does Corpora non agunt nisi fixata mean?
Entities do not act unless attached.
What does the Law of Mass Action state?
According to the law of mass action, a reaction’s velocity depends on the reactants’ concentrations.
Draw the Law of Mass Action and state the values
A+R (Equilibrium arrow) AR
Above arrow: K+1
Below arrow: K-1
A: Ligand
R: Receptor
k+1: association (forward) rate constant
k+2: disassociation (backward) rate constant
What can we assume in equilibrium regarding the Law of Mass Action ratio? What is the formula?
The rate of AR being formed equals the rate of AR dissociating
k+1[A][R] = k-1 [AR]
What do you form when you combine the association constant and disassociation constant?
The disassociation equilibrium constant for the binding reaction, KA
What are the two abbreviations of the disassociation constant?
Disassociation constant or the equilibrium constant
What equation models the relationship between ligand concentration and receptor occupancy? Draw it
The Hill-Langmuir
What is KD in binding experiments?
Relates to the concentration of antibody in a substance
What is KA equal to?
The concentration of ligand required to occupy 50% of the receptors
The lower KA, the greater the receptor’s affinity for the ligand. True or False?
Trueeeeee
What is receptor occupancy?
It measures the degree to which the test drug occupies its target receptor in the tissue or animal
What is receptor occupancy?
It measures the degree to which the test drug occupies its target receptor in the tissue or animal
Define efficacy
The tendency for an agonist to activate the receptor
Some agonists only needed to occupy a small % of receptors to give a maximal response. True or false?
True
Define Drug Potency
A measure of drug activity is expressed in the amount required to produce an effect of given intensity. Such as EC50
What two things does drug potency depend on?
Receptor (affinity, efficacy) and tissue (receptor numbers, drug accessibility) parameters.
What are partial agonists?
An agonist that in a given tissue, under specified conditions, cannot elicit as significant an effect (even when applied at high concentration with 100% receptor occupancy) as can another agonist acting through the same receptors in the same tissue
What is the most common and most important type of antagonist action?
Reversible Competitive Antagonism
The antagonist forms a long-lasting or irreversible combination with the receptor; what is the term used for this?
Irreversible Competitive Antagonism
What happens between antagonist and agonist in the reversible competitive antagonism?
They compete for the same binding site on the receptor.
In the presence of an antagonist, the agonist concentration-response curve is ‘shifted to the left’ with a change in maximal response or a change in slope. T or F?
FALSE. In the presence of an antagonist, the agonist concentration-response curve is ‘shifted to the RIGHT’ WITHOUT a change in maximal response or change in slope.
What is the ‘shift to the right’ best expressed by and what is it?
Concentration ratio! It is the factor by which the agonist concentration must be increased to restore a given response in the presence of an antagonist.
The antagonist action is insurmountable, i.e., the maximal response cannot be fully restored with increasing concentrations of agonist. True or False?
True
What is non-competitive antagonism?
Binds to an allosteric (non-agonist) site on the receptor to prevent receptor activation.
Can agonist and antagonist molecules be bound to the receptor simultaneously?
Yes
When can the receptor become active?
Only when the agonist site alone is occupied, not both the antagonist and agonist or antagonist alone.
Is antagonist action reversible or irreversible?
Both
What are the three other forms of antagonism not involving the receptor?
- Chemical antagonism
- Physiological antagonism
- Pharmacokinetic antagonism
Define chemical antagonism
The antagonist combines in solution directly with the chemical being antagonized
Define physiological antagonism
Two agonists produce opposing physiological actions and cancel each other out. Each drug acts through its receptors
What three drugs act as agonists at nicotinic acetylcholine receptors? And are they full or partial agonists?
- Acetylcholine (Full agonist)
- Nicotine (Full agonist)
- Varenicline (Partial agonist)
What substance is a full agonist at both nAChRs and mAChRs?
Acetylcholine
What is one surgery acetylcholine is indicated for?
Cataract surgery
Can partial agonists be used as an ‘antagonist’ to produce a clinical effect? What is an example?
Yessir. Varenicline
What is G-protein Coupled Receptors’ function?
Are integral membrane proteins that are used by cells to convert extracellular signals into intracellular responses, including responses to hormones, and neurotransmitters, as well as responses to vision, olfaction, and taste signals.
What is signal amplification?
An increase in the intensity of a signal through networks of intracellular reactions
What is an example of G-protein Coupled Receptors? And what are they activated by?
Adrenoceptors, activated by adrenaline and noradrenaline
What are the five adrenoceptors?
α1 α2 β1 β2 β3
What are the physiological effects of activation in the five adrenoceptors?
α1 = Vasoconstriction of blood vessels
α2 = Presynaptic inhibition of noradrenaline in the CNS
relaxation GI tract
β1 = Increased heart rate and cardiac muscle contraction
β2 = dilation of the bronchi
Increased heart rate and cardiac muscle contraction (lesser extent than β1)
β3 = Thermogenesis in skeletal muscle, lipolysis
What are Kinase-linked receptors also known as?
Enzyme-coupled receptors
What is the function of Kinase-linked receptors?
Are one of the main cell surface receptors that function similarly to other transmembrane receptors. They are an essential pathway in terms of messages transduction which mediates cells to communicate with each other. Kinase-linked receptors work as a gatekeeper of a company.
What is the function of nuclear receptors?
Once activated, nuclear receptors directly regulate the transcription of genes that control a wide variety of biological processes, including cell proliferation, development, metabolism, and reproduction.
Are nuclear receptors intracellular or extracellular?
Intracellular
What are nuclear receptors generally bound by?
Steroid hormones.
What are nuclear receptors?
These receptors are protein monomers located in the target cell’s nucleus and contain DNA-binding domains, allowing for the control of gene transcription.
Steroid hormones are hydrophobic/lipophilic. True or false?
True
What is the two-step process Steroid hormones activate when passing through the plasma membrane?
1) Activated hormone-receptor complex forms within the cell
2) The complex binds to DNA & activates specific genes
Gene activation leads to the production of key proteins
Draw the Nuclear receptor structure and label
Check-in notion.
What happens to the drug during absorption?
The drug undergoes absorption from the site of administration into the plasma
What happens to the drug during distribution?
Drug reversibly leaves the bloodstream and is distributed into interstitial and intracellular fluids.
What happens to the drug during metabolism?
The drug is transformed by metabolism by the liver and other tissues
What happens to drugs during excretion?
Drug and/or drug metabolites excreted in urine, feces and bile
What is the most crucial drug-metabolizing organ?
Liver
What other four organs/structures contribute to metabolism?
Kidneys, gut mucosa, lungs and skin
Metabolism in the liver (and/or gut) reduces _____ of drugs when administered by the ______
the bioavailability
enteral (oral) route
What are the four pharmacokinetics concepts?
- The Apparent Volume of Distribution (Vd)
- Bioavailability (F)
- Clearance
- Elimination half-life of a drug
Describe The Apparent Volume of Distribution (Vd) concept and its formula
The apparent volume of distribution (Vd) describes the extent to which a drug partitions between the plasma and tissue compartments.
Vd= Dose/[Drug]plasma
Describe the Bioavailability (F) concept and its formula
The amount of drug that eventually reaches systemic circulation (and hence is available for drug action on the target) of an administered drug dose is the drug’s bioavailability for that route of administration.
Formula:
F= Quantity of drug reaching systemic circulation (AUC) / Quantity of drug administered (Dose)
What can make bioavailability different between drugs?
The route of administration
Describe the clearance (CL) concept and formula
CL is the volume of blood removed (or cleared) of a drug per unit of time (e.g., L/hour or mL/minute). It is a flow parameter.
Clp= VDxKel
What other four CLs are there?
- Renal (CLR)
- Hepatic (CLH)
- Other elimination routes (CL0)
- Total clearance (CLT)
What is the bioavailability of medicines given intramuscularly?
100%
What three ways do drugs move around the body?
- Bulk Flow- This means via the circulatory system.
- Diffusion- Over short distances
- Solubility- lipid-soluble drugs are more likely to diffuse across lipid bilayer membranes
What four ways can small molecules cross cell membranes?
- Passive diffusion
- Facilitated diffusion
- Active transport
- Pinocytosis
What happens in Passive diffusion?
Drugs diffuse directly through the lipid or through aqueous pores formed by aquaporins that transverse the lipid bilayer. Many lipid-soluble drugs cross cell membranes in this way.
What happens in Facilitated diffusion?
Drugs diffuse via specialized carrier proteins that bind the drug on one side of the binding molecule on one side of the membrane, then change conformation and release on the other side. Does not require energy but does require a concentration gradient
What happens in active transport?
Drugs travel via specialized carrier proteins that require energy and can move drug molecules against the concentration gradient.
What happens in pinocytosis?
There is an invagination of a part of the membrane. The drug is encased in a small vesicle then ‘released’ inside the cell.
What is saturation kinetics?
Saturation kinetics refers to an enzyme reaction reaching a maximal velocity at high substrate levels.
What transport can show saturation kinetics?
Facilitated Diffusion
Active Transport
What are the five principal sites of carrier-mediated drug transport (both facilitated diffusion and active transport)?
- Blood-brain barrier
- Gastrointestinal Tract
- Placenta
- Renal Tubule
- Biliary Tract
What is essential for some drugs that are chemically related to endogenous substances such as neurotransmitters?
Carrier-mediated transport!
Vitamin B12 is absorbed by what method?
Endocytosis.
Many drugs are ___ acids or ___ weak bases
Weak, weak
What will these weak acids or weak bases drugs exist as?
Ionised and un-ionised forms
What does the proportion of ionization of a drug depend upon? (2)
pKa of the drug
Local pH
What does the pKa equal in relation to pH?
The pKa = pH at which 50% of the drug is ionized and 50% un-ionized
What happens between non-ionized drugs and the membrane?
For many drugs, the non-ionized form can permeate the membrane
What is the ionization reaction for acids? Formula
AH Equilibrium arrow A- + H+
What is the ionization reaction for bases? Formula
BH+ Equilibrium arrow B + H+
What is the Henderson-Hasselbalch equation?
The Henderson-Hasselbalch equation can be used to determine the proportions of ionized and un-ionized drugs in a given pH environment
What is the Henderson-Hasselbalch equation for acids? Do the three whole lines
pKa= pH + log(AH/A-)
pH - pKa= log(A-/AH)
10pKa-pH = (AH/A-) —> Final equation
What is the Henderson-Hasselbalch equation for bases? Do the three whole lines
pKa= pH + log(BH+/B)
pH - pKa = log(B/BH+)
10pKa-pH = (BH+/B) —> Final equation
What is the stomach and plasma pH?
Stomach = pH 1.5
Plasma = pH 7.4
What is the stomach and plasma pH?
Stomach = pH 1.5
Plasma = pH 7.4
Where do weak bases accumulate?
Weak bases accumulate in compartments with low pH
Where do weak acids accumulate?
Weak acids accumulate in compartments with high pH
What does the low pH in the stomach facilitate?
The low pH of the stomach facilitates absorption of weak acids
What does the higher pH of the intestine facilitate?
The higher pH of the intestine facilitates absorption of weak bases
Where does most oral route drug absorption occur and why?
It occurs in the small intestine due to the large surface area
What are the five Drug distribution body compartments?
-Total body water- small water-soluble molecules
-Extracellular water- larger water-soluble molecules
-Blood plasma- highly plasma protein-bound molecules, -large molecules, highly charged molecules
-Adipose tissue- highly lipid soluble molecules
-Bone and teeth- certain ions
How to determine the apparent volume of distribution (Vd) from drug blood plasma concentrations? (5 steps)
- Administer the drug dose
- Obtain a blood sample
- Separate plasma from erythrocytes
- Assay for [Drug]plasma
- Then calculate Vd with the formula:
Vd= Dose/[Drug]plasma
_____ (Vd ) in drugs that are retained in vascular compartments
_____ (Vd ) in adipose, muscle, and other non-vascular compartments (High or low)
High and Low
In blood, Initial restriction of the drug to highly vascularised parts of the body…
Hydrophilic or ionized drugs such as aspirin (Vd = 10)
In tissue, Eventual Free Drug Access to many Areas of the Body following slow equilibration…
Lipophilic drugs or un-ionised drugs such as amitriptyline (Vd = 1221)
For drugs of equal potency, a drug with a high Vd will require a ____ dose than a drug with a low Vd
Higher
What is the most abundant plasma protein?
Albumin
What binds to albumin and via what?
Many drugs bind with low affinity to albumin via electrostatic and hydrophobic forces.
What two things does the plasma protein binding reduce?
Plasma protein binding reduces the availability of the drug for diffusion to the drug target organ.
May also reduce the transport of the drug to non-vascular compartments
What is enzymatic conversion?
Catalytic decomposition of a chemical compound by reaction with water
