Weeks 1-5 exam Flashcards
How do drugs work?
by interfering with or inhibiting natural processes
Paul Ehrlich 1845-1915 discovered…
cells have chemical recognition sites for certain drugs, hence “receptors”
What regulatory proteins are the targets for drugs?
1 Carriers/ transporters
2 Enzymes
3 Ion channels
4 Receptors
The exception: DNA
What are carriers/transporters and what is their function?
- proteins that sit in cell membranes
- move nutrients and waste products into and out of cells and organs as molecules are often lipid insoluble
Carrier proteins as drug targets; give examples
the transport of ions and organic molecules across the -renal tubule
- intestinal epithelium
- blood-brain barrier
What is the function of enzymes as drug targets?
-drugs inhibit or promote protein concentrations (mostly inhibit) and produce bio-active products as a result of enzymatic activation
Drugs which promote enzyme activity are rare; eg MAO inhibitors
Enzymes as drug targets in action; give examples
- substrate equivalent that acts as a competitive inhibitor of the enzyme (e.g. captopril, acting on angiotensin-converting enzyme)
- false substrate that subverts normal metabolic pathway.
What are ion channels?
What are the two important types and their mechanisms of action?
What is their function as drug targets?
What are the 4 systems targeted by drugs via ion channels?
- gateways in cell membranes, that selectively allow the passage of particular ions, and are induced to open or close by a variety of mechanisms.
- Ligand-gated channels and voltage-gated channels.
- Ligand-gated channels open only when one or more agonist molecules are bound, and are properly classified as receptors, since agonist binding is needed to activate them.
- Voltage-gated channels are gated by changes in the transmembrane potential rather than by agonist binding.
- They also may affect channel function by an indirect interaction, involving a G-protein and other intermediaries. e.g. the action of local anaesthetics on the voltage-gated sodium channel, the drug molecule plugs the channel physically, blocking ion permeation.
- Systems where drugs target ion channels: Nerves, brain, kidney and the cardiovascular system
What are receptors?
What are the 4 types of receptors?
What is their function?
-Proteins that recognise drugs; the sensing element in the system of chemical communications that coordinates the function of all the different cells in the body,
4 superfamilies / types of receptors defined mainly on the basis of structure
- Linked to ion channels: affected by neurotransmitters
- G-protein linked: affected by a wide range of ligands
- Linked to kinase enzymes: affected by growth factors
- Nuclear: affected by steroids
What does (GPCR) mean?
G-Protein Coupled Receptor
What is Tachyphylaxis?
What are two scenarios that tachyphylaxis can occur?
What causes tachyphylaxis?
An acute (sudden) decrease in the response to a drug
Tachyphylaxis can occur both after an initial dose of medication or after an inoculation with a series of small doses. Increasing the dose of the drug may be able to restore the original response.
Tachyphylaxis can be caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug’s effect, or by the depletion of receptors available for the drug or neurotransmitter to bind to.
This depletion is caused by the cell’s reducing the number of receptors in response to their saturation.
Upregulation, Downregulation & Desensitization describes…
the level of expression of receptor proteins; as controlled by receptor-mediated events and synthesized by the cells that express them
Long-term regulation occurs through…
Give an example
an increase or decrease of receptor expression.
the proliferation of various postsynaptic receptors after denervation
the upregulation of various G-protein-coupled and cytokine receptors in response to inflammation
the induction of growth factor receptors by certain tumour viruses
Long-term drug treatment invariably induces adaptive responses. Discuss:
most common with drugs that act on the central nervous system
adaptive responses often form the basis for therapeutic efficacy
may take the form of a very slow onset of the therapeutic effect (e.g. with antidepressant drugs; see), or the development of drug dependence
adaptive changes in expression and function includes resistance i.e. cancer drugs.
What is down regulation?
Give an example…
the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable.
An example of downregulation is the cellular decrease in the number of receptors to a molecule, such as a hormone or neurotransmitter, which reduces the cell’s sensitivity to the molecule.
This phenomenon is an example of a locally acting negative feedback mechanism.
What is upregulation?
Give an example:
An increase of a cellular component
An example of upregulation is the increased number of cytochrome P450 enzymes in liver cells when xenobiotic molecules such as dioxin are administered (resulting in greater degradation of these molecules).
What causes withdrawal after long term drug/medication use?
most drugs that work as receptor agonists downregulate their respective receptor(s),
most drugs that work as receptor antagonists upregulate their respective receptor(s).
The disequilibrium caused by these changes results in withdrawal.
What are Tissue Organ Baths used for?
in vitro dose response experiments are used to investigate the physiology and pharmacology of tissue preparations from various species (e.g. chick, toad, rabbit, rat, guinea-pig, etc.).
Tissue-organ baths are used to maintain the integrity of the tissue for several hours, in a temperature-controlled environment, while physiological measurements are performed.
Typical experiments involve the addition of drugs to the organ bath or direct/field stimulation of the tissue.
The tissue reacts by contracting/relaxing and an isometric or isotonic transducer is used to measure force or displacement, respectively.
From the experimental results dose-response curves are generated (tissue response against drug dosage or stimulus potency).
Describe the difference between agonists and antagonists drugs
Agonist drugs activate receptors and mimic effects of endogenous ligand
Antagonists, combine at the same site without causing activation, and block the effect of agonists on that receptor.
Affinity vs Efficacy
The tendency of a drug to BIND to receptors is governed by its affinity,
The tendency of a drug to BIND as well as ACTIVATE the receptor is referred to as its efficacy.
Drugs of high potency generally have a high affinity for the receptors and thus occupy a significant proportion of the receptors even at low concentrations.
Agonists also possess significant efficacy, whereas antagonists, in the simplest case, have zero efficacy.
Drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is sub-maximal, are known as partial agonists, to distinguish them from full agonists (maximal tissue response)
Efficacy: max effect drug can have Often determined experimentally; HOW WELL A KEY FITS IN A LOCK
Dose response curves:
Describe Emax, EC50
The maximum effect is labelled the Emax.
The concentration at which the effect is 50% of the maximum is called the EC50
Describe Potency, Efficacy & Efficacy Selectivity
Potency: A > B Amount required for effect, depends on affinity & efficacy
Efficacy: A & B > C Once bound, how much effect?
Efficacy Selectivity: The more selective drug is for specific target / receptor: Easier to use therapeutically
Good selectivity important aim when designing drugs
Define Antagonists
HAS AFFINITY TO FIT INTO ELECTRICAL SOCKET BUT LIGHT DOES NOT TURN ON
Blocks or diminishes normal receptor function
Most drugs that act on receptors are antagonists
Their action can be: Reversible or irreversible
Competitive Antagonism:
Shift to right
Same slope, Same max
Dose response curve:
Full agonist vs partial agonist
Full agonist: produces a near-maximal response when only about half the receptors are occupied
Partial agonist: produces sub-maximal response even when occupying all of the receptors
An inverse agonist vs partial agonist
A partial agonist has a weaker preference than an full agonist for the same receptor and shift the equilibrium to a smaller extent than an agonist.
Inverse agonist has all the properties of a full agonist except that is shifts the equilibrium in the opposite direction to a full agonist.
Both antagonists and inverse agonists reduce the activity of a receptor and, in the presence of an agonist, reduce its activity.
Antagonists do not have any effect in the absence of an agonist, inverse agonists do.
What is Pharmacokinetics?
What drugs do to the body
Includes factors that govern drug concentrations at the site of action as a function of time ie: “ADME” Absorption Distribution Metabolism Excretion
Drug clearance as applied to: Absorption Distribution Metabolism Excretion
Drug clearance determines the steady-state plasma concentration during constant-rate drug administration
The characteristics of absorption and distribution plus metabolism and excretion determine the time course of drug concentration in blood plasma during and following drug administration.
Total Drug Clearance (CLtot):
- Rate of elimination?
- Clearance (CL) and steady-state plasma concentration (CSS)
- Vd (Volume distribution) and Clearance
- Loading dose (L) and Vd
Total clearance (CLtot) of a drug is the fundamental parameter describing its elimination
Rate of elimination: CLtot multiplied by plasma concentration.
CLtot determines steady-state plasma concentration (CSS):
CSS = rate of drug administration /CLtot.
Vd is an apparent volume linking the amount of drug in the body at any time to the plasma concentration.
Elimination half-life (t1/2) is directly proportional to Vd and inversely proportional to CLtot.
The loading dose (L) needed to achieve a desired initial plasma concentration (Ctarget) is determined by Vd:
L = Ctarget × Vd.
Drug Absorption
The process by which unchanged drug proceeds from the site of administration into the blood.
Drug Absorption Across Biological Membranes
- lipid rich vs fat-soluble (lipophilic) vs water soluble (hydrophilic) barriers
- describe diffusion
Lipid-rich biological membranes are the main barriers encountered by drugs
Generally, fat-soluble (lipophilic) drugs cross barriers easily, water-soluble (hydrophilic) & ionised drugs cross membranes poorly
Most drugs cross membranes by passive diffusion i.e drugs diffuse down concentration gradient
Some drugs are actively transported across membranes (energy-requiring process)
Factors Influencing Drug Absorption
- Nature of Absorbing Surface (e.g. single layer of epithelial cells in GIT easier than skin)
- Blood Flow (a rich blood flow e.g. sublingual/under tongue) enhances drug absorption compared to skin)
- Solubility of Drug (lipid solubility is important for drugs given orally)
- Formulation of Drug (drugs can be manufactured with enteric coatings to delay absorption)
- Ionisation of Drug: most drugs are either weak acids (H-donating) or weak bases (H-accepting), they are either unionised (lipid soluble) or ionised (H2O soluble) species
Drug Excretion by the Kidneys
The relation between dose rate, drug clearance and plasma concentration is illustrated by the cylinder model.
Dose rate is represented by tap flow, drug clearance by outlet size, and plasma concentration by the height of the water column. Adjust the tap flow, and the size of the outlet to see what happens to the height of the water column.
Plasma concentration (Cp) is directly proportional to the dose rate, and inversely proportional to the clearance (CL). i.e. Cp = Dose rate/CL
The steady state concentration (Cpss) is thus determined by the maintenance dose rate and the clearance.
Estimating renal clearance (CLren).
where Cu is the urine concentration of the substance of interest, Cp its concentration in plasma and Vu the urine flow rate in units of volume/time.
The overall clearance of a drug (CLtot)
The fundamental pharmacokinetic parameter describing drug elimination.
Defined as the volume of plasma containing the total amount of drug that is removed from the body in unit time by all routes.
Overall clearance is the sum of clearance rates for each mechanism involved in eliminating the drug, ie.
-renal clearance (CLren) -metabolic clearance (CLmet) plus any additional appreciable routes of elimination (faeces, breath, etc.).
It relates the rate of elimination of a drug (in units of mass/unit time) to Cp: Drug clearance can be determined in an individual subject by measuring the plasma concentration of the drug (in units of, say, mg/l) at intervals during a constant-rate intravenous infusion (delivering, say, X mg of drug per h), until a steady state is approximated
At steady state, the rate of input to the body is equal to the rate of elimination, so: Rearranging this, where CSS is the plasma concentration at steady state, and CLtot is in units of volume/time (l/h in the example given).
For many drugs, clearance in an individual subject is the same at different doses therefore knowing the clearance enables one to calculate the dose rate needed to achieve a desired steady-state (‘target’) plasma concentration from equation
Drug Clearance, kidneys and liver
Drugs are eliminated by excretion unchanged through the kidneys, or by metabolism to an inactive product usually in the liver.
The fraction excreted unchanged (fu) defines the renal elimination, while (1-fu) describes the metabolic elimination.
Drug elimination is the irreversible loss of drug from the body. It occurs by two processes: metabolism and excretion.
Metabolism consists of anabolism and catabolism, i.e. respectively the build-up and breakdown of substances by enzymic conversion of one chemical entity to another within the body, whereas excretion consists of elimination from the body of chemically unchanged drug or its metabolites.
The main routes by which drugs and their metabolites leave the body are: * the kidneys * the hepatobiliary system * the lungs (important for volatile/gaseous anaesthetics).
Most drugs leave the body in the urine, either unchanged or as polar metabolites. Some drugs are secreted into bile via the liver, but most of these are then reabsorbed from the intestine.
Steady State
The steady state concentration (Cpss) is determined by the maintenance dose rate and the CL.
Volume distribution (Vd)
The major compartments are: plasma (5% of body weight) interstitial fluid (16%) intracellular fluid (35%) transcellular fluid (2%) fat (20%).
Volume of Distribution is considered in relation to body “compartments”.
Vd determines the distribution of drugs between the blood and the rest of the body.
Some highly polar drugs, such as penicillins, distribute mainly into “central” compartments and have a small Vd, while highly lipid soluble drugs, such as tricyclic antidepressants, distribute far more widely and have a large Vd.
Drugs with small Vd stay mainly in the central compartment.
Volume of distribution “dilutes” as concentration enters ECF (extra-cellular fluid), ICF (intracellular fluid), muscle and fat.
Amount in body = Vd x plasma concentration
Ab = Vd x Cp
Vd = Ab/Cp
Lipid-insoluble drugs are mainly confined to plasma and interstitial fluids; most do not enter the brain following acute dosing.
Lipid-soluble drugs reach all compartments and may accumulate in fat.
For drugs that accumulate outside the plasma compartment (e.g. in fat or by being bound to tissues), Vd may exceed total body volume.
The apparent volume of distribution, Vd, is defined as the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma.
Effect of pH on Drug Absorption
If acid is added, eg. H+Cl-, the equilibrium moves to the right.
If alkali is added, eg. Na+OH-, then OH- ions and H+ ions neutralise each other to form water, and the equilibrium moves to the left.
Unionized drug crosses lipid biological barriers (e.g. membranes) better than ionized drug.
pH partition and ion trapping
Ionisation affects not only the rate at which drugs permeate membranes but also the steady-state distribution of drug molecules between aqueous compartments, if a pH difference exists between them.
Within each compartment, the ratio of ionised to unionised drug is governed by the pKa or acid strength of a drug in compartment solution and the pH of that compartment.
It is assumed that the unionised species can cross the membrane, and therefore reaches an equal concentration in each compartment. The ionised species is assumed not to cross at all. The result is that, at equilibrium, the total (ionised + unionised) concentration of the drug will be different in the two compartments, with an acidic drug being concentrated in the compartment with high pH (‘ion trapping’), and vice versa.
The pH partition mechanism explains some of the qualitative effects of pH changes in different body compartments on the pharmacokinetics of weakly acidic or basic drugs, particularly in relation to renal excretion and to penetration of the blood-brain barrier.
Weak Bases
May contain –NH2 or -NH group
Are ionised at gastric pH, nonionised at alkaline pH e.g. amphetamine, chloroquine, morphine
Definition of Drug Bioavailability
The proportion of an orally-administered drug dose reaching the systemic circulation intact
Drug Distribution
The reversible transfer of a drug from one location (e.g. blood) to another (e.g. heart or lung tissue)
Drug distribution initially greatest to organs receiving high blood supply (e.g. heart, liver, kidney)
Distribution to tissues receiving lower blood supply occurs more slowly (e.g. skeletal muscle, fat)
The major body compartments are: •Plasma (5% of total body weight) •Interstitial fluid (16%) •Intracellular fluid (35%) •Transcellular fluid (2%)•Fat (20%)
Drug-Protein Binding in Plasma
Certain drugs often strongly bind to proteins within plasma (e.g. warfarin is 99.9% bound to albumin)
Acidic drugs mainly bind to albumin, while basic drugs prefer α1- acid glycoprotein
Protein-drug binding is reversible
Only free drug is active in pharmacological terms
Drug doses may need to be altered in patients with diseases that alter plasma protein profiles (e.g. hypoalbuminemia)
Binding Properties of Plasma Proteins
The physical processes of diffusion, penetration of membranes, binding to plasma protein and partition into fat and other tissues underlie the absorption and distribution of drugs.
At therapeutic concentrations in plasma, many drugs exist mainly in bound form.
The fraction of drug that is free in aqueous solution can be less than 1%, the remainder being associated with plasma protein.
It is the unbound drug that is pharmacologically active.
Such seemingly small differences in protein binding (e.g. 99.5 versus 99.0%) can have large effects on free drug concentration and drug effect.
The most important plasma protein in relation to drug binding is albumin, which binds many acidic drugs (e.g. warfarin, non-steroidal anti-inflammatory drugs, sulfonamides) and a smaller number of basic drugs (e.g. tricyclic antidepressants and chlorpromazine).
Other plasma proteins, including β-globulin and an acid glycoprotein that increases in inflammatory disease, have also been implicated in the binding of certain basic drugs, such as quinine.
The amount of a drug that is bound to protein depends on three factors:
- the concentration of free drug
- its affinity for the binding sites
- the concentration of protein.
