Physical Sciences

Question 1

What is a drug?

Answer 1

A chemical substance of known structure, which when administered to a living organism, produces a biological effect

Question 2

What is a Medicine

Answer 2

A chemical preparation, usually containing one or more drugs, administered with the intention of producing a therapeutic effect.

Question 3

Pharmacology (kinetics/dynamics)

Answer 3

Pharmacology is the study of the actions of drugs and their metabolites in the body.

kinetics is what the body does to the drug.

Dynamics is what the drug does to the body

Question 4

AADME

Answer 4

Administration
Absorption
Distribution
Metabolism
Elimination

Question 5

Topical administration

Answer 5

Skin

Question 6

Intermuscular administration

Answer 6

Injection into muscle

Question 7

Subcutaneous administration

Answer 7

Injection under skin

Question 8

Intradermal Administration

Answer 8

Injection into dermis (below epidermis)

Question 9

Intraperitoneal Administration

Answer 9

Injection into body cavity

Question 10

Intrathecal Administration

Answer 10

Injection into cerebrospinal fluid

Question 11

Intra-arterial Administration

Answer 11

Injection into joint space

Question 12

Parenteral administration

Answer 12

Injection; rapid and used for drugs that are poorly absorbed/ are irritants.

Question 13

Oral administration

Answer 13

Convenient
First pass metabolism in liver via portal circulation

Question 14

Type of administration is determined by…

Answer 14

Lipid solubility
Area available for absorption
Possible specific carriers
Amount that reaches the target may be compromised by the “first pass” metabolism

Question 15

Bioavailability (F)

Answer 15

Is used to define how well a drug is absorbed and reaches its site of action. Usually determined by a comparison of oral and IV absorption.

F = Area under curve for oral/Area under curve for IV

Area under curve is the amount of drug absorbed in systemic circulation following oral/IV administration.

F is always 1 in IV as 100% of the drug reaches the site of action. F is a fraction/decima/%

Question 16

Half life (relating to drug in plasma)

Answer 16

T 0.5
Time taken for the plasma drug concentration to fall to half of its original value.

Question 17

Clearance

Answer 17

Clp = plasma clearance

Clearance is the rate of elimination of a drug

Clearance = rate of elimination / plasma drug concentration

Clp = F x Dose /AUC oral

Clp = Kel x Vd

Question 18

Zero order kinetics

Answer 18

Rate of elimination is constant and independent of drug concentration.
T 0.5 depends on amount of drug given and is longer when more drug is given.
Very few drugs behave in this way
For zero order, the plasma conc. (Cp) vs time is a straight line and half life is directly proportional to the amount of drug given.

Question 19

First order kinetics

Answer 19

Most drugs are eliminated this way
T 0.5 is constant
Rate of removal depends on how much drug is present

Normal plot is transformed by plotting plasma conc. as a log against time; this can be used in calculations.

c0 is the plasma conc. at time 0
css (av) is the average steady state conc. as drugs are often taken multiple times per day and the plasma concentrations fluctuate.

Question 20

Distribution of drugs depends on…

Answer 20

Perfusion rate of the tissue (blood flow through the tissue)
Physicochemical ability of the drug to cross membranes
Nature of membranes
Extent to which the drug is bound

distribution is dynamic

Question 21

Partition co-efficient (Kp)

Answer 21

The uptake of a drug is defined by its partition co-efficient.
The bigger the value of Kp the longer it takes to achieve distribution equilibrium.

Kp = drug conc. in tissue / drug conc. in blood

Question 22

Membranes

Answer 22

Lipid soluble molecules pass through more readily due to the lipid membrane.
ionised or polar molecules do NOT cross readily.
small polar molecules can pass but muscles will allow large polar molecules to pass.

Acid drug in acid conditions = very soluble = readily transported

basic drug in basic conditions = very soluble = readily transported

Acidic drug in basic conditions = insoluble and vice versa

Question 23

Volume of Distribution

Answer 23

Less traumatic than to sample urine and blood
Used to get a measure of drug levels in the body

Vd = amount of drug in body/concentration of drug in blood

Vd can exceed body volume

lipid insoluble drugs are mainly confined to plasma and interstitial fluid.
lipid soluble drugs can accumulate outside of the plasma conc. by being in fat.

Question 24

Elimination (Phase I/II)

Answer 24

Phase I metabolism typically makes drugs more water soluble buts its main job is to prepare the drug molecules for phase II. This phase includes; oxidation, reduction, hydrolysis, any reaction that uncovers functional groups.

Phase II reactions are conjugations whereby the drug is coupled to a second, fairly water soluble molecule. So this phase is largely responsible for the increase in water solubility.

Question 25

Pro drug

Answer 25

When metabolism results in a more active drug than the originally administered compound.

it is also possible that metabolism may produce a toxic metabolite.

Question 26

Sulphate conjugation of Paracetamol (Cytochrome P450)

Answer 26

Cytochrome P450 is an enzyme family that is located in the smooth endoplasmic reticulum of the liver.
The system operated by particular enzymes that metabolise the drug molecules.

Induction of cytochrome P450 isoenzymes by one drug can increase the rate of metabolism of another, lower plasma concentrations and a reduced effect so on withdrawal of the inducing drug, plasma conc. could increase leading to toxicity

Question 27

Enteral (oral) administration

Answer 27

Systemic (whole body effects)
Delivery by GI tract
Can be modified for extended release
+:Inexpensive, convenient, non-invasive.
-:Not appropriate for unconscious patients, requires time for absorption/distribution.

Question 28

Affinity

Answer 28

How well the drug binds to the receptor
Electrostatic forces initially attract a drug to a receptor, if the shape of the drug corresponds to the receptors binding site, it will be held there by weak bonds. The number of bonds determines the affinity of the drug to that receptor.

Greater number of bonds = better fit = higher affinity

Question 29

Efficacy

Answer 29

The strength of an agonist at stimulating a response.

Potent means only a small amount needed to stimulate an effect.

Question 30

Specificity

Answer 30

Is how selective a ligand is. A ligand that exhibits a high degree of specificity will only bind to certain receptors, this is somewhat dependant on the dose used.

Specificity can be specific to a receptor or group/type of receptors.

Question 31

Antagonists (inhibitors)

Answer 31

Molecules that reduce the actions of agonists, the agonists being endogenous or drug molecules. These form ligand/receptor complexes but do NOT evoke/stimulate any cellular responses. They are commonly referred to as blockers/inhibitors, many clinically useful drugs are antagonists, they produce a passive response.

Competitive (surmountable), non-competitive, irreversible, reversible, pharmacokinetic, chemical, physiological.

Question 32

Schild Plots and pA2

Answer 32

This was developed to identify reversible, competitive antagonism and to obtain an estimate of the affinity for antagonists for their receptors.

pA2 value (no units) for an antagonist is -log[antagonist] required to produce a two fold shift in the agonist dose-response curve. pA2 is an index of antagonist potency, larger the pA2, the more potent the antagonist.

After the organ bath bioassay experiment, it is possible to produce a schild plot with response (y) and log antagonists (x)

Question 33

Receptors (4 main types)

Answer 33

Receptors are molecule structures within a cell or on its surface membrane, which are characterised by selective binding of specific substances (agonists). They enable extracellular signals to be relayed to the inside.

Ligand Gated ion channels
G protein coupled receptors
Kinase receptors
Nuclear/intracellular receptors

Question 34

Ligand gated ion channels

Answer 34

AKA ionotropic receptors, these receptors are directly coupled to ion channels. eg. nicotinic, glutamate, GABAc, GABAa. These are all fast acting and involved in neurotransmission.

With all ionotropic receptors, ligand binding and channel opening occurs within a millisecond.

Question 35

Nicotinic receptor

Answer 35

Example of a ligand gated ion channel receptor.

The agonist (substrate) for a nicotinic receptor is acetylcholine (ACh), ACh can also bind to muscarinic receptors.

Nicotinic receptors are found on the plasma membranes of cells and are on of the most numerous in the body. They occur in the neuromuscular junction (NMJ), in the autonomic ganglia and in the central nervous system (CNS).

The receptors are made up of subunits: alpha, beta, gamma etc and each alpha subunit can bind to one molecule of ACh. There are many variants of the alpha beta and gamma subunits, these can be distinguished pharmacologically.

Question 36

Acetylcholine

Answer 36

When ACh binds to a nicotinic receptor the ion channel opens very quickly, which increases the plasma membrane’s Na+ and K+ permeability, so depolarising the cell and increasing the probability that an action potential will be generated.

The intracellular side of a plasma membrane is more negatively charged compared to the extracellular surface, so an inwards rush of positive Na+ ions will reduce this negative membrane potential, depolarizing the cell.

Question 37

Neuromuscular junction

Answer 37

The function of the NMJ is to transmit action potentials, conducted along motor (somatic) nerves, across the synaptic clefts that occur in motor endplates.

Question 38

ACh synthesis

Answer 38

ACh synthesis occurs in the motor neuron terminal and is catalysed by the cytosolic enzyme choline acetyltransferase (C.A.T). Acetyl groups are donated by acetyl coenzyme A, which is then covalently bonded to choline to form ACh. The ACh is then stored in vesicles, ready for release.

Question 39

Myasthenia gravis

Answer 39

A chronic disease characterized by an abnormal fatigability and weakness of skeletal muscles, which chiefly affects adolescents and young adults (under 40).

Other symptoms include ptosis (drooping of the upper eyelids), double vision and dysarthria (a speed disorder). It is an autoimmune disease affecting the neuromuscular junction transmission. IgG antibodies cause the loss of nicotinic receptors in the NMJ. The fatigue experienced might become so extreme that muscles become temporarily paralysed.

Treatment includes: administering anticholinesterases, using prednisone or azathioprine, performing plasmaphoresis and surgically removing the thymus

Question 40

ACh method of action

Answer 40

When action potentials conducted along the motor nerves reach their nerve terminals, depolarisation causes an influx of Ca 2+ ions, which triggers ACh release into the synaptic cleft, as vesicles now fuse with the terminal membrane.

Released ACh can now diffuse across synaptic cleft and bind to nicotinic receptors on the sarcolemma, causing a depolarization, which if large enough can stimulate an action potential in the muscle fibre, causing it to contact. ACh in the synaptic cleft also interacts with the enzymes acetylcholinesterase, which hydrolyses it to choline and acetic acid. The process occurs the whole time ACh is present in the the synaptic cleft. So, when no more ACh is being release from the neurone terminal, acetylcholinesterase reduces the synaptic concentration of ACh, terminating the response evoked.

Question 41

G-Protein coupled receptors

Answer 41

GPCR AKA metabotropic, 7-transmembrane spanning receptors, eg. muscarinic, adrenergic, dopaminergic, 5-hydroxytryptamine (5-HT), purine (adenosine, ATP) and opiate receptors.

Unlike ionotropic receptors, GPCRs are indirectly connected to the processes that they govern. So, these receptors use G-proteins to form the link between the receptor itself and the target process that is under control.

Question 42

GPCR structure

Answer 42

7 transmembrane spanning regions connected by extracellular and intracellular loops, this is a 3D structure that arrange their extracellular loops and some of the transmembrane regions into pockets that can accept ligands.

The one thing that these domains have in common is the fact that they contain disulphide bonds, which maintain the 3D structure.

G-proteins are made up of alpha, beta and gamma subunits. The beta/gamma form complexes together (very hydrophobic) and are able to freely move about.

The alpha subunit has 3 properties: can bind to guanine nucleotides, forms loose association with the beta/gamma complex, and it has the ability to catalyse the hydrolysis of GTP to GDP.

Question 43

GPCRs method of action

Answer 43

1. When an agonist binds to the receptor, a conformational change occurs that enables alpha subunit binding (leaves the weak bond it had with the bets/gamma complex).
2. Once bound, the alpha subunit releases its GDP and binds instead to GTP.
3. This now activated alpha-subunit now completely dissociates from the receptor and its beta/gamma complex, allowing it to diffuse across the membrane surface to stimulate its target.
4. By associating with the target the alpha-subunits GTPase activity is increased, so the bound GTP is hydrolysed to GDP and inorganic phosphate group, terminating the alpha-subunits activation.
5. The alpha-subunits can now re-associate with the beta/gamma complex and the whole process is now ready to be repeated.

Question 44

GPCR categories

Answer 44

3 categories: Gs, Gi, Gq.

Gs/Gi proteins produce either stimulation or inhibition of their targets respectively.

Activated Gq proteins activate phospholipase C

GPCRs are not as rapidly acting as ionotropic receptors (seconds NOT milliseconds), their advantage is that they can amplify a signal. Basically this means that one agonist/receptor can activate several alpha subunits and these can go on to stimulate several targets, thus producing amplification.

Stimulation of GPCRs can produce either stimulatory or inhibitory effects and this is determined by what sort of receptor is controlling what type of target, over 20 different alpha subunits have been identified.

Question 45

G-Protein targets

Answer 45

3 main targets:

Ion channels
Adenylate cyclase/cyclic AMP (cAMP) system
Phospholipase C/inositol phosphate system

Question 46

Muscarinic receptors

Answer 46

GPCR that is commonly encountered in the cardiovascular system.

Named after the drug muscarine, found on cells and tissues innervated by the parasympathetic NS. Like nicotinic receptors, ACh also binds to muscarinic receptors. The word cholinergic receptors can be divided into nicotinic and muscarinic subtype. The can be distinguished by the binding of different drugs.

The parasympathetic NS can be thought of as the body’s “resting and digesting” system so when muscarinic receptors of the heart are stimulated (either by the vagus nerve releasing ACh or by drugs), this reduces heart rate and force of contraction

Question 47

Muscarinic receptors method of action

Answer 47

Found on cardiac muscle cells are known to increase membrane permeability to K+ ion channel is closed. Once ACh binds to the receptors and the G-protein becomes activated, the G-protein can open the K+ ion channel, thus hyperpolarizing the cell.

The method of action behind the coupling of GPCRs and ion channels is unresolved

However it is known that opiate analgesics open K+ channels to reduce neurone excitability

Question 48

Adrenergic receptors

Answer 48

GPCR that is commonly encountered in the cardiovascular system.

Named from the fact that the neurotransmitter noradrenaline (norepinephrine) and the hormone adrenaline (epinephrine) can bind to them.

This class can be divided into alpha and beta subtypes which can then be further divided into a1,a2,b1,b2 subtypes. These receptor subtypes can be distinguished by the different level of responses obtained by different drugs selectively binding to them

Question 49

Adrenergic receptors method of action

Answer 49

In the body, adrenergic receptors are involved with the sympathetic NS, “fight or flight” response. So when the adrenergic receptors on the heart are stimulated, rate and force of contraction increase.

Unlike cardiac muscarinic receptors, which are fairly coupled to their ion channel, adrenoceptors use a system of second messengers. Second messengers are agents whose intracellular concentrations vary, depending on the levels of receptor stimulation, these agents can diffuse away from the cell membrane to alter the rate at which cellular processes occur. Common second messengers are Ca 2+ ions, cAMP, inositol-1,4,5-triphosphate (InsP3) and diacylglycerol (DG)

Question 50

Adrenergic receptors subtypes + functions

Answer 50

a1 receptors are generally stimulatory and in blood vessels will cause vasoconstriction.

a2 receptors are generally found on presynaptic nerve terminals and negatively feedback on neurotransmitter release.

b1 receptors are mostly concentrated in cardiac tissue and stimulate the heart to beat faster and with more force.

b2 receptors generally induce tissues to relax

Eg. when beta adrenoceptors are stimulated, cAMP is formed from ATP by the enzyme adenylate cyclase. cAMP then activates the enzyme protein kinase A, which then phosphorylates proteins to produce a physiological effect.

Question 51

Kinase linked receptors

Answer 51

These receptors are often linked to tyrosine kinase. The most well known receptor that binds to a kinase receptor is insulin. Kinase-linked receptors are found bound to membranes.

Question 52

Structure of kinase linked receptor

Answer 52

Contains extracellular and intracellular domains, with each domain between 400-700 amino acid residues. These two domains are connected together by a single alpha helix that spans the thickness of the membrane. Not all kinase receptors are constructed in the same way.

Extracellular domains from the receptors ligand binding sites, whilst the intracellular portions from the tyrosine kinase domains.

Since the extracellular domains contain a ligand binding sites, the amino acid residue sequences of these regions are very variable between different receptor subgroups, thus producing ligand sensitivity. Kinase enzymes are responsible for catalysing the phosphorylation of various cellular components, this process requires a source of phosphate groups, which the bound ATP can provide.

Question 53

Ligand binding (kinase receptor)

Answer 53

Due to the receptors structure, ligand binding to the extracellular domain does not result in a conformation change in the intracellular domain, since only a very simple alpha helix connects the two together.

Instead ligand binding results in a “dimerization” of receptors (two receptors pair up to form a dimer), when this happens autophosphorylation occurs, which basically means that the tyrosine residues of the intracellular domains become automatically phosphorylated. The phosphorylated tyrosine now become high affinity binding sites for various intracellular proteins.

The various intracellular proteins that interact with kinase receptors have one feature in common, they contain the highly conserved SH2 domains

Question 54

Cytokines

Answer 54

Small proteins or biological factors that are released by cells and have specific effects on cell-to-cell interactions. They are important for coordinating cellular communication and behaviour. Cytokines are very similar to hormones, but the term is convenient to use for agents as interleukins and several related signalling factors.

Many cytokines act on receptors, although they lack the intracellular tyrosine kinase domain.

Question 55

Cyclic guanosine monophosphate system

Answer 55

cGMP like cAMP is a second messenger. It is the most famous activator of guanylate cyclase, the enzyme that catalyses the synthesis of cGMP, is nitric oxide. The membrane bound form of this enzyme, however, has a structure similar to the tyrosine kinase family.

Question 56

Insulin receptor

Answer 56

Insulin is a polypeptide hormone that is produced by the beta cells of the islets of Langerhans in the pancreas. Insulin is important in regulating blood glucose concentration, with high blood sugar levels stimulating its secretion. The insulin receptor has 4 glycoprotein molecules (2 alpha/2 beta).

Less than 10% of insulin receptors have to be occupied to evoke a maximum response. The cellular events triggered by activating insulin are varied and can evoke short and long term actions.

Question 57

Insulin method of action

Answer 57

The short term actions are considered to be immediate metabolic effects, which are governed by regulating kinase and phospholipase enzymes, via the tyrosine kinase activity of the receptor. Insulin triggers the recruitment of glucose transporters which increases glucose uptake by cells, as well as increasing glycogen synthesis, reducing both gluconeogenesis and glycogen breakdown.

Insulin’s long term actions involve regulating the synthesis of specific messenger RNA molecules, thus controlling the synthesis of important molecules such as enzymes, which in turn regulates cellular processes such as cell replication/proliferation.

Question 58

Nuclear receptors

Answer 58

These receptors are not expressed on the cell membrane and are completely intracellular and are involved in regulating DNA transcription. Steroid hormones, thyroid hormone agents such as vitamin D and retinoic acid can bind to them.

Nuclear receptors are large monomeric (one single component) proteins. It contains two finger shaped loops of peptide chain, each being 15 residues long, which forms what are termed ‘zinc fingers’. This is because each finger contains a zinc ion, which is held in place by four cystine residues, this zinc finger domain forms the receptors DNA binding region, since the fingers are believed to be able to wrap around DNA helixes.

Question 59

Neurotransmitters/Hormones

Answer 59

Since both neurotransmitters and hormones can act on receptors the reason they are split into different categories is the difference in distribution.

Neurotransmitters are released from neurone terminals and transit action potential signals across synapses. Such synapses are minute and occur between neurone terminals and a wide variety of postsynaptic cells such as other neurons, muscle fibres and glands.

Hormones, however are substances that are produced by endocrine glands, which are then passed into the blood, where they are distributed around the body to modify the structure or function of specific organs or tissues.

Question 60

Ligand binding (nuclear receptor)

Answer 60

Since the receptors are intracellular the ligands must be lipid soluble in order to pass through the plasma membrane. Steroid molecules are highly lipid soluble and easily gain access to the intracellular compartment, where they can then bind to their receptors located in the nucleus.

When steroid binds to its receptor, it induces a conformational change in which the receptor unfolds to expose the zinc finger domain.

Ligand/receptor complexes can now bind to specific portions of DNA. These binding positions are well defined regions of the DNA that contain “hormone responsive elements” or “transcription factor activator proteins”. Within minutes there is an increased RNA polymerase activity, resulting in the production of mRNA. This mRNA leaves the to be translated.

Therefore actual physiological responses maybe delayed by several hours or even days, since the whole process is relying on protein synthesis.

Question 61

Inhibitors of acetylcholine synthesis

Answer 61

These drugs work by inhibiting choline transport. Hemicholinium and teriethylcholine are the two main drugs in this category, they are useful experimental tools but have no real clinical application.

Hemicholinium is a competitive inhibitor of choline uptake of choline uptake in the neurone terminal.

Triethylcholine also inhibits uptake, but is also transported into the neurone, where it is acetylated to form acetyltriethylcholine, this is then stored in vesicles in the place of ACh and is released as a false transmitter which means it has no depolarizing effect on the post synaptic membrane.

Another drug Vesamicol can inhibit ACh being packed into vesicles. This results in a neuromuscular blockade, which develops slowly.

Botulinum toxin is a very potent neurotoxin, with only a few molecules binding to each cholinergic nerve terminal being lethal.

Question 62

Anticholinesterases

Answer 62

This is a drug that inhibits the enzyme that is normally responsible for hydrolysing ACh to choline and acetate. These therefore prolong the presence of ACh in cholinergic synaptic clefts, so increasing ACh’s effect.

These drugs can be split into 3 categories: short acting (edrophonium), medium duration (physostigmine) and irreversible (dyflos)

These drugs can effect 3 main areas of the body: autonomic cholinergic synapses, NMJ, CNS.

Question 63

Monoamine oxidase (MAO) inhibition

Answer 63

MAO enzymes are found in most tissues. These enzymes catalyse the conversion of catecholamines to aldehydes so they are important for the degradation of neurotransmitters. They work by stopping the enzymes from catalysing the oxidation of neurotransmitters in the cytoplasm.

An example of MAO inhibitors include phenelzine, these drugs can be clinically used to treat depression.

One disadvantage of these inhibitors is that they enhance the effects of indirectly acting sympathomimetics (tyramine). Tyramine is a naturally occurring substance that is found in a wide variety of foods. Normally tyramine is metabolised by MAOs, so that very little enters the blood but under MAO inhibition dietary tyramine can be absorbed in the gut and distributed around the body. It will be taken up in neurone terminals, where it displaces Nora adrenaline from its vesicles. If enough escapes into synapses it can cause a hypertensive crisis and an intracranial haemorrhage.

Question 64

Fibrous/Globular proteins

Answer 64

Fibrous proteins have polypeptides arranged in long sheets, these proteins are insoluble due to hydrophobic amino acid residues. Eg keratin, silk fibroin, collagen (triple helix formed by extended protein chains that wrap around one another.

Globular proteins have different polypeptide chain segments fold back on each other to form a spherical shape. Eg. enzymes, transport protein’s, moto proteins, immunoglobulins, insulin and albumin. These are water soluble.

Question 65

Amino acids

Answer 65

Due to the structure of the amino acids, a polypeptide chain has directionality: it has two ends that are chemically distinct from one another.
At one end the polypeptide has a free amino group, at this end call the amino terminus (N-terminus)
The other end, which has a free carboxyl group, is known as the carboxyl terminus (C-terminus).

Zwitterions are both positive and negative. COOH = COO-
NH2 = NH3+

Nonessential (dispensable) can be made in the body
Essential (indispensable) must be obtained from food
Conditionally essential are needed from food IF they cannot be built due to lack of molecules.

Question 66

Acidic drugs

Answer 66

Aspirin

Paracetamol

Question 67

Basic drugs

Answer 67

Diazepam

Diphenhydramine

Question 68

Amphoteric drugs

Answer 68

Morphine

Adrenaline

Question 69

Supersaturated solution

Answer 69

Is obtained when the solute exists in solution above the solubility limit , this is by altering the temperature, volume or pressure.

Eg. Carbonated water (soft drinks) is a supersaturated solution of carbon dioxide in water, the gas is slowly released from the solution when the bottle is opened and the contents return to normal atmospheric pressure.

Question 70

Colligative properteries

Answer 70

These properties are dependant upon the ratio of solute molecules present in a solution, compared to the number of solvent molecules so its dependant on the amount of solute present and not upon the nature of the solute itself. Therefor molarity is used to represent concentration.

Molarity is the number of moles of a solute dissolved in one kilogram of solvent

Molarity = Amount of solute (moles) / mass of solvent (kg)

Question 71

Tonicity

Answer 71

The osmotic pressure gradient of two solution separated by a semipermeable membrane can be measured and is known as tonicity.

Question 72

Hypo/Hyper tonic

Answer 72

Hypotonic = water is less concentrated inside outside = water entering cell so possible cell burst or swelling.

Hypertonic = water is more concentrated inside so the cell will lose water and will shrivel.

Question 73

Miscibility & Partitioning

Answer 73

Due to hydrophilic/hydrophobic nature of liquids, not all liquids are miscible with one another and are not capable of forming a homogenous (single phase). When two liquids are immiscible they form two distinct layers with the most dense of the liquids at the bottom.

You can use the immiscible mixture to access the hydrophilic/hydrophobic nature of a third substance and this is called partitioning

Question 74

P (partition coefficient)

Answer 74

The partitioning of a substance between two phases can be quantified by the partition coefficient. This is a ratio of concentrations of a substance between two immiscible phases.

P = Non polar phase / polar phase.

AKA k or K (small ow)

Only valid for solutes that are not ionised (charged)

pH will dictate whether a compound will be ionised or not, hence its affinity for an aqueous or oily phase.

Question 75

Weakly acidic/basic drugs

Answer 75

Weakly acidic drugs:
Majority is unionised in gastric fluid (pH 1-2)
Majority is ionised in intestinal fluid (pH 7-8) therefore is most likely to be absorbed in the stomach.

Weakly basic drugs:
Majority is protonated in gastric fluid (pH1-2)
Majority is de-protonated in intestinal fluid (pH 7-8) therefore is most likely to be absorbed in the small intestine.

Question 76

Apparent partition coefficient (D or Papp)

Answer 76

D = P x f (unionised)

where f is the fraction of the total amount of drug unionised at that pH.

Log D optimum is between 0 and 3

Question 77

Log P

Answer 77

Is a measure of hydrophilic and hydrophobic nature and provides insights into drug bioavailability when it enters the body.

Log P must be less than 5 (optimum is 1.3-1.8)

To change back to P do 10 to the power of the log P value.

Estimation program interface (EPI) was developed by the US to be able to predict log P.

Question 78

Lipinski’s rule of 5

Answer 78

Molecular weight < 500
Log P < 5
Number of H-bond donors < 5
Number of H-bond acceptors < 10

Question 79

Aqueous solubility increases with…

Answer 79

Decreasing MP
Increasing temperature
Decreasing molecular weight
Increasing polarity
Increasing H-bonding

Question 80

Hydrophobicity increases with…

Answer 80

Increasing MP
Decreasing temperature
Increasing molecular weight
Decreasing polarity
Decreasing H-bonding

Question 81

Why is octanol used in log P determinations?

Answer 81

Octanol is routinely used as the non polar solvent in log P determinations. This is due to the structure, octanol resembles the approximate amphiphilic form of a phospholipid. Due to this octanol is used to represent the phospolipid bilayer of a cell membrane, and as such log P can indicate weather or not a substance may pass through a cell membrane and enter a cell.