Flügge

Question 1

Pharmacokinetics

Answer 1

Fate of the drug in the organism

Question 2

Pharmacodynamics

Answer 2

Physiological and biochemical interactions of drug and target tissue

Question 3

Biological effects of free drugs and metabolites

Answer 3

Regulation of enzymes

Regulation of channels

Binding to receptors

Binding to transporters

Question 4

Molecules passing walls of capillaries

Answer 4

Typical: small molecules by diffusion; small fenestrae for high volume passage

Brain: no intercellular clefts => hydrophilic molecules cannot pass; D-glucose and amino acids actively transported

Question 5

Liposomes

Answer 5

Artificially prepared vesicles formed by a lipid bilayer

For application of nutrients or pharmaceutical drugs

Question 6

Nanoparticles

Answer 6

Diameter 1 to 10,000 nm

May pass the ‘leaky’ blood vessels in a tumor for drug delivery

Question 7

Choroid plexus

Answer 7

Produces cerebrospinal fluid

Epithelial cells forming a boundary that can be passed by some drugs

Question 8

CSF

Answer 8

Cerebrospinal fluid

Produced by the choroid plexus

Fills subarachnoid space

Provides micronutrients, neurotrophins, hormones, etc

Question 9

Drug metabolism: phase I

Answer 9

Cytochrome P 450 metabolises drugs making them less lipophilic

Question 10

Drug metabolism: phase II

Answer 10

Conjugation with glucuronic acid making the drugs more hydrophilic

Question 11

Factors influencing drug metabolism

Answer 11

Enzyme induction (used repeatedly?)

Enzyme inhibition (several drugs?)

Drug competition

Genetic polymorphisms

Question 12

ED₅₀

Answer 12

Effective dose

Concentration which leads to the desired effect in 50 % of the subjects

Question 13

TD₅₀

Answer 13

Toxic dose

Concentration which induces toxic effects in 50 % of the subjects

Question 14

Binding of drug and ligand

Answer 14

Ionic/electrostatic interactions form bonds

Usually reversible

Question 15

B_max

Answer 15

Maximal number of binding sites

Question 16

K_D

Answer 16

Concentration of the ligand at which bound and unbound ligand molecules are in equilibrium

Low K_D => high receptor/ligand affinity

Question 17

IC₅₀

Answer 17

Concentration of a competitor that reduces the binding of a drug to 50 %

Low IC₅₀ => effective competitor

Question 18

Competitive antagonist

Answer 18

Binds to the same site on the receptor as the agonist

Antagonist displaces agonist

Question 19

Noncompetitive antagonist

Answer 19

Binds to another binding site than the agonist

Increasing the dose of the antagonist does not displace the agonist

Question 20

Major types of drug receptors

Answer 20

Ionotropic receptors: gate ion channels directly; e.g. NMDA, AMPA, GABA_A

Metabotropic receptors (G-protein coupled receptors, GPCRs): receptor and effector molecule separate; intracellular signalling cascade; e.g. adrenergic, dopaminergic, GABA_B, cannabinoid

Question 21

Catecholamines

Answer 21

Modulatory neurotransmitterers

E.g. dopamine, noradrenaline, adrenaline

Synthesised from tyrosine by tyrosine-hydroxylase

Question 22

Tyrosine hydroxylase

Answer 22

Tyrosine => L-DOPA

Rate limiting enzyme of catecholamine synthesis

Activated by: catecholamines (bind to it), high cAMP, phosphorylation

Inhibited by: high neurotransmitter release, AMPT

Question 23

Alpha-adrenoceptors

Answer 23

Bind NA and A equally well, better than agonist isopreterenol

Antagonist: phentolamine

Question 24

Beta-adrenoceptors

Answer 24

Bind isopreterenol better than NA and A

Antagonist: Propranolol

Stimulates adenylyl cyclase => more cAMP => stimulates PKA => stimulates CREB

Stimulates heart rate and LTP

Question 25

NA is produced by

Answer 25

Locus coeruleus

Question 26

DBH

Answer 26

Dopamine-beta-hydroxylase Dopamine =\> NA Needs ascorbate as cofactor

Question 27

VMAT

Answer 27

Vesicular monoamine transporter Transports dopamine from the cytosol into the vesicle Inhibitor: reserpine, induces vesicle depletion

Question 28

NET

Answer 28

Noradrenaline transporters Transports NA back into the neuron (in striatum: also DA) NET inhibitors: antidepressants

Question 29

MAO-A

Answer 29

Monoamine oxidase A Metabolises NA, A, serotonine In outer membrane of mitochondria Pargyline: inhibitor

Question 30

COMT

Answer 30

Catechol-O-methyl-transferase Metabolises NA and DA

Question 31

Alpha_2A-adrenoceptor

Answer 31

Presynaptic autoreceptor Reduces cAMP formation =\> blocks Ca²⁺ channels =\> opens K⁺ channels =\> hyperpolarises the neuron =\> inhibits NA release Lowering of blood pressure, analgesia, sedation

Question 32

Clonidine

Answer 32

Inhibits NA release Hypotensive, analgetive Can attenuate symptoms of opiate withdrawal