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Summary pharmacology and pharmacokinetics
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Pharmacology and pharmacokineticsInhoud
Part 1: An introduction to pharmacology and concepts of pharmacokinetics..........................................2
Absorption: transport of drugs across biological membranes............................................................2
Distribution........................................................................................................................................6
Elimination.........................................................................................................................................7
Pharmacokinetics.............................................................................................................................13
Pharmacodynamics..........................................................................................................................18
Routes of drug administration..........................................................................................................21
Part 2: Transmission systems in the peripheral and autonomous nervous system.................................22
Cholinergic transmission..................................................................................................................22
Adrenergic transmission...................................................................................................................27
Dopaminergic transmission..............................................................................................................36
Serotonergic and purinergic transmission........................................................................................36
Part 3: Drugs acting on the CNS...........................................................................................................38
Pharmacotherapy of depression.......................................................................................................38
Pharmacotherapy of psychosis and mania (antipsychotics and lithium)..........................................41
Pharmacotherapy of epilepsy...........................................................................................................43
Pharmacotherapy of Parkinson’s disease and Parkinsonism............................................................47
Pharmacotherapy of other movement disorders...................................................................................48
Skeletal muscle relaxants..................................................................................................................49
Pharmacotherapy of Alzheimer’s disease.........................................................................................49
Pharmacotherapy of pain.................................................................................................................50
Hypnotics/anxiolytics........................................................................................................................56
Part 4: Drugs related to the cardiovascular system...............................................................................59
Diuretics...........................................................................................................................................59
Pharmacotherapy of arterial hypertension.......................................................................................61
Pharmacotherapy of heart failure.....................................................................................................64
Pharmacotherapy of ischemic heart disease.....................................................................................65
Pharmacotherapy of hyperlipidemia................................................................................................67
Drugs related to coagulation...........................................................................................................68
Part 5: Pharmacotherapy of…...............................................................................................................71
Non-steroidal anti-inflammatory drugs (NSAIDs)............................................................................71
Glucocorticoids................................................................................................................................74
Second line antirheumatic drugs.......................................................................................................76
Allergy..............................................................................................................................................79
, Anaphylactic reactions.....................................................................................................................80
Asthma..............................................................................................................................................81
Diabetes mellitus..............................................................................................................................83
Cancer..............................................................................................................................................84
Gastrointestinal tract........................................................................................................................89
Part 1: An introduction to pharmacology and concepts of
pharmacokinetics
Absorption: transport of drugs across biological membranes
Oral, or other extravascular intake follows the same principles as the drug is transported across
barriers to reach the vascular compartments and cause systemic effects.
Oral drugs are usually taken when fasting, with water and usually don’t chew because
1. Active ingredient (API) is toxic for the mucosa
2. Prevent early exposure to the unstable molecules (too fast metabolised)
Once arrived in the stomach which has a H2O and low pH (acidic), it goes into the pharmaceutical
phase. This includes disintegration of the tablet (or capsule, etc.) and dissolution of the compound into
the watery environment of the stomach, so that it becomes available for
uptake.
After this, there is a longitudinal gastrointestinal transport where it gets
absorbed in the proximal small intestines. This absorption happens via
different modes of transport.
Transcellular transport
o Through the cell membrane
Passive diffusion
Transport mediated (active transport)
Paracellular transport
o Filtration through the pores between cells
, o Limited because they are waterproof and tight junctions
o E.g lithium
The enterocytes cells have a brush border which increases the absorption area.
Passive diffusion
Passive diffusion happens when the outside concentration (Co) is higher than the inside
concentration (Ci), which creates a concentration gradient.
The flux/velocity is determined by the concentration gradient and membrane (lipid layer)
P=partition coefficient
N-octanol (lipid) and water in tube put in the drug shake it and
measure the concentration of the drug in N-octanol and H2O.
P=[D]l/[D]H2O
o P= drug in fat / drug in water
o P=1 then drug happy in both environments
o Small P value is low diffusion (too hydrophilic)
o Need hydrophilic to go into dissolution but need lipophilic
for diffusion need good balance
Preclinical they try to predict the absorption by artificial membranes
Fick’s law of diffusion: V = D . P . (A/d) . (Co-Ci)
Fick’s law describes a linear correlation between the rate of diffusion and the concentration gradient.
V= rate of diffusion
D=diffusion constant
A= surface area
d= membrane thickness
P=partition coefficient
It can also be written as: V=K . (Co-Ci)
K= DP(A/d)
Diffusion increases (and thus absorption) when:
Higher D
o Small molecule (larger D) have a
higher absorption rate
Larger A
A larger P (lipophilic)
o But a too large P, drug can
accumulate in the cell membrane
no absorption
o Slope of the line is influenced by
P more hydrophilic, more horizontal (less absorption)
, o Ideal P value is 2-3
Higher concentration gradient (Co-Ci)
Active transport
Active transport can happen via different ways
Carrier mediated: polarized transport against concentration
gradient, which requires energy
o Important for hydrophilic transport
o The carrier protein is substrate-specific, can become
saturated and go into competition
Pinocytosis: via vacuoles or vesicles high molecular
compounds can be absorbed
Transcytosis: absorption via endocytosis
Facilitated diffusion: diffusion dependent on carrier protein
Carrier-mediated absorption is measured via Michaelis-Menten
law: V=(Vmax . C)/(Km+ C)
V= diffusion rate
Vmax= maximal transport
C= concentration of drugs
Km= Michaelis constant substrate concentration at which V is at 50%
It is a linear relationship, which can reach a plateau (Vmax). Since increased dose does not increase
efficiency once the plateau has been reached, increased frequency is the solution. It is important to do
this in a fasting state to prevent competition with amino acids.
Biopharmaceutical classification system (BCS)
I. NSAIDs are usually recommended with food to avoid local gastrointestinal problems, but will
delay onset of uptake
II. High P value Cyclosporin with food then it will go into solution and then get absorbed
III. Low P value Bifosfonates take in the morning (after overnight fasting) and be taken with
water and then wait 2 hours to start eating
IV. Usually very large molecules to treat intestinal local problems
Not only solubility and permeability influence the dissolution and absorption but also the pH and
ionization state (pKa). Ionization form determines their lipophilic (non-ionized) or hydrophilic state
(ionized). pH influences the degree of ionization. The pH partition theory states that a compound
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