Pharmacology and pharmacokinetics
Inhoud
Part 1: An introduction to pharmacology and concepts of pharmacokinetics ................................. 2
Absorption: transport of drugs across biological membranes ............................................................ 2
Distribution ......................................................................................................................................... 6
Elimination .......................................................................................................................................... 7
Pharmacokinetics .............................................................................................................................. 12
Pharmacodynamics ........................................................................................................................... 16
Routes of drug administration ........................................................................................................... 19
Part 2: Transmission systems in the peripheral and autonomous nervous system........................ 21
Cholinergic transmission................................................................................................................... 21
Adrenergic transmission .................................................................................................................... 26
Dopaminergic transmission............................................................................................................... 33
Serotonergic and purinergic transmission......................................................................................... 34
Part 3: Drugs acting on the CNS ........................................................................................................ 35
Pharmacotherapy of depression ........................................................................................................ 35
Pharmacotherapy of psychosis and mania (antipsychotics and lithium) .......................................... 38
Pharmacotherapy of epilepsy ............................................................................................................ 41
Pharmacotherapy of Parkinson’s disease and Parkinsonism............................................................ 44
Pharmacotherapy of Alzheimer’s disease .......................................................................................... 46
Pharmacotherapy of pain .................................................................................................................. 47
Hypnotics/anxiolytics ........................................................................................................................ 52
Part 4: Drugs related to the cardiovascular system ......................................................................... 55
Diuretics ............................................................................................................................................ 55
Pharmacotherapy of arterial hypertension ....................................................................................... 57
Pharmacotherapy of heart failure ..................................................................................................... 59
Pharmacotherapy of ischemic heart disease ..................................................................................... 61
Pharmacotherapy of hyperlipidemia ................................................................................................. 63
Drugs related to coagulation............................................................................................................. 64
Part 5: Pharmacotherapy of… ........................................................................................................... 66
Non-steroidal anti-inflammatory drugs (NSAIDs) ............................................................................ 66
Glucocorticoids ................................................................................................................................. 69
Second line antirheumatic drugs ....................................................................................................... 71
Allergy ............................................................................................................................................... 74
Anaphylactic reactions ...................................................................................................................... 76
Asthma ............................................................................................................................................... 76
1
, Diabetes mellitus ............................................................................................................................... 77
Cancer ............................................................................................................................................... 79
Gastrointestinal tract......................................................................................................................... 83
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 transported across
barriers to reach the vascular compartments and cause systemic effects.
Oral drugs are usually taken when fasting, with water and usually not chewed because
1. Active ingredient (API) is toxic for the mucosa
2. Prevent early exposure to the unstable molecules (too fast metabolised)
In the stomach which has 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 have tight junctions
o E.g. lithium
The enterocytes cells have a brush border which increases the absorption area.
2
,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
• 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)
3
, Active transport
Active transport can happen in 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 an 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). Ionisation form determines their lipophilic (non-ionized) or hydrophilic state
(ionized). pH influences the degree of ionisation. The pH partition theory states that a compound
accumulates on the side of the membrane with the highest degree of ionisation. This means that a
weak acid will be easily absorbed in a low pH and a weak base will be poorly absorbed.
4
Inhoud
Part 1: An introduction to pharmacology and concepts of pharmacokinetics ................................. 2
Absorption: transport of drugs across biological membranes ............................................................ 2
Distribution ......................................................................................................................................... 6
Elimination .......................................................................................................................................... 7
Pharmacokinetics .............................................................................................................................. 12
Pharmacodynamics ........................................................................................................................... 16
Routes of drug administration ........................................................................................................... 19
Part 2: Transmission systems in the peripheral and autonomous nervous system........................ 21
Cholinergic transmission................................................................................................................... 21
Adrenergic transmission .................................................................................................................... 26
Dopaminergic transmission............................................................................................................... 33
Serotonergic and purinergic transmission......................................................................................... 34
Part 3: Drugs acting on the CNS ........................................................................................................ 35
Pharmacotherapy of depression ........................................................................................................ 35
Pharmacotherapy of psychosis and mania (antipsychotics and lithium) .......................................... 38
Pharmacotherapy of epilepsy ............................................................................................................ 41
Pharmacotherapy of Parkinson’s disease and Parkinsonism............................................................ 44
Pharmacotherapy of Alzheimer’s disease .......................................................................................... 46
Pharmacotherapy of pain .................................................................................................................. 47
Hypnotics/anxiolytics ........................................................................................................................ 52
Part 4: Drugs related to the cardiovascular system ......................................................................... 55
Diuretics ............................................................................................................................................ 55
Pharmacotherapy of arterial hypertension ....................................................................................... 57
Pharmacotherapy of heart failure ..................................................................................................... 59
Pharmacotherapy of ischemic heart disease ..................................................................................... 61
Pharmacotherapy of hyperlipidemia ................................................................................................. 63
Drugs related to coagulation............................................................................................................. 64
Part 5: Pharmacotherapy of… ........................................................................................................... 66
Non-steroidal anti-inflammatory drugs (NSAIDs) ............................................................................ 66
Glucocorticoids ................................................................................................................................. 69
Second line antirheumatic drugs ....................................................................................................... 71
Allergy ............................................................................................................................................... 74
Anaphylactic reactions ...................................................................................................................... 76
Asthma ............................................................................................................................................... 76
1
, Diabetes mellitus ............................................................................................................................... 77
Cancer ............................................................................................................................................... 79
Gastrointestinal tract......................................................................................................................... 83
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 transported across
barriers to reach the vascular compartments and cause systemic effects.
Oral drugs are usually taken when fasting, with water and usually not chewed because
1. Active ingredient (API) is toxic for the mucosa
2. Prevent early exposure to the unstable molecules (too fast metabolised)
In the stomach which has 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 have tight junctions
o E.g. lithium
The enterocytes cells have a brush border which increases the absorption area.
2
,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
• 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)
3
, Active transport
Active transport can happen in 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 an 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). Ionisation form determines their lipophilic (non-ionized) or hydrophilic state
(ionized). pH influences the degree of ionisation. The pH partition theory states that a compound
accumulates on the side of the membrane with the highest degree of ionisation. This means that a
weak acid will be easily absorbed in a low pH and a weak base will be poorly absorbed.
4
