MPC Lecture 2: Pharmacodynamics
Targets of drug action
> receptors
- agonist (direct = ion channel open/close vs indirect = transduction mechanisms is altered)
- antagonist (“no effect”)
> ion channels
- blockers
- modulators (increase/decrease probability of opening of the channel)
> enzymes
- inhibitor
- false substrate (leads to production of abnormal metabolite)
- pro-drug (get converted into active drug by enzyme, ideal for localized administration since
there will be less adverse effects)
> transporters
- inhibitor (binds to (binding site on) transporter)
- false substrate (leads to accumulation of false substrate)
Types of receptors (4)
> ionotropic receptors
- ligand-gated ion channels
- ligand binds → channel undergoes conformational change (open/close)
> metabotropic receptors
- G-protein-coupled receptors
- ligand binds → intracellularly located G-protein becomes active and triggers second
messenger cascade
> kinase-linked receptors
- binding domain (extracellularly) and catalytic domain (intracellularly)
- ligand binds → function of catalytic domain (e.g. kinase) gets altered (stimulated/inhibited)
> nuclear receptors
- when inactive, located in cytosol
- ligand binds → ligand-receptor complex moves into nucleus and the DNA-binding domain
with zinc fingers interacts with DNA to modify DNA transcription
- all nuclear receptors are transcription factors (TF), but not all TF are nuclear receptors!
Characteristic selectivity of receptor proteins
> different receptors recognize only certain endogenous compounds (and drugs)
Specific effect of a drug
> a drug usually does not have a single molecular mechanism of action
> depending on the dose, a drug may mediate multiple effects via interactions with different types of
receptors proteins
> selectivity depends on binding affinity!
Efficacy (= maximum response that can be achieved with a drug)
> relationship between receptor occupancy (at a certain concentration or dose) and the ability to
initiate a response, which can be measured
> binding ≠ activation, activation (which eventually leads to a response) is governed by efficacy
,Intrinsic activity of a drug
> capacity of a single drug-receptor complex to evoke a response
> affinity of the drug-receptor complex for the signal transduction cascade
Receptor theory
> based on the following premises
- agonist has very high affinity for its receptor
- occupancy postulate (fraction/percentage of the total available receptors that is occupied
by the drug molecules)
- agonist binds in a reversible manner to its receptor
- agonist concentration is not altered as a consequence of binding to its receptor (the drug
concentration is so high compared to the receptor concentration, that the drug
concentration is not affected by binding to the receptors)
EA / Emax= α / (1 + KdA/ [A])
Antagonists (intrinsic activity is 0)
> competitive antagonist
- competes with agonist for the receptor
- if [competitive agonist] is high enough, it “wins” and the EC50 of the drug becomes much
higher (potency of drug becomes lower)
> non-competitive antagonist
- allosteric antagonist deforms the receptor → agonist can’t bind even if it is present
- lowers the biological effect (efficacy) of the drug
- EC50 (affinity) stays the same
> physiological/functional antagonism
- in smooth muscle cells → agonist A (positive) and agonist B (negative) bind at the same
time → effects of A and B cancel each other
> chemical antagonism
- milk and antibiotics → calcium in milk binds to antibiotics, preventing the antibiotics from
becoming active
Agonists
> full agonist
- produces complete activation of a receptor at high drug concentrations
- intrinsic activity is 1
> partial agonist
- binding results in less than 100% activation, even at high concentrations
- intrinsic activity is between 0 and 1
> inverse agonist
- reduces the activity of receptors that are constitutively active, the receptor gets “pushed
back” into its resting state
- intrinsic activity is -1
> partial inverse agonist
- intrinsic activity is between 0 and -1
, MPC lecture 3: Pharmacokinetics
Four processes of pharmacokinetics (ADME)
> absorption → GIT
> distribution → systemic bloodstream
> metabolism → liver
> excretion → kidneys, large intestine
Routes of drug administration
> by mouth (por os)
- oral (swallowed) → GIT
- sublingual (under the tongue) → systemic bloodstream
- buccal (in the cheek pouch) → locally
> injection
- intravenous (IV)
- intramuscular (IM)
- subcutaneous (SC) → under the skin
- intraarterial (IA)
- intrathecal → into subarachnoid space (directly into CNS)
> other routes
- pulmonary → locally via inhalation
- rectal → locally via GIT (for people who are unconscious)
- topical → (locally) via skin (creams or plasters)
ADME of an orally administered drug
> factors affection absorption
- formulation of the drug (pill or liquid)
- stability of the drug (to acid and enzymes)
- motility of the gut (how fast the movements of the gut are
- food in the stomach (can block/stimulate absorption)
- degree of first-pass metabolism
- liquid solubility (depends on pK of drug and pH of environment)
> routes by which solutes can transverse cell membranes
- by diffusion through lipids
- by diffusion through aqueous channels
- transportation by carriers
> rate/extent of resorption (=absorption) of a drug is determined by;
- concentration gradient of the unionised form of the drug across the membrane
- lipid solubility of the unionised form of the drug
- available resorption surface
> degree of drug ionisation is dependent on;
- ambient pH
- pKa- value (pH value at which 50% of drug is ionised ang 50% unionised)
Targets of drug action
> receptors
- agonist (direct = ion channel open/close vs indirect = transduction mechanisms is altered)
- antagonist (“no effect”)
> ion channels
- blockers
- modulators (increase/decrease probability of opening of the channel)
> enzymes
- inhibitor
- false substrate (leads to production of abnormal metabolite)
- pro-drug (get converted into active drug by enzyme, ideal for localized administration since
there will be less adverse effects)
> transporters
- inhibitor (binds to (binding site on) transporter)
- false substrate (leads to accumulation of false substrate)
Types of receptors (4)
> ionotropic receptors
- ligand-gated ion channels
- ligand binds → channel undergoes conformational change (open/close)
> metabotropic receptors
- G-protein-coupled receptors
- ligand binds → intracellularly located G-protein becomes active and triggers second
messenger cascade
> kinase-linked receptors
- binding domain (extracellularly) and catalytic domain (intracellularly)
- ligand binds → function of catalytic domain (e.g. kinase) gets altered (stimulated/inhibited)
> nuclear receptors
- when inactive, located in cytosol
- ligand binds → ligand-receptor complex moves into nucleus and the DNA-binding domain
with zinc fingers interacts with DNA to modify DNA transcription
- all nuclear receptors are transcription factors (TF), but not all TF are nuclear receptors!
Characteristic selectivity of receptor proteins
> different receptors recognize only certain endogenous compounds (and drugs)
Specific effect of a drug
> a drug usually does not have a single molecular mechanism of action
> depending on the dose, a drug may mediate multiple effects via interactions with different types of
receptors proteins
> selectivity depends on binding affinity!
Efficacy (= maximum response that can be achieved with a drug)
> relationship between receptor occupancy (at a certain concentration or dose) and the ability to
initiate a response, which can be measured
> binding ≠ activation, activation (which eventually leads to a response) is governed by efficacy
,Intrinsic activity of a drug
> capacity of a single drug-receptor complex to evoke a response
> affinity of the drug-receptor complex for the signal transduction cascade
Receptor theory
> based on the following premises
- agonist has very high affinity for its receptor
- occupancy postulate (fraction/percentage of the total available receptors that is occupied
by the drug molecules)
- agonist binds in a reversible manner to its receptor
- agonist concentration is not altered as a consequence of binding to its receptor (the drug
concentration is so high compared to the receptor concentration, that the drug
concentration is not affected by binding to the receptors)
EA / Emax= α / (1 + KdA/ [A])
Antagonists (intrinsic activity is 0)
> competitive antagonist
- competes with agonist for the receptor
- if [competitive agonist] is high enough, it “wins” and the EC50 of the drug becomes much
higher (potency of drug becomes lower)
> non-competitive antagonist
- allosteric antagonist deforms the receptor → agonist can’t bind even if it is present
- lowers the biological effect (efficacy) of the drug
- EC50 (affinity) stays the same
> physiological/functional antagonism
- in smooth muscle cells → agonist A (positive) and agonist B (negative) bind at the same
time → effects of A and B cancel each other
> chemical antagonism
- milk and antibiotics → calcium in milk binds to antibiotics, preventing the antibiotics from
becoming active
Agonists
> full agonist
- produces complete activation of a receptor at high drug concentrations
- intrinsic activity is 1
> partial agonist
- binding results in less than 100% activation, even at high concentrations
- intrinsic activity is between 0 and 1
> inverse agonist
- reduces the activity of receptors that are constitutively active, the receptor gets “pushed
back” into its resting state
- intrinsic activity is -1
> partial inverse agonist
- intrinsic activity is between 0 and -1
, MPC lecture 3: Pharmacokinetics
Four processes of pharmacokinetics (ADME)
> absorption → GIT
> distribution → systemic bloodstream
> metabolism → liver
> excretion → kidneys, large intestine
Routes of drug administration
> by mouth (por os)
- oral (swallowed) → GIT
- sublingual (under the tongue) → systemic bloodstream
- buccal (in the cheek pouch) → locally
> injection
- intravenous (IV)
- intramuscular (IM)
- subcutaneous (SC) → under the skin
- intraarterial (IA)
- intrathecal → into subarachnoid space (directly into CNS)
> other routes
- pulmonary → locally via inhalation
- rectal → locally via GIT (for people who are unconscious)
- topical → (locally) via skin (creams or plasters)
ADME of an orally administered drug
> factors affection absorption
- formulation of the drug (pill or liquid)
- stability of the drug (to acid and enzymes)
- motility of the gut (how fast the movements of the gut are
- food in the stomach (can block/stimulate absorption)
- degree of first-pass metabolism
- liquid solubility (depends on pK of drug and pH of environment)
> routes by which solutes can transverse cell membranes
- by diffusion through lipids
- by diffusion through aqueous channels
- transportation by carriers
> rate/extent of resorption (=absorption) of a drug is determined by;
- concentration gradient of the unionised form of the drug across the membrane
- lipid solubility of the unionised form of the drug
- available resorption surface
> degree of drug ionisation is dependent on;
- ambient pH
- pKa- value (pH value at which 50% of drug is ionised ang 50% unionised)
