Introduction to Pharmacodynamics Lecture (Dr. Konorev) Flashcards
Pharmacokinetics and Pharmacodynamics
PHARMACOKINETICS: - Effects of the body on drugs • Absorption • Distribution • Metabolism • Elimination
PHARMACODYNAMICS: - Effects of drugs on the body • Drug receptors • Dose-response curves • Mechanisms of drug actions
Types of Drug- Receptor Interactions
• COVALENT BONDS: IRREVERSIBLE; drug removal/receptor re-activation requires RE-SYNTHESIS of the receptor or enzymatic removal of the drug.
• NON-COVALENT BONDS: REVERSIBLE; most drugs bind to receptors via non-covalent bonds
Listed below from strongest to weakest:
– IONIC Bonds: electrostatic interaction between
Positively and Negatively charged ions
– HYDROGEN Bonds: electrostatic bond between the net Positive CHARGE of HYDROGEN atoms in many functional groups and the net Negative charge of an ELECTRONEGATIVE ATOM
– HYDROPHOBIC Interactions: between hydrophobic regions of the drug and the receptor
– VAN DER WAALS FORCES: Weak Electrostatic interactions involving DIPOLE moments within functional groups
Dose Response Curve
- The relationship between a DRUG DOSE and its EFFECTS can be described quantitatively using a dose- response curve
- When you plot drug dose ARITHMETICALLY on the x-axis vs. drug effect on the y-axis you typically get what is called a HYPERBOLIC CURVE
a) LINEAR PHASE: Beginning portion of the curve where there is a SHARP Slope
b) PLATEAU PHASE: End of the curve where there is a smaller slope
- It is more common for a concentration-effect curve to be presented by graphing the LOGARITHM of the drug dose vs. the response in which case you get a SIGMOIDAL curve
- The MAXIMAL EFFECT that can be produced by the Drug is the Emax
- The ED50 (Effective Dose 50) is the dose of Drug that produces 50% of it mAXIMAL EFFECT
Parameters Describing a Drug- Receptor Interaction
• The PHYSICAL PROPERTIES of drugs and/or receptors (e.g., Size, Shape, and Charge) determine the BINDING and INTERACTION of Drugs with their Receptors
• Parameters describing the interaction of a drug with a receptor
– AFFINITY
– SELECTIVITY
– INTRINSIC ACTIVITY
Affinity of a Drug for a Receptor
• The AFFINITY of a drug for a receptor describes how READILY and TIGHTLY that drug BINDS to its receptor
a) HIGH AFFINITY= GOOD Drug-Receptor interaction; LESS drug needed to produce a response
b) LOW AFFINITY = POOR Drug-Receptor interaction; MORE drug needed to produce a response
EXAMPLE:
1) Affinity for mu opioid receptor: Fentanyl > Morphine > Meperidine
2) Dose typically used for Analgesia:
fentanyl: 0.1 mg;
morphine: 10 mg;
meperidine: 100 mg
Affinity of a Drug for a Receptor
• Parameter describing the affinity – KD (EQUILIBRIUM DISSOCIATION CONSTANT)
– Drug concentration at which 50% of the Drug RECEPTOR BINDING SITES are OCCUPIED by the Drug
– Unit for KD = MOLAR CONCENTRATIONS (e.g., micromoles, nanomoles, etc…).
– The LOWER the KD, the HIGHER THE AFFINITY of a drug for a receptor
– The HIGHER the KD, the LOWER THE AFFINITY of a drug for a receptor
Kd = [L][R]/ [LR]
- Where [L], [R] and [LR] represent molar concentrations of ligand, receptor, and their complex
Relationship between Drug Effect and Receptor Binding
- Receptors determine the QUANTITATIVE Relationships between a DRUG and its EFFECTS
- The magnitude of a drug’s effects will be PROPORTIONAL to the DEGREE of its INTERACTION with (binding to) a Receptor
- EC50 = KD , or EC50 ≠ KD depending on the coupling of receptor occupancy and response to a drug
Drug Selectivity
• SELECTIVITY is a property of a drug determined by its AFFINITIES at various binding sites
– It is measured by comparing affinities of a drug to different receptors or by comparing ED50s for different effects of a drug
– A MORE SELECTIVE drug would affect FEWER targets over a specific concentration range (therapeutic range)
Intrinsic Activity
- INTRINSIC ACTIVITY describes the ability of a drug to CHANGE a Receptor FUNCTION and produce a PHYSIOLOGICAL RESPONSE upon its binding to a receptor
a) AGONISTS: bind to the receptor and STABILIZE IT in a particular conformation (usually, the active conformation), PRODUCING a PHYSIOLOGICAL RESPONSE
– HAVE an INTRINSIC ACTIVITY
b) ANTAGONISTS: Receptor antagonists bind to the receptor but do not change its function. However, they PREVENT ACTIVATION of the receptor in the presence of an agonist
–DO NOT HAVE an INTRINSIC ACTIVITY
Types of Drugs
1) FULL AGONISTS:
- FULLY ACTIVATE Receptors
- Produce a maximal pharmacological effect when all receptors are occupied
- MAXIMAL INTRINSIC ACTIVITY
2) PARTIAL AGONISTS:
- PARTIALLY ACTIVATE the receptor upon binding
- Produce a SUB-MAXIMAL PHARMACOLOGICAL EFFECT when all receptors are occupied
- Intrinsic efficacy varies depending on drug, but is always SUBMAXIMAL
3) INVERSE AGONISTS:
- DECREASE receptor SIGNALING
- DECREASE RESPONSE at receptors with a significant level of constitutive receptor activity
- INTRINSIC ACTIVITY is PRESENT and related to the INHIBITION of receptor function
4) ANTAGONISTS:
- DO NOT CHANGE the Function of the receptor upon binding
- NO PHARMACOLOGICAL EFFECT in the absence of an agonist
• NO INTRINSIC EFFICACY
Types of Agonists and their Pharmacological Effects
1) FULL AGONISTS: produce maximal pharmacological effects at full receptor occupancy
2) PARTIAL AGONISTS: produce sub-maximal pharmacological effects at full receptor occupancy
*** Emax is LOWER in PARTIAL Agonists than in FULL Agonists
3) INVERSE AGONISTS: produce an Effect OPPOSITE to a full or partial agonist
Types of Antagonism
1) PHARMACOLOGIC (receptor) antagonism (action at the SAME RECEPTOR as endogenous ligands or agonist drugs)
2) CHEMICAL ANTAGONISM (when chemical antagonist MAKES the OTHER DRUG UNAVAILABLE)
3) PHYSIOLOGIC ANTAGONISM (occurs between endogenous pathways REGULATED by DIFFERENT RECEPTORS)
Types of Pharmacologic Antagonists
1) COMPETITIVE Antagonists:
• COMPETE with ENDOGENOUS chemicals or agonist drugs for binding of the receptor.
• Can be DISPLACED from the receptor by other drugs (effects are surmountable)
2) NON- COMPETITIVE Antagonists:
• Receptor inactivation is NOT SURMOUNTABLE
a) IRREVERSIBLE Antagonists: IRREVERSIBLY bind to and occlude the agonist site on the receptor by forming COVALENT Bonds
b) ALLOSTERIC Antagonists: BIND to a SITE OTHER than the agonist site to PREVENT or REDUCE Agonist BINDING or activation of the receptor
Competitive vs Noncompetitive Antagonists
1) COMPETITIVE Antagonism:
- Agonist EC50 INCREASES
- Emax DOES NOT Change
2) NON-COMPETITVE Antagonism:
- Agonist Emax DECREASES
- EC50 DOES NOT Change
Beneficial and Adverse Drug Effects
1) FULL AGONISTS: MIMICKING the ACTIONS of Endogenous chemicals at receptors
- Example: Activation of mu opioid receptors by opioid analgesics (“pain killers”) such as morphine, codeine, and meperidine
2) ANTAGONISTS, PARTIAL and INVERSE AGONISTS: BLOCKING the ACTIONS of endogenous ligands at receptors
- Example: Blockade of the α1 adrenoceptors receptors by the antihypertensive drug PRAZOSIN
3) BENEFICIAL and ADVERSE EFFECTS are mediated by the SAME Receptors/ Signal transduction pathway on the same cell types
– EXAMPLE: Insulin
– How to MANAGE: a tight dose control
– How to CONTROL: Avoid systemic administration
4) BENEFICIAL and ADVERSE EFFECTS are mediated by DIFFERENT types of Receptors
– Highly SELECTIVE drugs have LESS Side Effects
– Lower SELECTIVITY leads to the INCREASED incidence of Side Effects
