Pharmacodynamics: Agonists and Antagonists

Pharmacodynamics

• Concerns what a drug does to the body.

Agonist

• A drug plus a receptor results in the drug-receptor complex, which leads to strong signal transduction and a maximum response.

Partial Agonist

• A drug plus a receptor results in the drug-receptor complex, leading to comparatively weak signal transduction and a submaximal response.

Antagonist

• A drug plus a receptor results in the drug-receptor complex, leading to no signal and no response.

Inverse Agonist

• A drug plus a receptor results in the drug-receptor complex, leading to an opposite signal and an opposite response.

Receptor Definition

• A receptor is a protein with a ligand-binding site.
• Affinity is the attraction between a ligand and a receptor.

Drug Examples

• Benzodiazepine plus GABA-A results in 100% sedation.
• Pipenidine-4-sulphonic acid plus GABA-A results in approximately 15-70% sedation.
• Flumazenil plus GABA-A stops sedation.
• B-carboline plus GABA-A causes awakening.
• GABA stands for gamma-amino-butyric acid.

Drugs Producing Effects Without Receptor Interaction

• Antacids cause a chemical reaction.
• Lactulose causes a physical reaction and is a purgative.
• Hydrochloric acid (HCl) + Al(OH)3 combines to create AlCl3 + H2O
• Hydrochloric acid (HCl) + NaOH combines to create NaCl + H2O

Receptor Types

• Location determines receptor type.
• Cell membrane or cell surface receptors exist.
• Intracellular receptors are either cytoplasmic or nuclear.
• Ligand-gated ion channels or ionotropic receptors exist and are the fastest-acting receptors.
• Examples of ligand-gated ion channels include GABA-A and Nicotinic-R.
• GPCRs (Metabotropic or 7-pass transmembrane or serpentine receptors) exist.
• Enzyme-linked receptors exist.
• RTKs (Receptor Tyrosine Kinase) is an enzyme-linked receptor.
• Jak-stat (Janus kinase) is an enzyme-linked receptor and is a signal transducer and activator of transcription.

GPCR Details

• GTP becomes GTP-ase (phosphatase).
• Phosphodiesterase breaks down cAMP.
• Pka is deactivated by protein phosphatase.
• Gs = *B1-adrenergic-R (Heart)
• Gi = *M2-cholinergic-R

Ga Details

• PIP2 is phosphatidylinositol bisphosphate.
• DAG is diacylglycerol.
• IP3 is inositol triphosphate.
• M3-cholinergic-R is found in the lungs.
• Flumazenil is a competitive antagonist.
• Bicuculline is a non-competitive antagonist.
• Heparin toxicity can be treated with protamine sulfate (a chemical antagonist).
• Heavy metal poisoning can be treated with activated charcoal (a physical antagonist and physiological antagonist).
• H1 + Histamine
• X1 + Adrenaline (physiological antagonist)

JAK-Stat Cascade

• Begins with P-JAK adding a P to Stat
• Separated P-Stat molecules bind and form P-S-S-P
• P-S-S-P activates transcription and causes a cell to elicit a response, such as cell growth or repair.

Enzyme-Linked Receptors (RTK)

• PIP adding a P becomes PIP3
• PIP3 activates P13K (-SH2)
• Activates DNA functions, such as cell growth, proliferation, or cell repair.
• Activation of PDK-1 results in response.
• GBR2 + P (-SH2) -> SOS
• Activation of cytoskeletal protein
• Results in translocation of transporter and activation of glycogen synthase

Intracellular Receptors

• Inactive intracellular is bound by HSP-90
• Active intracellular receptor travels to the nucleus

DRC (Dose Response Curve)

• Sigmoid Curve
• Hyperbola shape DRC

Response Types

• There is Graded Response
• There is Quantal Response
• Lethal response
• Toxic response
• Therapeutic Response
• Sub therapeutic Response

Therapeutic Index

• Measured as ED, TD, or LD.
• A higher therapeutic index results in a safer drug.
• A lower therapeutic index results in a less safe drug.
• TI (Human) = TD50 / ED50
• TI (Animal) = LD50 / ED50

Dose-Response Curve Slopes

• Flat DRC indicates Benzodiazepine
• Steep DRC indicates Barbiturates

Diazepam

• Potency = A=C>B, Efficacy = A = B > C
• Flumazenil is a competetive antagonist of Diazepam.
  • Blocks same site.
• Bicuculline is a non-competitive antagonist of Diazepam
  • Binds a different site.

Adverse Drug Reactions (ADR)

• Harmful effects of drugs that are unwanted.
• Type A (Augmented) ADRs are dose-dependent and predictable.
• Antihypertensives can cause hypotension when an increased dose is taken.
• Type B (Bizzaine) ADRs are dose-independent and not predictable.
• Penicillin or Sulfonamide allergies occur.
• Type C (Chronic) ADRs occur when using a drug for a long time, and the course of treatment is not finished.
  • Glucocorticoids can cause immunosuppression.
• Type D (Delayed) ADRs occur when using a drug for a long time, and the course of treatment is finished
• Anticancer therapy can cause cancer.
• Cisplatin is carcinogenic or mutagenic.
• Type E (End of treatment) ADRs occur when a drug is used for a long time and then stopped, and immediately after the treatment, can cause adverse effects.
  • PPI can cause rebound hyperacidity.
  • Withdrawal symptoms are observed.
• Type F (Failure of treatment) ADRs are tolerance on resistance of a drug because of improper use or abuse.
  • Antibiotic resistance or Drug tolerance occurs.
• Iatrogenic ADRs are drug-induced by a doctor.
  • NSAIDs cause gastric Acidity.
• Chronic or End of Treatment ADRs
  • Dependence is caused by deprivation of response
    • Sleeping pills
  • Addiction is dependence with withdrawl symptoms
    • Narcotics Cocaine, pethidine, Morphine

Drug Pregnancy Categories

• Category A Drugs are completely safe when tested in studies.
  • Levothyroxine, Paracetamol, vitamin-E, Folic Acid
• Category B Drugs are safe from animal testin studies only.
  • Pantoprazole, a-Methyldopa (Antihypertensive)
• Category C drugs pose more Benefits than Risks
  • Omeprazole, Nifedipine, domperidone
• Category D drugs pose more risks than benefits.
  • Lisinopril, Losartan, valporic Acid
• Category X drugs are contraindicated, possess the highest risks
  • Anticancer drugs, Thalidomide (most risky)

Topics

• Combination of drugs synergistics (Additives, supradditives)
  • Antagonistic
• Clinical trials (Phases)
• Tolerance
  • Tachyphylaxis
• Receptor up-regulation, down-regulation
  • Sensitization, (desensitization, Resensitization Supersentization).
• Pharmacogenetics

Drug Combinations

• Synergistic:
  • Additive: 1+1=2
    • Amlopidine + Atenolol = Antihypertensive Action
    • Aspirin + Paracetamol = Analgesic & Antipyretics
  • Supra-additive (Potentiation): 1+1 = 3
    • Penicillin + streptomycin = More strong Antibacterial Action
    • Levodopa + Carbidopa/Berseride = Better anti parkinson Management
• Antagonistic 1+1>1 - Calcium + Tetracycline = Chetation - Absorption (↓)

Tolerance + Tachyphylaxis

• Development of counter regulatory Mechanisms Subtherapeutic Action.
• Tolerance in case of AMA is known as resistance.
  • Acquired:
    • Pharmacokinetics tolerance
    • Pharmacodynamics tolranc
    • Phenobarbital Induce the microsomal enzyme:
      • Decreases Inactivate Fast
• Cross tolerance:
  • Chronic Alcoholic persons can't - get proper effect of general Anasthirsia, sleeping Pills. - Ex:- Partial - Morphine & Barbiturates. - Complete - Morphine & Pethidine

Down regulation

Arrestine

• Agonist = Longer time High Dose
• Down Regulation: - Receptor endocytosis (Internalization)
• Up Regulation Supersentization
• Antagonist = Longer time High Dose

Drug Responses

• Tolerance Response: - Dose Required - Is Normal - Duration of Drug is Longer - Lower Pharamacological Action - To Reverse/ Restore Require - Higher Drug Dosage

• Tachyphylaxixs Repsonse: - Dose Required: - High Dose -Duration - Short Peroid - Lower Pharamacological Action

Clinical Trials:

• IND application
  • New Drug Submission - Approval of submission for new study - Done by animal studies (3-4 years, with good results) - Application for NDA/BLA licensing - Phase Zero - (Micro-Dose levels for effects) - Phase 1 - (To Phase Infinity)

Drug Phase Tests:

• Drug Testing Type: - I Phase Test: - Sample Sizes = 10-100, or 20-80 tests (asian) - Type of Sample = Healthy People - Objective: saftey tolerability - Types of Study = open table - Duration: month - 1 year - Success Rate: ~50% - II Phase Test: -Sample Sizees: = 50-500 -Type of Samples: = Patients -Objective = Proof of Concept -Type of Sutdy = open/blind/single/double/ etc. -Duration - 1-2 years -Success Rate - ~25-30% - III Phase Test - Samples Size = 500-3000 - Types of Samples = Many Patients -Objectives = Efficacy + Conformation - Types of Studies - open + Blind - Duration = 3-5 years - Success Rate = ~50% - IV Phase Test: - Samples: patients on markets - Samples Types: Patients - Objectives - Long term side effects, rare of side effects - Types = Opento patients - Duration = continous porcess - SR =N/A

Pharmacogenitics:

   - Asian
   - Found in: South East Regions, Africans Regions, Areas people generally lack
           - G6PD - GLucose -6- phosphate dehydrogenase
    - Result
            - High Amounts of Free Radicals
           - Not Chloroquinine
           -  If drugs are taken (that cause this) -> hemolytic anemia 
                   - quinidine nitrofurantoin
                   - Sulfonamide - Dapsone
                   - Chloroquinolone - ciprofloxacine

Respitory Test:

   - 2 Endo trancheal:
           - Intubation - Succinly Choline Used
           - Pseudo
                   → Not Motabolized
                            → Apnea

Acteyl tests

    - Acetyl conjucation:
            - Testing For -> ACTEYL TRANSFERASE &  NAT2
             - If more Active
                 --> faster aceltater
                          --> Therapeutuic Faliure
             - IF Less ACtive :
                 --> slower Acetloter
                         -> results in Toxicity

Muscle Tests

     - Halothone is an test (inhilation = Anasethitics)
      - Abnormal
            - Ryonide Test ->Active(DAPR)
            -Increase to cause + Cat Realease
                   -- Rigity Muscule
                           --> Malignant Hypothermia
       -Antidote for test
            -. Dantrolene