General Pharmacology😊

Introduction

• Pharmacology: Science dealing with drugs.

• Branches:
• Pharmacokinetics: Effect of body on drug.
• Pharmacodynamics: Effect of drug on body.

• Rationale for drug use
• Right drug
• Right dose
• Right disease
• Right patient
• Right duration
• Right route with right dispension and monitoring
• Right price not included

Pharmacokinetics (ADME)

1. Absorption

2. Distribution

3. Metabolism

4. Excretion

1. Absorption

• Movement of drug from administration site to blood.

• M/c mechanism: Passive diffusion along the concentration gradient

• Key Factor: Lipid Solubility (most important).

• M/c site : Small intestine

• Poor oral absorption :
• Drugs with large size (Eg : Proteins Drugs with - tide -ase/-mab).

• Drug Absorption based on Medium

Drug Type	Medium	Form	Solubility	Cross
Acidic	Acidic	Non-ionized	Lipid Soluble	✓
Basic	Basic	Non-ionized	Lipid Soluble	✓
Acidic	Basic	Ionized	Water Soluble	x
Basic	Acidic	Ionized	Water Soluble	x

Bioavailability

• Fraction of given dose reaching systemic circulation.

Factors Affecting Bioavailability:

• NOTE: IV route drugs have 100% bioavailability.

• IV > IM/Subcutaneous (~75-100%) > Sublingual/Buccal > Inhalation > Oral > Transdermal
• ViMaL In OT
• VMS IOT

• Transdermal
• Postauricular skin > Scrotal > Armpit= Scalp > Back = Abdomen > Palm = under the surface of the foot.
• E (ear → postauricular) SAAP
  

Plasma Concentration Vs Time Graph

AUC (Area Under Curve):

• Total area covered by graph.
• Indicates Extent of absorption
• Aka bioavailability = AUC oral /AUC IV

Bioequivalence:

• 2 drugs are bioequivalent if absorption is within 80 - 125%

2. Distribution

• Amount of drug in tissues after absorption
• Depends on:
• Lipid solubility
• Plasma protein binding (PPB)

Plasma Protein Binding (PPB)

• Acidic drugs → bind to Albumin



• Aspirin
• Anti-coagulant (Warfarin)
• Anti-epileptics/Anti-psychotics/Anti-depressants
• Antibiotics (Sulfonamides)

• Basic drugs → bind to alpha-1 Acid Glycoprotein
• Mnemonic: AA BB TCA O
• Anti-arrhythmics (Amiodarone/Lidocaine)
• b-blockers
• Opioids
• Tricyclic anti-depressants

• High PPB drugs:
• ↓ Volume of Distribution (Vd)
• ↑ Duration of action
• ↑ Drug interactions
• ↓ Filtration
• Dialysis not useful in poisoning

Volume of Distribution (Vd)

• High Volume of distribution
• ↑ extravascular concentration.
• More drug is present in the tissues
• ↓ clearance on dialysis
• Drugs with ↑ Vd (BAD DOC):
• CHLOROQUINE
• Bulls eye maculopathy
• Conea verticillata
• Erythema multiforme
• Benzodiazepine
• Amphetamines
• Digoxin
• Opioids
• Cyclic antidepressants

• Low Volume of distribution
• ↑ intravascular concentration.

• Formula:
• Vd = Amount of drug given IV / Plasma concentration
• Vd = CL/kE
• Interpretation:
• Vd ∝ Amount of drug in tissues

• Mnemonic: ViDeo = DOwnloader/CONverter
• Vd = Dose via IV route (Loading dose)/ Initial PC
• E.g. To achieve a target Cp of 1.5 µg/L for digoxin (Vd = 500 L)
• LD (µg) = 500 (L) X 1.5 (µg/L) = 750 µg

• Mnemonic: ViDeo = CLear/KlEar
• Vd = CL/kE
• E.g. A 2,000 mg dose with a concentration of 600 mg/L has a clearance of 0.05 L/hr. What is the elimination rate constant (KE)?
• Vd = CL/kE = 0.05/kE
• Also, Vd = D/Co = 2000/600
• i.e. 0.05/kE = 2000/600
• kE = 0.05 X 600/2000 = 0.015 hr

Loading Dose (LD)

• Formula:
• LD = Vd × Target Plasma Concentration
  Bioavailability

Maintenance Dose (MD)

• Formula:
• MD = Clearance (CL) × Target Plasma Concentration
  Bioavailability
• Maintenance dose = Dosing rate X Dosing interval

3. Metabolism

Aim:

• 1st aim → To make a drug water-soluble (Polar).

• 2nd → To convert to active metabolite

Prodrugs :

• Proguanil.

• Ramipril & other ACEi (except Captopril, Lisinopril).

• Oxcarbazepine

• Omeprazole.

• Dipivefrine

• Levodopa.

• Racecadotril.

• 5- Fluorouracil.
• Capecitabin

• Gemcitabine.

• Phenyl butyrate

• Fluticasone

• Carbimazole (Prodrug) → Methimazole (Active)

• Latanoprostene bunod (Prodrug)
• breaks down into → Latanoprost + Butadenol (Unstable)

• Sulfasalazine

• Mycophenolate

• Acyclovir/ Gancyclovir

• Enzymes
• Microsomal:
• Present in smooth endoplasmic reticulum.
• Can be induced or inhibited.
• Mic (Microsomal ) ilu glucose(Glucornidation) is smooth (SER) and can adjust the volume (induced or inhibited)
• Non-microsomal:
• Present outside SER.
• Cannot be induced or inhibited.

Cytochrome P450 Enzymes (CYPs):

• Microsomal enzymes.

• CYP2C19 drugs:
• Activates Clopidogrel
• Metabolises Omeprazole
• Competitive inhibitors
• 2 substrates 1 enzyme
• Omeprazole → ↓ Clopidogrel effect → PPIs avoided with clopidogrel

• CYP2C9 drugs:
• Warfarin
• Phenytoin
• Benzbromozone (Suicidal inhibition)
• Mnemonic:
• C → Coagulant → warfarin
• 9 → P → Phenytoin

• All Antibiotics except Griseofulvin (Inducer)
• Are Inhibitors

• CYP ⛔ and QT ↑↑
• Ketoconazole
• Ciprofloxacin
• Erythromycin

4. Excretion

Glomerular Filtration

• Filters:
• Both lipid-soluble and water-soluble drugs

• Filtration ↓ with:
• ↑ Plasma Protein Binding

Tubular Reabsorption

• 99% of GFR is reabsorbed

• Lipid-soluble drugs:
• Reabsorbed back
• Example (in poisoning):
• Aspirin, barbiturates (acidic drugs)
• Urine alkalinisation with bicarbonate → prevents reabsorption

• Water-soluble drugs:
• Remain in urine → excreted

Tubular Secretion

• Occurs in proximal tubule

• Active transport via saturable pumps/transporters

Note

Enzymes

Classification of Receptors

ㅤ	Type	Speed of Action	Description
1	Ionotropic Receptors	Fastest acting ↳ (in CNS)	• Receptors on ion channels Examples • GABA-A, NMDA, NN, NM, 5HT3
2	Enzymatic Receptors	Slow	• Aka Tyrosine Kinase Receptors • Cell membrane, intracellular & extracellular ends. • Drug binds outside, activates intracellular enzyme. Examples • Cytokines, Prolactin, Insulin, GH
3	GPCR	Moderate	• Work via cAMP, Ca2+, or ion channels opening. Examples • Most other receptors
4	Intracellular Receptors	Slowest acting	• Cytoplasmic or Nuclear. • Only lipid-soluble drugs. • Work through DNA (nuclear mechanism). Examples • Cytoplasmic: ↳ Vit D, Glucocorticoids, Mineralocorticoids • Nuclear: ↳ Vit A, Thyroid hormones, Sex hormones.

• GPCR G-Protein Types:

Type	Mechanism	Second/Third Messenger
Gs	Stimulate adenylate cyclase	↑ cAMP → Activate Protein Kinase A
Gi	Inhibit adenylate cyclase	↓ cAMP
Gq	Convert PIP2 to IP3 and DAG	IP3, DAG → ↑↑ Calcium (intracellular)

Classification of Drugs

Pregnancy Categories

• Drugs categorized into 5 groups based on safety in pregnancy:
• Category A: Safest.
• Category B
• Category C
• Category D: Can be given in pregnancy, if benefit>risk (Valproate)
• Category X: Contra-indicated in pregnancy (e.g., Thalidomide).
• Mnemonic: C X → Carrying No

• Note:
• Schedule X drugs:
• Narcotic and psychotropic drugs (e.g., Ketamine).
• Different from Category X.
• Mnemonic: S X → Sex and Narcotics
• Schedule H drugs:
• Require prescription
• Prescription/legend drugs
• Mnemonic: H → from Hospitals

Safe and Unsafe Drugs in Pregnancy

P Medicines and STEP Criteria

• P medicines = Physician’s drugs / Personal drugs

• Regularly prescribed by a doctor for common conditions

• Doctor is well-versed with:
• Drug name
• Dosage
• Schedule
• Duration of use
• Indication for the ailment

STEP Criteria

• S.T.E.P. is an acronym used for selecting P medicines:
• S – Safety of the medication
• T – Tolerability
• E – Effectiveness
• P – Price / Cost of the drug

Steps in Choosing a P Medicine

1. Describe the medical diagnosis

2. State the therapeutic goal

3. List effective medicine groups

4. Use STEP criteria to choose best group

5. Select a specific P medicine from the group

Types of Drugs

Orphan drugs:

• Rare diseases

• ↓ Profitability

• ↓ Development

• Some of the orphan drugs include:
• clofazimine,
• carboprost,
• rifaximin,
• rituximab
• busulfan.

• Receptors with no known endogenous mediator or ligand.

Essential drugs:

• Inexpensive.

• Non-toxic.

• Easily available.

• Efficacious.

• Safe.

• Single molecule (Not fixed dose combination).

The Drugs and Cosmetics Act

• Regulates import, manufacture, distribution, and sale of drugs.

Medical products	Meaning
Misbranded Drug/ Counterfeit	• Intentionally made to deceive. • Not labelled correctly, or label makes false claims. • A drug stating 500mg of paracetamol per tablet but containing only 200mg is a misbranded drug.
Sub-standard/ Out of specification	• Authorized medical products that do not meet quality standards.
Falsified/ Spurious Drug	• Deliberately misrepresent identity or source of composition. • Imitation or substitute, deceptive name • (e.g., small company imitating known brand). • Punishable: Life Imprisonment • Furious → Imprison for life • North indian companies making fake branded products
Unregistered	• Not evaluated or approved.
Adulterated Drug	• Contains filthy, putrid, or decomposed substances.

Enteric Coating of Drugs

• Coating dissolves only in alkaline medium.

• Uses:
• Protects acid-labile drugs from gastric acid (e.g., Proton Pump Inhibitors).
• Protects gastric mucosa from irritant drugs (e.g., NSAIDs).
• Increases absorption of drugs absorbed distally to stomach.

Uses of controlled/sustained release :

• ↑ Duration of effect

• ↓ no. of doses (Useful if t1/2/< 4h)

• ↓ Risk of acute toxicity :
• D/t lower/absent peak concentration.

Fixed Dose Combinations (FDC)

• Two or more drugs combined in a specific ratio.

• Advantages:
• Improved compliance.
• One drug may reduce adverse effects of another.
• Increased efficacy.
• Reduced cost.

• Disadvantages:
• May lead to irrational use.
• Difficult to ascribe adverse effects to a single drug.
• Cannot combine drugs with different pharmacokinetics.
• Individual drug dose cannot be altered independently.

Prescription Writing

• Written order from doctor to pharmacist to dispense medication.

• Essentials:
• Must include date and signature (or initials) for validity.

• Dos and Don'ts:
• Drug name: Never in short form (e.g., write "paracetamol," not "PCM").
• Abbreviations: Do not use OD, BD, HS.
• Dose Notation:
• Leading zeros: Always mentioned (e.g., 0.5 mg, not .5 mg).
• Trailing zeros: Never mentioned (e.g., 5 mg, not 5.0 mg).
• Units: Microgram should be written as mcg, not μg.

Temperature Definitions

General Temperature Ranges

• Excessively hot:
• > 40 °C

• Warm:
• 30 - 40 °C

• Room temperature:
• Average temperature in a workspace

• Cool:
• 8 to 25 °C

P-glycoprotein (Pgp) and MDR1 Pump

Active Transport

• Most common type of ABC pump (ATP-Binding Cassette transporter)

Function of P-glycoprotein (Pgp) Pump

• Small intestine, liver
• Clinical relevance:
• Digoxin dosage is adjusted based on loss via efflux

• Blood-Brain Barrier (BBB)



• Example: Loperamide
• Does not cross BBB due to:
• MDR1 efflux
• Water solubility

• Placenta
• Restricts maternal-to-fetal drug transfer

• Bile Acid Excretion
• Mediate bile acid and drug excretion

• In Bacteria / Tumor Cells
• Leads to:
• Drug efflux
• Drug resistance

Pharmacological Significance of P-glycoprotein

Pharmacodynamics

Agonists

Classification of Drugs (by Intrinsic Activity)

Mixed Agonist/Antagonist:

μ & κ

---

• Morphine → More μ & κ + → Morphine more (μ & κ )

• Pentazocine → Partial μ & κ +

• Buprenorphine → bU → μ → Partial μ, Antagonist at κ

---

Generic Name	μ	κ
Morphine	++	++
Buprenorphine	±	-
Pentazocine	±	++

• +++: Strong agonist

• ±: Partial or weak agonist

• - : Antagonist

 

• Agonists at one opioid receptor subtype (κ) and

• partial agonists/antagonists at another (μ).
• Cause less respiratory depression than full opioid agonists.
• Can cause less opioid withdrawal symptoms than full opioid agonists.
• Not easily reversed with Naloxone.

Other Types of Antagonism

Suicide Inhibition

• Definition:
• Unreactive substrate analogue binds to active site of enzyme
• Modified by the enzyme → produce reactive group → reacts irreversibly →
• Form covalent bond → form stable inhibitor-enzyme complex

• Suicide Inhibitors are unreactive until within the enzyme's active site.

• Examples:
• Mnemonic: Santhaclose () cycleil () Pii Pii (PI) vannapo → odichu (ornithine) → Benzill (Benzbromozone) → Return (Retonavir) varan paranju

Inhibitor	Enzyme Targeted
Allopurinol	Xanthine oxidase
Difluoromethyl ornithine	Ornithine decarboxylase
Aspirin	Cyclooxygenase
Benzbromozone	CYP2C9
MAO inhibitors	Phenelzine
PPIs	ㅤ
Retonavir	PI

Hit and Run

• PPI

Log Dose Response Curve (Log DRC)

• S-shaped (Sigmoid Curve)

• clinically useful

 

1. Potency: curve for A is left of B
• X axis; P → Pettannu
• ⇒ A has lower EC50
• ⇒ A is more potent

2. Efficacy:
• Y axis → Efficacy → hEight
• A and B reach the same
• Both has same efficacy

Provides 3 parameters:

 

1. Potency

• Definition:
• Lower dose needed to produce same effect → More potent

• Graph:
• Left-shifted curve = Higher potency
• D>A>C>B>D

2. Efficacy

• Definition: Maximum effect achievable regardless of dose

• Graph:
• Higher curve (Y-axis) = Greater efficacy

3. Slope

• Indicates: Magnitude of effect with dose change

• Steeper slope → Dangerous

Quantal Dose-Response Curve

• Used for "All or None" phenomena
→ Response cannot be graded

• Measures variation in drug responsiveness to a fixed dose across individuals

Axes and Interpretation

• Y-axis: % of subjects responding

• X-axis: Drug dose

• Represents effect in a population

Key Terms

• LD₅₀: Dose lethal to 50% of animal population

• ED₅₀: Dose effective in 50% of population.

• TD₅₀: Dose producing toxicity in 50% of human population
• Used instead of LD₅₀ in humans

Therapeutic Index (TI)

• Mnemonic: TILE

• Formula:
• Classical (Animal studies):
• TI = LD₅₀ / ED₅₀
• Human (Clinical use):
• TI = TD₅₀ / ED₅₀

• Indicates the margin of safety of a drug
• Higher TI = Safer drug
• Eg: Penicillin.
• Lower TI = unsafe
• Eg: Digoxin, Lithium, Theophylline, Warfarin, Gentamicin

Therapeutic window

• Area between the dotted lines

• It is the range of steady-state concentrations of a drug that provides therapeutic efficacy with minimal toxicity.

Therapeutic Drug Monitoring (TDM)

• Mneumonic: DAT LAAT MC

TDM Drugs

Digoxin

Aminoglycosides

Theophylline

Lithium

Anti arrhythmics

Antiepileptic (Phenytoin )

Antidepressants (TCA)

Methotrexate

Calcineurin Inhibitor