Pharmaceutical Routes & Metabolism PDF

# Routes of drug administration ## Oral/Enteral route - Oldest, earliest, commonest mode of drug administration - Drug administration by ingestion - Given in form of drenches or mixed in feed/water - For rapid effect - before meal - For irritant drug - after meal/during meal - Example - Capsule, b...

# Routes of drug administration ## Oral/Enteral route - Oldest, earliest, commonest mode of drug administration - Drug administration by ingestion - Given in form of drenches or mixed in feed/water - For rapid effect - before meal - For irritant drug - after meal/during meal - Example - Capsule, bolus, suspension, mixture, powder, syrup, elixir ### Advantages - Safe, commonest, least expensive - Convenient as no puncture or no sterile environment - Suitable for gastrointestinal tract infection and parasitic - Large volume of liquid drug can be administered ### Disadvantages - Large volume of liquid drug - Not suitable for emergency situation due to slow absorption of drug. - Not suitable route for uncooperative, unconscious or vomiting patients or wild animals - Some drugs (peptide, acid labile) are ineffective by oral route because they are destroyed rapidly in stomach and rumen. - Oral route becomes inefficient due to large amount of ingesta in rumen - Poor administration may lead to bronchopneumonia - Not suitable for drugs which undergo extensive portal or hepatic first pass effect - Long term administration result in destruction of rumen microflora → Supra infection. ## Parenteral route - Administration of drugs by injection under one or more layers of skin or muscle membrane - Mostly used for systemic effects of drug. - Rapid effect, but avoid first pass effect - Syringe, needle or similar instrument are a prerequisite ### Intravenous route (I/V) - Drug injected directly into veins - Single dose administration - I/V bolus, I/V injection - Continuous infusion - I/V drip, I/V infusion - Small amount of drug - Injection - Large amount of drug - Infusion - Used for irritant solution of drugs ### Advantages - Quick onset of action [drug - Vein - heart - whole body] - Precise dose administered quickly, controlled manner - Reliable for emergency, intensive care therapy - Rapidly metabolized drugs can be infused slowly for constant pharmacological effect - 100% bioavailability of drug can be given. - Highly irritant, non-iotonic drug can be given ### Disadvantages - Dangerous, drug by-passes defense system exposed to organs - Drug should be properly sterile, pure, soluble, not useful for insoluble drug, suspension, oil substances - Extravasation of irritant drug - Phlebitis, necrosis of adjacent tissues - Restraining of animal is required - Once injected, can't be recovered - Poor technique - air emboli (Life threatening) ### Intramuscular route - Drug directly injected in deep layers of large skeletal muscle - Lipid soluble drug diffuse freely through capillaries and well absorbed when given I/M - Polar, low mol.wt drugs are absorbed rapidly as compared to high mol.wt drugs - Aqueous drug - quickly absorbed. - Suspension/depot preparation - gradually absorbed. ### Advantages - Fairly rapid absorption, suitable for fractious, wild animals - Large volumes of fluid can't be injected ### Disadvantages - Large volume of fluid leads to nerve damage - Faculty administration leads to necrosis of muscle - Repeated administration difficult esp. for poorly soluble drugs - Not suitable for emergency situation ### Subcutaneous route - Drug preparation is deposited in loose S/C tissues, just below the skin - Smaller sized drugs and soluble drugs in S/C tissue are readily supplied with nerves but less lymphatic drainage, thus route is more useful when slow and continuous absorption is required - Vascular and non-irritant (sustained release product) ### Advantages - Large volume of drug can be administered - Suitable for depot preparation (sustained release product) - Rate of absorption can be manipulated - Vasoconstriction/cold (↓) and heat manage (↑) can cause tissue necrosis ### Disadvantages - Not suitable for less irritant drugs - Drug formulation should be strictly isotonic and at physiological pH - Not suitable in shock state ### Intraperitoneal route - Administration into peritoneal space - Peritoneum provides large surface area for absorption - Not useful for the drugs which undergo hepatic first pass metabolism because absorption of drug from injected site is via portal system - Suitable for large vol. of drug. ### Advantages - Rapid absorption due to large surface area - Suitable for large vol. of drugs - Suitable for small sized and less animals ### Disadvantages - Not suitable for large animals - Risk of peritonitis, puncture of abdominal region ### Intrathecal administration - Drugs are administered into subarachnoid space → intra spinal administration of anesthesia - Drugs are injected by inserting needle through vertebral intraspinach space into spinal fluid (not lumbar region) - Not suitable for animals ### Intra-arterial route - Drug administered directly in an artery - Produces high concentration of drug in the dependent area for a short time - Used in chemotherapy, radiographic or imagining techniques eg. vasodilator drugs for vasospasm - Thrombolytic drugs for embolism ### Epidural route - Drug is deposited through a vertebral interspace into epidural space. - Needle doesn’t penetrate meninges hence less risk - Common site: b/w 1st and 2nd coccygeal vertebra. - Commonly used for epidural anesthesia ### Intramedullary/Intrathecal route - Injected unto bone marrow - Ex: Blood transfusion, fluid therapy when IV is not possible in neonates ### Intra-articular route - Injected into joint space - Used in inflamed joint ### Intra-cardiac route - Administered into heart muscle directly - To stimulate heart function ## Inhalation/Pulmonary administration - Administration by nasal or oral inhalation - Drugs are given as gas or by atomization into smaller particles for easy passage through trachea, bronchi, lung capillaries - Penetration of drug into lung depends on size of droplet/physico-chemical property - Smaller droplet absorbed easily → systemic effect - Larger droplet absorbed → local effect ### Advantages - Lipd soluble, volatile gases absorbed rapidly - Rapid systemic action as alveoli are highly vascularized - Avoid loss through hepatic and intestinal first pass. ### Disadvantages - Special technique or device required - Difficult to regulate dosage - Not suitable for irritant/local application ## Topical administration - Application of drug on body surface like skin/mucous membrane - Depending on site of drug action and penetration ### Skin - **Epicutaneous** (Outside skin) → delivers active principles to the site of application and produce localized effect. - **Percutaneous** (through skin) /transcutaneous/ transdermal - crosses the intact skin, produce systemic effect - Absorption by skin depends on type of drug, species, size of animal, type of action. - **Spot on** - Application of semisolid or liquid drug on skin - **Pour-on** – Application of oily rub/liquid drug ### Mucous membrane - **Absorption more than skin** as stratum corneum epid and rich blood supply. - **Sublingual and buccal** → soft tablet - sublingual, hard tablet - buccal, bypass hepatic and intestinal bypass effect. - **Rectal/Per-rectal route** → administration directly into rectum in form of suppository or enema, main use is as laxative to clean the lower bowel prior to examination or surgery - **Intra ocular**- into conjunctiva as drops/gel/ointments - **Intra mammary** - into the teat using a teat siphon → in treatment of mastitis - **Intravaginal** - into vaginal mucous membrane → in treatment of gynecological disorders. ### Specialized drug delivery systems - **Transdermal patches** - medicine are in the form of patches kept on animals body. - **Liposome** → may not enter into all cells, so liposome are lipophilic in nature, they can be given for rapid absorption into target cells. - **Dermojet** - used in case of mass inoculation, drug is sprayed through the skin due to high force. # Metabolism/Biotransformation of drugs - Conversion from one chemical form of a substance to another. - **Lipid soluble/non-polar drug** → **water soluble/polar drug** (excretion) - Metabolism is necessary biological process that limit the pharmacological actions and life of drug in the body. - **Liver is primary site for metabolism of almost all types of drugs** because of presence of various enzymes in liver - **Large variety of enzyme** present in liver help in biotransformation - Classified into: - **Microsomal enzyme** - Synthesized in microsome - Inducible by drug/diet - Most oxidative reactions - Some reductive, some hydrolytic - **Non-microsomal enzyme** - Not synthesized in microsome - Not inducible - Few oxidative, reductive, hydrolytie reaction - All conjugative reactions - Except glucuronidation. ### Function of metabolism - **To convert lipophilic substances to hydrophilic substances** - **To convert inactive form of drug to active form.** (prodrug) - To eliminate drug from body - **Example:** - **Convert inactive form of drug to active form** - Phenacetin (inactive) → Paracetamol (active) - **Convert active form to inactive form** - Phenobarbitol (active) → P-hydroxy phenobarbital (inactive) - **No change in pharmacological action** - Digitoxin → Digoxin - **Change in pharmacological action** - Iproniazid (antidepressant) → Isoniazid (antitubercular) # Pathway of biotransformation - **Phase I** - Non-synthetic/Non-conjugative phase. - Hepatic microsomal enzymes/Cytochrome P450 - CYP3A4, CYP2D6 → Hepatic microsomal enzymes are involved in phase I reaction - **Phase I reaction** - **Oxidation**: Addition of oxygen - *R + O2 + NADPH + H+ → monoxygenase → ROH + NADP+H + H2O (mixed function oxidase)* - **Example:** Morphine, Nicotine - **Reduction**: Removal of O2 (add H) - **Example:** Protonsil, Azo reduction, Sulphonamide - **Hydrolysis**: Addition of drug in the presence of H2O - **Example**: Acetylcholine + H2O cholinesterase → Choline + Acetic acid - **Phase II** - Synthetic/Conjugative phase - All reactions require endogenous substances - **Glucuronide conjugation**: - - **Drug + UDPGA (endogenous substance) transferase → drug glucuronide + UDPGA** - Drug formed are more hydrophilic and less lipophilic. - 80% they are eliminated. - Cats and fishes do not contain this reaction (UDPGA- UDP glucuronic acid) - **Example**: Morphine, Paracetamol - **Phase II reaction** - **Acetylation**: - *Drug + Acetyl-CoA → N-acetyl transferase → drug acetylated* - **Example:** Dogs are deficient in → Sulphanilamide group of antibacterial agents - **Methylation**: - *Substrate + S-adenosyl methionine → methyl transferance → methylated drug* - **Example**: Nor epinephrine → Epinephrine - **Glutathione conjugation**: - *Drug + Glutathione → glutathione conjugate* - Glutathione acts as natural antioxidant in body. - **Example**: Paracetamol - **Amino acid conjugation**: - *Drug + Amino acid → drug + conjugate* - **Example**: - *Drug + ornithine → hippuric acid* - *Drug + glycine → * in humans - *Drug + ornithine* in birds - **Sulfation**: - *Drug + PAPS (phosphoadenopyrosulphate) → sulfonyl transferase → sulfated form of drug* - **Example**: Pigs are deficienct in sulfation - **Thiol conjugation**: - *Addition of thiol group specific for cyanide detoxification* - **Example**: HCN + SH → thiol transferase → thiocynate (sulphahyolreyl group) # Microsomal enzymes - Classified into: - **Inducers**: e.g. Anesthetics like barbiturates enhances their own action. Autoinduction → drug itself decreases dosage interval - **Inhibitors**: Co-administration of drug, in which one drug is microsomal enzyme inhibitor then it reduces rate of metabolism, so the drug interval will be prolonged e.g. Erythromycin, quinolones # Non-microsomal enzymes - Can’t be induced - **Inhibitors**: eg. MAO (mono amino oxidase inhibitors) - **Example:** Pargyline, Selegiline # Plasma drug concentration-time profile - The graphical representation of plasma drug concentration vs time. - **Cmax**: Maximum plasma drug concentration. - **AUC**: Area under the curve - **Tmax**: Time required to reach maximum plasma concentration - **Onset time (OT)**: Time required to initiate pharmacological effect or minimum effective concentration - **Maximum safe concentration/minimum toxic concentration (MSC/MTC)**: Concentration of drug in plasma above which it give toxic effect - **Therapeutic range**: Lies between MEC and MSC - **Peak effect**: Pharmacological effect produced by drug at its Cmax - **Duration of action of drug**: The time period during absorption phase (α) - **Elimination phase (β)**: The time period during which pharma co logical effect is observed in the body. - **AUC (area under curve)** - Represents bioavailability of drug. # Orders of pharmacokinetics - Classified into: - **Zero order kinetics**: The constant amount of drug is eliminated per unit time. - **Example**: 100 mg → 50 mg → 25 mg → 12.5 mg / 12.5 mg. - Half life of drug is dependent on the initial concentration. - **First order kinetics**: The constant fraction of drug is eliminated per unit time. - Most drugs follow first order kinetics. - Half life is constant, dose independent. - **Mixed order kinetics**: It follows both zero order and 1st order kinetics. - At lower concentration - 1st order - At higher concentration - zero order # Pharmacokinetic models - **Compartmental model**: - Body is assumed to behave in diff compartments. - Drug is central compartment, drug is distributed to peripheral compartments ie all the A, D, M, E processes undergo simultaneously (Absorption, Distribution, Metabolism, Elimination) - **Compartmental model** - **Two compartmental model**: Entire animal body is divided into 2 compartments (hypothetically) i.e. central and peripheral compartment. Drug moves from (heart, liver) central compartment to other (skin, muscle) peripheral. - **Three compartmental model**: Highly perfused organ, moderately perfused organ, less perfused organs - **Non-compartmental model/One compartmental model**: Mostly used for single dose of administration. # Pharmacokinetic determinants - **Bioavailability**: Fraction of drug that is present in systemic circulation. - Denoted by 'f'. - Area under the PDC-time curve - F is maximum for I/V, almost 100%. - Relative bioavailability = f through oral route / f through IV route - Bioequivalence - If both formulations have same f, then called as bioequivalence. - **Half-life**: Time required for a drug to become half of its initial concentration, or time required for 50% elimination of drug. **t_1/2 = 0.693 / β** - **β** - elimination rate constant - **Volume of distribution of drug (Vd)**: Apparent volume of body fluid into which the drug is distributed. - **Vd = amount of drug in body/ plasma drug concentration = dose/PDC** - **If Vd is high**: Drug accumulated in a particular tissue, pharmacological response is high. - **If Vd is less**: Drug is cleared by plasma, pharmacological response is low. - **Clearance**: Amount of drug cleared by plasma - **Dose**: The amount of drug administered at a single time. - **Dosage regimen**: The manner in which drug has to be administered to produce action. - **Steady state concentration**: Drug remain in plasma concentration period even though there is 1 in concentration of drug that is going to be constant for certain time - **Steady state concentration** # Pharmacodynamics - Branch deal with mechanism of action of drug. - **Receptors**: A macromolecular substance, which may be present within or on the cell membrane to which drug may attach and interact to produce response. - **Classification** - **G-Protein Coupled Receptor** - **Enzyme linked receptor** - **Steroid Receptor** ### 1) Ligand gated/ionotropic receptor: - The receptors are directly linked to ion channels present on cell membrane, mostly dimeric. - They have 2 terminals, NH2 terminal and COOH terminal. - NH2 terminal present outside the membrane. - Ligand binding sits - Amino terminal. - **Example**: Nicotinic receptors, GABA, Glycine - 5 subunit - 2 α, 1 β arranged as petals of flower - 1 γ, 1 δ receptor. - Drug comes and binds to receptors → conformational changes → Influx of Na+ ions → alters the membrane potential (pharmacological response) Depolarization. ### 2) G-protein coupled receptors/Serpentine receptor/transmembrane receptor/G protein linked receptor - Membrane bound receptor/G protein linked receptor - There are proteins having polypeptide chain and 2 terminals, NH2 T (outside) and COOH T (inside) . - Has 7 helical structures. - Ligand attaching site between helical strands, 1 COOH terminal - G protein is activated as drug binds to receptor and hence it's called messenger. - G protein then further act on effector protein. - **Example**: Muscarin R, Histamine R, adrenergic R - **Signaling mechanism** - In resting stage α, β, subunits of G protein are in bound state. - When drug bind to receptor, G protein is activated and GDP is converted to GTP. - α subunit of G protein bind to βγ dimer. - αβγ complex acts on effector protein and produce different types of protein. **Different types of protein** - **Gs (Stimulatory):** - αGTP → Adenylate cyclase → cAMP ↑ Na+ ↑ cAMP - **Gi (Inhibitory):** - αGTP → Adenylate cyclase → ↓ cAMP → ↓ rate of contraction of heart - αGTP → phospholipase C → contraction of smooth muscle - **Gq (quiescent)** : αGTP → skeletal muscle contraction. - **Go**: αGTP → required some time **Different effector protein** - **Adenylate cyclase**: - αGTP → Adenylate cyclase → cAMP (accumulation) - cAMP → proteiniknase - Proteiniknase → phosphorylates protein → alters func of enzymes → - removes, - glycosylation, - glycolysis, - contraction of heart - **Phospholipase C**: - αGTP → Phospholipase C → PIP2 (phosphatidylinositol biphosphate) - PIP2 → IP3 (inositol triphosphate) - IP3 → → → Diacyl glycine (DAG) - ↑ Ca2+ level in circulation → phosphorylation of target protein - Contraction of smooth muscle, release of hormones, relaxation of muscle, inflammatory response - **Phospholipase A2**: - αGTP → Phospholipase A2 → Production of arachidonic acid - Arachidonic acid → membrane phospholipid → eicosanoids - Eicosanoids → prostaglandine, leukotriene, thromboxane - Prostaglandine → receptors ### 3) Enzyme linked receptors: - **Receptor** is linked to **enzyme** - **Ligand binding site**: NH2 terminal - Drug will bind to receptor, it going to activate enzyme linked to the receptor, majority of receptors are linked to enzyme tyrosine kinase. - **Tyrosine kinase activation**: Dimerisation of receptor - **Activation of protein kinase**: ↓ - **Phosphorylation of target protein**: ↓ - **Phospholipase C → release of hormone**. ### 4) Steroid receptor/intracellular receptor/cytosol receptor: - Not membrane bound but intracellular. - Most steroid hormone act through this pathway. - Both NH2 terminal and COOH binding domain. - Ligand binding site is COOH terminal - In between 2 terminals one DNA binding domain is present which contains 4 cysteine AA surrounding Zn and hence called Zinc finger. - Zn present in extracelluar membrane - **Intracellulaar** (involving the inside of a cell) - Receptor binding to ligand forms: - **ligand receptor complex**: ↓ - **Dimerisation**: ↓ - **Zinc fingers**: ↓ - **DNA**: ↓ - **Transcription**: ↓ - **mRNA**: ↓ - **Protein**: ↓ - **Cellular effects** # Dose-response curve - A graphical representation of dose to its corresponding response. - The curve is called **dose-response curve**. - Classified into: - **Graded dose relationship/Gradual response curve**: Cumulative Dose response - All or none phenomenon - **Quantal dose relationship/All or none response curve**: Graded dose relationship/Gradual response curve ### Graded dose relationship/Gradual response curve: - **Emax**: Maximum response - **ED50**: Dose required to produce 50% of the maximum response - **Threshold dose**: Minimum amount of drug that is required to produce pharmacological response - **Ceiling effect**: Maximum response produced by particular drug. The dose of drug beyond which we can't observe (or) increase in the response. - **Ceiling dose**: - Dose at the ceiling effect. - **Effective Dose 50 (ED50)**: Dose required to produce maximum response produced by the drug. "Dose that is going to produce 50% of desired pharmacological effect in 50% of exposed population. ### Quantal Dose Response Relationship: - All or none phenomenon - Certain dose of any drug is given in a population and observe the response. - The extent of response is not studied, only the number of individuals in population which show response are taken into account - **LD50 (Lethal Dose 50)**: Dose of drug that produces lethal effect in 50% of population. - **Therapeutic index**: LD50/ED50 - factors/parameters to determine safety of the drug. - **Therapeutic ratio**: LDSO/ED75 - **Standard safety margin**: LDI/ED99 - **Parameters from DRR graphs** - **Efficacy**: Determined by height of graph - **Potency**: Amount of drug required to produce efficacy. **Efficacy A > Efficacy B, Potency: A > B** - **Affinity**: Given by the slope of dose response relationship graph - **Variance**: Change in the magnitude of response in a population if same dose of drug is given to all. # Drug interactions - When drugs are given over another, the effect of one drug on another is called **drug interaction**. - **Additive effect**: The magnitude of response produced by combination of drugs is equal to summation of individual drug. - **Example**: Sulphametizine + Sulphamethazine - **Potentiation**: The combination enhances the pharmacological effects. One drug on its own bot increases, one drug has no effect, but other drug when administered in combination --> - **Example**: Carbiclopa ↑ Levo Dopa, Probenecid ↑ Penicillin - **Synergism**: The combination of two drugs which produce the response that is more than summation of individual drugs. - **Example**: Carbontetrachloride + ethanol (Hepatotoxicants) - **Antagonism**: One drug opposes the action of other drug. - **Types of Antagonism**: - **Chemical antagonism**: When 2 drugs form complexes with each other, hence no effect. - **Example**: Heparin + Protamine, Arsenic + Dimercaprol - **Physiological antagonism**: When 2 drugs produce opposite effects on same target/receptor - **Example**: Insulin + Glucagon, Acetylcholine + epinephrine - **Dispositional antagonism**: 2 drugs compete for plasma protein binding. Drug which has more affinity for plasma protein, displace the other drug - **Example**: Warfarin + salicylates ### Receptor mediated antagonism - **Competitive antagonism**: Both agonist and antagonist compete for same binding site or receptor. - If agonist concentration is increased, it can displace antagonist over the receptor - Also called reversible/surmountable antagonist. - **Example**: Acetylcholine for muscarinic receptor for secretion of exocrine glands - ↑In dose of agonist, leads to displace of antagonist. Called shift to right. - **Non-competitive/Irreversible/Non surmountable antagonism**: Antagonist bind to allosteric site of receptor and brings about some sort of conformational change in the binding site of agonist. - No increase in effect of agonist even after ↑ in dose of agonist # Neurohumoral transmission in sympathetic nervous system - The transfer of information from one neuron to other with the help of neurotransmitter or neurohumoral substance is called neurohumoral transmitter - **Most important neurotransmitter in SNS is norepinephrine** ### Different steps of NHT - **Axonal conduction**: Passage of impulse along the length of neuron - Normal resting potential (-75 mV) - Na+ ions move in → depolarisation → action potential - Action potential is generated which is a prerequisite for synthesis, storage and release of neurotransmitter. - **Synthesis**: - Precursor required for synthesis of norepinephrine is tyrosine. - **Biosynthetic pathway:** - **Tyrosine → tyrosine hydroxylase → L-dopa (dihydroxy phenylalanine) → dopa decarboxylase → Dopamine → β-hydroxylase → Nor-epinephrine → N methyl transferase → Epinephrine (hormone)** - **Rate limiting step**: Tyrosine hydroxylase. - **Storage**: Once synthesis is over, neurotransmitter is packed into vesicles and stored within neuron. - **Release**: All the vesicles fuse at the end of neuron and release neuro-transmitters. - **Reuptake**: 70% of released neurotransmitters are taken back by the pre-synaptic neuron. Reuptake by pre-synaptic neuron is called **Reuptake I** - **Reuptake by extra-neuronal tissues** (liver) is called **Reuptake II** - **Metabolism**: - Metabolism is by enzymes: - **Monoamie oxidase (MAO)** (intra-neuronal) - **Catechol-O-methyl transferase (COMT) (intra-circulatory)** - **Metabolised product of norepinephrine**: Vanilly Mandelic Acid (VMA) - **Release** by feces and urine. # Drugs involved in adrenergic neurohumoral tranmission - **Axonal Conduction**: inhibited by - *Saxo toxin* - *Tetrodotoxin* - *Lignocaine* - **Synthesis**: - **L-tyrosine/phenylalanine**: - *Tyrosine hydroxylase* is inhibited by *α-methyl tyrosine* - *Dopa decarboxylase* is inhibited by *Carbidopa*. - **Dopa → Dopamine**: *Dopa decarboxylase* is inhibited by * α-methyl dopamine, Disulfiram* - *Transport of NE is inhibited by Reserpine.* - **Storage**: Not inhibited. - **Vesicular transport**: Inhibited by - *Bretylium*, - *Guanthidine* - **Release**: Inhibited by - *Bretylium*. - **Metabolism**: Inhibited by - *monoamine oxidase inhibitors: Selegiline, Pargyline* - *Catechol-O-methyl transferase inhibitors: Entacapone* - **Reuptake**: Inhibited by - **Reuptake I**: - *IB→ Cocaine, Simipramine* - **Reuptake II**: - *IB→ Glucocorticoids* # Neurohumoral transmission in parasympathetic nervous system - **Cholinergic neurohumoral transmission** - **Axonal conduction**: - **Synthesis, storage, release** - **Choline + Acetyl-CoA → Choline Acetyl transferase → Acetylcholine (precursor)** - Stored in vesicles, Ca2+ influence exocytosis of Ach - Stored together with Ca2+ in synaptic neuron, receptors interact with post synaptic neuron receptors. - **Receptor events**: - **EPSP** - **IPSP** - **Metabolisn and elimination**: - **Acetylcholine → Acetylcholinesterase → Choline + Acetic acid** - **Taken back by neuron, transmission** # Drugs involved in cholinergic neurohumoral transmission - **Axonal conduction**: - Inhibited by - **Saxo toxin**, - **Tetradotoxin**. - **TB deficiency of choline** - **Vesicular transport** inhibited by *veramical* - **Release**: - **Transport** inhibited by Ca2+ influx - **Release of NT**: - **Inhibited** by *Nicotine, Streptomycin* - **Inhibited** by *Amino glycoside group (Streptomycin)* - **Inhibited** by *Botulinum, Tetanus toxin* - **Inhibited** by *Inhibition of protein synaptoblebine* - **Inhibited** by *No attachment of vesicles with pre-synaptic neuron* - **Inhibited** by *Hemicholinium* - **Reuptake**: **Inhibited** by *Hemicholinium* - **Reversible**: ↑ Conc. of substrate inhibition action overcome - **Metabolism**: - Inhibited by *Acetylcholinesterase enzyme inhibitors* : - **Neostigmine, Physostigmine** - **Irreversible enzyme inhibitors**: - **Organophosphate** group of insecticide, - **Malathion** → ↑ ACh in circulation → continuous contraction → muscle paralyzed → death of insect - **Parathion** → ↑ ACh in circulation → continuous contraction of skeletal muscle → death of insect - **Latrrodotoxin** → ↑ ACh in circulation → continuous release → restore enzyme action - **Cholinestercare reactivators**: - **DAM (Diacetyl monoxime), 2-PAM (2-pyridine aldoxime methyl chloride)** # Receptors in the Autonomic Nervous System - **Receptors in sympathetic nervous system**: Are a protein coupled receptors - **Types of receptors**: α1, α2, β1, β2, β3 - **Receptors** are **excitatory except receptors are present in GIT (inhibitory)** - **All receptors are present in GIT (inhibitory) except receptors on heart (excitatory)** - **All β receptors are inhibitory except receptors on heart (excitatory)** - **α1 receptors (post junctional):** - **Preesent majorly on** small B.V/arterioles of skin, renal, mesentery, mucosal PR, peripheral blood vessels, vascular smooth muscle. - **Preesent on** sphincter muscle, radial muscle, cause contraction - **Result** in ↑ peripheral vascular resistance, ↑ blood pressure - **Present** in radial muscle of eye → contraction → dilation of pupil - **Used as** vasoconstrictors - **Used as** mydriatics - **α2 receptors (pre and post junctional):** - Inhibitory in nature - Inhibit release of norepinephrine from presynaptic neurons, cause contraction. - Present on platelet aggregation of platelet - Preesent on smooth muscle, promote release of glucagon - Inhibit release of insulin - **ß1 receptors**: - **Majorly located on heart** (SANode, Avnode, Ventricles) - **+ ionotropic effect**: ↑ force of contraction of heart - **+ chronotropic effect**: ↑ rate of contraction of heart - **Preesent in kidney**: release renin - **ß2 receptors**: - **Majorly present on non-vascular, smooth muscle** - **Preesent on**: bronchial, uterine, blood venel of skeletal muscle - **Relaxation** of above muscle. - **Preesent primarily on** adipose tissue - **Cause** ↑ lipolysis → ↑ prece fatty acid in blood # Adrenergic agonist/Sympathomimetics - Substances that mimic the function of sympathetic nervous system. - **Classified into** - **Non-selective** - **Selective** ### Non-selective adrenergic receptor agonist: - Acts on both α and β receptors - **Catecholamines**: - Have catechol nucleus - **Natural**: Epinephrine, norepinephrine, Dopamine - **Synthetic**: Isoprenaline, metaraminol, basantrian - **Basantrian**: have 2, 4 dihydroxy phenylalanine, acting in stro. - **Non-catecholamines**: - Do not have catechol nucleus. - **Example**: Amphetamine, phenylethrine ### Selective adrenergic receptor agonist: - Agents which selectively act on one type of receptor - **α1**: Phenylalanine, methoxamine - **α2**: Xylaxine, clonidine - **β1**: Dobutamine - **β2**: Clenbuterol, Terbutaline, Salbutamol ### Based on mode of action - **Direct acting**: Directly acting on adrenoregic receptors - **Example**: Norepinephrine, epinephrine - **Indirect acting**: Without binding to adrenergic receptors. Indirectly mimics the sympathetic NS function - **Example**: Amphetamine - **Mixed acting**: Act both directly and indirectly. - **Example**: Dopamine # Sympatholytics/Anti-adrenergic drugs - Agents which block the adrenergic receptors and reduce sympathetic activity. - **Classified into**: - **Non-selective**: - **α**: *Phenoxybenzamaine, propanolol, methoxamine* (action on α1 and α2) - **β**: *Timolol, pindolol, labetalol, carvedilol* - **Selective**: - **α1**: *Prazosin, Terazosin* - **α2**: *Yohimbine, atipamezole* - **β1**: *Atenolol, metoprolol* - **β2**: *Butoxamine* ### Indirect acting: - Do not directly interact with the receptors. - **Agents that inhibit synthesis of NE**: - α-methyl-p-tyrosine, α- methyl dopamine, disulfiram - **Inhibit storage**: *Reserpine* - **Inhibit release**: *Bretylium, guanthidine* - **Inhibit uptake**: *Cocaine, imipramine* - **Inhibit reuptake**: *Glucocorticoids* - **Clinical uses**: - **β receptor antagonist**: Used in treatment of hypertension. ### Clinical uses - **Agonists**: - **Phenylalanine**: vasoconstrictor, ↑ BP, decongestant - **α1: Xylazine**: pre-anesthetic drug - **α1: Clonidine**: sedative, stimulate the heart - **β1: Dobutamine**: increase the heart rate, release renin - **β2: Salbutamol, Terbutaline**: Bronchodilators, treatment of asthma - **Antagonist**: - **α1 → ↓ BP**: treatment of overdose of *xylazine*