Pharmacology Year 1 Notes PDF

PHARMACOLOGY  Pharmacokinetics ADME What is pharmacokinetics? Absorption It is the study of what the body does to the drug while pharmacodynamics is the study of what the drug does to the body...

PHARMACOLOGY  Pharmacokinetics ADME What is pharmacokinetics? Absorption It is the study of what the body does to the drug while pharmacodynamics is the study of what the drug does to the body ↓ 1. Drug Absorption Passes through Drugs can be administered intravenously (IV), intramuscularly, subcutaneously, topically, membrane orally, sublingually, intrathecally(through cerebral spine fluid), transdermal,y, and by to blood inhalation GI tract-> liver-> systemic circuit (whole body) Oral route: blood goes from GI and gets absorbed by small intestine ( tablets, capsules, ↓ most drugs) small intestine Sublingual: drug gets placed under tongue-> bypasses first pass metabolism-> systemic circuit (quite fast) ↳ Rectal: through anus into rectum (lower bowel). Suppositories (once inside they dissolve) to Note: very few drugs are absorbed from stomach due to complications of delivery transported The small intestine is the main absorption surface (large SA) liver Gastric emptying (digestion and absorption in duodenum) is important because some drugs can slow it down. Example= migraine opioids ↓ Bioavailability is the amount of drug that is actually reaching the systemic circuit The type of absorption process matters in determining bioavailability first pass Example: first pass metabolism (passing through liver) and food can decrease the metabolism bioavailability 2. Drug Distribution ↓ The drug is distributed everywhere in the systemic circuit and then it gets Distribution comparmentalised Protein binding is when drugs are bound to plasma proteins (big) in the blood The kidney then separates true drug and puts it back into the blood to be distributed ↓ The reason it is so important is because it increases the bioavailability metabolism Acidic drugs bind to albumin and basic drugs bind to a1- acid glycoprotein Limitations: ↳ Perfusion rate limitation is the struggle of trying to get the blood to the tissue (once the leave cell blood gets there it can easily get into the tissue) Permeability rate limitation is the struggle of trying to cross the membrane to the tissue (is ↓ done slowly) What is blood brain barrier? excretion For medication to enter the brain it has to go through the blood brain barrier (strictly regulated) Very specific membrane (allows smaller fat soluble , hydrophobic molecules) Some drugs work slower because acidic brain cells traps the weak bases They accumulate causing toxicity Example of morphine: 1. Morphine dissociates to pass through brain barrier 2. The brain cells ionize morphine again and trap it causing increased levels of toxicity in brain The placenta protects the fetus from getting affected by drugs Example: lipid soluble mostly unionized drugs can pass while polar and ionized cannot JOIN THE DARKSIDE 3. Drug Metabolism Fat soluble drugs go to get matabolised while non fat soluble drugs go for excretion 2 phases of drug metabolism: 1. Phase 1 Chemically alters drug The process of reduction, oxidation, or hydrolysis to convert drugs into more polar molecules by adding polar functional groups Example: lidocaine 2. Phase 2 Adds something on to the drug to form a conjugate Involves the attachment if an ionized group to the drug Example: sulphate, glutathione, sugar glucuronide Cytochrome P450 are a large group of liver enzymes CYP3A4 is the largest group of enzymes that has 3 mechanisms: inhibitors (inhibit), substrates (acted upon, drug) inducers (promote) Examples: when erythromycin inhibits ( stops its activation) CYP3A4 metabolism midazolam plasma concentration increases When rifampicin induces (accelerates) CYP3A4 metabolism midazolam plasma concentration decreases Not everyone has the same enzymes Some drugs have to be activated by the liver to be effective (example; rampiril) 4. Drug Excretion Water soluble drugs are excreted in kidney Fat soluble have 3 steps: 1. Glomerular filtration: unbound drugs are filtered in the Bowman’s capsule. Protein bound drugs are too big and are poorly excreted 2. Active Tubular Secretion: drugs are actively secreted into proximal tube. The tube has 2 pumps (acid and base). These type of drugs can be unbound and bound 3. Passive Tubular Secretion: water soluble drugs can become urine. Lipid soluble drugs can go into blood to get diffused JOIN THE DARKSIDE  Drug Development Definitions Non protein drug targets (DNA) Drug: a chemical substance that is administered to a living organism producing a Replication can be achieved by by binding bases biological effect. covalently or placing false substrates into the DNA ribbon Medicine: a chemical preparation that contains one or more drugs producing a (azathioprine) therapeutic effect. There are 3 different names associated with medicine: chemical name, approved Modern Technology name, trade name Recombinant DNA Technology Many drugs are low molecular weight organic compounds (less than 1kD) This is the idea that bacteria can be reprogrammed to produce human proteins Medicines Insulin was the first medicine made by recombinant tech Botany This reduced the possibility of allergic responses Foxglove (digitalis purpurea) was used to treat drospy (heart failure) This technology was also able to modify the amino acid Increased urine production was the first sign of its effectiveness sequence of insulin producing longer lasting or shorter Digoxin is the generic medicine from foxglove that forces the heart muscle to effects contract Other plant medicines include morphine, vincristine, and artemisinin Immunotherapy- monoclonal antibodies Physiology Now known as immunotherapy (using mice) Plants are also useful in understanding chemical transmission in nerves Cytokines are chemical mediators of the immune system For example, acetylcholine is a neurotransmitter that can be mimicked by plant Fully human monoclonal antibodies are now available alkaloids like atropine to treat bradycardia Have been developed against growth factors Organic Chemistry Anaesthetics are an example of organic molecules that give pain free surgery Biosimilar antibodies are antibodies that might have minor Phenol (an antiseptic) was developed to reduce post surgical infection differences in structure but produce the same function Inorganic compounds are also able to treat many issues (lithium for bipolar disorders) Gene therapy uses recombinant nucleic acid to regulate, Immunotherapy repair, replace, add, or delete a genetic sequence Using rabbits and horses to produce antibodies is now know as immunotherapy Zolegsma is a form of gene therapy that aims to reverse It was an issue because they were administering large doses of foreign protein into muscle paralysis. Only 1 dose is required. human body The problem with gene therapy is that it is very specific Modern Pharmacology and cannot be used for problems like cystic fibrosis Paul Erhlich introduced the idea that drugs have to bind with so,enlarged of the body substance to act Living drugs This idea was based on dyes binding to cloth Used go treat a form of childhood cancer by using a Protonsil Red which is dye that contains sulphonamide blocks the synthesis of folic child’s own T lymphocytes and modifying it to contain a acid which is vital for DNA synthesis in bacterial cells receptor (CAR T) to bind to a protein that’s causing the Sulphonamide increased urine flow and reduced blood sugar cancer Receptors This T cell is then reintroduced into the bone marrow and The concept of receptors was later introduced and this idea brought on the idea of grows there purposefully creating drugs rather than just finding them It is not risk free Stereoisomers also were discovered and gave the idea that they can have different pharmacological effects Animals Insulin was first extracted from cow and pig pancreas. It was the first protein to be synthesized (cannot be taken orally because its effect gets degraded) Steroids Steroids are like neurotransmitters (act on specific receptors);except their receptors are in the cytoplasm (this results in a slower transcription response) while neurotransmitter receptors are on the cell membrane Steroids although useful can have serious effects including hypertension, increased body fat, and poor wound healing JOIN THE DARKSIDE  Pharmacodynamics 1: Drug Targets Pharmacodynamics is the study of how drugs affect the body A drug is natural or synthetic chemical that causes a physiological response when brought into the body Terms Ligand: something that binds to a target Endogenous ligand: a natural chemical produced in the body Drug: an exogenous (outside) ligand that causes a physiological response Mechanism of action: the interaction between a drug and its target (how the drug has an effect on the body) Mode of action: the cellular and physiological effects that create a clinical effect (it’s a change that results from being in contact with a substance) Drugs target PROTEINS Other drugs and targets include: Drugs are complicated and go to many different locations before their initial targets Pathogens, fungi, parasites (antibiotics) Dietary supplements (vitamins) Direct DNA interaction Amino acids Chemical messengers (antibody drugs) Receptors are key players in cellular communication Types include endocrine, paracrine, juxtacrine, autocrine Families include G-protein coupled, ligand gated ion channels, kinase linked receptors, and nuclear receptors Receptors are generally named after ligands (endogenous, pharmacological) G-protein coupled Talked about this in MCB GS - It is metabotropic meaning it initiates a number of steps to modulate cell activity This can be illustrated with cAMP % ·o JOIN THE DARKSIDE Examples of G protein coupled receptors Muscarinic acetylcholine receptors Adrenergic receptors Histamine receptors Prostaglandin receptors Opioid receptors Ligand gated ion channels 1. Specific ligand binds to receptor 2. Channel opens 3. Ions flow through very fast Ionotropic is when ions pass through in response to Kinase linked receptors neurotransmission Form dimers Examples Phosphorylation of proteins Nicotinic acetylcholine receptors NDMA glutamate receptors GABAA receptors (mainly inhibitory) P2X receptors Enzyme-linked & Nuclear receptors Activated by signalling molecules (cytokines, hormones) Examples of enzyme linked include receptor tyrosine kinase (RTK) Nuclear receptors are mostly targets of hormones Found in either nucleus or cytoplasm Regulate gene transcription Can recognize foreign molecules and initiate metabolic processes Ligand has to pass through membrane Ion channels Types Ligand gated (usually receptors) Leak channels (always open) Voltage gated (at certain voltage ions are able to pass) Other gated channels (TRP channels) Membrane transporters either use concentration gradients or ATP hydrolysis They also move ions by co-transport or exchange Specificity and selectivity Specific ligands: more effective Selective ligands: mid to moderate effectiveness Non specific/non selective ligands: minimal effectiveness Drug Effects Synergistic: when the combined effect of 2 or more drugs is greater than the individual effects Antagonistic: substance that blocks effect of another substance Tolerance: drug becomes less effective due to repetitive use (some can be rapid) Withdrawal: symptoms that occur when someone suddenly JOIN THE DARKSIDE stops or cuts back use of an addictive substance  Pharmacodynamics 2: Receptor Theory Receptors The idea that things gave to bind to something in the body in order to activate “Drug receptor” is anything a drug interacts with that causes an effect Drug receptor = Drug target Receptors have an active binding site (orthosteric) so that an activating ligand (agonist which induces a change) can bind to it Binding sites are very specific and can contain secondary binding sites known as allosteric binding sites Note: receptors are NOT like enzymes; enzymes catalyze reactions and receptors don’t Pharmacology is based on measuring the effect of a drug Concentration effect is measuring effect of drug AT target site Dose response curve measures the response of an organism when a drug is administered Examples of what it can measure include: Cellular, Physiological, Subjective, Population Some terminology: square brackets around a name indicates concentration of that substance [aspirin]= concentration of aspirin Doses are in mg or ml Emax= maximal effect Important Terms EC50= concentration (x-axis) where the effect is half maximal Affinity: ability of a ligand to bind to a target Potency= concentration of drug required to cause effect measured Efficacy: ability of a ligand to generate an effect by EC50 Potency: affinity and efficacy to generate a response Lower EC50= HIGHER POTENCY IC50= potency in terms of response reduction Agonists Full agonists: induce maximal response when receptors are saturated * Partial agonists: induce submaximal response when receptors are saturated (smaller effect and weaker efficacy JOIN THE DARKSIDE CONT'D > -  Histamine receptors have activity Inverse agonists: shuts down receptors effectiveness (does without agonists attached the opposite of endogenous agonist) Antagonists Competitive antagonists: compete for binding site preventing receptor activation Non competitive antagonists: bind somewhere else preventing receptor activation Reversible antagonists: bind weakly to receptor and are able to dissociate easily from receptor allowing action to still take place Irreversible antagonists: bind strongly and permanently disable receptor (cannot be removed) Irreversible antagonists Reversible competitive antagonists. Non competitive antagonists t T agonist agonist JOIN THE DARKSIDE Allosteric Modulators Modulators bind to sites other than the active site This creates changes to receptor This can either positively or negatively alter the ability of the receptor to bind to ligands or generate a response NOTE: positive allosteric modulators cannot generate a response even if an agonist is absence Adverse Drug Reactions Can occur due to excessive activity by drug at specific target or other targets Therapeutic range= the range usually expected to achieve desired therapeutic effect (can be very harmful) Steep dose response relationships (DRR): small changes in dose will have larger therapeutic (toxic) effects Flat DDRs: small changes in dose have little clinical effect (usually safer) Terms ED50= median therapeutic does (benefits 50% of patients) LD50= median lethal dose (kills 50% of patients) Therapeutic index= LD50/ED50 Factors that contribute to individuals: Genetics Ageing Disease Tolerance Other drugs JOIN THE DARKSIDE  The Autonomic Nervous System Enteric Nervous System · There are more neurons here than every part of the body except the brain · It is usually automatic · It is mostly independent (some CNS control) · The SNS & PNS influence its activity Sympathetic and Parasympathetic Nervous System Unconscious control of internal organs (under independent control) · It is important to note that both systems are not active at once (one can be more dominant) · They perform opposite effects (one excites the other relaxes) · Parasympathetic nerves are craniosacral meaning they exit from the CNS through cranial and sacral spinal roots Sympathetic nerves are thoracolumbar meaning they exit from the - CNS through thoracic and lumbar spinal nerves ANS & Central Control The ANS is primarily controlled by the hypothalamus i Further processing happens in the brain stem nuclei Sympathetic spinal tracts They are preganglionic cell bodies located in the intermediolateral grey matter NOTE: preganglionic cell bodies are in the CNS while postganglionic are found in the ANS ANS is disynaptic (2 neurons) Nicotinic acetylcholine receptor (nAChR) 5 subunits arranged around central pores. It is permeable to the mentioned ions that allows excitation of postganglionic nerve Autonomic ganglia Ganglia are nerve cell clusters which the ANS nerves pass through Parasympathetic ganglia are in or near the target organ Sympathetic ganglia are located in the paravertebral ganglia (sympathetic chain). This chain in lateral and ventral to the spinal cord JOIN THE DARKSIDE  Nicotine The Sympathetic Nervous System Enhance sympathetic and parasympathetic activity Noradrenaline is the postganglionic neurotransmitter in the : EFFECTS: sympathetic nervous system that can be released as a hormone. Increase BP Adrenaline is a hormone released from the adrenal gland Increase heart rate 5 receptors for adrenaline/noradrenaline Increase activity of GI tract Auto receptors are receptors located on the presynaptic · Increase blood glucose membrane. They can be activated by neurotransmitter release. Usually primary autonomic disorders are rare and secondary They are often inhibitory and used to prevent over activity autonomic disorders can occur from neuropathies or damage. But Eg: a2 adrenoreceptors, 5-HT1 receptors many drugs are not intended to target the ANS Exceptions where SNS doesn’t release noradrenaline · Acetylcholine is released through sweat glands and adrenal glands. These tissues do not have parasympathetic innervation Adrenaline ↑ Increases heart rate, opens airways, and reduces swelling · It is an agonist that is good for anaphylaxis · Also called epinephrine JOIN THE DARKSIDE  The Parasympathetic Nervous System & Cholinergic Signalling · Postganglionic neurotransmitter in the PNS is acetylcholine · Preganglionic is Nicotinic acetylcholine receptor (ligand gated ion channels) · Postganglionic is Muscarinic acetylcholine receptor (G protein coupled receptors) Muscarinic receptors · G protein coupled receptors- Gq, Gi · Five subtypes (3 common in ANS): M1, M2, M3 Parasympathomimetics (Muscarinic agonists) · They increase the activity of parasympathetic and sympathetic systems Anticholinergic side effects Somatic Nervous System Control of voluntary movement and muscle contraction · It has no ganglia instead motor axons direct from CNS information is passed back to CNS through nervous system JOIN THE DARKSIDE Neuromuscular Junction (NMJ) Nicotinic Acetylcholine Receptor Antagonists Suxamethonium- nAChR Agonist · Curare- tubocurarine, pancuronium, Muscle paralysis as well atracurium, depolarizing blockers · Voltage gated ion channels stay inactivated and · Cause muscle paralysis muscle can’t contract again May cause malignant hyperthermia · Botox Is painful Clinical uses: muscle spasms, muscle over activity, cosmetic surgery Side effects: muscle weakness, flu like symptoms, allergic reactions Cholinergic transmission occurs at: · Autonomic ganglia Parasympathetic nervous system · NMJ CNS JOIN THE DARKSIDE