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Pharmacology Midterm Review

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Pharmacology and Toxicology
PHAR 100
Bill Racz

Drug Advertising, Trails and Placebo Effect  Drugs barely altered, instead “me-too” drugs created to benefit large companies instead of moving drugs forward (Over 57$ billion used in marketing)  MDs enticed to prescribe drugs; an example where Pfizer had to pay a fine of 2 billion because they promoted drugs where they were not approved through wining and dining with physicians.  Ethics: Doctors prescribe medicine and consumer has little to no say in what they must take. Therefore, the healthcare professional should make informed, correct decisions.  Advertising techniques: catch attention, authorities to endorse product, fear, easy solution to problem, before/after techniques  “Miracle drugs” showing they can solve any problems – perhaps problems that may not even exist (problem child for example) Drug Trials  Two experiences led to improved regulations: Sulfonamide with toxic solvent which led to deaths and Thalidomide which was found to be a teratogenic later on but given during pregnancy  For a trial: submit proof of efficacy and safety, methods to be used in trial, drug given to investigators, preclinical testing to show efficacy of drugs and show results on rodent species + in-vitro, in-vivo toxicology screening also required to do (in animals) – takes years for drug to complete - then inserted into humans and monitored  Phase I – One or two doses in healthy volunteers (Absorption, distribution, elimination and adverse effects (limited)  Phase II – Short-term efficacy study. Determine dose for phase III. Safety. Proof of concept.  Phase III – Long-term study for efficacy and safety. Randomized controlled trials.  Phase IV – Often referred to as post-market surveillance – look for possible rare toxicities.  Phase III: comparator (placebo/standard of care), patient selection, randomization, blinding, outcome measure, all parameters are controlled  Placebo: an inert substance masquerading as a drug. Placebos can have side effects.  Beecher found in his studies that 35% of patients were effected by placebo if they had angina pectoris, cold, anxiety, cough or moodiness along with asthma  Designing a trial: study population, comparator, randomization (patients allocated by computer or double-blind), outcome (what is being measured? Is it the appropriate outcome?)  Cross-over designs: compare drug A and drug B. Group A gets A and while Group B gets B for three weeks and then they switch and get the other drug. Each patient is their own control standard. Can be used for stable chronic diseases (short term) such as infections. 1 Drug Response and Selective Toxicity  Potency: amount of drug that must be given to obtain a particular response  Efficacy: maximal response that can be obtained with the drug  As dose increases, so does the response. There can be variability between individuals as well as between drugs.  Therapeutic dose < toxic dose  Therapeutic index = Lethal or Toxic Dose/Median Effective Dose where the higher the number, the less chance of adverse effect  Selective Toxicity: harm to one organism without harming another kind (example: weed killer that doesn’t harm the crop or killing a parasite without harming the host [bacterial infections, cancel cells])  Herbicides can accumulate, for example sulfuric acid  Chemotherapy: in early theories, people believed the body was overcome by evil spirits.  Pasteur and Koch believed that some diseases caused by microbes where some agents were selectively toxic to a specific micro-organism.  Paul Ehrlich argued that dyes buildup in tissues and the right drug would bind to a specific parasite where human cells would not be harmed. “Bodies do not act unless fixed”  Critics believed that drugs work by strengthening defense mechanisms of body by Ehrlich thought that drugs must bind to organism before it can kill it. Example atoxyl (antibacterial) which worked inside the body but not in vitro. Ehrlich said it was because atoxyl is converted to active form inside the body. 2  Organo-arsenicals were first selectively-toxic drug for treatment of syphilis.  “Money, patience, cleverness, luck” components of success in Science – Ehrlich  Sulfonamides: Domagk found that prontosil effective against streptococcal infections. It was converted to sulfanilamide in the body.  Selectively toxic because all organisms require folic acid and organisms must make their own. This acid is made from p-aminobenzoic acid and since sulfanilamide resembles this, it can block the enzyme for making folic acid.  Antimetabolites: design of anticancer drugs where the fundamental difference between cancer cells and normal cells can be taken advantage of. Cancer cells divide continuously so by blocking DNA synthesis, it would have a larger effect on the cancer cell than the normal cell.  Penicillin: bacteria have cell walls whereas human cells do not. Penicillin blocks cell wall synthesis with no effect on the human cell which means it has a wide margin of safety.  Newer antibiotics have less of a difference between the microbe and human cells which makes them more toxic. Drug Toxicity and Routes of Administration  Acute and chronic drug toxicity  Poisoning: ASA and Acetaminophen, Iron tablets for children, Barbiturates, Benzodiazepines (often with alcohol)  Adverse effects: dose, individual (genetics), age, disease state Types of Adverse Effects  Extension of therapeutic effect: over sedation with barbiturates or benzodiazepines  Unrelated to main drug: such as digitalis and nausea or NSAID with its GI erosions  Idiosyncrasy: usually genetic where body can lack and enzyme which leads to the body behaving a certain way with the drug  Drug allergy: need prior exposure to form antibodies to the drug (example penicillin) Toxicity  Toxicity is rare and not always detected in tests or in animal testing (headache, insomnia, depression), sometimes showing up years later.  Usual dose can sometimes have effect in some individuals but be toxic in others. Wide differences in response to drugs. After absorption however, good relationship between blood concentration and effect. However, relationship between dose and concentration in blood can vary. 3  Absorption and elimination factors: Genetics, environmental factors, disease, presence of other drugs  Therapeutic monitoring needed for some drugs such as phenytoin Routes of Administration  Enteral routes: oral/swallowed which is most drugs and can be self-administered; rectal administration when one if vomiting or is unconscious; under the tongue such as nitroglycerin  Inhalation: used directly to lungs such as asthma or for systemic effect  Intranasal: nose sprays; oxytocin to induce labor; peptides or proteins such as insulin  Parenteral Routes: intramuscular, subcutaneous(just beneath skin/fat), intravenous, intrathecal (spinal), transdermal (patches)  Intravenous: no delay for absorption, large volumes, diffusion continuously, less pain than other methods; however, drug can’t be recovered if given by mistake, meaning immediate toxicity, rate of infusion must be controlled, infection can happen because of unsterile needles or pyrogens (fever causing) can be found on needle  Intramuscular: drugs rapidly absorbed because deep muscle, drugs can be stored within tissue  Subcutaneous: into fat, poorer blood flow so slower effect after injection, can also be “reposites/stored” such as insulin  Transdermal: skin provides some barrier, lipid soluble compounds absorbed (nicotine, estrogen, insecticides, nitroglycerin) Drug Absorption, Distribution, Metabolism and Excretion  Receptors: binding sites where specific macromolecules play a role in body’s biological processes  Sometimes drugs are non-specific in their interaction such as osmotic diuretics or general anesthetics  Agonist, competitive inhibitor, allosteric activator (makes more effective), allosteric inhibitor (less effective, worse than competitive)  Drug effect relative to concentration of drug at receptor/action site. But concentration here can’t be measured, so concentration in plasma is measured instead.  Drug has to cross various membranes in the GI system to reach the blood. The drug can exist in two forms: the free form or as bound to a protein. If it is bound to a big protein, it won’t be able to cross membranes. But the free drug can easily reach the site of action. However, the body does not always cooperate, and the free drug will go to unwanted sites of action, it could cause sedation or upset stomach. If it is fat soluble, it will distribute throughout the body and will reach tissue or muscle fat. If pregnant, it can even reach the fetus. 4  The body has two mechanisms to rid itself of drug: biotransformation (metabolism) done 90% in liver where drug is made more water soluble and changed so it can be moved back to blood and kidney filters the water soluble drug which is excreted in the urine. Some drugs can be excreted unchanged, but they must be water soluble.  The rate of absorption is important, and is different for all individuals (how much fat there is to store, how actively it can be metabolized or excreted, how fast it is distributed). All these factors alter the amount of drug at the site of action.  Concentration at action site factors: amount to be given, extent and rate of absorption, redistribution to other tissues, biotransformation, excretion  Membrane transport: filtration via pores, passive diffusion, active transport, pinocytosis  Absorption by the lungs: some anesthetics administered this way because they are transferred from lung to the blood and carried to the brain until the concentration is high enough for anesthesia to work.  Also a route for pollutants in the air.  Used for asthma as well where the drug needs to reach the bronchi and alveoli and must cross membranes in the process.  For enteral route, rectum is not very well absorbing. By mouth however, tablets disintegrate, dissolute, and get absorbed usually through passive diffusion.  To exert effect, oral drug must: be taken, released from dose, dissolve in G.I fluids, then absorbed.  To work, tablets must have stated amount of active ingredient, and tablet must disintegrate in a test tube.  Generic: the revamped versions of the innovator product. Sometimes these drugs would not work because right dosage was not released. Now, drugs are tested and only released after the proper concentration in blood is found to match the innovator drug. 5  Bioavailability: measure the rate and extent of release of the drug (amount in the blood) after taking a tablet or capsule. This is used to compare a generic with the original product – bioequivalence.  Claims that some products have better release properties.  Ontario Drug Formulary lists drugs are considered equivalent because they are closely evaluated and standardized.  The Medical Letter is expert opinion that tests drugs in large trials and gives you the bottom line is two pages. Mechanism of Termination of Drug Action  Redistribution, excretion, biotransformation  Redistribution: does not eliminate drug. Thiopental (barbiturate) used as an anesthetic where once given, patient falls asleep quickly and wakes after 30 minutes. This is because blood takes thiopental to the brain and gets high concentration there – anesthesia. As the blood then begins to reach other tissue over time, the concentration in the brain decreases and the patient wakes up.  Excretion: Kidney plays a major role. Must be water soluble for renal excretion. Fat soluble are slowly and rarely excreted. Feces are also a way of excretion, along with limited milk, saliva or sweat.  Biotransformation: liver contains enzymes that convert drugs to water soluble products which are released in urine. Everyone handles drugs differently and the enzymes present in the body determine the way in which biotransformation will occur. Main enzyme system Cytochromes P450 because many drugs work on this receptor. Biotransformation leads to inactivation.  Drug Interaction: one drug changes the response of another drug  Most patients that take various drugs – they alter the response of each other  Mechanisms: absorption, where one drug may prevent absorption of both drugs by binding in the G.I tract or drugs that cause diarrhea which don’t allow enough time for absorption  Displacement: many drugs are bound to plasma protein and only the free drug can reach action site. One drug can displace another from the binding site so more free drug present, leading to larger effect. For example, anticoagulants.  Liver handling of drug: Enzymes such as CYP 450 (inactivates drug) can be increased so one drug may stimulate synthesis of this enzyme, and the second drug is then removed at a faster rate. A drug could also inhibit this enzyme which reduces rate of removal of second drug.  Excretion: drugs can enhance or decrease the renal excretion of drugs Toxic substances in food  Substances in food can affect drug response; for example, Tyramine found in old cheese is broken down by an enzyme -monoamine oxidase. There is a class of drugs used to treat depression which inhibit MAO as part of their mechanism of action. If give MAO inhibitor with old cheese may get increased levels of tyramine and tyramine toxicity (high blood pressure). 6 Physiological and Pharmacological Aspects of the Central Nervous System  Cerebral cortex: largest part of the brain. Divided into two parts. 4 lobes: vision, hearing, sensory perception and higher-level cognitive functions.  Thalamus: relay station for sensory information to cerebral cortex  Hypothalamus: autonomic nervous system (sleeping, body temp); controls hormonal output of the pituitary gland  Pituitary gland: hormone secretion  Brainstem: connected to spinal cord. Three parts: midbrain, pons, medulla. All impulses between brain and spinal cord pass through brainstem. Regulates vital body functions: blood pressure, heart rate, respiration. Behavioural responses also, such as attention or arousal.  Cerebellum: connected to brainstem. Responsible for integration of movement and posture. Alcohol depressed cerebellum leading to loss of balance.  Glial cells provide metabolic and structural support Neurotransmission  Major neurotransmitters in CNS: Acetylcholine – excitatory in the brain. Drugs that block this produce amnesia (Alzheimer’s). Norepinephrine/epinephrine – usually excitatory. Some antidepressants enhance this system. Dopamine – one excitatory and one inhibitory. Involved with motor coordination, motivation and reward. (Parkinson’s, schizophrenia). Serotonin – excitatory. Hyperactivity and hypoactivty so responsible for anxiety and depression. Glutamate – major excitatory in brain. Found in almost all neurons, involved in learning. GABA – major inhibitory in brain. CNS depressants such as benzodiazepines bind to GABA receptors. Opioid – both inhibitory and excitatory. Pain regulation, motivation and reward.  Termination of Synaptic Transmission: enzymatic degradation – break down transmitter in cleft. Example acetycholine broken down by acetylcholinesterase. Reuptake into presynaptic neuron – transporter proteins take transmitter back into neuron followed by degradation. Example norepinephrine.  Drugs can: mimic neurotransmission (occupy receptor sites and cause effect), block receptor, actively release or block neurotransmitter from presynaptic neuron, block reuptake or breakdown of neurotransmitters 7 Physiological and Pharmacological Aspects of the Autonomic Nervous System (Peripheral Nervous)  Peripheral nervous system has motor neurons and sensory neurons  Sensory recognize change in the environment and carry signals to the CNS  Motor respond to the changes and carry signals from the CNS to control centres of muscles and glands  Somatic Nervous System controls voluntary movement, whereas Autonomic controls involuntary movement.  Somatic controls skeletal muscle by stimulating release of Acetylcholine. Ach interacts with nicotinic receptors on skeletal muscle and this synapse is called neuromuscular junction.  This is used in surgical procedures to paralyze muscles or to reduce spasticity through use of muscle relaxants.  Autonomic controls responses by influencing organs, glands to regulate breathing, heart rate etc to maintain stable internal environment  Autonomic consists of Parasympathetic(rest and digest, conserves energy) and Sympathetic(fight or flight, burns energy) divisions Parasympathetic  Neurotransmitter: Acetylcholine. Receptor: Cholinergic receptors – muscarinic and nicotinic  Muscarinic: heart/smooth muscle, glands – decreased heart rate, smooth muscle contraction  Nicotinic: skeletal muscle/ganglia – skeletal muscle contraction, impulse taken to postganglionic neuron  Long preganglionic fibers release Ach, binds to Nicotinic receptors  Short postganglionic fibers release Ach at the target organ and binds to Muscarinic receptors  All autonomic ganglia have nicotinic receptors  All target organs of parasympathetic have muscarinic receptors  Cholinergic drugs stimulate parasympathetic nervous system and exert effect on ACh receptors in skeletal muscle or CNS (example toxic nerve gas)  Anticholinergic drugs inhibit parasympathetic by blocking muscarinic receptors Sympathetic Nervous System  Neurotransmitters: Norepinephrine, Epinephrine. Receptor: Adrenergic Receptors  Activity terminated by reuptake, then degradation by Monoamine Oxidase and Catchol-O- methyltransferase  Receptors - Alpha and Beta, subdivided into Beta 1 and 2 located in specific target organs 8  Alpha found in smooth muscle, leads to contraction of the muscle. Beta found in heart, Beta 2 in lungs, vessels, increase heart rate and beta 2 relaxes smooth muscle  Short preganglionic fibers release ACh and binds to Nicotinic receptors  Long postganglionic fibers release NE at target organ which binds to alpha or beta receptors  Adrenergic drugs stimulate nervous system with primary effects on heart, bronchial tree and nasal passages  Similar effect to anticholinergics  Alpha: phenylephrine used for nasal congestion. Beta: dobutamine used for heart failure. Beta2: sulbutamol/ventolin used for asthma.  Adrenergic blocker drugs inhibit sympathetic nervous system, most widely prescribed to decrease blood pressure and slow heart rate. Non-selective beta blockers used for hypertension and cardiac rhythm abnormalities Summary  Drugs that mimic effect of sympathetic: epinephrine  Drugs that block sympathetic: propranolol  Drugs that mimic parasympathetic: acetylcholine  Drugs that block parasympathetic: atropine Sedative-Hypnotics: Reference Chapter 7  Sedative-hypnotic agents are drugs that produce a dose-dependent depression of the CNS  Low dose = anti-anxiety  sedation  hypnosis  High dose = anesthesia  Produce a graded depression of the reticular activating system (regulates arousal and sleep/wake cycle)  Types: Benzodiazepines (example valium), Barbiturates (barbitals), Ethanol, Chloral hydrate, Over the counter agents such as Antihistamines  Barbiturates widely used for 100 years, gold standard for treating anxiety and insomnia but high dependence liability with adverse side effects  Benzodiazepines synthesized later on. Some are more sedative while others are more hypnotic, and speed of action also differs  Rohypnol: used as a party drug with alcohol, highest illicit used in 1995 Routes of Administration  Readily absorbed from digestive tracts, where rapid effects require IV injection but can be given orally for long term-use 9  Highly lipid soluble agents enter cell more readily  Alcohol increases absorption of drug because of the additive effect GABA  GABA has two receptors: A and B  Barbiturates and Benzodiazepines bind to GABA(A) on specific sites different from GABA bind sites  Interaction with the receptor leads to opening of chloride channel and more Cl- ions flowing into the neuron  the inside becomes more negative and action potential is unable to form  Benzodiazepines can easily pass through the placenta and found in breast milk  Alcohol inhibits BDZ metabolism which increases BDZ half-life  body takes longer to produce effects.  Bodies have enzymes that break down the drug, but sometimes breakdown products (metabolites) have drug effects + additional effects. This means that the drug continues to dose, and now new drugs attempt to remove the possibility of active metabolites.  BAR and BDZ increase GABA’s tendency to bind to its receptor and open Cl- channels  BAR increases the duration of the channel opening  BDZ increases the frequency of the channel opening BAR & BDZ  Barbiturates: at low doses can only make GABA more effective and doesn’t alter operation of CL-channels; at higher dose, it can open Cl- channels. High enough dose can cause death/suicide  Benzodiazepines: at low and high doses, makes GABA more effective and cannot open Cl- channels directly. They have more appeal in medicine because it can’t lead to heart attacks or death by overdose.  BAR: low therapeutic index, but can treat full spectrum of CNS depression. Suppresses REM- type sleep (dreams) so when you stop taking it, you get vivid rebound REMs. Long-acting bar such as valproic acid can work as anticonvulsant. High abuse potential  BDZ: very high therapeutic index, produces relief from anxiety, sedation, amnesia, some effective hypnotics, skeletal muscle relaxation. Also suppresses REM-sleep so you wake up feeling not very rested. Low abuse potential but it can be abused  BDZ: effects of memory with anterograde amnesia which is loss of memory for events while on the drug and memory problems can last months after drug is discontinued (such as rohypnol where victims have little memory of assault). BDZ given to make “conscious sed
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