Week 6 Chemistry / Physics
Class Outline

  1. Organic and Biochemistry Concepts:
    1. Hydrocarbons and anesthetic activity- All hydrocarbons will have anesthetic property with CNS depression. Unfortunately they also affect the whole body and not just the brain. Cyclopropane is very explosive. The more #wise of halogenated products on the hydrocarbon chains the less water soluble and the greater the molecular weight. Aliphatic and alicyclic hydroc are pharmacologically active and also depress the CNS. Inert gases undergo no chemical changes in the body. The lower molecular weight groups are usually gases. Can usually replace H with a halogen group to get a halogenated hydrocarbon, which is poorly soluble in water and the unsaturated ones are more reactive. By adding a double bond will increase potency and the margin of safety. The higher the molecular weight compounds will increase CNS excitability. Enflurane will increase muscle twitching and so don’t do an EEG at this time! Desflurane can incre HR and can incr it by 20-30% if incr vol% too fast.
    2. Structure and potency- The more double bonds the more potent and the safe (as in flammability). Triple bonds will really increase potency but will not change the safety. Volatility, water solubility, flammability all decrease as molecular weight increases. Cyclic compounds are more potent than straight chains. The toxicity of an agent will depend on the complexity of the molecule. To increase the complexity will give an increase potential for adverse reactions such as excitability:

      3. Halothane will cause an increase in cardiac irritability

      Desflurane increases the HR the most.

      Enflurane causes more twitches and movement on high doses.

    3. Alcohols – derived when a hydroxyl group designated as –OH replaces an H. If it replaces the H with methane you get methyl alcohol which has a distinctive taste and burns readily and can enter into many chemical reactions. Some are readily soluble in water. Alcohols come in 3 types. The difference is the position of the OH group.

      4. a. Primary – OH attached to C at end of straight chain.

      b. Secondary – The OH group is bonded to a carbon atom that has one H atom on it. The OH group is away from the end of the chain.

      c. tertiary – The OH group is on a carbon that has no hydrogen atoms on it. The OH group is on a C atom that is on the base of a cross.

      Alcohols undergo 4 major types of reactions:

      Ether formation – 2 alcohols combine to form a longer chain and a molecule of water. Often called a condensation reaction and the reverse is called hydrolysis

      Ester formation – an alcohol combines with an organic acid to form a larger molecule (the ester) and water.

      Oxidation – the oxidation that occurs depends on the type of alcohol since primary alc oxidize to aldehydes; secondary ones oxidize to ketones, and tertiary ones don’t oxidize.

      Dehydration – alc may lose a water molecule and form a C-C double bond

      Aromatic alcohols or phenol groups are caustic to cells – do produce surface anesthetic but are caustic to the skin. As you add OH groups you increase water solubility and decrease volatility. Alc are then less lipophillic and are more hydrophillic. The anesthetic potency increases as molecular weight increases to max of 8 carbons. Ketones have no anesthetic property. Halogenated ketones are the starting point of hypnotics.

    4. Aldehydes- Formed from the oxidation of a primary alcohol and occurs when hydrocarbon atom is replaced by an OH group

      5. Denoted by –CHO. Two most important are formaldeyhde – preservation of tissue and acetylaldehyde which is the breakdown of ethyl alcohol. Both are gases at room temp, have a suffocating odor and are strong reducing agents. Aldehydes further oxidize to organic acids.

    5. Ketones- are formed by the oxidation of a secondary alcohol. Acetone is a familiar one and comes from isopropyl alcholol. It is an excellent solvent and adhesive remover and has a sweet smell. - Such that in DKA the pt would have fruity breath! Ketones can be aromatic or alicyclic, are water soluble, are usually liquids, the lower wt ones are flammable, and as molecular wt increases volatility decreases, water solub decr and flammability decreases. Many narcotics are heterocyclic ketones.
    6. Organic acids- hydrocarbons in which one or more H replaced by a carboxyl group –COOH. Acetic acid. Esters are formed by the interaction of alc with an acid. These are very volatile but have a pleasant odor. Isoamylnitrate is a smooth muscle relaxor for pts with angina. Esters can also be local anesthetics. The ester of aminoparabenzic acid is paraaminobenzoic acid (PABA) tetracaine, cocaine. The –COOH is the acidic component of organic compounds. They are made up of fatty acids; if the COOH group replaces H atom on benzene ring it forms benzoic acid. By adding carboxyl gourps the water solub increases. In an aqueous solution, organic acids ionize to produce H atoms. You neutralize org acids by adding mineral salts. The COOH group enters into a compound with anesthetic activity and this activity is stopped. General formula is R-COO-R
    7. Organic ether- Ethers are organic oxides. 2 org radicals are attached to an atom of oxygen. They can be symmetrical where they have the same group on the same side or unsym with different groups. For alkyl substances they yield aliphatic ethers, which has anesth properties. Aromatic ethers have no anesth prop. These original ones of diethyl ether and dibynal ether are no longer used since they are very volatile and explosive. They have since been replaced by halogenated nonexplosive ethers. Aliphatic ethers can replace H with halogen to form a halogenated ether or can replace H with OH to form hydroxyl ether. Unsaturated ethers are more potent than saturated ether. Volatility increases as you incr the # of C and molecular wt. Ethers are prepared from alcohols. Water solubility is low and is always less than the alcohol it was made from. They are lipophillic. If hydroxylate an aliphatic ether will reduce its narcotic potency (abil to produce analgesia). If you halogenate it will decrease volatility, incr potency, irritability and toxic properties. Ethers are flammable but as you increase molecular wt, flammability goes down. If you spill ether, the fumes will stay on the ground since the density is higher than air. General formula is R-O-R
    8. Amines- have the general formula R-NH2. Amines are derived from ammonia- which is NH3. Can divide the amines into primary, secondary, and tertiary. Can combine the amine with a benzene ring to produce an aromatic amine - Catecholamines and other sympathomimetics such as norepi, epi and phenylephrine. Amines are different from amides which have the N bound to a carbonyl radical while amines have saturated C atoms attached to a N. If N is attached to 4 C radicals is has a quaternary base. This is important because is has bacteriostatic and germacidal properties. The structure of muscle relaxants and ganglionic blocking agents is here. It is hard for them to pass the blood/brain barrier such as glycopyrelate doesn’t have the central effects of pupil dilation or become crazy

      9. * Delineate amides from ester: If 2 "I"s in word then it’s an amide, one "I" is an ester. This pertains to local anesthetics like lidocaine or bupivicaine are both amides.

    9. Thiols- occurs when the oxygen containing organic molecules have oxygen replaced by an atom of sulfur. Thiopental is one as are other thiobarbiturates. They are highly alkalized with a pH of 9-11. They are soluble in water. Most are short or ultrashort activity wise. Based on a benzene ring – substitute the compounds where exchanging the oxygen will determine the compound – ie brevital.
    10. Halogens- Halogens are chlorine, fluorine, bromine and iodine. Iodine is less useful especially for narcotics since it yields compounds which are either toxic or non anesthetic. Chlorine and bromine convert many aliphatic compounds of low narcotic potency to more potent drugs. Fluorine converts little or no narcotic effects. Fluorine has the most anesthetic properties and though it weighs less than Cl or Br, it doesn’t add molecular weight so has less complexity. Halogenated hydrocarbons are very lipophillic (fat soluble).
    11. Methods of Halogenation- can halogenate by substitution or can add directly to an unsaturated compound without displacing any other atom. Saturated hydrocarbons form substitution while alicyclic, aromatic, and certain hetercyclic compounds either add or substitute halogens. Hydroxyl or carbonyl aldehyde – with halogenating group the reaction will depend on what is on the ring. It doesn’t prevent halog. From occurring but it does influence where the halogen is going. Alcohols are oxidized into aldehydes in the presence of halogens. Aliphatic hydrocarbons, alc, and aldeh containing Cl, Br, and some Fl are most important to anesthetics.
    12. Potency and activity of halogenated organic compounds- By halogenating will change the chemical properties:
    1. Chemical structure of inhalation anesthetic agents

See notes for diagrams

    1. Review: nucleic acids, carbohydrates, proteins, lipids
  1. Chemical Reactions- Anabolic is to build up and Catabolic is to break down
  1. Combination, decomposition, single or double displacement
    2.

    Combination reactions: A+B=AB

    Decomposition: AB=A+B

    Singular displacement: AB+C=A+BC

    Double displacement: AB+CD=AC+BD

  2. Oxidation, reduction, hydrolysis, conjugation –Oxidation is the transfer of negative charge from one reactant to another or to lose electrons. The opposite is reduction, which is to gain electrons. Primary alcohols oxidize to form aldehydes, which oxidize to form organic acids. These can be reduced back to the original alcohol. Secondary alcohols oxidize to form ketones and can be reduced back. Hydrolysis is the reaction that esters undergo in water to form carboxylic acid and an alcohol.
  3. Phase I and Phase II reactions- Phase I reactions are oxidation, reduction and hydrolysis which is to gain water. Phase II reactions are conjugations or conjunction which will change the way a drug works. Can add proteins to increase water solubility to be able to get rid of it.
  4. Cytochrome P450 – Most drugs are broken down in the liver. This can be done by hydrolysis or by conjugation and to a lesser extent by oxidation or reduction. Oxidative metabolism is to lose electrons and can be done by hydrolylization, deamination, desulfurization, dehalogenation, and dealkylization. If the pt is a fast acetylator (can add acetyl groups and break down groups faster in the liver) then the drugs you give will be broken down faster and you will need to use more agent. Pts on dilantin or tegretol are fast acetylators since they must do this with the drugs already being taken so will need to use more anesthetic agent. Another common pathway for drug breakdown is by enzyme such as cytochrome P450. The ability to break down drugs is dependent on age, genetics, and hepatocellular disease. The enzymes can be inhibited by competitive inhibition such as cimetidine, by blockade of drug-binding site on cytochrome. This can enhance anesthetically since it’s not broken down as fast if binding sites are taken up by the tagamet. Enzymes function as catalyst in chemical activities and reduce total energy to either start or reduce a chem reaction in the body. The are very specific such as protease only works on proteins and not lipids or carbohydrates. Enzymes are made up of proteins and a coenzyme portion, which goes into ATP, etc. To help the reaction work and to reduce the amt of energy needed overall.
  1. Acid, Base and pH/pKa
  1. Bonsted-Lowry definition – States that acids are substances than donate protons (H+) and bases are substances that accept protons.
  2. Henderson-Hasselbach equation- The relationship of the pH to the ratio of ionized to un-ionized drug is given as: pH=pK + log({proton acceptor]/[proton donor]). This equation can also be used for acids and bases. For acids: pH=pK + log([ionized acid]/[un-ionized acid]) and

    3. For bases: pH = pK + log([unionized base]/[ionized base])

  3. Sorenson abbreviation – termed pH for the power of hydrogen. This value is equivalent to the negative log to base 10 of the hydrogen ion concentration
  4. Review: ABG’s – Normal values: pH = 7.35-7.45, HCO3 = 22-26, CO2 = 35-45. Must be able to determine if it is metabolic or respiratory and compensated or not and whether acidotic or alkalotic. Determinants of pH are pCO2 and HCO3 levels. Metabolic acidosis occurs in pts with renal failure, type I DM, shock. Body fluid levels increase the [H+] or decrease the base. Metab alkalosis occurs in pts with diuretic therapy, NG sx, vomiting. Body fluid loss decreases the [H+] or increases the base. Resp acidosis occurs with narcotics, neuromuscular blocking agents, COPD. Hypoventilation – the CO2 level rises and the pH decreases. Resp alkalosis occurs with hyperventilation or mechanical ventilation. As you lose acids from the body the pH rises. Most often postop would see resp acidosis due to the narcotics and blocking agents since the pts can’t blow off enough CO2 or the breathing muscles are blocked still. If the pH came back at 7.2 and a normal CO2 you must think of other things but if the CO2 is high then think of reversing the block and then trying a small amt of narcan. If still acidotic then begin to think of stroke. If the pts are metab acidosis or alkalotic then the resp system will try to compensate. They can’t always completely compensate but can come close. The metabolic system will take a while to compensate but can -like pts with COPD and a high CO2 level. CO2 production will stay stable. CO2 levels increase by 5mmHg in the 1st min of apnea and then by 3 every min thereafter

    5. Golden rule: For q 10mmHg change in pCO2 the pH will change 0.08 – 0.1.

    Oxygenation does not play a role in pH determination. Hypoxemia is to have decreased levels of O2 at the tissue level. Watch the pts O2 Sats. An O2Sat of 90% will = pO2 of 60. This is the point on the oxyhemoglobin dissociation curve drops sharply down

    Alveolar Air Equation: paO2 = (FiO2 x 713) – paCO2/resp quotient of .8 in normal people

  5. Clinical application of acid/base balance – Pts with high acidosis will have tissue destruction. Pts with more bicarb are more basic which is more lipophillic and will then cross the blood/brain barrier. Weak acids become more nonionized as pH falls – as the body becomes more acidic – have more nonionized. If a basic drug and you increase the pH the nonionized will go up.

    6. Anion gap: not caused by the loss of HCO3. Must look at Na-Cl-HCO3. The gap is the +ions minus the –ions. As the body loses HCO3 it will tend to gain Cl- in order to compensate. Babies with pyloric stenosis have metab acidosis and hyperchorinic – they throw up HCl but reabsorb Cl- thus this will decrease the HCO3. The body senses a decrease in [H+] so decreases the HCO3 and Cl- rises to make up the difference.

  6. Dissociation constants and pKa – If you have water or H-OH, it will dissociate into H+ and OH- ions. When dissociated the [H+] is 1 x 10 to the –7 moles /liter which is the pH of the solution. Many drugs are combined with salts so they dissociate or dissolve in an aqueous solution. Na Pentathol – the Na allows it to dissolve in water easier. Salts or drugs don’t always dissociate completely but they will equilibrate. The ionized ions will not cross cell membranes while the non-ionized form of the drug will cross cell membrane. With the use of drugs we must consider the affect of pH and pKa. Most drugs are weak acids or weak bases and are ionized and/or non-ionized. The degree of ionization will depend on the pH of the solution and its dissociation constant or pKa. The pKa of a drug is the pH at which a compound exists as 50%ionized and 50%non-ionized. When pKa is close to surrounding pH a smaller change is pH will produce greater changes in degree of ionization.
  1. Clinical application of ionized/unionized anesthetic agents – the pKa of thiopental is 7.6. If you give this to an alkalotic pt with a pH of 7.6 then 50% will be ionized and 50%nonionized. But if you give it to a normal pt with a pH of 7.4 then (since thiopental is a weak acid and has more of a basic solution that it is dissolved in, close to 8, this will cause the ionized portion to be high so it stays in solution when mixed) if you inject the thiopental into the lower pH it will now have more nonionized. Barbiturates are weak acids, which become more nonionized when pH falls so 50% at 7.6 will then be 60-65% when injected into the 7.4 pt. If injected into a pt with a pH of 7.2 you will get even more nonionized of the drug. The higher the pKa of a weak acid, the more nonionized form at a physiologic pH of 7.4.
  2. Protein binding – Drugs exist in the blood dissolved in plasma or bound to proteins – albumin and alpha one acid glycoprotein (AAG). If the drug is highly protein bound, it will produce a small volume of distribution, which limits the amt of drug going into tissues. This also influences the clearance of the drug. Unbound is available for metabolism or clearance by the liver and kidneys. Albumin is the major drug binding protein in the body and attracts mostly acids. AAG binds mostly basic drugs like fentanyl, beta blockers like metoprolol and amide local anesthetics like lidocaine or bupivicaine. The degree of protein binding is higher with drugs with lipid solubility. pH disturbances will affect the drug binding. Drugs that are highly protein bound are more affected than less protein bound drugs. A decrease from 98% to 94% bound will triple the fraction of free drug – you would have more drug available. A decrease from 68%-64% results in a smaller % in available drug. You wouldn’t see as much available drug. It is very sensitive to protein levels. If you give a dose of drug with pt with beta blocker and you have more free drug available you will have more anesthetic affect if the drug is bound and not able to be used. If the albumin level is low – burns, liver disease, ETOH, poor nutrition, etc and you give a drug you will see more effect at a lower dose. Basic drugs are bound to AAG so it doesn’t matter what their albumin levels are. Pts with neoplasm’s, other tumors, MI, inflammatory disease like lupus or arthritis will have increased levels of AAG. Fentanyl binds to AAG so if they had a neoplasm you would need higher dose to be effective.
  3. Ion Trapping – When a pregnant woman is given an IV injection of local anesthetic the nonionized portion will cross the placenta and be changed to ionized and then the ionized form can’t cross back. This can occur is you are putting in an epidural and you accidentally injected into an epidural vein or if giving a paracervical block and hit the vascular area. The drug will continue to enter fetal circulation and could make the baby very acidotic. You must make sure the block is not vascular as in check cath placement, give a test dose of Lido and Epi and wait. You would see a HR increase. Must also aspirate the catheter. This is most likely to happen if the Mom is moving and the catheter migrates during labor.

 

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